Seyden-Penne, J. - Reductions by The Alumino and Borohydrides in Organic Synthesis

Reductions by the
Alumino- and
Borohydrides
in Organic Synthesis
Second Edition
Jacqueline Seyden-Penne
8WILEY-VCH
NEW YORK I CHICHESTER I WElNHElM I BRISBANE I SINGAPORE I TORONTO
Jacqueline Seyden-Penne
Le Vallat de Vermenoux
84220 Goult
France
English Language Editor
Dennis P. Curran
Department of Chemistry
University of Pittsburgh
Parkman Avenue & University Drive
Pittsburgh, PA 15260
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Library of Congress Cataloging in Publication Data:

Seyden-Penne, J.
[Riductions par les alumino- et borohydmres en synthtses organique. English]
Reductions by the alumino- and borohydrides in organic synthesis I Jacqueline Seyden-Penne.
- 2nd ed.
p. cm.
Includes bibliographical references and index.
ISBN 0-471-19036-5 (cloth : alk. paper)
I. Reduction (Chemistry) 2. Hydrides. 3. Organic compounds-Synthesis. I. Title.
QD63.R4S4913 1997
547l.23-dc2 1 96-49776
Printed in the United States of America

Contents
Preface ix
Foreword xi
Abbreviations xiii
1. Description and Characteristics of the Main Reagents

1.1 Lithium and Sodium Aluminohydrides: LiAlH, (LAH),
NaAlH, (SAH) I 1
1.2 Lithium and Sodium Alkoxy- and Aminoaluminohydrides I 2
1.3 Sodium bis(methoxyethoxy)aluminohydride:
Na (OCH,CH,OCH,), AlH, (Red-Al) 1 3
1.4 Diisobutyl Aluminum Hydride: i-Bu2A1H (DIBAH) I 4
1.5 Aluminum Hydride (AlH,), Aminohydrides, and Aluminum
Chlorohydrides (AlH2Cl, AlHCl,) I 4
1.6 Sodium and Potassium Borohydrides: NaBH,, KBH, 1 5
1.7 Lithium Borohydride: LiBH, I 6
1.8 Tetrabutylammonium Borohydride: n-Bu,NBH, 16
1.9 Calcium Borohydride: Ca(BH,), I 7
1.10 Zinc Borohydride: Zn(BH,), I 7
~i CONTENTS
Sodium and Tetrabutylamrnonium Cyanoborohydrides:

NaCNBH,, n-Bu,NCNBH, / 7
Zinc Cyanoborohydride / 8
Cuprous bis(dipheny1phosphine) Borohydride and
Cyanoborohydride / 8
Potassium Triisopropoxyborohydride: K(i-PrO),BH / 9
Lithium Aminoborohydrides / 9
Lithium Triethylborohydride: LiEt,BH (Superhydride) / 9
Lithium and Potassium Tri(s-Butyl) Borohydrides (Li and K
Selectrides): Li or K(s-Bu),BH / 10
Lithium Alkylborohydrides / 10
Borane: BH, / 10
Amine-Boranes: R,N.BH, / 11
Substituted Boranes / 12
Alurnino- and Borohydrides in the Presence of Transition
Metal Salts / 12
2. Cleavage of the Carbon-Heteroatom Single Bond

2.1 Halides / 14
2.2 Sulfonates and Esters / 19
2.3 Epoxides / 22
2.4 Alcohols, Ethers, and Acetals / 27
2.4.1 Alcohols / 27
2.4.2 Ethers / 29
2.4.3 Acetals and Orthoesters / 30
2.4.4 Ozonides / 34
2.5 Ammonium Salts / 34
2.6 Phosphorus Derivatives / 35
3. Reduction of Double Bonds

3.1 Nonconjugated Carbon-Carbon Double Bonds / 37
3.2 Carbon-Oxygen Double Bonds / 37
3.2.1 Aldehydes and Ketones / 37
3.2.2 Stereoselectivity of the Reduction of Aldehydes and
Ketones / 45
CONTENTS vii
3.2.3 Asymmetric Reductions / 55

3.2.4 Functionalized Aldehydes and Ketones / 65
3.2.5 Esters, Lactones, and Thiolesters / 84
3.2.6 Carboxylic Acids, Acid Anhydrides / 92
3.2.7 Acid Chlorides / 98
3.2.8 Amides and Imides / 99
3.2.9 a$-Ethylenic Carbonyl Compounds: a$-Ethylenic
Aldehydes, Ketones, Esters, and Amides / 110
3.3 Carbon-Nitrogen Double Bonds / 122
3.3.1 Imines and Iminium Salts / 122
3.3.2 Enamines / 130
3.3.3 Nitrogen Heterocycles / 130
3.3.4 Oximes and Hydrazones / 138
4. Reduction of Triple Bonds

4.1 Carbon-Carbon Triple Bonds / 145
4.2 a$-Acetylenic Ketones and Esters / 148
4.3 Carbon-Nitrogen Triple Bonds: Nitriles / 149
4.4 a$-Unsaturated Nitriles / 154
5. Other Derivatives
Nitro and Nitroso Derivatives / 157
Azides / 160
Organometallics / 161
5.3.1 Organomercurials / 161
5.3.2 Palladium Complexes / 161
Sulfides, Thioethers, Sulfoxides, Sulfones, and Amine-
Oxides / 164
Phosphine Oxides and Phosphates / 166
Silyl Derivatives / 167
Boron Derivatives / 167
Synoptic Tables
References
Index
Preface
Alumino- and borohydrides and, to a lesser extent, boranes form a part of the
chemist's classic arsenal of reducing agents employed in organic synthesis. A num-
ber of these compounds are commercially available, but the study of their proper-
ties, the introduction of improved reagents, and the development of new reaction
conditions continue to be important areas of research. Selectivity is imperative in
modem organic synthesis, especially when multifunctional molecules are involved.
The reagents chosen at each stage of a chemical transformation must not affect other
functional groups in the molecule. Moreover, functional groups can influence a
reaction process by altering regioselectivity or stereoselectivity.
In this book, we compare the synthetic potential of the most important commer-
cial hydrides and their readily available derivatives. All these hydrides are easy to
use, and the book is organized so that the reader can match the appropriate reagent
to a given transformation. The book emphasizes:
Compatibility between the reduction of the target group and the other function-
al groups present in the molecule;
The possibilities for partial reduction;
The regio- and stereoselectivity of reductions that are altered or controlled by
other neighboring groups;
Asymmetric reductions. These reactions have rapidly developed since the First
Edition. In addition to chiral hydrides, other strategies for asymmetric reduc-
tion include the use of reagents such as chiral chloroboranes or hydrogenation
in the presence of catalysts bearing chiral ligands [S3].
This second edition has been broadly updated, but it is no longer exhaustive. As
in the previous edition, the examples are selected in order to cover problems that are
frequently encountered in synthesis.
X PREFACE
The present book is organized in the following fashion:
Chapter 1 introduces the most useful reagents and indicates their stability and
solubility characteristics and their main applications;
Chapters 2-5 present the reduction of the main functional groups by these
reagents, with reference to features of selectivity (chimio-, regio-, stereo-, and
enantioselectivity) and compatibility;
At the end of the book, synoptic tables indicate how to obtain the main func-
tional groups by hydride reduction.
I am particularly grateful to Mr. Fenouil (Lavoisier-Tec-Doc), who allowed me to

publish this Second Edition with a free hand, and to the staff of the library of the
University of Aix-Marseille-St-Jerhe, who allowed me to work there as often as I
wanted. I am also grateful to the members of the Orsay laboratory, who supplied all
the documents that I needed, namely, Robert Bloch, Yves Langlois, and above all
Tekla Strzalko. My husband, Bob, handled the production aspects of the work,
typing the manuscript and drawing the figures on the computer. I also thank Suzanne
Curran and Valerie Wadyko for correcting the files according to the proposals of
Dennis Curran, who revised my text and my English. Again, I greatly appreciated
the improvements he brought to this book.
Coult, France
Foreword
Although it may be difficult to imagine now, it was not that long ago that the basic
reduction of one organic functional group to another was a demanding proposition.
Choices of reagents were very limited, and reaction conditions were harsh. Enter the
alumino- and borohydrides. Lithium aluminohydride and sodium borohydride were
introduced by Schlesinger and Brown in 1953. Lithium aluminohydride was useful
because it reduced so many things, while the milder sodium borohydride effected
certain kinds of selective reductions in organic molecules. Soon the complexity of
molecules grew, and along with this complexity came the need for more reducing
agents with different properties and selectivities. So a few new alumino- and bor-
ohydrides were introduced. But the spiral did not stop there. The complexity of
molecules grew rapidly, reductions became more and more demanding, and even
better and more selective reducing agents were introduced in response to this de-
mand. The response to the need for chiral reducing agents has recently sent this
spiral to new heights.
So it would appear that synthetic organic chemists should be happy, because for a
given kind a reduction-even a very demanding one-there is probably already an
alumino- or borohydride reducing agent and a set of reaction conditions that is up to
the task. But there is still unhappiness because finding the right combination from
the maze of catalogs, papers, and experimental procedures can itself be a daunting
task.
From out of this maze springs this book. Professor Jacqueline Seyden-Penne is
an acknowledged expert in the area. The book is a major update of the First Edition,
which was published in 1991 by VCH Publishers (a translation from the popular
first French edition). It includes the important developments that have occurred in
the intervening half-dozen years (notably in the area of asymmetric reductions).
Professor Seyden-Penne first describes the features of more than two dozen of the
xii FOREWORD
most powerful and commonly used alumino- and borohydrides, and then goes on to
detail in individual chapters their reactions with important classes of organic mole-
cules. There is a strong emphasis on selectivity at every level (chemo-, regio-,
diastereo-, and enantioselection), and experimental practicality is also directly ad-
dressed. Synoptic tables present much information at a glance, and extensive refer-
ences (about 1000) lead the reader back to the original papers and experimental
procedures.
The book is in effect a road atlas that allows the organic chemist to maneuver
rapidly through the maze of information on reductions of organic compounds by
alumino- and borohydrides to locate the desired goal. For anyone trying to navigate
in this area, this road atlas is indispensable.
Pittsburgh, PA
Abbreviations
Ac acetyl
AcOEt ethyl acetate
Ar aryl
BOC t-butyloxycarbonyl
Bz benzoyl
DMA dimethylacetamide
DME dimethoxyethane
DMF dimethylformamide
DMSO dimethylsulfoxide
Et ethyl
Et,O diethyl ether
HMPA hexamethylphosphorotriamide
i-Pr isopropyl
Me methyl
MeCN acetonitrile
MEM methoxymethyl
Ph pheny1
s-BU sec-butyl
Sia iso-amyl
TBDMS t-butyldimethylsilyl
xiii
X~V ABBREVIATIONS
t-Bu tert-butyl
THF tetrahydrofuran
THP tetrahydropyranyl
To1 p-methylphenyl
Reductions by the Alurnino- and
Borohydrides in Organic Synthesis
Chapter 1
Description and
Characteristics of the
Main Reagents
This chapter lists and describes the characteristics of the main reagents. Cross
references are made to the corresponding sections of the other chapters for more
complete details.
1.1 LITHIUM AND SODIUM ALUMINOHYDRIDES:

LIAIH, (LAH), NaAIH, (SAH)
Lithium aluminohydride (LiAlH,, LAH) is soluble in ethers. In diethylether and

dioxane it forms tight ion pairs, but in THF and in DME it forms loose ion pairs
[ADI, WSl]. LAH is used either in solution, as a suspension, or in a solid-liquid
phase transfer medium (benzene, 15-crown-5) [DCl, GL41. It is also used adsorbed
onto silica gel [KH2, KH3J; however, its reducing power is so diminished under the
latter conditions that it can selectively reduce ketoesters to hydroxyesters or amide
esters into amide alcohols [ K S ~ ] .
LAH reacts violently with water and must be handled away from moisture.
Decomposition of an excess of LAH can be carried out either by careful treatment
with water-saturated diethylether or by addition of ethyl acetate, which is reduced to
ethanol, before treatment with water. Crude reaction mixtures can be treated either
in acidic or basic media, by complexation with tartaric acid, or even by the addition
of a stoichiometric quantity of water to form LiOH and AI(OH),, which precipitate
and are coated by solid MgSO, and Na,SO,, through which they are filtered [H3]. If
the reaction leads to aminoalcohols, which are good ligands for aluminum, it is
sometimes difficult to recover the product of the reduction, but treatment with
(HOCH,CH,),N before the addition of water allows isolation of the product in good
yield [PJl].
2 DESCRIPTION AND CHARACTERISTICS OF THE MAIN REAGENTS
LAH shows very high reducing power and consequently does not appear to be
very selective, even when the conditions of medium and temperature are varied.
Alcohols and phenols react with LAH in controlled amounts to produce alkoxy-
aluminum hydrides, whose reducing power can be modulated (see the following).
Reaction with secondary amines forms aminoaluminohydrides. Some of these have
been characterized by X-ray crystallography [HS5]. With tertiary amines, com-
plexes can be formed. For example, N-methylpyrrolidine gives an air-stable com-
plex [FS 11 whose reducing properties are similar to those of LAH. The use of this
complex does not require special procedures for exclusion of moisture and air and
after reduction, workup is done by addition of water. Treatment of LAH with
pyridine produces a special reagent, lithium tetrakis N-dihydropyridinoalumino-
hydride [LLl]. There is a review devoted to the rearrangements of various carbon
skeletons observed during reduction by LAH [C2].
Sodium aluminohydride (NaAlH,, SAH) in THF is somewhat less reactive than
LAH toward carboxylic acids, anhydrides, epoxides, amides, and nitro compounds
[CB5], and it can be used for selective reductions. However, it is as sensitive to
moisture as LAH; so similar precautions must be taken.
1.2 LITHIUM AND SODIUM ALKOXY- AND

AMINOALUMINOHYDRIDES
The reaction of stoichiometric quantities of alcohols with LAH leads to the forma-
tion of alkoxyaluminohydrides. The problem most often encountered in this reaction
is disproportionation according to the following equilibria [HM3]:
LiAl H, + ROH + Li(RO)AlH, + H,
Li(RO)AlH, + ROH + Li(RO),AIH, + H,
Li(RO),AIH, + ROH + Li(RO)AIH, + H,
Li(RO)AIH, + ROH + ROLi + (RO),AI + H,
Because of this disproportionation, some solutions of alkoxyaluminohydrides con-

tain essentially the alcoholates and LAH, and thus they present the same characteris-
tics as LAH itself. This is especially the case when R = Et or i-Pr [WSl].
The following reagents are nevertheless stable:
Li(MeO),AlH is a dimer in THF [BK5, MI, M3]: Its interest resides in the 1,2
attack of a-enones (Section 3.2.9).
Li(t-BuO),AlH (LTBA) is a monomer in THF, and its reductive properties have
been well studied [BK5, MI, M3, W3]. Its principal applications are the reduc-
tion of acid chlorides and imidazolides to aldehydes at low temperature. Be-
cause of its bulkiness, a high stereoselectivity during the reduction of carbonyl
compounds often makes the reaction more selective than with LAH. At low
temperature, aldehydes can be reduced in the presence of ketones, and only
slightly hindered ketones can even be reduced in the presence of more hindered
ones (Section 3.2.1). Likewise, LTBA attacks saturated ketones more rapidly
than a-enones (Section 3.2.9). LTBA leaves ethers, acetals, epoxides, chlorides
1.3 SODIUM BIS(METHOXYETH0XY)ALUMlNOHYDRlDE 3
and bromides, and nitro derivatives intact. Aliphatic esters are reduced only
slowly; in contrast, phenyl esters are converted into aldehydes (Section 3.2.5).
Na(t-BuO),AlH can be prepared in a similar way. Sparingly soluble in THF, it
may be used in DME-THF mixtures and is recommended for reductions of
acid chlorides to aldehydes [CB6].
Li(t-BuEt,O),AlH is a bulky reagent that has been used in stereoselective
reductions of prochiral ketones [BD2], and it reduces aldehydes selectively in
the presence of ketones [K4].
Li(EtO),AlH (LTEA) and Li(EtO),AlH, can be produced in situ and have
some interesting properties, but because they rapidly undergo disproportiona-
tion, they must be used very soon after their formation to reduce sufficiently
reactive substrates. They reduce nitriles into imines, which can then be hydro-
lyzed to aldehydes (Section 4.3), and they also convert tertiary amides into
aldehydes (Section 3.2.8).
Reducing agents having special properties are obtained by the reaction of
alkoxyaluminohydrides with CuBr [CAI, SSI]. These reduce the double and
triple bonds of a,@unsaturated carbonyl compounds (Sections 3.2.9, 4.2, 4.4)
and allow one to obtain N-acyldihydro-1,Cpyridines(Section 3.3.3.3).
Various sodium aminoaluminohydrides have been proposed for selective reduc-

tion of esters and aromatic nitriles to the corresponding aldehydes [CK3, CK5, CJ1,
YA21. Chiral alkoxy- and aminoaluminohydrides have been used in asymmetric
reductions of ketones and imines, and these will be described in the corresponding
chapters (Sections 3.2.3 and 3.3.1).
1.3 SODIUM BIS(METHOXYETH0XY)ALUMINOHYDRIDE:

Na(OCH2CH20CH3),AIH2 (Red-Al)
An interesting feature of sodium bis(methoxyethoxy)aluminohydride is its solubility

in aromatic hydrocarbons [MI, MC1, W3]. It is also soluble in ethers. Most fre-
quently, reductions are carried out in a benzene or toluene solution to which are
added various cosolvents. The reaction of Red-A1 with water is less violent than that
of LAH, which facilitates workup. As with LAH, hydrolysis can be carried out in
acidic or basic media or with a minimal amount of water. In the last case, the
addition of a small amount of acid to neutralize the NaOH that forms is recom-
mended.
The features of Red-A1 are the following: It easily reduces halogenated deriva-
tives even if acetylenic (Section 2.1); tertiary amides lead to aldehydes (Section
3.2.8); and propargylic alcohols and amines are reduced to corresponding allylic
alcohols and amines (Section 4.1). Epoxides remain intact unless they carry an
alcohol functional group at the a position: The reduction is then regioselective
(Section 2.3). Aromatic nitriles are reduced, but aliphatic nitriles are not affected
(Section 4.3).
In the presence of CuBr in THF, Red-A1 gives rise to an interesting reagent [SSI]
that is especially good for selective reduction of the carbon-carbon double and
triple bonds of unsaturated ketones, esters, or nitriles (Sections 3.2.9, 4.2, 4.4),
leaving the functional group unchanged.
1.4 DIISOBUTYL ALUMINUM HYDRIDE: i-Bu,AIH (DIBAH)
This reagent [BK5, W1, W3, YGl] is both soluble and stable in toluene or hexane. It
is also soluble in ethers (diethylether, THF, DME, glymes), but these solutions are
stable only at low temperature. It is a particularly strong Lewis acid. At high
temperature, DIBAH hydroaluminates carbon-carbon double and triple bonds
[HHI]. The usual workup after reduction consists of addition of methanol then
water to the solution, followed by separation of the aluminum salts that have
precipitated. Alternatively, the mixture can be treated with dilute aqueous HCl
followed by extraction, or else addition of tartaric acid in ethanol followed by
addition of NaSO, and celite and then filtration [BL2].
This reagent presents .the following characteristics: It allows carbon-halogen
bonds to remain unperturbed (Section 2.1). It can cleave aromatic ethers (ArOMe)
to give phenols (Section 2.4) and acetals to give ethers (Section 2.4). Nitriles are
reduced to imines, hydrolysis of which gives aldehydes (Sections 4.3, 4.4). Esters
are generally reduced selectively to aldehydes at low temperature; however, if they
are a$-unsaturated, allylic alcohols are produced (Sections 3.2.5, 3.2.9). The reduc-
tion of acid esters to lactones can be easily performed [S02]. Lactones are reduced
to lactols (Section 3.2.5) and imides to a'-hydroxyamides (Section 3.2.8). DIBAH is
the reagent of choice for selectively reducing the carbonyl of a$-unsaturated al-
dehydes and ketones (Sections 3.2.9, 4.2) in toluene at low temperature. By way of
contrast, in the presence of HMPA, sometimes with addition of a catalytic amount of
MeCu, DIBAH reduces a$-ethylenic ketones and esters to saturated ketones and
esters (Section 3.2.9) and a$-acetylenic ketones and esters to a$-ethylenic deriva-
tives (Section 4.2).
Because of the Lewis acid properties of DIBAH, the reduction of functionalized
carbonyl compounds often shows an interesting stereoselectivity (Section 3.2.4).
DIBAH forms ate complexes by action of n-BuLi in hexane [KAI]. In THF-
hexane, these ate complexes selectively reduce esters to alcohols, tertiary amides to
aldehydes (at O°C), and a-enones to ally1 alcohols (at -7g0C). Primary and secondary
amides as well as nitriles are unaffected at low temperatures. Primary halides are only
reduced at room temperature; so these reagents perform selective reductions accord-
ing to the reaction conditions (Sections 2.1,3.2.5,3.2.9). The uses of DIBAH-i-Bu,Al
ate complexes have also been described [PP2].
1.5 ALUMINUM HYDRIDE (AIH,), AMINOHYDRIDES, AND ALUMINUM

CHLOROHYDRIDES (AIH,CI, AIHCI,)
The reagents AlH,, AIHCI,, and AlH,Cl are obtained by reaction of a limited
quantity of AlCl, with a solution of LAH in diethylether. AlH, can also be prepared
by the action of H2S04 on LAH in THF [BYI], but the so-formed reagent slowly
1.6 SODIUM AND POTASSIUM BOROHYDRIDES 5
cleaves THF at room temperature [CB7]. This drawback has been overcome by
generation of AlH,.Et,N. A solution of this reagent in THF is stable for at least 1
month [CB7]. These reagents are just as sensitive as LAH toward water and must be
decomposed under the same conditions as LAH. The ready generation of a dimeth-
ylethylamine-AlH, or N-methylpyrrolidine-AlH, complex, which can be used in
toluene-THF and whose reducing properties are similar to those of AlH, in THE has
been described [MP2].
These reagents are strong Lewis acids that cleave THF and acetals (Section 2.4).
Nevertheless, they leave bromo- and chloroderivatives intact (Section 2.1). The
regioselectivity of the opening of epoxides is opposite to that observed for LAH in
THF (Section 2.3). Diarylcarbinols can be reduced to hydrocarbons (Section 2.4),
and a$-unsaturated carbonyl compounds to allylic alcohols (Section 3.2.9). The
reduction of amides to amines is easier than with LAH (Section 3.2.8), especially in
the case of a$-ethylenic amides or of 9-lactams. These reagents do not reduce NO,
groups.
Aluminum bis-(N-methylpiperazino)hydride, obtained by combining 2 equiva-
lents of N-methylpiperazine and a solution of AlH, in THF, is especially recom-
mended for the reduction of esters or acids to aldehydes (Sections 3.2.5, 3.2.6)
[MM3].
1.6 SODIUM AND POTASSIUM BOROHYDRIDES: NaBH,, KBH4
The sodium and potassium borohydrides [BK5, PSI, W3, W4] are soluble in water,
alcohols, glymes, and DMF. They are not very soluble in diethylether and are
slightly soluble in cold THF, but are more soluble under heating. Basic aqueous
solutions are relatively stable, but solutions in methanol or ethanol are rapidly
decomposed to borates, which in turn reduce only very reactive substrates. Solutions
in i-PrOH or glymes are more stable and are often used. If the substrates or products
of the reaction are fragile in an alkaline medium, the solutions can be buffered by
B(OH), [DSI]. These reagents are useful in phase transfer systems (liquid-liquid or
solid-liquid) [BK8, MLl], on solid supports in the presence of THF or diethylether
[BIl], on resins [NSl], in micelles [FR2, NS41, or in microemulsions [FR2, JWl].
An increase in the degree of reducing power of NaBH, in hot THF'by addition of
methanol after reflux has been noted [Sol].
The most frequent workup treatment after reduction is the addition of an acid.
When the alkoxyboranes or arninoboranes are formed, the decomposition of these
intermediates may require heating in a strong acid medium or even treatment by
H,O, in an alkaline medium [PSI, H3]-a problem that often arises with reducing
reagents derived from boron.
Sodium and potassium borohydrides are above all used for reducing aldehydes
and ketones (Sections 3.2.1, 3.2.2); a$-ethylenic ketones are converted to mixtures
[W3]. In alcoholic media or THF, they leave epoxides, esters and lactones, acids,
amides, and most nitro compounds unreacted, but they reduce halides (Section 2. l),
anhydrides (Section 3.2.6), quarternary pyridinium salts (Section 3.3), double bonds
conjugated to two electron-withdrawing groups (Sections 3.2.9, 4.4), and CUPd
6 DESCRIPTION AND CHARACTERISTICSOF THE MAIN REAGENTS
and C-Hg bonds (Section 5.3). However, in the presence of hot methanol in THF,
NaBH, reduces esters to alcohols [Sol], and in refluxing pyridine some tertiary
amides are reduced [KII].
Compounds able to undergo solvolysis to sufficiently stable cations are reduced
via these carbocations by NaBH, in alcoholic media sometimes in the presence of
acid. Diarylketones (Section 3.2) or the di- or triarylcarbinols are reduced to hydro-
carbons (Section 2.4), imines and the iminium salts are reduced to amines (Sections
3.3.1, 3.3.2), and imides to a'-hydroxyamides (Section 3.2.8).
In the presence of organic acids, sodium and potassium borohydrides form
acyloxyborohydrides that show some remarkable characteristics [GNl]. Their reac-
tion path depends on the quantity of acid present, which leads to either mono-
acyloxy- (NaRCOOBH,) or trisacyloxyborohydrides [Na(RCOO),BH]. The reduc-
tion can be performed in the presence of a cosolvent (dioxane, THF, ethanol) or in
pure organic acid (AcOH, CF,COOH most frequently). Acyloxyborohydrides are
easily decomposed by water. Aldehydes and ketones react more slowly with these
reagents than with the borohydrides in alcoholic media [GNI]. Given an acidic
medium, these reagents reduce di- and triarylketones and alcohols to hydrocarbons
(Sections 2.4, 3.2. l), acetals to ethers (Section 2.4), and nitriles to amines (Section
4.3). Their most interesting application consists of the reduction of C=N double
bonds to amines. Imines, oximes, enamines, iminium salts, and numerous nitrogen
heterocyclic compounds are reduced (Sections 3.3.1 -3.3.4). These are the reagents
of choice for effecting reductive aminations (Section 3.3.1) or the reductions of
tosylhydrazones to hydrocarbons (Section 3.3.4). Depending on the substrate,
NaBH, may be used, but it is preferable to substitute NaCNBH, while operating
under the same conditions [GNl].
Under the action of Lewis acids such as BF,, AlCl,, I,, and Me,SiCl, the
borohydrides are converted into boranes, which then become the reducing agents
(see the following).
1.7 LITHIUM BOROHYDRIDE: LiBH,
LiBH, is soluble in alcohols and ethers [BKS, PSI, W3]. In an diethylether or THF
medium, the Lif cation is a stronger Lewis acid than Naf, which gives to this
reagent an increased reducing power. Epoxides, esters, and lactones may then be
reduced (Sections 2.3, 3.2.5), while amides and nitriles remain intact unless one
adds hot DME or methanol. Under these conditions, tertiary amides give alcohols
(Section 3.2.8) and nitriles give amines (Section 4.3).
LiBH, can also be activated by adding (MeO),B or Et,B in diethylether. With
this reagent, esters are rapidly reduced, tertiary amides and nitriles are also reduced,
but sulfone, sulfoxide, and NO, groups remain intact [BN3, YP21.
1.8 TETRABUTYLAMMONIUM BOROHYDRIDE: n-Bu4NBH4
This reagent is soluble in alcohols, ethers, CH,C12, and toluene [PSl, RGl]. In hot
CH,C12, it decomposes slowly to borane. It is usable on solid supports [BIl].
1.11 SODIUM AND TETRABUTYLAMMONIUMCYANOBOROHYDRIDES 7
n-Bu4NBH4 is a very mild reducing agent. The reactivity order in CH,Cl, is as

follows: RCOCl > RCHO > RCOR' >> RCOOR', esters being reduced only
under reflux. This reagent reduces aldehydes selectively in the presence of ketones
(Section 3.2.1). In organic acid media, tetrabutylammonium acyloxyborohydrides
are formed. Under reflux in C6H6, these reagents also reduce aldehydes selectively
without affecting the ketones (Section 3.2.1) [GNI]. Borohydrides supported on
exchange resin [GB5, GW3, YK5, YP3] exhibit a similar, although weaker, reduc-
ing power to the standard reagents.
1.9 CALCIUM BOROHYDRIDE
Calcium borohydride is generated in methanol or ethanol from CaCl, and NaBH,

[BR3]. It reduces esters to alcohols, leaving acid salts intact, thus allowing the
formation of lactones from hemiesters [LRl] (Section 3.2.5). It has also been used in
stereoselective reduction of a$-epoxyketones [TF2] (Section 3.2.4).
1.10 ZINC BOROHYDRIDE: Zn(BH4),
Zinc borohydride [BK5, KHI, ON1, R3, W3], which exists in the dimeric form 1.1,
(on page 11) is obtained by adding ZnC1, in diethylether to a solution of LiBH, in
this solvent. It has also been prepared from NaBH, and ZnC1, in THF or DME, but
under these conditions the reagent is a mixture of several components [SB3]. It has
also been used on silica gel [R3]. Its complex with polypyrazine is stabilized and
can be used as a reagent [TLI]. This relatively strong Lewis acid reduces
a$-ethylenic ketones to allylic alcohols (Section 3.2.9). It also reduces esters and
azides in DME [R3, RS I] as well as acids into alcohols in THF [NM3] or in DME in
the presence of (CF,CO),O [R3]. As a good chelating agent, it can be used in some
very stereoselective reductions of ketones bearing heteroatoms at the a or P posi-
tion, especially a- and P-ketoesters, ketoamides, or even epoxyketones (Section
3.2.4). Ester, amide, nitrile, and nitro groups and halogens are not usually affected;
however, the reduction of tertiary halides can be carried out [KHI].
A complex Zn(BH,),-1.5 DMF has been described [HJl]. This shows a greater
selectivity than Zn(BH4), in diethylether and does not react with the a-enones. In
MeCN, this complex allows the reduction of aldehydes in the presence of ketones,
the reduction of some sterically unhindered ketones in the presence of other less
accessible ketones, or even the reduction of aliphatic ketones in the presence of
aromatic ones (Section 3.2.1).
1.11 SODIUM AND TETRABUTYLAMMONIUM

CYANOBOROHYDRIDES: NaCNBH,, rrBu4NCNBH,
The Na and tetrabutylammonium cyanoborohydrides [BK5, HNI , L1, PSI, W3] are
soluble in water, alcohols, organic acids, THF, and polar aprotic solvents. They are
insoluble in diethylether and hydrocarbons and may be used under phase transfer
conditions [HMI]. One feature of the cyanoborohydrides is their stability in acid
media at about pH 3. It is thus necessary to treat the crude reaction mixture with a
strong acid to decompose the intermediates formed. The use of resin-supported
cyanoborohydride has also been described [HN3].
These reagents are interesting because aldehydes and ketones are affected in
acidic media only, which permits the reduction of carbon-halogen bonds (Section
2.1) without affecting carbonyl groups, esters, or nitriles.
In organic acid media, NaCNBH, is converted to acyloxycyanoborohydrides
whose reactivity is comparable to that of NaBH, in CF,COOH, especially concern-
ing the reduction of imines to amines, tosylhydrazones to saturated hydrocarbons,
oximes to hydroxylamines, or reductive amination. Depending on the substrate,
NaBH, or NaCNBH, is recommended (Sections 3.3.1, 3.3.4) [GN I].
1.12 ZINC CYANOBOROHYDRIDE
Zinc cyanoborohydride [KOI, LDI] is formed by reaction of ZnC1, in diethylether

with a solution of NaCNBH, in this solvent [KOl] or by the reaction of ZnI, with
NaCNBH, in CH,Cl, [LDI].
In ether media (diethylether or THF), the nature of the reagent is ill defined. It
reduces aldehydes, ketones, and acid chlorides, but leaves esters, anhydrides, and
amides unchanged. In methanol, the reduction of enamines and imines to amines
may be effected in the same way as the reduction of tosylhydrazones to hydrocar-
bons (Section 3.3.4).
The reagent formed by reaction of ZnI, with NaCNBH, in CH,Cl, allows the
reduction of aromatic aldehydes and ketones as well as benzylic, allylic, and tertiary
alcohols to hydrocarbons, probably by a radical process [LDl] (Section 2.4). Some
comparable reductions are carried out in ether media starting from tertiary, benzylic,
or allylic halides (Section 2.1).
1. I 3 CUPROUS BIS(DIPHENYLPH0SPHINE) BOROHYDRIDE

AND CYANOBOROHYDRIDE
These cuprous borohydrides [DFI, FHI, FH2, HM2, SPI, W41 are isolated com-
plexes of the structure 1.2 (on page 1I), which transfer only a single hydride. They
can be supported on ion-exchange resins [SPI].
In neutral media, they leave carbonyl derivatives intact but reduce tosylhydra-
zones to the corresponding hydrocarbons under reflux of CHCI, (Section 3.3.4).
This reduction is compatible with a-enone, epoxide, or lactone groups present in the
molecule [GL3]. In cold acetone, these reagents reduce acid chlorides to aldehydes
[FHl] (Section 3.2.7). In the presence of Lewis acids or gaseous HCI in CH,CI,,
they reduce aldehydes and ketones. The selective reduction of aldehydes in the
presence of ketones can also be realized (Section 3.2.1). These reagents also reduce
aromatic azides to amines (Section 5.2).
1.16 LITHIUM TRlETHYLBOROHYDRlDE 9
1.14 POTASSIUM TRllSOPROPOXYBOROHYDRIDE: K(i-PrO),BH
This borohydride [BC3], obtained in THF by adding 3 moles of i-PrOH to a solution

of KBH,, essentially reduces aldehydes, ketones, and halogenated derivatives. Its
principal use is for the reduction of the haloboranes RR'BC1 or RR'BBr to boranes
RR'BH (Section 5.7). This process allows sequential hydroborations, first by a
halogenoborane, which is then reduced to a hydrogenoborane that can undergo a
new hydroboration, giving access to mixed trialkylboranes. This reagent also trans-
fers KH similarly to hindered trialkylboranes, thereby forming KR,BH.
1.1 5 LITHIUM AMINOBOROHYDRIDES
Lithium aminoborohydrides are obtained by the reaction of n-BuLi with amine-

boranes [F'F2, FH5, NT21. They can be generated in situ as THF solutions or as
solids when formed in diethylether or hexane (n-BuLi must then be used in sub-
stoichiometric amounts). They are stable under dry air and are slowly decomposed
by water [NT2] or methanol so that workup of the reactions mixtures can be carried
out with 3M HCI. They reduce alkyl halides (Section 2.1), epoxides (Section 2.3),
aldehydes, and ketones (Section 3.2.1) (in the latter case with an interesting stereo-
selectivity [HFI]), and esters to primary alcohols (Section 3.2.5). a$-Unsaturated
aldehydes, ketones, and esters are reduced to ally1 alcohols (Section 3.2.9) [FF2,
FS21. Depending on the bulkiness of the amines associated with the reagent and to
the substrate, tertiary amides give amines or alcohols (Section 3.2.8) [F'Fl, FF21.
Amines are also formed from imines (Section 3.3.1) [FB 11 and from azides (Section
5.2) [AFI]. However, carboxylic acids remain untouched.
1.I6 LITHIUM TRIETHYLBOROHYDRIDE: LiEt,BH (SUPERHYDRIDE)
LiEt3BH [BK5, BK6, BN4, KB3, KB5, W3] is soluble in ethers (diethylether, THF,
glymes) and hydrocarbons. Rapidly decomposed by water or alcohols, it must be
handled away from moisture. The workup of the crude reaction mixture consists of
hydrolysis, sometimes in the presence of acid, followed by the action of alkaline
H202 to oxidize Et,B (a byproduct of the reduction) to ethanol and boric acid, both
of which are soluble in water.
Although it is much more reactive than LiBH,, the triethylborohydride shows an
analogous reactivity spectrum. It reacts particularly well with primary and second-
ary alkyl halides and tosylates, even when hindered, with an inversion of configura-
tion (Section 2.1), and with epoxides at the least sterically hindered site (Section
2.3). It reduces ammonium salts to tertiary arnines. The reduction of cyclic or
functionalized ketones and imines by LiEt3BH in THF can be very stereoselective
(Sections 3.2.2, 3.3. l), but in general Li(s-Bu,)BH is preferable. Tertiary amides are
reduced first to aldehydes then to alcohols (Section 3.2.8), and nitriles are reduced to
imines, which are hydrolyzed to give aldehydes (Section 4.3). The use of KEt3BH
for chemoselective reduction of carboxylic acid esters has been suggested [YYl].
1.17 LITHIUM AND POTASSIUM TRl(sBUTYL) BOROHYDRIDES

(Li AND K SELECTRIDES): Li OR K(sBu),BH
The Li and K Selectrides [BK5, W3] are soluble in ether media (diethylether, THE
glymes). The treatment after reduction is identical to that employed for LiEt3BH.
The principal interest of these reagents resides in their bulkiness. The reductions
of slightly hindered cyclic ketones and imines occurs on the equatorial face (Sec-
tions 3.2.2, 3.3.1), and aliphatic carbonyl compounds are reduced with a high
stereoselectivity (Section 3.2.2). The Li and K Selectrides selectively reduce the
carbon-carbon double bond of n-enones and n,a-ethylenic esters unless the
position is disubstituted (Section 3.2.9); in the latter case, the carbonyl of the
n-enones is reduced.
Li and K trisiarnyl borohydrides, which are even bulkier, are sometimes used [KB8].
1.18 LITHIUM ALKYLBOROHYDRIDES
These can be easily prepared by reaction of di- or trialkylboranes with lithium

aminoborohydrides [HAl]. The properties of two types of reagents have been ex-
plored: Li(n-Bu)BH, [KM2] and the boratabicyclononane Li 9-BBN-H 1.3 (on page
11) [BMl, KBI]. No special features have been pointed out in relation to other
reducing agents.
The treatment of the crude reaction mixture after reduction by Li 9-BBN-H
requires the action of H,02 in an alkaline medium to convert the intermediate
borane to water-soluble or volatile compounds.
Chiral Li alkylborohydrides have been used in asymmetric reductions (Section
3.2.3) [BJl, BR41.
1.19 BORANE: BH,
Rarely used in its gaseous dimeric form (B2H6), borane is generally employed as a
solvate with THF or Me2S. BH,.THF is employed in ether media. BH3.Me2S is
soluble in ethers, hydrocarbons, and CH2C12.Borane can also be generated in situ by
reaction of NaBH, with iodine [BB7], HCI, MeS03H, or sulfuric acid [AM21 or
trimethylsilyl chloride [DA2]. Under such conditions, there is no need to use dry
solvents.
Borane reduces carboxylic acids in the cold without attacking esters or nitriles,
and it reduces halogenated derivatives (Section 3.2.6). Enantioenriched amino acids
can be transformed into amino alcohols without epimerization [AM2, DA2, 5521.
Borane easily reduces amides in refluxing THF (Section 3.2.8). Esters can also be
reduced at higher temperatures (Section 3.2.5). An important limitation is compet-
ing hydroboration of carbon-carbon double and triple bonds [BK7, HH1, L2],
although this can be avoided when reducing acids at 0°C [BP5].
1.20 AMINE-BORANES 11
1.20 AMINE-BORANES: R3NaBH3
These complexes are more stable than the borane complexes with diethylether or
Me,S. They are soluble in water and alcohols and stable in the presence of acetic
acid. Their decomposition requires the action of a strong acid or decomplexation by
an amino alcohol.
With respect to reactivity, the amine-boranes lie somewhere between BH,.THF
and NaBH,. They reduce aldehydes and ketones without affecting ester, ether, SPh,
and NO, groups (Section 3.2.1). The reduction of ketones can be accelerated by the
addition of Lewis acids or when carried out in acetic acid [PSI]. On alumina or
silica supporrts, amine-boranes can selectively reduce aldehydes without affecting
keto groups (Section 3.2.1) [BSl]. Chiral amino acids can be reduced to amino
alcohols without epimerization [PS 11.
Ph,NH.BH, is a recommended reagent because its stability and reactivity are
superior to those of amine-boranes formed from aliphatic amines [Cull. Pyridine-
borane reacts slowly with carbonyl compounds and has been suggested for carrying
out reductive aminations (Section 3.3.1) [PR2]; however, in the presence of AcOH,
it reduces aldehydes, leaving ketones untouched [CWl].
Some amino alcohols react with borane to generate oxazaborolidines, which have
been mainly used in asymmetric reduction of ketones (Section 3.2.3) and imines
(Section 3.3.1) [NNl , S3]. In addition, they can also perform some chemoselective
reductions [IWI].
1.21 SUBSTITUTED BORANES
Substituted boranes are obtained by hydroboration of relatively hindered olefins

such as trimethylethylene, tetramethylethylene, and 1,5-cyclooctadiene, which, by
action of BH,, lead, respectively, to diisoamylborane, Sia,BH 1.4 (on page 1l),
thexylborane, ThexBH, 1.5 (on page 1 l), and 9-BBN 1.6 (on page 11). These
reagents are used in THF. Thexylchloroborane is obtained by reaction of
ClBH,.SMe, with tetramethylethylene. ThexBHCl.SMe, 1.7 (on page 11) in solu-
tion in CH,Cl, or in THF, where it is less stable, is also recommended, as is
Cl,BH.Me,S [SB3]. The crude reaction mixture is hydrolyzed in a hot acid medium.
The reactions of these reagents reflect their sterically hindered and Lewis acidic
characters. This is why the reduction of relatively hindered acyclic ketones by
Sia,BH 1.4 shows the opposite stereoselectivity to that observed with the alumino-
or borohydrides (Section 3.2.2) [HWl]; the reduction of hindered cyclanones by
ThexBHC1-SMe, leads to the least stable alcohol [BNS]. a$-Ethylenic aldehydes
and ketones are reduced by 9-BBN or ThexBHCl.SMe, to allylic alcohols, with a
better selectivity than that observed with BH,.SMe, or ThexBH, (Section 3.2.9).
Acids are selectively reduced to aldehydes by ThexBHC13Me2 (Section 3.2.6)
[BCS]. Tertiary amides are reduced by 9-BBN to alcohols and by Sia,BH and
ThexBH, to aldehydes (Section 3.2.8), while BH, transforms these tertiary amides
to arnines and ThexBHCl reacts with them slowly. Cl,BH.SMe, is recommended
for selective reduction of azides (Section 5.2) [SB3].
Catecholborane 1.8 (on page 11) is a mild reducing agent that is not sensitive to
moisture [KB7]. It can be used without solvent or in CHCI,, and it reduces al-
dehydes, ketones, hydrazones, and acetals. It also reduces acids if used in excess at
room temperature. Esters are reduced in refluxing THF, and alkenes are hydrobo-
rated in similar conditions.
1.22 ALUMINO- AND BOROHYDRIDES IN THE PRESENCE OF

TRANSITION METAL SALTS
Solutions or suspensions of LAH in diethylether or THF in the presence of iron

salts, CoCl,, TiCl,, or NiCl, [AL 1, GO21 are used as reducing agents. Similarly, Li
or NaBH, in methanol, THF, or DMF may be used in the presence of salts or
complexes containing nickel, cobalt, tin, copper, palladium, or lanthanides [ALl,
CY2, DG1, G02, PV1, YC2, YLS]. The structures of these reagents are often not
1.22 ALUMINO- AND BOROHYDRIDES IN THE PRESENCE OF TRANSITION METAL SALTS 13
well known. However, it is thought that Ni,B is formed from NaBH, and NiCl, in
MeOH. Titanium salts and complexes are also proposed as addends [B4, B5, BH5,
BS6, DK3, LS4, RB3, RC2].
Each reagent shows some particular characteristics, but a certain number of
transformations merit emphasis. These include:
The reduction of alkenes with LAH-FeCI,, CoCl,, TiCI, or NiCI,, or NaBH,-

CoCl,, all of which do not modify aromatic derivatives (Section 3.1);
The reduction of the aromatic moieties with NaBH,-RhCI3 in ethanol;
The reduction of aromatic nitrogen-containing heterocycles with NaBH,-
NiCI, in methanol, which does not perturb aromatic carbon-containing rings
(Section 3.3.3);
The reduction of aromatic or alicyclic halogenated derivatives with NaBH,-
NiCI, in DMF either in the presence of Ph,P or with LAH in the presence of
various transition metal salts (Section 2.1);
The reduction of nitriles and nitro derivatives to amines with NaBH4-CoCl, in
methanol (Sections 4.3, 5.1);
The reduction of oximes and nitro derivatives to amines with NaBH, in the
presence of nickel or copper salts (Sections 3.3.4, 5.1);
The reduction of arylketones to hydrocarbons with NaBH,-PdC1, in methanol
(Section 3.2.1);
The reduction of allylic acetates to saturated hydrocarbons with NaBH4-NiCl,
(Section 2.2);
The reduction of azides to amines with NaBH,-Ni(OAc), (Section 5.2);
The reduction of a-enones to allylic alcohols with NaBH,-CeCl, in methanol
or with (i-PrO),TiBH,, generated from (i-PrO),TiCl, and benzyltriethylam-
monium borohydride in a 1:2 ratio, in CH,CI, (Section 3.2.9) [RB3].
Chapter 2
Cleavage of the Carbon-
Heteroatom Single Bond
2.1 HALIDES: >c-x
LAH in THF reduces chlorides, bromides, and iodides to hydrocarbons, whatever

their degree of substitution (primary, secondary, tertiary, aromatic, vinyl, and cyclo-
propyl). The order of reactivity for a given hydrocarbon residue is iodide > bromide
> chloride. For a given halogen, the order of reactivity is: ArCH,X = allylX >
RCH2X > R2CHX > R,CX.
Aliphatic and alicyclic iodides and bromides are reduced at room temperature,
while the aromatic, vinyl, and cyclopropyl bromides as well as the chlorides can be
reduced only under reflux. For example, the selective reductions shown in Figure
2.1 can be performed [Pl 1.
In the presence of CeC1, in cold DME or under reflux in THF, LAH reduces all
the halides [G02].
The mechanism of these reductions is a bimolecular nucleophilic substitution for
the reaction of LAH with most primary and secondary halides [BK5, PCl]. A
single-electron transfer (SET) has been proposed in the reduction of sterically
hindered primary iodides [AD3, AG1, Awl], although some doubts have been cast
[PCl] on this mechanism with bromocyclopropanes [HW2] and aromatic or vinyl
halides [Cl], especially in the presence of CeCl, [G02]. In this case, some rear-
rangements may be observed. SET does take place in the reduction of geminal
dihalides by LAH [AD41 as well as in the reduction of bromocyclopropanes in the
strict absence of molecular oxygen [PNI]. In the presence of oxygen, the C-Br
bond of 2,2-diphenyl-1-bromocyclopropanecarboxylic acid is left unchanged [PNI].
The alkoxyaluminohydrides reduce aliphatic and alicyclic iodides and bromides
but not the corresponding chlorides. An exception is Red-A1 in benzene, which
reduces all halides, as well as the cyclopropyl and aromatic derivatives. The reduc-
2. I HALIDES 15
Figure 2.1
tion of 1-bromoalkynes by the latter reagent cleanly gives the debrominated alkyne,
unlike other aluminohydrides that give a mixture. Difluoroalkenes, meanwhile, are
converted to the monofluoro derivatives [MI] (Figure 2.2).
LAH or AIH,-amine complexes reduce alkyl bromides and iodides as well as
benzyl chloride and bromide [FSI]. They leave other chlorides unchanged, thus
allowing the selective reduction of 2.1 to the corresponding chloroalcohol [MP2].
On the other hand, the selective reduction of an a$-ethylenic-a-chloroester 2.2
to an a-chloroallylalcohoI 2.3 [DWI] comes from the inability of DIBAH to react
with halogenated derivatives in cold toluene [YGI] (Figure 2.2).
DIBAH-n-BuLi ate complex in hexane-THF reduces primary bromides and
chlorides at room temperature to hydrocarbons. Secondary halides react more slow-
ly, while tertiary and aryl halides remain unchanged [KAl].
The reduction of the fluorides requires the electrophilic assistance of a Lewis
acid in breaking the C-F bond: AIH, in Et20 and LAH-CeCI, in DME are
adequate reducing agents [G02, Pl]. AIH,, however, leaves the aliphatic C-Br and
C-Cl bonds intact [BK5, PC11 (Figure 2.2).
The alkaline borohydrides are less reactive toward halides. NaBH, in DME or
DMSO or in the presence of polyethylene glycols [SF21 reduces only primary or
secondary bromides upon heating; with chlorides the reaction is even slower [PSI].
NaBH,-Ni(OAc), in MeOH has shown some efficiency [FMI]. The dibromo-
16 CLEAVAGE O F THE CARBON-HETEROATOM SINGLE BOND
1
Red-Al-Benzene,
PhCH=CH2
99%
CICHzCHzCOOH * CICHzCHzCHzOH
2.1 AlH3.NEtMe2,
toluene
2.2 2.3
Figure 2.2
cyclopropanes can be selectively reduced to monobromocyclopropanes by heating

with NaBH, in DMF [PSI]. The reduction of aromatic halides under these condi-
tions requires UV irradiation, and these reductions undoubtedly take place via a
radical pathway. Reductions of primary, secondary, and aryl bromides and iodides
by NaBH, in hot toluene in the presence of benzo- 15-crown-5 and a polymer-bound
tin halide catalyst have been described [BWI]. Glycosyl bromides are reduced by
titanocene borohydride [CS2]. Aryl bromides and iodides are also dehalogenated by
NaBH,-CuC12 in MeOH [NHl], while chlorides and fluorides remain unaffected.
Aryl bromides are inert in the presence of NaBH,-ZrCl, in THF [ISI]. LiBH,
leaves halogens intact in the selective reduction of 2.4 [BK5] (Figure 2.3). Lithium
aminoborohydrides reduce aliphatic iodides as well as benzyl bromide at room
temperature [FF2].
LiEt,BH in THF is the reagent of choice for the reduction of primary and
secondary halides; the latter reduction takes place by an SN, mechanism with
inversion of configuration and without rearrangement as shown in Figure 2.3 [BKI,
BK5]. The neopentyl or norbomyl skeletons, which easily undergo rearrangement,
thereby remain unchanged (Figure 2.3). Similarly, hexen-5-yl iodide 2.5, capable of
cyclization via a radical pathway, is transformed into a linear olefin, without mod-
2.1 HALIDES 17
96%
Me3CCH2X-Me3CCH3
LiEt3BH-THF
reflux
X = CI, Br, I
R R
2.5 R = Me, Et
Figure 2.3
ification of the carbon skeleton [AGl] (Figure 2.3). When the same reduction is
performed with LAH in THF, it gives 81% cyclic product [BK5].
It is beneficial to use 2 equivalents of LiEt,BH per mole to reduce a given halide
because the byproduct of the reduction is BEt,. This forms a complex with LiEt,BH
[Et3BH,BEt3]Lit, which is much less reactive. Aromatic and tertiary halides remain
intact under these conditions [BKI].
The selective reduction of the primary halides can also be accomplished with
NaCNBH, in HMPA or DMSO or even by NaBH, in warm DMSO. Epoxides,
nitriles, amides, ketones, and esters are not affected under these conditions [HKl,
Ll], as illustrated in Figure 2.4. n-Bu,NCNBH, or resin-supported cya-
noborohydride is even more selective, since each reduces only the primary iodides
and bromides, leaving the chlorides unchanged [HN3].
Figure 2.4
18 CLEAVAGE OF THE CARBON-HETEROATOM SINGLE BOND
X = Cl, Br, I
-
Q C&
BH3*THF
Figure 2.5
Q C&
Borane leaves the halides intact in an ether medium, allowing the selective reduc-
tions shown in Figure 2.5 [PI],
In the presence of transition metal complexes such as (Ph,P),Ni, halogenated
aromatic derivatives are reduced by NaBH, in DMF [W4] or NaBH,-PdCI, in
MeOH [GOZ]. The DDT and 2,4 D classes of pesticides are also dechlorinated by
NaBH,-Ni,B in alcohol [GO21 or by NaBH,(OCH,CH,OMe),-NiC1, in THF
under reflux [TPl]. Titanium complexes also catalyze the dechlorination of poly-
chlorinated aryl halides by NaBH, in DMF via a nonradical process [LS5], leading
to dimethylamino-substituted byproducts along with hydrocarbons. In DMA or in
ethers, a radicaI-based reaction takes place, leading only to dechlorinated products
[LS4, LS51.
In protic media (alcohol or aqueous diglyme), tertiary halides undergo solvolysis
and lead to the corresponding carbocations, which are reduced by NaBH,. If the
carbocations are able to undergo rearrangement much faster than reduction, a rear-
ranged alkane product is obtained [BBI]. Borane in CF,COOH shows a similar
behavior [MMI] (Figure 2.6).
Borohydrides associated with a Lewis acid such as Zn(BH,),, NaCNBH,-ZnI,,
or NaCNBH,-SnCl, can also induce, in ether, the cleavage of the C-X bond of
halides, which lead to sufficiently stable carbocations. An analogous mechanism can
be proposed to explain the reaction of LAH with secondary allylic chlorides such as
2.6 in ether, a process that takes place with rearrangement [HN2]. In contrast,
primary derivatives such as 2.7 are reduced without rearrangement [HN2] (Figure
2.6). Similarly, propargylic chlorides are converted to allenes (Figure 2.6).
Zn(BH,), in Et,O reduces tertiary and benzylic halides at the corresponding
carbon sites, but the allylic derivatives give polymers [KHl]. However, NaCNBH,-
ZnI, in Et,O or NaCNBH, in the presence of SnCl, selectively reduces tertiary,
benzylic, and allylic halides without affecting primary or secondary halides, esters,
and amides [KKI, KK61. The ate complex formed by the reaction of n-BuLi with
9-BBN in hexane has an identical behavior: tertiary, allylic, and benzylic halides are
reduced, while primary and secondary halides remain intact [TYl].
2.2 SULFONATES AND ESTERS 19
R3C-X -----D R~c+- R3C-H

MeOH NaBH4
X = C1, Br, I,OTs
Figure 2.6
2.2 SULFONATES AND ESTERS:S C - 0 ~ 0 , ~ fC-OCOR

;
LAH in Et,O reduces sulfonates, requiring the electrophilic assistance of the Lif
cation in the cleavage of the C - 0 bond. This is why it is possible to reduce at will
the C-Br bond or C-OTs of the bifunctional compound 2.8 by changing the
solvent [Kl] (Figure 2.7). In DME, where the Lif cation is well solvated, electro-
philic assistance does not take place.
LiBH,, LiEt,BH, or DIBAH in THF also reduce primary and secondary sulfo-
nates to hydrocarbons [BK5, BN3, KB 1, YGl] even if they bear benzyloxy substi-
tuents [YS2]. However, if the substrate is too sterically hindered such as 2.9 (Figure
2.8), the attack of the reducing reagent takes place on the sulfur, and the correspond-
ing alcohol is formed [GL5, SH4, WS21. This phenomenon is not observed with
LiEt,BH, as shown in Figure 2.8 [KBl]. In the case of 2.10 [HS3], which is a
hindered mesylate, the reaction with LiEt,BH did not produce the alkane but rather
the corresponding alcohol. The authors therefore recommend the use of iso-
propanesulfonate 2.11, which, when treated with LiEt,BH, is not attacked at the
sulfonate site (Figure 2.8).
NaBH, in hot DMSO can also reduce primary sulfonates [HH2, PSl], and this
78%
I
LAH-DME
Figure 2.7
method has been applied to various sugar derivatives lKS2, WWl 1. Primary allylic
tosylates such as 2.12 are reduced to the corresponding olefins by LAH [HN2], but
secondary tosylates do not react at all (Figure 2.9).
Acetates, whether primary or secondary, allylic, propargylic, or benzylic, are also
reduced by NaBH,-NiCl, in MeOH to hydrocarbons [HP2, 121, but the double
bond, in general, is not preserved (Figure 2.9).
2.11
Figure 2.8
2.2 SULFONATES AND ESTERS 21
Figure 2.9
The problems of solvolysis and possible rearrangements with sulfonates are similar
to those of halides. For example, the reduction of tricyclic tosylate 2.13,
whose structure is such that its double bond can participate in the reaction, leads to
the formation of a cyclopropane via an intermediate carbocation [KNl] (Figure
2.10).
R = H,n-alkyl, Ph R' = COO i-Pr

Figure 2.10
Cyclic sulfates of 1,2-diols 2.14 are transformed into monoalcohols by

NaCNBH, in refluxing THF at pH 4-5 followed by hydrolysis, or regioselectively
to P-hydroxyesters by NaBH, in DMA when R = COOi-Pr [GS3] (Figure 2.10).
2.3 EPOXIDES: >C,-P(

0
The cleavage of the C - 0 bond of epoxides requires the electrophilic assistance of a

reagent, which can either be a Lewis acid (Li+) or behave as such (AIH,, DIBAH).
Reduction of epoxides by SAH and by borohydrides is slow [BK5, CB5] unless one
adds strong Lewis acid. For example, NaCNBH, in the presence of BF,-Et20 [HTl]
or LiBH, in the presence of BEt, [YO11 or of methoxyborane [BN3] is used.
Therefore, alkali borohydrides may reduce carbonyl compounds, leaving epoxides
unchanged. Lithium arninoborohydrides are, however, efficient in reducing epox-
ides [FF2]. Their reduction with BH, is also assisted by the presence of BF,.Et20
[L2, PSI], but is more difficult when it is carried out with bulky substituted boranes
(Sia,BH, 9-BBN, or ThexBHC1) [BIG, BN5, G4]. Red-A1 is not very efficient
either, except with the epoxides carry an alcohol functional group at the ci position
[FKl, Ml]. Zn(BH,), on silica gel or on AIPO, also reduces epoxides [CCl 1, R3].
>95%
____C
LAH-THF or
Na piperidino
Et2ALy O°C
>95%
PhCHOHCH3 + PhCH2CH2011
Lit3BH-THF, >98 4
Red AI-C gH6
PhCHOHCHzMe
Figure 2.12
The regioselectivity of the opening of disymmetrical epoxides depends essen-

tially on the strength of the Lewis acid-base interaction between the partners. If this
interaction is rather weak, then the reduction takes place at the least substituted
epoxide's carbon. Such is the case with LAH or LiEt,BH in THF or Li 9-BBN-H
[G4] or with the complexes LAH-N-methylpyrrolidine [FS 11, AlH,.Et,N [CB7] and
Na piperidinoEt2A1H [YA2] (Figure 2.1 1). The mechanism of the reaction is SN2
assisted by the Lewis acid; its stereoselectivity is therefore a trans-diaxial opening
(Furst-Plattner rule) [G4], as shown in Figure 2.1 1 by reduction of steroidal epox-
ides 2.15 and 2.16 [BK5, BK6, BMl, BN4, RPl, Wl].
With a stronger Lewis acid, the regioselectivity is reversed, and the reduction
takes place at the most substituted epoxide carbon. The hydride attacks preferen-
tially the carbon that is better able to stabilize a carbocation. This is the case when
one uses BH,, even in the presence of 2-aminoethanol, NaCNBH, in the presence of
BF,, AlH, in Et,O, DIBAH in THF, toluene, or hexane, LiBH4-BEt, or Zn(BH4),
on SiO, [E2, G4, HTl, IWl, L2, M1, PSI, R3, YGI, Y01, W l ] (Figure 2.12). The
regioselective reduction of styrene oxide 2.17 to 2-phenylethanol can be performed
2.21 LAH 15
LiEt3BH 93
Figure 2.13
with BH, or NaCNBH, in the presence of BF,.Et,O or by Zn(BH,), on SO,. The

other reagents give mixtures of primary and secondary alcohols. Such is also the
case in the reduction of cis-2-methylstyrene oxide by LAH. Unexpectedly, reaction
of this epoxide with LiEt,BH gives 1-phenyl-propanol [BN4] (Figure 2.12). The
reduction of the epoxide of 1 -methylcyclohexene under these conditions leads to
cis-2-methylcyclohexanol 2.18 [HTI] (Figure 2.12).
In certain cases, whenever the Lewis acidity of the reagent is high enough and
whenever the structure of the molecule is favorable, the reaction involves the forma-
tion of a carbocation, which can undergo migration leading from epoxide 2.19 to an
aldehyde 2.20 that is later reduced [HTl] (Figure 2.13). The carbocation can rear-
range in a different way so that the alcohol obtained has a modified carbon skeleton.
Such is the case in the reduction of 2.21. However, the use of LiEt,BH minimizes
these rearrangements [G4] (Figure 2.13).
Epoxides undergo decomposition under the influence of the acyloxyboranes in
organic acids [MMI]. Being bulky, LTBA in THF leaves the epoxide unattacked in
the cold and leads to the selective reduction shown in Figure 2.14 [MI]. The
Figure 2.14
Figure 2.15
primary alcohol that is formed from the aldehyde 2.22 undergoes lactonization, but
the epoxide and the ester are not reduced.
The presence of a functional group in the vicinity of the epoxide can lead to
interesting results. Such is the case for the epoxy-2,3 alcohols 2.23, which can be
obtained in a nonracemic form by asymmetric epoxidation of the corresponding
allylic alcohols [KS3]. The action of LAH in THF or better yet of Red-A1 in the
same solvent [MM2, V l ] or preferably in DME [GS4] selectively leads to the 1,3-
diols 2.24, while DIBAH [FKl] or LiBH4-(i-PrO),Ti in C,H, [DLl] gives access to
the 1,2-diols 2.25 (Figure 2.15). The hydride attack is stereospecific, and in the
nonracemic chiral molecule 2.26, the reaction proceeds with inversion [FKl] (Fig-
ure 2.15). If the alcohol residue is transformed into a methyl ether, Red-A1 does not
promote any reduction [FKl].
A limitation of the Red-A1 method is steric hindrance. If the carbon atom bearing
the primary alcohol is disubstituted such as in 2.27, the other regioisomer is formed
[Vl] (Figure 2.15).
Vinylic epoxides such as 2.28 can be reduced by attack on the epoxide carbon
atoms according to the usual rules, or they can undergo conjugate reduction, as
shown in Figure 2.16 [LKl]. LAH attacks the epoxide at the least substituted
carbon, and DIBAH in THF mainly attacks the epoxide at the most substituted one,
whereas DIBAH in hexane gives only the conjugate reduction. Acetylenic epoxides
are reduced by LAH into homopropargylic alcohols [HDI].
Epoxytosylates 2.29 can be reduced by DIBAH (3 equiv.) at -40°C in CH,CI, to
RRkOTs 83 - 95%
DIBAH, CH2Ci2,
-40°C OH
2.29
Figure 2.16
2-hydroxytosylates [CJ2]. This reaction is stereospecific. If the reaction is run in

hexane, overreduction of the tosylate to a methyl group takes place (Figure 2.16).
The reduction of cis- or trans-4-benzyloxycyclohexeneoxide c-2.30 and t-2.30
with LAH in ether or pentane at room temperature is regioselective towards cis- or
trans-3-benzyloxycyclohexanol (Figure 2.16). However, in the presence of 12-
crown-4, which hinders chelation, the cis derivative is preferentially transformed
2.4 ALCOHOLS, ETHERS, AND ACETALS 27
into cis-4-benzyloxycyclohexanol [CC5, CC8] (Figure 2.16). Similar but less selec-
tive reductions are observed with five-membered analogs [CC8].
2-Methylglycidic acid is regio- and stereoselectively reduced to 2-deutero-3-
hydroxybutanoic acid by NaBD,-DO- in D 2 0 [MV3], while in the presence of LiBr
the regioselectivity is lower. F-Alkyl-a,P-epoxyesters are also reduced to diols by
NaBH, in alcoholic media [LPl].
Oxetanes are also reduced by aluminohydrides [SP2]. When Zsubstituted by an
aryl group, the Lewis acidity of the reagent and the electronic character of the aryl
substituent determined the relative amounts of primary and secondary alcohols so
formed [BL5, SS8].
\ /
OR
2.4 ALCOHOLS, ETHERS, AND ACETALS: >C-OR; C
' 'OR
2.4.1 Alcohols
Alcohols are generally converted to alcoholates by the alumino- and borohydrides.
The cleavage of the C-0 bond can take place upon warming with Red-A1 [Ml], or
it can occur under solvolytic conditions starting with appropriate alcohols such as
benzylic or allylic alcohols that give stable carbocations. The carbocations thus
formed are then reduced to hydrocarbons. Therefore, the diaryl- and triarylcarbinols
are reduced by NaBH, in CF3COOH [GN 11 or (CF3COO),BH in THF-CF3COOH
[MMl] (Figure 2.17).
When using suitable experimental conditions, electron-donor-substituted primary
benzyl alcohols can also be reduced to substituted toluenes [NB2]. However,
NaBH,-CF3S03H in Et20 is superior to NaBH, in CF,COOH in reducing 2-ar-
yladamantanols to the corresponding hydrocarbons [Owl]. Under the same condi-
tions, adamantylmethanol leads to homoadarnantane. Similarly, other carbocyclic
substituted methanols give ring-expanded cycloalkanes [OW2].
Figure 2.17
Figure 2.18
NaBH,-AlC1, in THF or AlH, in Et,O also reduce diarylcarbinols or the ar-

ylalkylcarbinols to hydrocarbons [E2, M1, OS21 (Figure 2.18). In the presence of
NaCNBH,-ZnI,, allylic, benzylic, and even tertiary alcohols are reduced to hydro-
carbons via the corresponding carbocations [LDl] (Figure 2.18). In some cases, the
reaction probably takes place by a radical process. The dimerization observed from
2.31 and the stereoconvergence of the reduction of indan-1-01s 2.32 and 2.33 [AB I]
have been interpreted in this way (Figure 2.18). Ferrocenyl alcohols suffer reductive
deoxygenation with NaCNBH,-TiCl, [B6].
Ally1 alcohols can also be transformed into olefins by NaCNBH,-BF,.Et,O, but
some isomerizations can occur [SVl]. The reduction of primary alcohols as well as
ally1 and benzyl alcohols into hydrocarbons by NaBH, can be carried out via
alkoxyphosphonium salts 2.34 generated in situ [HS6] (Figure 2.19).
The cobalt complexes derived from tertiary propargylic alcohols 2.35 are reduced
by NaBH, in CF,COOH to hydrocarbons via the corresponding carbocations,
which, after decomplexation, yield substituted acetylenes. These compounds are
much less easily prepared otherwise [N3] (Figure 2.19). The reduction can also be
carried out by BH,.Me,S in CF,COOH [PLl]. Such methodology also applies to
iron complexes [DS4].
Figure 2.19
2.4.2 Ethers
Aliphatic ethers are generally inert in the presence of alumino- and borohydrides,
although oxabicyclic [3.2.1] compounds are reduced by DIBAH [LCI]. Aromatic
ethers can be cleaved to give phenols using DIBAH [MH2, Wl], while benzylic
ethers are cleaved by Red-A1 in xylene under reflux [Ml]. An example is given in
Figure 2.20: The hindered ketone group of 2.36 is not reduced in these conditions.
LiEt,BH or Li (s-Bu),BH in excess also cleaves arylmethylethers [MZl]. The
reaction is run in glyme or THF at 67°C. Selective demethylation of 2.37 and 2.38
can be performed (Figure 2.20). C-CI or C-Br bonds are left intact.
90% Ir
LiEt3BHor Li s-Bu3BH-
EtO
2.37
THF, reflux
92 - 98%
as above
2.38
Figure 2,20
OTBDMS >99% OH
*
Ph AX LAH-THF, reflux PhAX
OTBDMS >99% OTBDMS

D
LAH-THF, reflux
R= Me, OMe R'= Me or H
OTBDMS OTBDMS
98%
Ph KEW 2.40
L A H - ~reflux*
, Ph
Figure 2-27
In the presence of Pd(PPh,),, allyl ethers are reduced by LAH or LiEt,BH in

THF (Section 5.3). Methyl or trimethylsilyl allyl ethers are reduced to the corre-
sponding unsaturated hydrocarbons by NaBH,-NiCI, in EtOH [G02]. Lactones
and epoxides remain intact under these conditions, as do ethers of saturated alcohols
(Figure 2.21).
Trimethylsilyl ethers (ROSiMe,) are cleaved by aluminohydrides and bor-
ohydrides [G3]. Aluminohydrides and DIBAH also reduce some unsymmetrical
methylated silyl ethers [CGl, CG2, Fl]. However, more hindered silyl ethers such
as ROSiMe,t-Bu or ROSiPh,t-Bu seem to resist these reducing reagents, partic-
ularly if the reactions are carried out at low temperature [G3]. If a functional group
bearing a relatively acidic proton (amine, alcohol) or precursor of an alkoxyalu-
minoborohydride (ketone, ester) is adjacent to the OSiMe,t-Bu group, intramolecu-
lar cleavage occurs, so that LAH in THF can transform TBDMS ethers 2.39 into
alcohols [VBl] (Figure 2.21). The selective cleavage of 2.40 has been easily per-
formed (Figure 2.21).
2.4.3 Acetals and Orthoesters

Acetals associate with DIBAH at low temperatures and are cleaved into ethers only
at room temperature or by heating, depending on the substrate [TAl, Wl]. An
-
72 84%
m 3 ' E t 2 0 , reflux $+-
or BH3, THF, r.t.
-7S°C,then 0°C
Figure 2-22
excess of reagent must be used. Similarly, orthoesters are cleaved by DIBAH at 0°C
[TNl]. The reducing agents AlH, [E2, EB1, MK31, BH,.THF [H3, L2, PSI],
BH,.Me,S-BF,.Et,O [SK6], A1Br2H, AIC1,H [MFl], and ClBH2.Me2S [BB3]
have sufficient Lewis acid character to convert acetals to ethers. The mechanism of
these reductions involves the formation of an oxonium ion, which is then reduced
(Figure 2.22). On the other hand, LAH and LiEt,BH leave acetals untouched, except
in the presence of TiC1, [MAl, NG2] or other Lewis acids that eventually induce the
formation of tricoordinated aluminohydrides.
An application of these reactions is the regeneration of alcohols from the tetra-
hydropyranyl (THP) ethers 2.41 used as protecting groups, Reaction of THP ethers
with AlH, (most frequently formed in situ starting from LAH in ether solution by
adding AlCl, or BF,.Et,O) provides the expected alcohols. If the product alcohols
are likely to form carbocations, these are in turn reduced to hydrocarbons (tertiary,
benzylic, allylic alcohols) (Figure 2.22). Improvements in this reaction involve the
use of BH,.THF [CB8] or NaCNBH,-BF3.Et20 [SS5]. Under the AlH, conditions,
dioxolanes 2.42 lead to glycol monoethers (Figure 2.22).
The cleavage of orthoesters 2.43 is regioselective when they are dissymmetrical:
Primary alcohols are formed rather than secondary ones [TNl] (Figure 2.22).
Other reducing reagents leave acetals intact [BKS, Ml] except in acid media,
where the oxonium ions are likely to be generated. Oxonium ions can be formed and
reduced with NaCNBH, in MeOH-HCI, NaCNBH3-BF3.Et20 [HJ3, NG2, SV2],
NaBH,-CF,COOH in THF, NaCNBH,-CF3COOH in DMF, or NaCNBH,-
90% D
Me0 OMe
Zn(BH4)2-Me3SiC1,
Et20, r.t.
MeY-cOOMe
OMe
85%
r +
NaCNBH3-CF3COOH,
DMF
ArT* 2.44
OR
76% e
NaCNBH3-Me3SiC1,
MeCN
Figure 2.23
Me,SiC1 in MeCN [GNI, JS 1, MK31. The last three reagents cleave only the
dioxolane derivatives of aromatic ketones, whereas the first ones are more reactive
and have a broader scope of application (Figure 2.23).
At ambient temperature, Zn(BH,), in Et,O, in the presence of trimethylsilyl
chloride, transforms acetals and ketals into ethers. Under these conditions, esters
remain intact, but the double bonds are reduced [KUI] (Figure 2.23). According to
the experimental conditions, the regioselectivity of the cleavage can vary [JSI], as
shown by the reduction of sugar derivative 2.44 (Figure 2.23).
NaCNBH,-TiCl, can also be used for acetal reduction. Esters are left unchanged
under these conditions. For instance, a benzylidene acetal formed from tartaric acid
2.45 can be transformed into a chiral monoether [AS I] (Figure 2.24). Other examples
are described in the literature [MAI]. The carbon-oxygen bond of hemithioketals
2.46 is hydrogenolyzed by AlH, in Et20, while the CUS bond remains unchanged
[E2] (Figure 2.24). Dithianes, in contrast, are not affected by aluminohydrides,
borohydrides, or boranes [NG2].
The treatment of the acetal derivatives of chiral diols 2.47 with DIBAH, or better
with AlHBr, or AlHCl, (obtained by combining 3 equivalents of AlX, with LAH in
Et,O), leads to an enantioselective cleavage to an ether-alcohol 2.48, which can
then be oxidized to a nonracemic alcohol with Swern reagent [MFI, MI11 (Figure
M ~ O ~ COOMe
O
7 1% overall e
;"(I*
OH OH'
(R) ee 84%
2-DIBAK O°C
Figure 2.24
2.24). The method is applicable to acetals of a$-acetylenic ketones such as 2.49

[IMI] (Figure 2.24). The other enantiomers can be obtained by using Et,SiH-TiC1,
on the same acetals [IMl, IM2, MIl]. This methodology provides a reduction of
ketones to chiral alcohols that is complementary to the reduction effected by the
chiral alumino- and borohydrides (Section 3.2.3).
The stereoselectivity of the reduction of bicyclic 1,3-dioxolanes 2.50 has been
studied [IM3, KU2, KU31. DIBAH in excess leads predominantly to trans-substi-
tuted isomers, while Et,SiH-TiC1, or Zn(BH,),-TiC1, in CH2C1, gives the reverse
stereoselectivity (Figure 2.25). Other reagents such as AlHBr, or AlHCl, are less
stereoselective [KU4].
A solvent effect has been observed in the DIBAH reduction of the bicyclic 1,3-
dioxane 2.51 [IM3] (Figure 2.25). In CHC1, or CH,Cl,, the trans isomer 2.53 is
predominantly formed, while in THF, the cis isomer 2.52 is the major product. With
AlHBr, in Et,O, the stereoselectivity is even higher [IM3] (Figure 2.25). These
results have been interpreted in terms of conformational effects, emphasizing the
importance of the size of the acetal ring (six-membered vs. five-membered).
DIBAH-CHCI 3 8
DIBAH-hexane 44
DIBAH-THF 82
AIHBrz-Et20 97
Figure 2.25
2.4.4 Ozonides
Ozonides are reduced to alcohols by LiAlH, [MS3] and NaBH, in alcohols [CH4,
H3]. However, it appears that the best reagent is BH,.Me,S in CH2C12 at room
temperature, a method that is compatible with carboxylic esters [FGl] (Figure 2.26).
Ozonolysis of olefins followed by reduction can be performed sequentially in a one-
flask operation.
2.5 AMMONIUM SALTS: N+R,,X-
LAH in THF reduces ammonium salts to amines. However, the best reagent for this
reaction is LiEt,BH in THF at 25°C. Methylammonium salts are selectively de-
methylated [BK5, CP1, NM1, PSI] (Figure 2.27). This method has found numerous
applications in synthesizing natural products [NMI].
The reduction of ammonium salts, formed by reacting Me2S0, with benzylic
Mannich bases 2.54, by NaCNBH, in HMPA at 70°C, leads to methylated aromatic
Figure 2.26
2.5 AMMONIUM SALTS 35
>95% D
KOMe4Red AI-THF or Li s-Bu3BH-
Figure 2.27
derivatives [YIl] (Figure 2.27). This method preserves the R group in the following
cases: C1, COOEt, CH,CN, and NO,. Reduction of allylic derivatives such as 2.55
with LAH in an ether medium can lead to mixtures of regioisomers [HN2] (Figure
2.27). If milder reducing agents such as NaBH,, Red-Al, or Li(s-Bu,)BH are used,
the reaction can be regioselective [GL6] (Figure 2.27). NaCNBH, in i-PrOH under
reflux does not react at all with ammonium salts.
2.6 PHOSPHORUS DERIVATIVES: >c-P
Single P-C bond cleavage has been described. For example, phosphonium salts
2.56 are reduced to phosphines by LAH in THF under reflux; the cleaved bond
corresponds to reduction of the most stable carbanion [H2] (Figure 2.28). The P-C
bonds of allylic phosphonates 2.57 or phosphonium salts can also be cleaved by
ph$F I-
Me CH2Ph LAH-THF, reflux
* PhCH3 + ~ mMe
;
Et
2.56
* Rj C 0 O E t
LTBA-THF
--
NaBH4-EtzO,
boric acid
p(o)(oEt)2
R'= COOEt or Ph
Figure 2.28
LAH in Et20. This reduction occurs with allylic transposition and leads to a trans-
olefin [HJ2, HN2, KN2] (Figure 2.28).
LTBA can also cleave selectively the P-C bond of acyl phosphonates 2.58,
while preserving other functional groups [DSl] (Figure 2.28). Nevertheless, the
reduction of similar compounds such as 2.59 by NaBH, in EtOH buffered by boric
acid does preserve the P-C bond and leads to diastereomeric a-phosphorylated
alcohols [BS5, DSl] (Figure 2.28). After enolization by NaH, the P-C bond
cleavage of acylphosphonates (EtO),P(O)CH,COR can be realized with LAH
[HS7].
Chapter 3
Reduction of
Double Bonds
Boranes add to carbon-carbon double bonds even if they are not activated by an
electron-withdrawing group. These hydroboration reactions lie outside the scope of
this book; nevertheless, it is important to recognize that most boranes cannot be used
when it is necessary to preserve the C=C bond in a molecule (unless it is partic-
ularly hindered). However, (CF,COO),BH.THF leaves the double bonds of styrene,
1-decene, and Ph,C=CH, intact [MMl].
The other hydrides and borohydrides do not affect the isolated C=C bonds
except in the presence of transition metals [CY2, G02, MI, W4]. As shown in
Figure 3.1, only the least hindered double bond of 3.1 is reduced (Figure 3.1).
Unsubstituted and substituted styrenes can be reduced by LiEt,BH in hot THF or by
NaBH,-BiCI, [RP2, RP41, but the Selectrides, Li(s-Bu),BH and K(s-Bu),BH leave
them intact. The double bonds of certain allene alcohols 3.2 and 3.3 can also be
reduced [Ml] (Figure 3.1). However, mixtures of alcohols and dienes are formed.
The reduction of the double bonds conjugated to electron-withdrawing groups is
examined later (Section 3.2.9).
3.2 CARBON-OXYGEN DOUBLE BONDS: >C=O
3.2.1 Aldehydes and Ketones

Aldehydes and ketones are generally reduced to primary and secondary alcohols by
all the reagents studied with the following exceptions:
37
38 REDUCTION OF DOUBLE BONDS
MeCH=C=CH-CHOHMe
3.3
-H-
'lMeom3-
THF, reflux
- -.
H
+
CHICHOHMe
MeCHzCH-CH-CHMe
Figure 3.1
Reduction with sodium and ammonium cyanoborohydrides in neutral or basic

protic media [LI] allows the reduction of halides while leaving the carbonyl
groups intact (Section 2.1);
Reduction with (Ph,P),CuBH, in neutral media allows the selective reduction
of acid chlorides [FHl] (Section 3.2.7). The reduction of aldehydes by this
complex, however, takes place in an acid medium or in the presence of Lewis
acids.
Although single-electron transfer is proposed in the reduction of aromatic ke-

tones by AIH,, BH,, and LAH-pyridine [AG2], the reductions of aldehydes and
ketones by alumino- and borohydrides and boranes occur mostly by nucleophilic
attack of hydride on the carbonyl carbon. This process has been the subject of
numerous theoretical [ESI, HW1, N2, W2] and mechanistic [CBI, N5, W2, W4]
studies.
In certain cases, the reduction can take place without electrophilic catalysis (n-
Bu4NBH4 or phase-transfer conditions), but most frequently it requires the coor-
dination of the carbonyl group by a Lewis acid before nucleophilic attack [S2]. The
Lewis acid may be the cation associated with the reagent, an added acid, or even the
boron or aluminum atom of tricoordinate reagents (AIH,, DIBAH, boranes). The
importance of this phenomenon has been shown by the introduction of coordinating
macrocyclic molecules into solutions of LAH and LiBH,. This considerably retards
the reduction of carbonyl compounds in an ether medium [DCI, HPl]. Electrophilic
catalysis is more important when the lowest unoccupied molecular orbital (LUMO)
3.2 CARBON-OXYGEN DOUBLE BONDS 39
Figure 3.2
of the carbonyl compound is relatively high lying [LS2]; electrophilic assistance by

the Li cation lowers the LUMO level. The observed sequence of the relative binding
strength to the Li cation is the following [LS2]: cyclohexanone > 4-MeC,H4CH0
> PhCHO > 4-ClC6H4CH0.
In protic media, it is the solvent that plays the role of the acid catalyst and
provides electrophilic assistance by hydrogen bonding [ESI, PSI, WZ]. In alcoholic
media, it has been shown that the transition state for the reduction by borohydrides
involves an alcohol molecule that is converted to the corresponding borate (Figure
3.2).
Reductions by LAH in ether solvents have transition states that are reactantlike
[HWl, N2], whereas for reductions involving borohydrides, the transition states
occur later along the reaction coordinate [CBl, ES1, W2, YHl]. With reagents
having tetracoordinated aluminum or boron, the formation of the C-H bond is the
rate-determining step. Chloral (Cl,CCHO), whose lowest-lying vacant orbital is low
in energy, is indeed reduced more rapidly than pivalaldehyde (Me,CCHO), whose
LUMO lies higher in energy [BK5]. A review of these mechanistic considerations
has been published [W6].
In contrast, with reducing agents whose central atom is tricoordinated and thus
display a strong Lewis acidity (boranes, AlH,, DIBAH), the coordination of the
reactants with the carbonyl oxygen is the dominant factor controlling rate [D3].
Pivalaldehyde, whose carbonyl oxygen is more basic, reacts more rapidly with
BH,.THF than does chloral [BK5]. This difference in behavior has some important
implications with regard to the stereoselectivity of these reductions by these two
types of reagents (Section 3.2.2).
Aldehydes and ketones may be reduced to alcohols by LAH and SAH in an ether
medium [BK5, CB51, by LAH on a solid support [KH2, W4], and by alkoxy- and
aminoaluminohydrides [Ml, YA21, AlH, in Et20 or AlH,.Et,N [CB7], Red-A1 in
C6H6 [Ml], borohydrides in the solid state [TK2], under PTC conditions [BIl, BK8,
FR2, GB5, IL2, ML1, YP31, in alcoholic media or ethers or glymes [BK5, R3]), by
aminoborohydrides [FF2, FH51, by boranes and acyloxyboranes [BK5, GN1, IW1,
KB7, MM1, PSI], and by trialkylborohydrides [BK5], or ate complexes [BMl,
KAl]. In the presence of metal alkoxides, the rate of reduction of ketones by
catecholborane or BH,.THF is enhanced [LD2].
The reduction by alkaline cyanoborohydrides takes place at pH values less than 4
[Ll]. The reduction of ketones by Zn(CNBH,), is efficient only in Et20 [KK5] and
ArCOR or
ArCOAr'
.
NaE3H4 (aq. at acid pH)
ArCH2Ror
ArCHzAr'
NaBH4-AIC13-THF
3.4 LAH-AICI3
NaBH.,-CF3COOH
(diilawtone)
3.5
R = Ph, Mc
Figure 3.3
is relatively slow when NaBH, is used in organic acid media [GNl]. These reduc-
tions are in general sensitive to steric hindrance around the carbonyl, so that the
experimental conditions must be appropriate.
In acid media or in the presence of Lewis acids, diary1 ketones and alkylaryl
ketones 3.4-3.6 are reduced by LAH or NaBH, to the corresponding hydrocarbons
[DN2, E2, GK1, GNl,OS2] (Figure 3.3). However, LAH-AlCl, gives poorer yields
[GN 1, KG 1, KLl]. NaBH,-ZrC1, in THF reduces PhCHO and PhCOCH, to the
corresponding alcohols [IS 11. Flavanones are reduced by NaCNBH, in CF,COOH
either to flavanes or 1,3-diarylpropanes, depending on their substituents [LBl].
Aromatic aldehydes and ketones substituted by electron-donating groups are also
reduced to hydrocarbons by BH,.THF [L2] and NaCNBH,-ZnI, in CH,Cl, [LDl].
NaBH, in MeOH in the presence of PdCI, gives analogous results [GO21 as does
ion-exchange resin borohydride-Ni(OAc), in MeOH [BK9]. Acylferrocenes are
reduced to the corresponding hydrocarbons by AIH,, NaCNBH,-TiCI, in THF, or
NaBH,-CF,COOH [B6, B7, RE21.
Arylalkyl ketones (ArCOR) do not react with Me,N.BH, alone, but benzyl
bromides (ArCHBrCH,) are formed when the reaction is run in the presence of Br,
[LGI]. Moreover, t-BuNH2.BH3-AlCl, in CH,C12 also reduces arylalkyl ketones to
the corresponding hydrocarbons (ArCH2R). This transformation is compatible with
ester groups, as well as chloro, bromo, nitro, and phenylthio substituents in the aryl
ring; however, carboxylic acids are reduced to primary alcohols [LTI].
It is possible to reduce aldehydes and ketones selectively in the presence of
isolated double bonds, halides, sulfonates, phosphonates, acetals, esters, amides,
nitriles, acids, and NO, groups by using NaBH, or n-Bu,NBH, in various media
[DA3, JB2, PSI, TY3, WG21. The examples given in Figure 3.4 illustrate this
~ C O O M ~ ~ C O O M ~
0a0 COOEt
(5
PhCOCOOEt
COOEt
84Yo
.) PhCHOHCOOEt
BH3*NH3-Et20
Figure 3.4
compatibility. The in situ formation of lactones 3.8 and 3.10 results from the selec-
tive reduction of the ketone functionality of 3.7 and 3.9. Likewise, the amine- or
amino alcohol-boranes effect the reduction of ketones in the presence of esters [Al,
IWI] (Figure 3.4). On the other hand, LiBH, also reduces the ester group of 3.9
[JB2].
NaBH, on alumina appears to be a very mild reducing agent. Under these
conditions, it is possible to avoid the hydrolysis of esters, which sometimes occurs
due to the basicity of NaBW, in aqueous-alcoholic solutions. This is particularly
interesting for the case of en01 acetates such as 3.11, which are fragile in protic
media [W4] (Figure 3.5). The selective reduction of the chlorinated ketolactone 3.12
is another illustration of this useful selectivity [WVl] (Figure 3.5). Borane-eth-
3.12
Figure 3.5
anolamine also leaves C-Cl and C-Br bonds untouched so that 2-haloketones can
be transformed into halohydrins [IWl].
LAH on silica gel reduces ketoesters to hydroxyesters in Et20 [KH3]. The
reduction of epoxy ketones to epoxy alcohols is easily accomplished by action of
Zn(BH,), in Et20 or NaBH, in MeOH, sometimes in the presence of CeCl,. The
stereoselectivity of the reaction is usually high [BB6, BC2, CP3, NTl] (Section
3.2.4).
The selective reduction of aldehydes in the presence of ketones has been ob-
served using the following systems:
NaBH, in cold i-PrOH [BIG], or in EtOH-CH2C12 at -78°C [WR2];

n-Bu,NBH, in CH2C12 [RGl, SPl] or exchange resin borohydride in MeOH
[GB5, YP31;
n-Bu,NCNBH, in an aqueous 0.1 N HCl solution [W3];
(Ph,P),CuBH, in acid medium [FHl];
Na(AcO),BH or better n-Bu,N(AcO),BH in C,H, under reflux [GFl, GNl,
NGl], as shown in Figure 3.6 (if the molecule bears an alcoholic functional
group at the a or P position to the ketone, this is also reduced [SM2]);
Na(OAr),BH in THF [YKll;
Li(OCEt,),AlH or LBTA in THF [K4, Ml];
BH,-Me2S or BH,-LiCI [HCI , YCI 1;
Zn(BH,), in THF at - 10°C [R3] (Figure 3.6);
Amine-boranes in Et20 at O°C, t-BuNH,.BH, [All being the most effective;
pyridine-borane on A120, [BSl] or in the presence of AcOH [CWl];
NaBH,-SnC1, in THF, which reduces aromatic aldehydes without affecting
ketones [OHl].
A noteworthy result is that ketones can be reduced without affecting aldehyde

groups by using NaBH,-CeCl, in aqueous MeOH or EtOH at - 15°C [GLI, GL21.
C6H6,reflux I
COMe
Figure 3.6
This is due to a rapid and selective transformation of aldehydes under these condi-
tions to ketals or hemiketals, which are not reduced (Figure 3.7). The same type of
situation permits the relatively rapid formation of ketals of unhindered ketones in
the presence of HC(OEt),, whereby the selective reduction of the most hindered
ketone group of 3.13 is possible [GLl] (Figure 3.7).
Because of the sensitivity of the reduction of some ketones to steric hindrance, it
is possible with a judicious choice of reducing reagents to reduce selectively the
least hindered carbonyls in a di- or triketone. The most effective reducing reagents
in this regard are the complex Zn(BH,),.1.5 DMF in MeCN [HJI], amine-boranes
in Et20 [All, LTBA in THF [Ml] or K(s-Bu)~BH,as shown in Figure 3.8. The
examples 3.14-3.17 are chosen from steroid series, in which the ketone at the
3-position is selectively reduced in accord with the stereochemical rules to be
discussed later (Section 3.2.2) [GOl, TKl, WBl]. In the case of progesterone 3.17,
it is necessary to use the very bulky K Sia,BH to observe the selective reduction of
- - $ 76%
NaBH4-CeC13-
.&cooMe
"CHO "'CHO
EtOH aq., -1S0C
1. EI€I~-HC(OE~)~-M&H
2. NaBH4 then H30+
3.13
Figure 3.7
Figure 3.8
the 3-keto group [WDl] (Figure 3.8). A case of selective reduction of the most
hindered carbonyl group of a dialdehyde by NaB(OAc),H has been recently pub-
lished [SW2].
The different reactivities of aromatic and aliphatic ketones can be exploited in the
same way by carrying out the selective reduction of the latter. Reduction with
Zn(BH,),-1.5 DMF in MeCN or Zn(CNBH,), in Et,O in the presence of trace
amounts of water is a good choice [HJl, KK51, as is NaBH, in i-PrOH or LiBH, in
diglyme [PSI] (Figure 3.9). Titanocene borohydride also reduces aliphatic ketones
faster than aromatic ones [BS6]. ,
If very bulky Lewis acids such as methylaluminum bis-(2,6-di-t-butyl-4-meth-

ylphenoxide) (MAD) are added, the reverse reactivity is observed. Selective com-
plexation of the most accessible carbonyl group takes place, so that this group is no
longer accessible for reduction. Under these conditions, DIBAH or AIHBr, reduces
PhCO-t-Bu in the presence of PhCOMe or camphor [MA2]. However, discrimina-
tion between an aldehyde and a ketone is unsuccessful under such conditions.
CHzCHzCOMe CH2CH2CHOHMe
Q
PhCO
NaBHpPrOH
0
Flgure 3.9
PhCO
The competition between ketone and cx-enone will be examined later (Section
3.2.9).
3.2.2 Stereoselectivity of the Reduction of Aldehydes and Ketones

The stereoselectivity of the reductions of aldehydes and ketones has been the object
of in-depth mechanistic and theoretical studies [BR4, CB 1, CH5, CL4, CL5, ES 1,
HWI, M5, N2, N5, NN 1, W2, WN 1, WTl]. According to the Lewis acid strength of
the reducing agent, two models can interpret the observed results:
When the reductions are carried out with reagents whose central atom (A1 or B)
is tetracoordinated, the Felkin-Anh model is usually invoked [CP2, HWI, M5,
MWI, N2, NNI, WHI, WH2, WTl]. This aids in comparison of the interac-
tions involved in the nucleophilic attack of the hydride on the C = O bond;
When the reductions are carried out by means of reagents whose central atom is
tricoordinated, Houk's model is often used. This model takes into account the
predominant interactions during the coordination of the carbonyl oxygen with
the Lewis acid before any hydride transfer [HP3, HWl, M5, NNI].
When the reduction substrate can follow either of the two pathways, it is possible
to obtain selectively one isomer or the other by carrying out the reduction either
with an alumino- or borohydride, or with DIBAH or a borane. The first author to
exploit this dichotomy was M. Midland [MKI]. The principal types of interactions
to be taken into consideration are those of stereoelectronic origins, steric, torsional,
and orbital interactions, and also the position of the transition state (early or late)
along the reaction coordinate (see the following).
The Felkin-Anh Model [CPP, G5, M5, N2, N5, NN1, WH1, WH2, WP2,
WTI] The attack of a hydride H- on a prochiral carbonyl group can be accom-
plished either on the Re or Si face of the carbonyl, leading to a pair of diastereomers,
as shown in the models in Figure 3.10. In these models L represents the most bulky
group, P the most polar, and S the smallest group. Initially Cram [CA2] proposed
model 3.18 to interpret the formation of the major isomer, This is called "Cram" in
Figure 3.10, and the other isomer is labeled "anti-Cram."
The model to which most authors actually refer is a modification of the 1952
Cram scheme. This transition-state model, proposed by Felkin and Cherest and
3.18 Cram Anti Cram
Cram model
3.21
Felkin-Anh model
Figure 3.10
supported by calculations of Nguyen Trong Anh and Eisenstein, considers that the
transition state most resembles the ketone and hydride reagents. The attack of the
hydride takes place anti to the most bulky (L) or polar (P) group. In agreement with
the proposals of Dunitz and Burgi, this does not take place perpendicular to the
plane of the carbonyl group, but with an attack angle of about 109". To minimize
steric and torsional interactions, the attack preferentially involves the ketone con-
former 3.19 and not 3.20,as indicated in the Newman projections shown in Figure
3.10. The favored attack on 3.19 thus leads predominantly to the "Cram" stereo-
isomer 3.21 (Figure 3.10).
In the absence of other steric constraints, stereoisomer 3.21 is favored when the
reductions are performed on acyclic prochiral ketones. Several examples are given
in Figure 3.1 1 [SKI]. The stereoselectivity of the reduction is improved as the
reducing reagent becomes more bulky. In the reduction of 3.22 and 3.23,the phenyl
or unsaturated substituent plays the role of the bulky (L) or polar (P) groups; the
methyl group being M and hydrogen being S. Some other examples are given by
Cherest and Prudent [CP2]. However, if the carbon skeleton of the ketone to be
reduced is substituted in such a manner that conformer 3.19 is very sterically
hindered, the reduction takes place on conformer 3.20, and the stereoselectivity is
reversed. Examples of this are given in steroid series (Figure 3.1 1). When R is an
unsaturated group such as in 3.24, the interaction between this substituent and the
axial methyl at position 18 is not sufficient to disfavor the participation of conformer
3.19 during the reduction; by using Li(s-Bu),BH, which is bulky, one obtains
preferentially the (S)-22-alcohol [Toll. However, when R is a branched saturated
chain as in 3.25, a steric interaction between this chain and the 18-methyl group
& && Cram
____IC
+
Anti Cram
.' (R)
Lir-Bu3BH-THF 93
3.24
DIBAH 3
20 80
Figure 3.11
disfavors conformer 3.19, and 3.20 can participate, leading to the other 22-isomer.
The reduction of such carbonyl compounds by LAH gives a mixture of (S)- and
(R)-22-alcohols in a 4: 1 ratio [PR3] (Figure 3.1 1).
There has been some debate among the theoretical chemists as to whether the
hydride should attack anti to the best acceptor or to the best donor group (L or P on
Figure 3.12
conformers 3.19 and 3.20) [C6, CT3, FK4, LLS, MS, N2, WHI, WTl]. However,
this debate only takes into consideration orbital interactions. Taking into account all
the different factors including electrostatic, steric, and torsion interactions [WTl],
and the position of transition state along the reaction coordinate (early or late)
[AM3], it is possible to obtain more reliable trends. Moreover, solvent effects should
not be neglected [AM31 (see the following).
The reduction of cyclic ketones can be interpreted by a similar approach [N2, NS,
W2]. Stereoelectronic control favors axial attack on the rigid cyclohexanones. But
steric interactions, as a result of either the substituents of the molecule or the
structure of the reagents, can work against this pathway. The following results
illustrate these trends [H3] (Figure 3.12). LAH reduction of 4-t-Bu-cyclohexanone
3.26 in diethylether gives mainly the equatorial alcohol 3.27. Li(s-Bu),BH or Li
(t-BuEt,O),AlH [BD2] is very bulky, and it enters from the least hindered face of
the molecule to give rise selectively to the axial alcohol 3.28. LAH reduction of
3,3,5-trimethylcyclohexanone3.29, whose axial attack is hindered by the presence
of an axial methyl group, gives more equatorial attack than that of 3.26 (Figure
3.12).
In the steroid series, LAH preferentially attacks 3.30 from the axial face of the
ketone at the 3-position, while Li(s-Bu),BH does so at the equatorial face. One can
thus selectively obtain the 3-cholestanol 3.31 with an equatorial OH or its stereo-
isomer 3.32 with an axial OH, depending on the reducing agent employed [DAl]
(Figure 3.13). Some other examples are described by Ohloff and co-workers [OM2].
In the coprostane series, where the cyclic AB ring junction is cis, the same reagents
selectively give rise to either 3.33 or 3.34 [OM21 (Figure 3.13). The reduction of
I-oxosteroids has been reviewed recently [WLl].
Similarly, K(s-Bu),BH provides stereoselection in favor of the diaxial 3,7-diol
from the starting corresponding dione 3.35; the ester functional group remains
unchanged [TFl] (Figure 3.13). The stereoselectivity of the reduction of polymer-
supported 6-ketosteroids by aqueous KBH, has been examined. This depends on the
polymer used and on whether a phase-transfer catalyst is added or not [BH4].
Ring substituents other than alkyl groups can also influence the stereoselectivity
of the reduction. The presence of a CN group at the P-position with respect to the
3.35
Figure 3.13
carbonyl on either face of a decalone orients the reduction by LTBA in THF to the
preferential generation of the axial 3.36 or equatorial 3.37 alcohols [AF2, CB I]
(Figure 3.14). Other related examples have been recorded by Caro and co-workers
[CBl]. These results have been ascribed to remote electrostatic effects [WTl].
In the cyclic series, a problem arises due to the relative rigidity of some mole-
cules. The antiperiplanarity requirement between the nucleophilic hydride and the
CUL(P) bond as indicated in the Felkin-Anh model is sometimes difficult to attain
at the transition state. The flatness and flexibility of the ketone to be reduced have to
be considered [HM4, N2, WH3, WH41. Cyclohexenones, which are flatter than
cyclohexanones, give more product of axial attack [CG7, KY3, WH3, YK6] (Sec-
tion 3.2.9). The reduction of 3-ketosteroids such as 3.30 by NaBH, results in 80%
axial attack (Figure 3.15). Reduction of the 7-keto analogues 3.38 under similar
conditions gives only 45% axial attack [WM I]. Kinetic studies indeed showed that
this stereoselectivity was due to a decrease in the rate of only axial attack, possibly
because the steroid B ring is less flexible than the A ring (Figure 3.15). The
reduction of I ,3-dioxane-5-one 3.39 and 1,3-dithian-5-one 3.40 by LAH in Et20
CN
>95%
LTBA-THF
0
Figure 3.14
15
Figure 3.15
3.43
Figure 3.16
gives comparable results [JKI, KL31 (Figure 3.15). In the first case, 94% axial
attack is observed, while in the second one only 15% axial attack takes place. This
apparent discrepancy has been interpreted in terms of the ring structures of these
ketones: The six-membered ring of 3.39 is quite flat, while that of 3.40 is signifi-
cantly puckered [N2, WH41. Antiperiplanarity between the incoming bond and the
vicinal axial C-H bonds is difficult to attain during the axial attack of 3.40. Similar
results have been observed in reduction of 16-oxa- and 16-thiahomosteroids [T021.
In the norbornane series, the attack of LAH in Et,O takes place on the exo face,
leading to endo-norbornanols 3.41. These are the thermodynamically less stable
products. Therefore, the reductions performed by LAH do not follow "product
development control," but essentially depend on stereoelectronic factors [AB2]
(Figure 3.16). The same exo attack is observed in other strained bicyclic systems. In
general, Li(s-Bu),BH in THF at -78°C is more stereoselective than LAH in THF
[KG2].
The reduction of the chromiumtricarbonyl complexes of indanones and tetralones
3.42 and 3.43 [JMl] are interesting in terms of steric hindrance. The hindered
organometallic group blocks the attack of the hydride on the same face of the
molecule. Because it is possible to obtain the corresponding ketones in nonracemic
form, one has access to enantiomerically pure stereoisomers after decomplexation
(Figure 3.16).
The Houk Model [CL4, CL5, HP3, HW1, PRl] The intervention of a favored
conformation through which the reduction occurs can depend on the stereo-
electronic interactions in a Lewis acid-base complex that is formed between a
tricoordinated reducing agent (boranes, DIBAH) and a carbonyl compound. The
complex associates in a way that minimizes the different repulsive interactions, and
the transfer of the hydride takes place in second stage. Accordingly, the conforma-
Houk model
Figure 3.17
tion of the ketone in this complex 3.44 is more favored when the substituents on the
boron or aluminum atom are bulkier. As previously mentioned, the hydride transfer
takes place in the anti position with regard to the most bulky (L) or polar (P) group.
Under these conditions, the reduction leads to the "anti-Cram" diastereoisomer
(Figure 3.17). In cyclohexanones, the interaction with the axial vicinal C-H bonds
is the same as in the previous case [CL5].
In addition to the pioneering work by Midland [MKl], a certain number of
reports in the literature show a reversal of stereoselectivity as the reducing agent is
varied. For example, the reduction of steroidal prochiral ketones 3.45 and 3.46
either by alumino- and borohydrides or by boranes and DIBAH gives different
stereoisomers, enabling the process to be interpreted either by the Felkin-Anh or the
Houk model [MKI, SH7, SKI, TO11 (Figure 3.18). Similar results are obtained in
the reduction of cyclopropyl ketones either with Li (s-Bu),BH or with DIBAH
[OS4]. However, when starting from 3.47, the size of the L substituent is such that a
similar selectivity is observed whatever the reducing agent used. If the double bond
of 3.47 does not carry a trimethylsilyl (SiMe,) group, reduction by DIBAH gives a
greater proportion of the other isomer.
In most of the examples discussed above, stereoselectivity is high either because
the structure of the ketone shows two sufficiently different faces in terms of steric
hindrance or because the reducing reagent is bulky. In many other cases, the stereo-
selectivity is decreased because the different factors more or less compensate.
Indeed, it is necessary to consider the position of the transition state on the reaction
coordinate. Transition states are early with aluminohydrides and late with bor-
ohydrides in alcoholic media [CB 1,CL4,N2]. The possibility of electrophilic assis-
tance by the alkaline cation is another important factor [N2, S2]. The latter effect
especially facilitates the axial attack of cyclohexanones. In the presence of
[2.l. llcryptand, which prevents electrophilic assistance by the Li cation, the amount
of axial attack of 3.26 by LTBA decreases [AKl] (Figure 3.19). The size of the
reducing agent, the structure of the ketone, and the possibilities of conformational
equilibria must be taken into account [GZl, KW31. Indeed, the reactive conformer
may not be the most stable one [N2, S2, S3]. For example, Table 3.1 indicates the
stereoselectivity of the reduction of two rigid ketones, 3.26 and 3.48, and of a
conformationally flexible ketone 3.49, with different reagents [BD2, BS6, CBl,
DL2, FF2, GL2, HF1, M l , PSl, RC2] (Figure 3.19).
R' Me R' Me
3.47 ~i S-BU~BH-THF >99 <I

DIBAH-toluene >90 <lo
Figure 3.18
Adsorption of the ketone on montmorillonite clay enhances the axial attack of

NaBH, reduction to >99% for 4-r-butylcyclohexanone 3.26 and 78% for 3,3,5-
trimethylcyclohexanone 3.29 [SRI]. Other hindered substituted borohydrides also
give higher levels of equatorial attack [CY I]. From the numerous studies to date, it
appears that torsional and steric factors are very often predominant, as illustrated by
the reduction of eight-membered cyclic taxme derivatives [SH7]. An interesting
solvent effect in the reduction of a sugar derivative has been recently shown. The
reduction of a substituted rigid six-membered ketone with DIBAH in CH2C12 or
54 REDUCTlON OF DOUBLE BONDS
LTBA-THF(100%) 90 10
LTBA-(2.I . 11-THF(70%) 70 30
0
&H3 - +
p OH
@
3.49
Figure 3.19
TABLE 3.1 Percent axial attack in the reduction of 3.26,3.48, and 3.49
Reagent 3.26 3.48 3.49
LAH-THF 90 76 ' 76
LTBA-THF 90 98.5 70
Li(t-BuEt,O),AIH 95 >99
LiBH,-THF 86-93 71 70
NaBH4-MeOH 81 81 70
NaBH4-CeC1,-MeOH 94 >95 70
NaBH4-H,O-glycosidic 98
Surfactant
Cp2TiBH4-THF 97
(i-PrO),TiBH4-CH2C12 97 97
Li n-Pr2NBH3-THF 99
LiMe2NBH3-THF 95 64
Li(s-Bu),BH-THF 7 1
K(s-Bu),BH-THF 1 8
LiSia,BH-THF 0.5
AIH3-Et,O 85
DIBAH-toluene 61
9-BEN-THF 92 60
ThexylBHCI.Me,S 44 5.5
X = Ar, t-Bu, F, C1, OH, CF3 R = C02Me, CH20Me,

CH = CH2, Et
____)
LAH-Et 20or THF,

X
x NaBH4-EtOH
X X
R=ClorF 86 - 99 14- 1
R=H 43 57
Figure 3.20
pentane is poorly stereoselective. On the other hand, axial attack is highly predomi-
nant in THF. This has been explained by the relative bulkiness of the reagent, which
is trimeric in CH2C12 and pentane and monomeric in THF [HP4].
However, the stereoselective reductions of the 5-substituted adamantanones 3.50
[CT2, G5, KA4, LL51, and bicyclo-[2.2.2]-octan-2-one 3.51 [MK5] have been
interpreted in terms of Cieplak's model [C6, CT31. Unfortunately, the observed
stereoselectivities are low (de <40%), so that it is difficult to dissect the various
parameters involved in such reductions [CH5, N2]. The electronic contribution to
the stereoselectivity of the reduction of substituted 9-benzonorbornenones 3.52 is
very important [G5, OTl,OT2] (Figure 3.20). Halogen substituents on the aromatic
ring favor syn attack by all hydrides on those very rigid systems. Electrostatic
effects have been invoked to interpret these results [PW2, WTl].
3.2.3 Asymmetric Reductions

The enantioselective reduction of ketones has been the goal of numerous intensive
studies in recent years [BD3, BJl, BR4, DS5, N5, NNl, S3, S4, WM2]. Chiral
alkoxy- or aminoaluminohydrides have been used to perform asymmetric reductions
Figure 3.21
of ketones or aldehydes. The most efficient chiral alkoxyaluminohydrides [BP2,

CHI, IS3, NNl, S3] are generated in situ from solutions of LAH by addition of
(lR,2S)-N-methylephedrine 3.53 and 3,s-dimethylphenol or 3,s-dimethyl-N-ethy-
laniline in a 1:1:2 molar ratio. Polymer-grafted ephedrine can be used for a similar
purpose [FB2]. Chiral C, symmetrical diethanolamines 3.54 also give interesting
selectivities as LAH modifiers [VB2], as does Chirald 3.55 or its enantiomer [NNl]
or 2-isoindolinylbutan-1-01 [BL4, BL61. Reaction of (R)- and (S)-binaphthol 3.56
with LAH and EtOH in a 1:1:l ratio allows the preparation of (R)- or (S)-Binal
[NNl, BD31. Proline-derived diamines such as 3.57 [NNI, TK3] (Figure 3.21) are
also interesting chiral modifiers. Depending on the additive, the chiral reagent is a
rigid mono- or dihydride such as 3.58,3.59, and 3.60 (Figure 3.2 l), although, due to
disproportionations, the reagents must be carefully prepared and used [NS].
Most of these reagents reduce arylalkylketones and some a-enones with a high
enantiomeric excess provided that the alkyl group (R) is not too bulky (Figure 3.22).
The reagent generated from Chirald 3.55 is useful for the enantioselective reduction
of a-ynones [MW2, NN1, PC2, S3], although some limitations are known [Moll
(Figure 3.22).
Compared to the other reagents, (R)- and (S)-Binal in THF have a broader range
of application. Many arylalkylketones, a-enones, and a-ynones are reduced at
-78°C by (R)-3.60 to (R)-secondary alcohols and by (S)-3.60 to (S)-enantiomers
[DK2, HMS, NN1, S3, S4]. These reagents also reduce a-deuteroaldehydes such as
3.61 at - 100°C to a-deuterated primary alcohols and acylstannanes 3.62 and 3.63
R = H, Me, Et, n-Pr, i-Pr
w-
as above
R = Me, Et, n-CSHI1,i-Pr, t-Bu
LAH, (1 12,253-3.53, p&t

R = Me, Et, n-Pr, n-Bu, i-Pr
/~3~7n. as above t
C
R as above
85%
m
LAH, 3.55-Et20
R
R=H, Me, TBMSOCH2, Me3Si, n-C7HI5
-
Ph 4 85 90%
LAH, 3.51 (I?= Me)
R = Me, ~ t i-Pr
,
w-
~ h +
ee 90 - 95%
Figure 3.22
give a-stannyl alcohols with excellent enantioselectivity [S3] (Figure 3.23). Reduc-
tions of trifluoromethylarylketones occur with poor enantiomeric excesses with the
exception of 2,2,2-trifluoromethylanthrone [CMl]. To overcome the disappointing
results that are usually obtained in reductions of dialkylketones, crown-ether groups
have been introduced on Binal and preliminary results are promising [YUl].
Tartaric acid derivatives (TADDOLs) and a hexamethoxy substituted 1,l'-bi-
phenol give rise to reagents having similar potential [BD3, RMl].
Among the chiral borohydrides, ate complexes generated from a-pinene, such as
Alpine-hydride 3.64 and related reagents, reduce 2-octanone or acetylcyclohexane
OSiRMez
R = n-Bu, I, Br, C-C5H9,r)(
R'= Me, n-C5H,I
,,
R = Me, Et, n-C$I, i-PI
Figure 3.23
at - 100°C with a high enantiomeric excess [BJ2, BR4, WR51. A reagent generated
from N-benzoylcysteine 3.65, t-BuOH, and LiBH, reduces arylalkylketones to (R)-
alcohols with a 90% ee [NNI, SY21. Similar selectivities are observed with Li
glucoride 3.66 derived from diacetoneglucose [BPI, NNI]. NaBH,-tartaric acid
also gives interesting results, but only with ketones functionalized in the a- or
P-position with chelating residues such as OR, esters, or amides [Y03]. The reduc-
tion of some arylketones with alkali borohydrides in the presence of catalytic
amounts of chiral (P-oxoa1diminato)-cobalt complexes gives secondary alcohols
with a high ee [NY2]. NaBH,-(R)- or (S)-t-leucine in the presence of AcOH pro-
motes the enantio- and stereoselective reduction of a prochiral ketone, precursor of
diltiazem, a drug [YMl].
Borane derivatives have been widely developed for asymmetric reductions [BR4,
DS5, N5, NN1, S3, S4]. Although isopinocampheylborane 3.67 and diisopinocam-
pheylborane 3.68 are good asymmetric hydroborating agents, they proved unsat-
isfactory as chiral reducing agents of prochiral ketones [BJl, BR4]. While NaBH, in
the presence of P-cyclodextrins gave disappointing results, pyridine-borane under
such conditions reduces PhCOMe and PhCH2CH2COMe with 90% ee [SI2]. The
asymmetric reduction of aralkylketones by BH, in the presence of chiral ami-
noalcohols such as 3.69 was discovered by Itsuno in 1981 [DS5, IN1, IS1, IS2,
NN1, S4]. These reductions occur near room temperature, giving ee's greater than
95%. The selectivity is lower with dialkylketones (55-73%). Itsuno and co-workers
developed this methodology using, among other things, polymer-supported ami-
noalcohols [DS5]. In 1987, Corey and co-workers [CB2, CB31 demonstrated that
Itsuno's reagent was indeed an ate complex 3.70 of an oxazaborolidine and BH,.
These authors broadened the scope of application of these systems (CBS reagents)
designing new oxazaborolidines [DS5, S4, WM2] and showing that they could be
used in catalytic amounts with the achiral reducing co-reagents being BH,.THF
[CC3, CG6, CK6, CL2, CL10, CR2] or catecholborane [CB4, CH6, CL2, CL6, CL7,
CL91. Corey's oxazaborolines 3.71 are stable, and they bear the (R)- or (S)-proline
skeleton. Several synthetic pathways have been described [CLlO, MJ1, S41, as has
the preparation of crystalline borane complex of (S)-3.71 (Ar = Ph, R = Me)
[MT6]. This complex has been characterized by X-ray crystallography [CA3, MT61.
Chiral reductions are now quite common with these reagents when used either in
stoichiometric amounts [CT4, MT6, SCl] or in catalytic amounts in the presence of
BH,.THF, catecholborane [G6, GB6, QW1, SK.51, or BH3.Me2Sas achiral reducing
co-reagent [DS6, JM3, N5, S5, SC1, SM6, TA3, TB1, YL41. The asymmetric
reduction of aldehydes, various ketones, a-enones, and a-ynones usually take place
with an excellent enantiomeric excess [BB13, CL2, CL6, CR2, CT4, DS5, DK2,
GB6, MT6, NN1, PL2, S4, SM6, WM2] (Figure 3.24). The reduction of ketones is
carried out between -20°C and r.t., while that of aldehydes requires - 126°C for a
good asymmetric induction.
Both enantiomeric (R)- and (S)-oxazaborolidines are available; so it is possible to
obtain at will either enantiomeric alcohol. The selectivity depends upon the geome-
try of the complex formed by coordination of the carbonyl oxygen to the Lewis
acidic heterocyclic boron atom, complex 3.72 being favored. The catalytic cycle is
shown in Figure 3.25.
The Ar and R substituents in 3.71 that give the best results vary from case to case.
Moreover, catecholborane is less reactive than borane; therefore, it must be used
when the carbonyl compounds are sufficiently reactive (for example, aldehydes or
trihalomethylketones) and the reduction is only performed via the chiral reagent.
THF
(Ar = 2-Np, R = Me or n-Bu)
R = H, Me, C1, Br, MeOCOCH2CH2
> 95%
Ir
as above
,
R = c-C,H, ,t-Bu
-
80 98% L
as above
(k= 2 - N p , . ~= n-Bu)
R = n-C,H,,, c-C6H,,, Ph, 4-BrC6H,
(S)-3.71, BH3*THF
(Ar = Ph, R = Me)
w
...IOH
(Ar = Ph, R = n-Bu)
Figure 3.24
Catecholborane, as an achiral co- reagent, has also been recommended for the
reductions of ketophosphonates [ML2, ML41, a P-aminosubstituted or-enone [Loll,
cyclopropylisopropylketone3.73, some cobaltcarbonyl complexed ynones 3.74, and
unsymmetrically substituted benzophenones 3.75 [CH6, CH7] (Figure 3.26). The
reduction of 2,2-diphenylcyclopentanone3.76 by (S)-3.71 (Ar = Ph, R = Me) leads
Figure 3.25
to the (R)-cyclopentanol, which is itself a useful chiral auxiliary [DS6] (Figure

3.26). Ketones that contain heteroatoms capable of coordinating boranes, partic-
ularly nitrogen, can be reduced with high ee's. With compounds such as
acetylpyridines, the amount of oxazaborolidines must be increased, but the selec-
tivities are not greater than 80% [QWl]. Ferrocenylketones are also useful sub-
strates [LR3, SK5, WF21. Benzils are selectively reduced to syn diols [PJ2].
The synthetic routes to a number of optically active drugs include, as one step, a
reduction of a prochiral keto group by CBS reagents [see, for instance, CH8, CLlO,
CP4, CT4, HG2, JM3, SCI, TA3, TB I]. From chiral 1-trihalo-2-alkanols, one may
prepare chiral a-aryloxy-, a-hydroxy- and a-amino acids [CL7, CL91. In some
cases, the presence of Et,N in the reaction medium increases the enantioselectivity
[CT4].
The influence of temperature on the selectivity of the reduction of acetophenone
and cyclohexylmethylketone by various oxazaborolidines 3.71 (Ar = Ph, R = Me,
Bu, Ph) has been examined [S5]. The use of polymer-bound 3.71 has also been
proposed [FS3]. Some mechanistic [DTI] and theoretical investigations of the re-
ductions have also been carried out [DLl, LS6, N4, NU2, QBl].
Other amino alcohols have been transformed into oxazaborolidines that have
been tested as precursors of CBS reagents [DSS, MS9, NN1, PM2, RW1, S4, SM7,
WM21. Analogs of 3.71 in which the proline ring has been either enlarged, dimin-
89%
w
as above, toluene
-
88 90%
F I)H
as above, toluene A rAA r'
-
ee 81 95%
THF,40°C
Figure 3.26
ished [WD2, WM21, or rigidified by fusion of an aromatic ring [WM2] have been
proposed. Diethanolamines gave disappointing results [DF2], as did (1R,2S)-nor-
ephedrine grafted on polymer [CC6, CE3, DL31. Reductions of arylalkylketones
with reagents generated from (S)-prolinol3.77 [BM5], cis-1-amino-2-indanols 3.78
[DL3, DS7, HG2] and indolinemethanols 3.79 [KP3] give selectivities similar to
those obtained in reductions with reagents generated from 3.71. From methionine or
cysteine, sulfur-substituted amino alcohols 3.80 and 3.81 have been prepared
[MM6, MM71. The corresponding oxazaborolidines, generated in situ with
BH,-THF, also reduce arylalkylketones with an excellent ee. Interesting reagents
were obtained from (1S,2R)- and (lR,2S)-2-amino- l,2-diphenylethanol 3.82. The
corresponding oxazaborolidines 3.83, (R = Me, n-Bu, or Ph) were prepared in the
usual fashion. Used in catalytic amounts in the presence of BH,.Me,S at room
temperature, these reagent effect the reduction of various ketones with useful ee's
[QW2] (Figure 3.27). Reagent 3.83 (R = H) is prepared in situ. One advantage of
such reagents is the good enantiomeric excess obtained in the reduction of
acetylpyridines, although higher amounts of BH,.THF must be used (Figure 3.27).
(R,S)-3.83 has also been used in stoichiometric amounts in the presence of
BH,.Me,S to reduce symmetrical diketones 3.84 to (S,S)-diols, which are formed
along with about 15% of one meso isomers [QKl] (Figure 3.27). (R)- and (S)-1-
MeS
Ph,.
riOH
NH2
R
(84-3.83
R = H, Me, n-Bu, Ph R = Me, t-Bu, CH2CI
> 90% C
as above R q e
R = n-C4H9,t-Bu, Me2NCH2 ee 75 - 92%
> 90%
as above
*
as above
n = 2,3,4 ee 92 - 94%
3.86
Figure 3.27
diphenyl-2-phenylaminoethanolhave also been used to generate oxazaborolidines.

These reagents give high selectivities in the reduction of rr-enones [BB8]. The
stereoselectivity of the reduction of 17-oxosteroids is increased in the presence of
CBS reagents [RM2].
Oxazaphospholidines such as 3.85 [BP6, CF1, PM 11 and P-hydroxysulf~ximines
3.86 [BF3J have been proposed as chiral additives in borane reductions. With 3.86,
3.87 3.88
R = Me, n-C5Hl,, n-C6H13
R'= PhCH2, t-BuCH2, i-Pr, i-Bu, c-C6Hl,, t-Bu
Figure 3.28
borane is generated in situ from NaBH, and Me3SiC1 [BS7]. Under various condi-
tions, the results are not better than those obtained with 3.71. N-Sulfonylox-
azaborolidines give lower enantiomeric excess [OIl],
Chiral titanates have also been used as additives in the reduction of acetophenone
by catecholborane. At best, the ee was 80% [GDl].
Another method of asymmetric reduction of unsymmetrical dialkylketones is to
use chiral borane 3.87 [IT2, NNl, S3, S4] (Figure 3.28). As shown by Masamune
and co-workers, asymmetric induction occurs by coordination of the carbonyl group
of the ketone to mesylate 3.88, which is present in catalytic amounts. This is
followed by hydride transfer in such a fashion that steric interactions are minimized
(Figure 3.28). However, the chiral reducing agent has to be used in stoichiometric
amounts.
Borane in the presence of (R)-binaphthol-La(0-i-Pr), reduces various ketones
but with a low ee [ZYI]. Other chiral boranes can be used to carry out enantioselec-
tive reductions [ACl, BP2, BR4, DS5, M2, NNl, S3, S4], but the transferred
hydride comes from the carbon skeleton; therefore, these reagents are outside the
scope of this book,
3.2.4 Functionalized Aldehydes and Ketones

If heteroatoms are present in the vicinity of the carbonyl group, the formation of
chelates around an alkali, another cation, or the aluminum or boron atom can
influence the course of the reduction by playing the role of a Lewis acid. The Lewis
acid-base interaction can be quite strong depending on the nature of the heteroatom
and its substituents, on the ligands attached to boron and aluminum, and finally on
anti SYn
Zn (BH4),-Et20, O°C 85 15
LAH-Et 20 70 30
Figure 3.29
the solvent. In this way, the stereoselectivity of the reduction can be modulated
[EGl, G5, N5, R4, S3] (see the following).
The stereoselectivity of the reduction of a-hydroxyketones [ONl, PR41, a-ketoe-
thers [B2, CN2, El, KT1, MK2, R o l l , and a-epoxy ketones [B2, BB6, El, ON1,
RC3, TF21 has been reexamined, and conditions have been described that allow the
highly stereoselective synthesis of each diastereomeric alcohol. Thus the reduction
of an a-ketoalcohol 3.89 by Zn(BH,), in Et,O leads to the anti diol with good
selectivity [ONl]. When one uses LAH in Et20, this selectivity is lower. On the
other hand, the reduction of the corresponding silyl ether 3.90 by Red-A1 in toluene
gives predominantly the silyl ether of the corresponding syn isomer [ONl], which,
in the presence of n-Bu,NF, generates the syn diol. (Figure 3.29).
In the first case, chelation between the carbonyl group and the zinc atom of the
alcoholate that is formed facilitates a cyclic transition state 3.91 (Cram cyclic
model), the hydride being subsequently transferred to the side bearing the least
bulky substituent H. In the second case, one can propose a Felkin-Anh transition
model 3.19, with the most polar group (P) being OSiR, and the smallest one (S)
being H (Figure 3.29). Again, according to steric hindrance and conformational
effects, the reductions can be more or less stereoselective [SK4].
I)H OH
75%
_____C
CZH5+ LAH c 2 H 5 w +c2Hr*
Me OR' Me OR' Me OR'
R' = PhCH20CH2 (Et20) 98

R'= SiPh2t-Bu(THF) 5
Figure 3.30
The possibility of chelation at the transition state can also be envisioned during
the reduction of the a-alkoxyketones RCOCH(OR1)R". This depends above all on
the nature of the R ' group. If this group is PhCH,OCH, or MeOCH,, chelation may
take place. On the other hand, as seen in the reduction of 3.90 when R' = SiPh,-
r-Bu, chelation does not take place and the Felkin-Anh model applies. If R' = alkyl,
the reductions are slightly stereoselective. The stereoselectivity of the reduction of
3.92 according to R' is a striking example of this dichotomy [OM11 (Figure 3.30).
Similar results have been obtained starting from the alkynylketones [TMI]. In
certain cases, the stereoselectivity is low in the presence of Zn(BH,),, but this can
be enhanced by using an excess of DIBAH, which is a stronger Lewis acid and a
bulkier reagent (Figure 3.30). Comparable results have been obtained with the
nonracemic acyl-4-butanolides 3.93 [LL2] (Figure 3.30) and other chiral a-alkoxy-
ketones [GB4].
In contrast, 2-methoxy-l,2-diphenylethanoneis reduced to the anti a-methoxy
alcohol with good stereoselectivity whatever the reducing agent (LAH, DIBAH,
NaBH,, or K(s-Bu),BH [FH4]. Epoxy ketones such as 3.94 are also reduced highly
stereoselectively by NaBH,-CeC1, [BB6], NaBH,-CaCl,, or LaCl, [TF2] (Figure
3.30). NaBH,-SmCI, can also be used to reduce a-alkoxyketones or their precursors
[YNI]. A chelate is formed around the metal and reduction occurs from the least
hindered side.
The reduction of aminoketones by LAH, LTBA, and borohydrides has been well
studied [N5, T21. Highly stereoselective reductions have been observed in certain
cases [BLl, El, KL5, T2]. As early as 1972, it was shown that the reduction of
a-aminoketones by LAH in Et20 could be highly stereoselective. According to the
size of the nitrogen substituent of 3.95, the reduction takes place either with or
without chelation control [DD3] (Figure 3.31). Similar results were observed with
a-aminocyclanones [T2].
The reduction of 2-acyl-1,3-oxathianes such as 3.96 (X = S) or of 2-acyl-3-oxa-
N-benzylpiperidines 3.96 (X = NCH2Ph) can also take place with or without
chelation control [El, EF1, EH2, KE1, KF41. In cases of chelation control, the
oxygen atom of the heterocycle participates in the chelation process (Figure 3.32).
When the reaction is carried out with Li(s-Bu),BH in the presence of LiI as an
additive, the reduction occurs under chelation control. However, when using two
equivalents of DIBAH, each of them coordinates to a one basic site, and no chela-
tion takes place. The use of these chiral auxiliaries allows the synthesis of non-
racemic a-hydroxyaldehydes or a-hydroxyesters with a high enantiomeric excess
[NNl, 531.
This method can also be applied to a-phenylthioketones 3.97. Their reduction by
Li(s-Bu),BH leads very selectively to the syn isomer, whereas Zn(BH,), preferen-
tially gives the anti isomer with lower stereoselectivity [SMl] (Figure 3.32). The
problem of the reduction of 2-methylthiocyclohexanones has also been examined
[CDl].
Other additives can induce the formation of chelates. a-Phosphinyloxyketones
3.98 undergo a stereoselective reduction to anti alcohols with NaBH,-CeCl, in
Figure 3.31
Li s-Bu3BH
Lil, toluene, -78OC 91 -98
DIBAH 2 eq.
toluene, -78OC 9-11
RJ$Rl -
SMe or SPh
70%
OH
+
SMe or SPh
RqR*
SMe or SPh
3.97
Figure 3.32
MeOH or LiBH4-TiC1, [BBI I] provided that Rr is bulky, while syn alcohols are
obtained without CeCl, [CW3, EWI, HJ51 (Figure 3.33). Hydroxy substituents on
R' can induce good stereoselectivity [CW3, GW2]. a'-Phosphinyloxy-a-enones
3.99 do not suffer a stereoselective reduction by NaBH4-CeCl, unless the R" group
is bulky enough (i-Pr, cyclohexyl). In these reactions the anti isomer is predominant,
in agreement with a chelated transition state [CW3, EHI] (Figure 3.33). The exten-
sion of this method to a-phosphinoxyketones bearing an oxazolidine substituent has
3.99 de > 90%

Figure 3.33
&.- COOMe
_____)
NaBH4-CaC12
MeOH, O°C
90 - 96%
Li(OCEt3)3AlH,
THF,O°C
Figure 3.34
1
been examined [OW3]. P-Ketophosphonamidates can also be reduced under chela-

tion control with NaBH,-CeCl, with a high selectivity [DA3].
In the case of polysubstituted derivatives, such as a,@-dialkoxycarbonyl com-
pounds, Li(s-Bu),BH and Zn(BH,), lead each to a different isomer, but the stereo-
selectivity is lower than in the former cases because of competition among the
different association sites [FK3, IY 1, YK3, YK41. Analogous problems also arise in
the chemistry of sugars [MT2].
The stereoselective reduction of a-ketoesters and a-ketoamides can also be per-
formed. a-Ketoesters may form five-membered chelates that suffer reduction from
their least hindered side. For example, ketoester 3.100 is reduced by NaBH,-CaCl,
to the syn hydroxyester with a good selectivity, while NaBH, or Li(s-Bu),BH gives
a mixture of stereoisomers [FB3] (Figure 3.34). Similarly, LiAl(OCEt),H in THF at
0°C reduces the chiral ester 3.101 to the (S)-a-hydroxyester under chelation con-
trol [XS 11 (Figure 3.34). Li(s-Bu),BH-ZnC1, also promotes the reduction of 3.102
via chelation control, while the other isomer is formed in the presence of K
(s-Bu),BH-18-crown-6, where chelation is impeded [GCl] (Figure 3.34). K
(s-Bu),BH reduction of phenmenthyl phenylglyoxylate follows the same pathway
[SB4].
The reduction of the chiral ketoamide 3.103 by LiBH, in THF in the presence of
Rw -3.103 OMe
60-896
3.2 CARBON-OXYGENDOUBLE BONDS
0
O OMe OMe
71
K S-Bu3BH-THF,-78OC 21 79
Red-Al-THF, -78OC 16 84
Figure 3.35
LiBr leads selectively to one of the diastereomers [SIl], but with DIBAH, the
reduction appears to be less selective (Figure 3.35). The most interesting results are
obtained if the heterocycle carries two methoxymethyl [KF3] or CH,OMEM groups
[KF5] such as in 3.104 (Figure 3.35). The reaction of Zn(BH,), is not stereoselec-
tive, whereas the use of NaBH, or KBH, in i-PrOH is clearly less interesting than
that of LiEt,BH. If one employs a secondary cyclic amide such as 3.105, the
stereoselectivity is low [OSl] (Figure 3.35). When the reductions are carried out at
low temperature or at O°C, the amides are not affected (Section 3.2.8).
Stereocontrolled aldol reactions have been the subject of many recent studies
[H4, KW4, P21, and the reduction of P-hydroxyketones or their ethers to 1,3-diols
has been extensively studied. This reduction can be extremely stereoselective. Thus,
from P-hydroxyketones, one obtains syn diols very selectively either by the action
of DIBAH in THF or Et,O at low temperature [KK4, M6, PC4, SL2] or with
LiAlH,-LiI in Et,O at - 100°C [MK4]. Syn diols may also be obtained after the
initial formation of an alkyl borate 3.106 with n-Bu,B, Et,B, BJ6, KPI, NPl] or
better yet Et,BOMe [CG4, CH1, HH4, PC31, and subsequent reaction with NaBH,
in THF (Figure 3.36). The diol is obtained after H,O,-NaOH treatment. An im-
provement to this method is the use of n-Bu,BOMe in THF-MeOH, followed by
PhCHzO - 82%
as above
PhCH20
Figure 3.36
reduction with LiBH, at -78°C [PC4, PP51. In some cases, the reaction is poorly
stereoselective so that the aldol borate 3.106 (R" = c-C,H, ,) obtained by reaction of
an aldehyde with a boron enolate is directly reduced in situ by LiBH,, leading thus
to a higher selectivity [PC4, PP5] (Figure 3.36). The reduction of trifluoro P-ketoal-
cohols 3.107 by DIBAH also leads very stereoselectively to syn diols [LY 11 (Figure
3.36). Provided that the ketone is substituted by large groups, such as 3.108 or
AcOH-MeCN, -40°C
THF
Figure 3.37
3.109, excess catecholborane at - 10°C also reduces P-hydroxyketones to syn 1,3-

diols, most likely via an intermediate borate [EH3]. In some cases, catalysis by
Rh(PPh,),Cl improves the selectivity. Syn 1,3-diols can also be formed by TiCl, or
BC1,-mediated reduction of (3-hydroxyketones [SC2] via chelation control. Depend-
ing to the substituents, one or the other co-reagent is recommended.
The anti diols are obtained in a stereoselective manner by reaction with
Me,N(AcO),BH in MeCN-AcOH [ECl, EC2, LY l ] (Figure 3.37). The reduction
takes place by an intramolecular hydride delivery via the least hindered chairlike
transition state 3.110 (Figure 3.37). These methods are compatible with functional
groups such as esters or amides. For instance, from polyfunctional (3-hydroxyketone
3.111, either diastereoisomeric diol is obtained with a high selectivity [EG2]. In
some cases, N ~ ( A c O ) ~ Bcan
H be used instead of the ammonium salt.
When the P-hydroxyketones carry an alkyl substituent in the a-position, the
relative stereochemistry of the R" group and the hydroxyl group define the stereo-
selectivity [NPl]. If these two groups are in a syn relationship, one obtains selec-
tively the syn,syn 1,3-diols by reaction with n-Bu,B followed by NaBH, in THF
(Figure 3.38). The syn,anti isomers can be obtained by action of Me,N(AcO),BH in
AcOH-MeCN [EC 1, EC21 (Figure 3.38). Many applications of these reductions to
the synthesis of polyketide natural products have been published [ERl, H51. Cyclic
p- or y-hydroxyketones such as 3.112 or 3.113 also experience a highly stereoselec-
CH20H
CH20CH2Ph
81%
AcOH
HO
M e 4 ~ ( ~ ~ c ) 3 ~ g
L
CHzOCHzPh
Figure 3.38
tive reduction by Na or Me,N(AcO),BH [HW3, NS5, RS2, SLI, TM2, TY3]

(Figure 3.38).
On the other hand, if the OH and R" groups are in an anti relationship, one
obtains a mixture of stereoisomers in the acyclic 3.114 as well as in the cyclic 3.115
series [NPl, TM2] (Figure 3.39).
With regard to the reductions involving the intermediate alkylborates, chelated
chairlike intermediates 3.116 and 3.117 can be suggested (Figure 3.39). The course
of the reduction depends on the relative configurations of R" and the hydroxyl
group. When R' and R" are on the same side of the plane of the chelate 3.116, the
hydride approaches the carbonyl on the side opposite to the substituents, and the
reduction is stereoselective. On the other hand, when R' and R" are on opposite
sides of this plane as in 3.117, either approach of the hydride is constrained, and
stereoselectivity is no longer observed (Figure 3.39).
Furthermore, when the R' and R" groups are too bulky, chelation becomes
unlikely. With either Li(s-Bu),BH or DIBAH, the reaction yields the product
expected from the Felkin-Anh model [SS2], as shown in Figure 3.40. Similar
results are observed in the reduction of 2-fluoro-2-trifluoromethyl-3-hydroxy-
ketones [IY3].
Similarly, the Felkin-Anh products are formed when chelation is prevented by
the formation of t-BuMe,Si ethers of P-hydroxyketones 3.118 and 3.119. This
allows access to syn,anti or anti,anti a-alkylated diols, depending on the configura-
bh0 gH
81%
Na(OAc]$H
AcOH
*
OH OH OH OH
3.115
I: !,
3.116 3.117
Figure 3.39
tion of the starting P-hydroxyketone [BG3] (Figure 3.41). The stereoselectivity is

poor when R' = H [BG3]. A similar stereoselection is observed in the reduction of
substituted 2-cyclobuten-1-yl methyl ketones with LTBA [HW3], or in reduction of
I-alkoxy-2-phenylalkan-3-ones with Li(s-Bu),BH [GBS]. If suitable conditions are
used, other functional groups can remain intact. The reduction of 3.120 by LiBH, at
room temperature transforms the benzoate into the corresponding alcohol [PWI],
while at -7S°C, the ester group remains untouched (Figure 3.41).
When less bulky ethers (Me or PhCH,) of P-hydroxyketones are reduced, LTBA
LiEt3BH-THF
DIBAH-THF
OCHzPh
.
LiEt3BH-THFor
CsH17
?i!m2ph de > 98%
Me3Si
DIBAH-THF
Figure 3.40
R = i-Pr, Ph R' = i-Pr, Ph, Et R" = J3, Me
q z t - B u 90% QH 0SiMe2f-Bu
PhCOO
LiBH4-THF,r.t.
~e Me
3.120
86 - 94%
OH OMe
&
R TiC14-Et4NCNBH3-CH2C12,
-78°C
R = Ph, t-Bu
Figure 3.4 1
or DIBAH promotes reduction with chelation control, while 1 does not.

Moderate siereoselectivities are observed [ED2, MK61 even when using P-keto-1,3-
oxazolidinones [PP3]. A refined model to interpret these results has been proposed
by Evans and co-workers [ED2].
In order to promote chelation control, addition of TiC1, to P-methoxyketones
3.121 prior to reduction has been recommended [SG2]. The best reducing system is
tetraethylammonium cyanoborohydride in CH2C1, at -78°C (Figure 3.41). Benzyl
or MOM ethers give interesting selectivities as well, but disappointing results are
obtained when R = Me. Other P-benzyloxyketones are stereoselectively reduced by
Li(s-Bu),BH-MgBr2.Et20 in CH,C12 [TCI].
The reduction of the 1,3-diketones 3.122 and 3.123 to diols can also be stereo-
selective and can lead to either syn,syn 1,3-diols or to syn,anti 1,3-diols, depending
LTBA-THF, -30°C 98
LTBA-TiC14-CH2C13 25°C 3
LTBA-THF, -30°C A:B:C,:D= 34:6:56:4

LTBA-Tic14-CH2C12,25°C A:B:C:D = 13:85:1:1
Figure 3.42
on chelation. Chelation control is obtained by adding TiCI, after the formation of

the alcoholate that results from the initial reduction [BR2, MS71. The selectivity is
higher when the environment of the two carbonyl groups is similar (Figure 3.42). A
very stereoselective reduction of a bicyclic [3.1.O] diketone by NaBH,-CeCl, at
low temperature has been described [KS6]. LiBEt,H gives the other stereoisomer,
while reductions by LAH and LiBH, are poorly stereoselective.
P-Aminoketones can also be reduced in a stereoselective fashion [N5, TZ]. For
instance, the reduction of 3.124 by LAH in THF is stereoselective when R = Ph
(Figure 3.43). However, when R = Me or CH2Ph, the selectivity is poor, The
reduction of 3.125 by LAH in THF is stereoselective as well, but better results are
obtained in the presence of TiCI, [ B o l l or by reduction with DIBAH-ZnCl, at
-78°C with 3.126 [BV2] (Figure 3.43). When the reduction is carried out at reflux
in CH2C12, the corresponding amides can be used [BA3]. A highly selective reduc-
tion of ketone 3.127 by Zn(BH,), has been described [GM3] (Figure 3.43). How-
ever, when the Me group is located on the other side of the carbon skeleton, the
selectivity is low (40%). The reduction of triazolylketones with n-Bu,NBH4 gives
the isomer predicted by the Felkin-Anh model, while chelation control operates
when the reduction is carried out in the presence of TiCl, [TSZ].
The reduction of P-ketoesters such as 3.128 or P-ketoamides such as 3.129 by
Zn(BH,), is extremely stereoselective in favor of the syn P-hydroxy isomer, while
KBH, or n-Bu,NBH, in EtOH or, better, K(s-Bu),BH, lead selectively to the anti
R
. > 95%
LAH-THF, O0C
Ph
3.124
de 94%
Figure 3.43
isomer [IKl, ON11 (Figure 3.44) from racernic or nonracemic series. Similarly,
P-keto-N-acyloxazolidinones3.130 are stereoselectively reduced to syn alcohols by
Zn(BH,), in CH2Cl, [NFI] (Figure 3.44).
As before, when the cation associated with the reducing agent or when the
reagent itself is a strong Lewis acid, one can consider a chelated transition-state
model 3.131 (Figure 3.45). In the absence of chelation, a Felkin-Anh transition-
state model 3.19 is envisioned. The attack of the hydride takes place on the face
opposite to the most polar (P) group, in this case, the ester or amide group (Figure
3.45). When the reduction is carried out with LiEt3BH, the results (low stereoselec-
tivity) show that the two possible transition-state models can be considered. Chela-
tion control operates during the reduction of cyclic ketoamides such as 3.132 by Li
(s-Bu),BH in THF at low temperature. The observed stereoselectivity is opposite to
that using K(s-Bu),BH in Et20 at 20°C (Figure 3.45). Other reagents are less
selective. Chelation is favored by entropic effects due to the lowering of the tem-
perature [PAI]. Similar results have been obtained for related cases [SK2].
Other substituents in the vicinity of the ketone group can also influence the
stereochemical course of the reduction. An OMe group or a fluorine atom at the
Figure 3.44
ortho position in an arylketoester 3.133 induces an opposite stereoselectivity de-

pending on the reagent employed [BFl] (Figure 3.45). The presence of a fluorine
atom on the a-alkylated carbon diminishes the stereoselectivity of the reduction of
P-ketoesters 3.134 by Zn(BH,), [KK7] (Figure 3.45).
Finally, the introduction of additives may allow the stereoselectivity of the reduc-
tions to increase. Thus the addition of ZnC1, to Zn(BH,), or the coordination of the
carbonyl group by a bulky Lewis acid such as diisobutylaluminum 2,6-di-t-Bu-4-
methylphenolate (BHT) induces high and opposite stereoselectivities from chiral
P-ketoesters 3.135 (Figure 3.46). In the first case, chelation is strengthened, and the
reduction involves a cyclic transition state. In the second case, chelation is dis-
favored, and the other isomer is formed [TDI]. Chelation may also be promoted in
reductions of P-ketoesters or amides by addition of TiC1, [SG2] or MnCI, in
catalytic amounts [FO11.
The reduction of the 14-membered ring P-ketolactone 3.136 by Li(s-Bu),BH in
THF or by NaBH,-MnCl, in MeOH is also highly stereoselective, while NaBH,
gives a mixture of stereoisomers [NO11 (Figure 3.46). The poor selectivity in the
absence of chelation has been ascribed to conformational factors. This problem has
also been raised in some other cases [W7].
Me& M e
~h H
&I H Ph
COOMe
3.133
zn(BH4)z-THF 6
K3H4-MeOH 84
R = F, OMe
Figure 3.45
When the chelating group is located in the y-position, stereoselective reduction

can also be observed. For example, y-0x0-y-phenylbutanoic acids 3.137 are reduced
to syn y-hydroxyacids by DIBAH-ZnCl,. The other reducing agents are far less
stereoselective [FK2] (Figure 3.47). N-Acylamides such as 3.138 have been reduced
with a high stereoselectivity by NaBH,-CeCl,. Chelation takes place between the
keto group to be reduced and the BOC residue [AC3] (Figure 3.47). Similar results
were observed with other amides such as 3.139 [WH5]: One stereoisomer was
generated under chelation control and the other one without chelation (Figure 3.47).
3.135 ZnC1Z-Zn(BH4)z
toluene, -78OC 92 8
OAl s-Buz
DIBAH,
Figure 3.46
Other examples were described in similar systems [GP2, KK12, R5] and with
N-sulfamides, where chelation involves one of the SO residues [MP3].
P-Ketosulfoxides 3.140 can be reduced in a stereoselective fashion and, depend-
ing on the conditions chosen (i.e., DIBAH or DIBAH-ZnCl,), they can lead to
either of the two possible diastereoisomers [CDI, CG5, KK3, SDI, SGI, SS6]
(Figure 3.48). The transition-state models 3.141 and 3.142 for this reduction are
chelated, and the hydride attacks the carbonyl on the face opposite to the tolyl group
(Figure 3.48). ZnC1, can be used in catalytic amounts [SS6]. The interest in these
reductions lies in the access to chiral alcohols after the cleavage of the C-S bond
by aluminum amalgam. Starting from these types of compounds, one can also obtain
chiral epoxides and lactones. This methodology has often been used in the synthesis
of drugs or natural products [BL3, S6, SA2, SS71. It has also been applied to the
stereoselective reductions of different P-sulfoxides [CC7, LT21.
The reduction of ketosulfoxides by BH,.THF, Zn(BH,), in Et,O-THF, LTBA in
Et,O, or NaBH, in EtOH is poorly stereoselective [KK3, GPI], as is the reduction
of chiral ketosulfoximines [JS3]. The stereoselective reduction of chiral P-ketosul-
fones has been described [BB12].
Long-range chelation control has been observed in the reduction of y-ketobor-
onates 3.143 and 3.144 [CM2, MB3, MB4] (Figure 3.49). Among the various
h J y COOH
DIBAH-ZnCl2,b hJ+C0OH Me
Me
toluene-THF, -78°C
3.137 de 98%
Po
t-BUCOO.,,,
CH2Ph CHzPh
3.139
LTBA-THF, 0°C 85
Ks-Bu3BH-THF, -78°C 3
Figure 3.47
reagents tried, BH,.SMe, gave the best selectivities. These results have been inter-
preted in terms of intermolecular hydride delivery on a boron chelate [CM2], al-
though the hypothetical intermediate 3.145 could not be observed by IR or NMR
spectroscopy [MB3] (Figure 3.49). The formation of a bicyclic metal chelate species
has also been proposed to interpret the stereoselectivity of the reduction of 3.146 by
(R)-Alpine hydride or Zn(BH,), [ZCl, ZH2] (Figure 3.49).
When the ketones to be reduced are substituted by several groups capable of
chelating the reducing agent or the associated cation, the reactions are only slightly
stereoselective unless one of the groups bears a substituent that disfavors chelation.
The reduction of aminoketoesters 3.147 is poorly selective except if R' = CH,Ph
[R4] and if the reduction is performed in a slightly acidic medium [GB 1, GB3, RD 11
(Figure 3.50). Chelation with nitrogen is prevented in acid, and reduction takes
place preferentially on a rigid chelate system with hydrogen bonding involving the
ketone and the ester groups. An analogous example is compound 3.148, whose
reduction is not stereoselective in neutral media [OF11 (Figure 3.50). A similar
stereoselectivity towards the syn isomer has been observed in the reduction of
2-methyl-2-thiophenyl-p-ketoesters by Ca(BH4)2in MeOH-THF [SS4]. Similarly,
only Li(s-Bu),BH in THF selectively reduces the multifunctional compound 3.149,
wherein the transition state concerned is of the Felkin-Anh type [MTl]. Similar
results are obtained for other aminoketones 3.150 that lead predominantly to syn
isomers with Li or K(s-Bu),BH in THF and to anti isomers with LiBH, in i-PrOH
*
LAH
Figure 3.48
[RRl] (Figure 3.50). The use of unsymmetrical ketodiethers such as 3.151 also
allows the stereoselective reduction of the carbonyl group under chelation control.
Their reduction by DIBAH-MgBr, in diethylether leads selectively to one di-
astereoisomer 3.152 because chelation does not take place with the bulky OSiPh,-
t-Bu group. The best results are obtained when R' is 4-MeOC,H,CH20CH, [BG4,
GB7] (Figure 3.50).
Similar observations have been made concerning the reduction of P-pyrid-
ylketosulfoxides [GPI]. Some stereoselective reductions have been performed when
substituents able to induce chelation are located on each side of the carbonyl group
[HJ4, MS4, MT31.
-
71 92% OAc y e
R 1- BH3.THF, -78°C
*
R
LOA
2- H202,NaOH de 90 - 98%
3.143
3- AcZO
R = Me, Et, i-Pr, Ph
O0C
2- H202,NaOH
ee 92 - 98%
0 0
3,2.5 Esters, Ladones, and Thiolerters: ~q,R-(
OR' SR'
Esters and lactones can be partially reduced with the participation of a single
hydride. Starting from esters, aldehydes are formed via the corresponding hemiace-
tals. Starting from lactones, the products are generally lactols (Figure 3.5 1).
These transformations are still difficult to realize in practice. LTBA in THF at
0°C sometimes allows phenyl esters to be transformed to aldehydes with good
yields, while the reaction of aliphatic esters is much slower [BIG, C5, M3] (Figure
3.52). Aluminum bis(N-methy1piperazino)hydnde in THF at 25OC allows this trans-
formation to take place starting from alkyl esters [C5, H3, M3]. The use of LAH in
the presence of diethylamine in pentane has been proposed for monoreduction of
esters [CKl, CK31. Na(Et,N),AlH seems more useful; alkyl esters are transformed
into the corresponding aldehydes in THF at -78°C [CK5] (Figure 3.52). Sodium
diethylpiperidinohydroaluminate reduces ethyl esters of aromatic acids to aldehydes
in good yields at 0°C in THF-toluene. However, esters of aliphatic acids give
mixtures of aldehydes and alcohols, while lactones are not transformed into lactols
under these conditions [YA2].
DIBAH in toluene at low temperature in stoichiometnc amounts is often recom-
mended for carrying out the reduction of saturated esters to corresponding al-
de 80 - 92%
R = n-Bu, CH2=CHCH2,i-Pr, Ph, CH2=CH,CH2=C(Me)
Figure 3.50
dehydes [C5, K2, W1, YGl] (Figure 3.52). In the presence of o-anisidine, yields are
improved [KK9]. The reduction is compatible with an a-SePh substituent, whose
absolute configuration in a chiral molecule is retained [DDl]. Use of i-Bu,AlD
leads to deuterated aldehydes [KWl] (Figure 3.52). The intermediate hemiacetal
may, in some cases, be reacted in situ with another reagent [DRl]. For example,
protected a-amino esters 3.152 react sequentially with DIBAH or i-Bu,Al-DIBAH
and then with PhMgBr. This process provides the corresponding a-amino akohols
in excellent chemical yield with good stereoselectivity [PP2] (Figure 3.52). A simi-
lar two-step process can also be realized by reduction of ethyl esters by limited
amounts of LiBH, in the presence of an organomagnesium reagent [CH2] (Figure
3.52).
Figure 3.51
The reaction of DIBAH with ketones is, however, more rapid. The selective
reductions of ketoesters (Section 3.2.4) have already been described. Moreover,
a$-unsaturated esters give rise to allylic alcohols, even if a less than stoichiometric
amount of reagent is used (Section 3.2.9).
Reductions of lactones, under the same conditions, or in Et,O, lead to the come-
sponding lactols [BG5, DT2, M3, SY4, Wl], as shown in Figure 3.53. One of
Corey's early syntheses of prostaglandins involves the reduction by DIBAH of
lactone 3.152a [W 11, followed by a Wittig reaction, which can be carried out
directly on the lactol. The reduction of multifunctional lactone 3.153 respects the
integrity of the other groups [WVl] (Figure 3.53). Thiolesters are also reduced by
DIBAH in toluene at low temperature into aldehydes [GM2, GW4]. Under these
conditions, the 1,3-oxazoline functionality of 3.154 remains untouched (Figure
3.53). Sia,BH reduces lactones to lactol borates, which, after hydrolysis, give
y-hydroxyaldehydes [BK5] (Figure 3.53).
Esters and lactones are reduced to alcohols or diols by numerous reagents (Figure
3.54). LAH in ethers and on silica gel converts these groups to alcohols resulting
from a double reduction. At low temperature, a mixture of aldehydes and alcohols is
usually obtained [BK5, H3, KH2, M3]. Reduction of ethyl trans-3,4-epoxycyclo-
pentanecarboxylate to the corresponding alcohol, without epoxide ring opening can
be performed with 0.5 equiv. LAH in THF at -78°C [MN2]. The reduction of esters
by LAH may allow alcohols to be prepared from acetates. This is a useful method
for acetate cleavage when hydrolysis would induce side reactions, such as epimeriz-
ation (Section 2.2). An example is given in Figure 3.54 for the reduction of 3.154
[AK2].
NaAlH, [CB5] or LAH-N-methylpyrrolidine [FSI] is also an efficient reducing
agent, as is excess AlH,.Et,N [CB7]. All these reductions are run in THF at 0°C or
at r.t. Ate complexes formed from DIBAH and n-BuLi in THF-hexane at r.t. also
give alcohols from esters [KAI]. Red-A1 in petroleum ether allows the selective
reduction of long-chain bromoesters to bromoalcohols [W8].
Since LTBA reacts slowly with esters at low temperature, selective reductions of
ketones can be performed [KW5, M3]. AlH, also reduces esters to alcohols [BK5],
67-70% RCHO
RCOOPh
LTBA-THF, 0°C
RCOO alkyl
-
65 95%
cRCHO
Na(%N)W-THF,
EtOCO
-COOEt -as above OHC
-CHO
RCOOR' DIBAH-foluem, * RCHO + R'OH

-78°C
0
p h 2 c = ~ A ~ ~ ~
R
DIBAH or
-
i-Bu3AI-DIBAH
\ 1
$KOH
Ph2C=d,,koEt
3.152 CH2Ci2,-78°C R
R = H, Me, PhCH2
I
global yield PhMgBr then
75 - 86% H,O+
RCOOEt + R'MgX + LiBH 4
I
61 - 74% THF, -20°C
RCHOHR'
R = PhCH2CH2,Ph R' = Me, Et, n-Bu, i-Pr, Ph
Figure 3-52
as does LiBH, in hot DME or LiBH, in refluxing Et,O or in THF at r.t. [BK5, BS1,
PWl]. The reduction requires electrophilic assistance since it is faster with LiBH,
when the solvent is not a good solvating agent of the cation: Et,O > THF DME-
> i-PrOH [BNl]. It is therefore possible to perform the selective reduction of the
keto group of a-ketoester 3.155 by LiBH, in THF at -78"C, while both functional
MEMO
J-&IM~ 93% t
global yield 74%

OH
Figure 3.53
groups of 3.156 are reduced at r.t. [PWl] (Figure 3.54). Other examples have been
given in Section 3.2.4. As acids are inert to LiBH,, it is possible with this reagent to
reduce selectively the ester group of hemiesters of diacids [BG2, BK5, OKl].
LiBH, can be generated in situ from NaBH4-LiC1 in THF-EtOH [HIl, HS41. With
this system, chiral amino esters can be reduced to amino alcohols without epimeriz-
ation [JF2]. Ca(BH4),, formed from CaC1, and NaBH, in aqueous ethanol, can also
be used for this purpose [BR3, HC2, LRl]. This reagent does not reduce alkali
carboxylates; so it is possible to perform selective reduction of the ester group of
3.157, which is followed by lactonization in situ [LRl]. Similarly, N-(ethoxycar-
bony1)amino esters are reduced to N-(ethoxycarbonyl)amino alcohols [LM3]. The
selective reduction of an ester functionality in the presence of a secondary tosylate
can be performed with LiBH,-LiBEt,H in Et,O-THF at O°C [AS]].
The reduction of esters by LiBH, can be accelerated by the addition of other
Lewis acids such as Et,B [YP2], B(OMe), [BN3], or methanol [S03]. In the last
case the reduction is carried out under reflux in Et,O in the presence of 4 equiva-
lents of MeOH. Acid, C1, and NO, groups remain unchanged under these condi-
tions.
RCOOR' RCH20H + R'OH
~ C H ~ P ~
3.154
Me OCH2Ph
PhCOO 78% *
0 OH LiBH4-THF,
-78OC
3.155
Figure 3.54
LiBuBH, reduces esters in Et,O at O°C, but leaves them untouched in toluene-
hexane at -78°C [KM2]. Lithium trialkylborohydrides as well as lithium ami-
noborohydrides in THF transform esters to alcohols and lactones to diols [BK5,
FH51. Steric hindrance around ester groups can allow the regioselective reduction of
the least hindered functional group of an unsymmetrically substituted diester by
LiEt3BH in THF at 0°C [FRl]. An ester group can be reduced in the presence of an
amide or a carbamate [TY3]; the reduction of 3.158 illustrates this compatibility
(Figure 3.55). KEt,BH in THF at r.t. reduces esters quickly enough to leave epox-
ides, amides, and nitriles unchanged [YYI I. Moreover, K(s-Bu),BH in THF at 0°C
M~OCOCH~@*'
3.161 reflux
R = Me, Ph R'= Me, Et, n-BU
COOEt CH20H
H2N COOEt
70%
NaBH4-EtOH,
5°C H2N
-@ COOEt
Me Me
3.162
Q OCOPh
3.163
> 95%
Zn(BH4),-DME
))) - OCOPh
Figure 3.55
reduces lactones to diols faster than PhCOOEt or ethyl caproate [YH2]. However, at
-78"C, lactones are left unchanged, thereby allowing the selective reduction of the
keto group of 9-0x0-7-tetradecen-13-olide 3.159 by K(s-Bu),BH [KWS] (Figure
3.55).
n-Bu,NBH, in CH2C12 does not react with esters [RGl], and reductions by
NaBH, in alcohols or on alumina are very slow (Section 3.2.1). However, 2,4-
dinitrophenyl esters 3.160 are easily reduced to alcohols [PSI] (Figure 3.55). This
reduction takes place in the presence of ethylene glycol oligomers at 80°C [SFl].
Reduction can also be accomplished in the presence of additives. The action of
NaBH, on esters in THF or refluxing t-BuOH in the presence of MeOH [Sol], or in
refluxing EtOH [OS3], or even in water [BP3] leads to the corresponding alcohols.
Under these conditions, primary amides, acids, and NO, groups remain inert. Thus,
starting from ketoesters 3.161, one can obtain diols [SO21 (Figure 3.55). NaBH, in
EtOH allows the selective reduction of the less sterically hindered ester group of
diester 3.162, while LiBH,, DIBAH, or Selectrides are unable to differentiate them
[BH6] (Figure 3.555).
Moreover, a-cyano-a-epoxy esters are easily reduced to a-cyano-a-epoxy alco-
hols by NaBH, in aqueous THF [MR4]. Ethanedithiol can also be an additive for the
reduction of esters by NaBH,, except t-butyl esters. Nitrile groups remain unper-
turbed under these conditions [GEI]. Methyl benzoate is reduced to benzylalcohol
by NaBH,-ZrC1, in THF [ISl].
Esters are much less sensitive than ketones to Zn(BH,), or cyanoborohydrides
[PSI], and the selective reduction of the ketone groups of a- and P-ketoesters can be
accomplished without problems (Section 3.2.4). Moreover, Zn(BH,), in DME under
sonication reduces acetates or cyclohexanecarboxylates while benzoates are left
untouched [R3]. The chemoselective reduction of the acetate residue of 3.163 can be
performed under these conditions (Figure 3.55).
BH,.THF or BH,.SMe, reacts very slowly with esters in THF at room tempera-
ture even in the presence of amino alcohols [BK5, IWI, L2, PSI]. Under reflux,
BH,.SMe, reduces esters to alcohols [BCl], as does the in situ generated borane
[BB7]. Nevertheless, a-hydroxyesters can be reduced at room temperature by
BH3.SMe2 in THF in the presence of a catalytic amount of NaBH,. The selective
reduction of 3.164 is an example of this reaction [SHl] (Figure 3.55). y-Carboxyes-
ters also undergo reduction of the ester group by BH3.SMe2 [FC2]. The reduction of
esters to alcohols by catecholborane also takes place in refluxing THF [KB7].
Most acyloxyboranes [MMI] and aminoboranes [All do not react either with
esters or with lactones. However, Ph2NH.BH3reduces aliphatic esters [CUI]. Sub-
stituted boranes are more efficient. 9-BBN reduces esters under reflux in THF
[PSI], while ThexBHCl gives rise to alcohols with heating [BN5]. Finally, the ate
complex Li 9-BBNH reduces esters to alcohols and lactones to diols. Acids, amides,
nitriles, and halogenated derivatives remain intact under these conditions [BMl].
It has clearly been emphasized that ketones are'reduced more rapidly than esters
(Section 3.2.4). It is nevertheless possible to reduce ketoesters such as 3.165 to
corresponding ketoalcohols [BH2, KF2] by forming the corresponding lithium enol-
ates in a first step (Figure 3.56). The limitation of the method is the stability of the
COOEt i-Pr2NLi-THF, -78°C COOEt
Figure 3.56
enolates formed and the need for the absence of labile hydrogen at the a position of
the ester group. Competitive enolization decreases the yield for reduction of malo-
nates to 1,3-diols. In this case, good reagents for avoiding this side reaction are
electrophilic hydrides such as AlH, or, better, DIBAH in THF [CE2]. The reduction
of bromoesters 3.166 to bromoalcohols by AlH, in Et,O leaves the carbon-halogen
bonds unchanged [BK5, E2] (Figure 3.56).
Thiolesters (RCOSEt) are reduced to alcohols by LiBH, in Et,O or by an excess
of n-Bu,NBH, in refluxing CHCl,, but are inert in the presence of borane [KH5,
LL41. Dithioesters and thioxoesters are reduced to thiols by BH,,Me,S [JS4].
3.2.6 Carboxylic Acids, Acid Anhydrides: RCOOH, RCOOCOR'

Again, reduction can lead to aldehydes or alcohols, and the choice of reducing
reagent and reaction conditions dictate the formation of one or the other functional
group.
The reduction of acids to aldehydes may be accomplished by aluminum bis(N-
methy1piperazino)hydride in THF in excellent yields, starting from both aliphatic
and aromatic acids [C5, H3, HEl, MM31. On the other hand, the use of DIBAH on a
preparative scale does not appear to give satisfying results [YGI]. Likewise, Thex-
BHCl.Me,S in CH,Cl, as well as 9-BBN in excess also give aldehydes [BC4, BC5,
C5, COl], and these reductants are compatible with aliphatic and other halogenated
substituents and with NO,, CN, and ester groups (Figure 3.57). Another method
consists of treating acylboranes obtained by the action of 9-BBN on acids with 1
equivalent of Li 9-BBNH [CK2], the reduction being compatible with the same
groups as before.
LAH, SAH and AlH, in ethers, LAH-N-methylpyrrolidine complex, AlH,-Et,N,
Li(MeO),AlH, or Red-A1 in C6H6 at 80°C can be used to reduce acids and an-
hydrides to the corresponding alcohols [BK5, BY1, CB5, CB7, FS1, H3, M3].
Cyclic anhydrides are transformed into diols (Figure 3.58). Sodium diethyl-
YOOH CHO
I
Q CN
Thex BHCbMe 2S-CH2C12,
20°C *Q CN
Br(CH2)5COOH *BI-(CH~)~CHO
Thex BHCI-Me 2S-CH2C12,
2O0C
EtOCO(CH2)4COOH *EtOCO(CH2)5CH0
Thex BHCbMe 2S-CH2C15
2O0C
Figure 3.57
piperidinoaluminate does not reduce acids [YA2]. With a limited amount of LAH,
cyclic anhydrides can be reduced to lactones at low temperature [M3] (Figure 3.58).
Reductions with LiBH, in THF at 25OC [Nl], NaBH, in THF at 25°C in the
presence of methanol added dropwise, DIBAH in the presence of n-BuLi [KAI], or
lithium trialkylborohydrides in THF [BK6] also lead to lactones. The enantioselec-
tive reduction of meso anhydrides such as 3.167 can be performed with Binal [MI21
(Figure 3.58).
The reduction of unsymmetrical anhydrides is regioselective: Hydride attack
takes place on the carbonyl group that is vicinal to the most substituted carbon, as
LAH or AIH 3-Et20* a C H CHzOH

2 O H
0
X = 0, CH2, CHzCHz
Figure 3.58
94 REDUCTON OF DOUBLE BONDS
*
LAH or LiBH4-THF
Figure 3-59
shown in Figure 3.59 [KMl, M3, VNl]. Similar results are also obtained with
aspartic anhydride [MH4]. NaBH, in DMF may lead to the same regioisomer [BJ2].
However, bulky complex metal hydrides such as K or Li(s-Bu),BH lead to a
complete reversal of regioselectivity [M3] (Figure 3.59). For example, alkoxy-
substituted phthalic anhydride 3.168 lead regioselectively to the lactone resulting
from reduction of the carbonyl group that is away from the OMe group (Figure
3.59). Contrary to another report [MM4], NaBH, and LiBH, in THF are poorly
regioselective in this case.
An easy and clean method of reducing acids to alcohols consists of transforming
them into mixed carboxylic-carbonic anhydrides by reaction with ClCOOEt-Et,N.
These are easily reduced by NaBH, in THF, sometimes in the presence of MeOH or
by borohydride exchange resin-Ni(OAc),. This method does not affect double
bonds or NO,, CN, CONH,, and COOR groups, as shown in Figure 3.60 [BM9,
IK2, SYl]. It can be applied to N-protected anhydrides of amino acids, leading thus
to N-protected 1,2-amino alcohols [FC3, K5, RLl]. In the presence of MeOH, the
reduction takes place at 1O0C, and aromatic halides are not affected [SY I] (Figure
3.60).
In certain cases, reduction of mixed anhydrides of unsaturated acid such as 3.169
by NaBH, can be delicate [JUl]. NaBH,-CeCl, in MeOH does not appear to be
efficient, as the formation of the methyl ester hinders the reduction. The use of
NaBH,-SmI, in THF leads to the expected allylic alcohol (Figure 3.60). Some
COOMe COOMe
HOOC
71%
1- ClCOOEt-THF
H NEt3, 0°C H
2- NaBH4-Sm13-THF,
3.169 5 - 15°C
Figure 3.60
authors have recommended the use of mixed carboxylic phosphoric anhydrides, but
the yields are not very high [KY 11.
A method involving the in situ transformation of carboxylic acids into
acylfluorides that are reduced by NaBH, in MeOH has been recently proposed
[KN4].
Carboxylic acids are not reduced by alkali borohydrides [BK5], ami-
noborohydrides [FH5], trialkylborohydrides [BIG], 9-BBN, or Sia,BH at room
temperature [BIG], or by the acyloxyboranes [HM 1, GNl]. The activation of LiBH,
by MeOH in refluxing THF induces the reduction of carboxylic acids to alcohols
[S03], but in the presence of B(OMe),, the reduction is incomplete [BN3]. NaBH4-
ZrC1, in THF also reduces benzoic acid to benzyl alcohol [ISl], while NaBH4-
TiCl, in DME [KT21 or (i-PrO),TiBH, in CH,Cl, [RC2] transforms all acids into
alcohols. The reduction of acids into alcohols can be performed by Zn(BH,),, either
in DME in the presence of (CF,CO),O [R3] or in refluxing THF [NM3], although
there are some limitations to these methods.
Methods for performing the reduction of acids to the corresponding alcohols use
an excess of BH,.THF or catecholborane [BK5, KB7, PSI]. These reagents react
more rapidly with aliphatic acids than with aromatic ones. The reaction process
70 - 84%
R ~ c O O H NaBH4-12-THF, reflw* R ~NCHH~ 2 0 H
NH2
3.171
R = i-Pr, t-Bu, Ph, PhCHz
PhCH2~Co0H
73 - 83% P y ~ CH20H
NHCOR' NaBH&THF, reflux NHCH2R'
R' = Me, Ph 3.172
Figure 3.61
(Figure 3.61) implies the formation of a triacycloxyborane. This is reduced by

excess of BH,.THF to a cyclic borate 3.170, which is hydrolyzed to the correspond-
ing alcohol. The intermediate triacyloxyborane obtained by reaction of 3 equivalents
of acid with BH,.THF can also be reduced to the corresponding alcohol by NaBH,
in an alcoholic medium (Figure 3.61). Borane can be generated in situ by action of
Me,SiCl, I,, H2S0,, or MeS03H on solutions of LiBH, or NaBH, in THF or else
NaBH,-BF3.Et,0 in THF [AM2, BB7, DA2, DC2, GS2, JJ2, MB5, MM2]. This
methodology has been applied to the reduction of chiral amino acids 3.171 to related
amino alcohols without epimerization (Figure 3.61). This transformation can also be
run with NaBH,-ZnCl, in THF. If the free amhe is transformed into an N-acetyl or
N-benzoyl group, N-alkylamino alcohols 3.172 are formed [AM2, MM8] (Figure
3.61). However, NHCOOCH,Ph and NHTs residues remain unaffected [AM2]. The
reduction of NHBOC-protected amino acids can be performed with (i-PrO),TiBH,
in CH2C12 [RC2].
When using boranes, esters, halogen derivatives, nitriles, amides, and nitro com-
pounds are inert [BF2, BK5, HCI, HII, OKs, YPI]. This makes possible the
BH3-THF,heat * wcH3
Figure 3.62
selective reductions shown in Figure 3.62. In some cases, the reduction may proceed
directly to the hydrocarbon, as shown in the case of 3.173 [PSI] (Figure 3.62). Such
is also the case for cyclane-substituted carboxylic acids, which lead to ring-ex-
panded cycloalkanes by action of NaBH,-HOTf in Et,O at - 78°C [OW2].
When starting from substituted malonic acids, the reduction by BH, in THF does
not give good yields because of competing formation of an enolborate. This can be
prevented if the reduction is run at -20°C [CEI]. However, reduction of a chiral
malonic acid monoester 3.174 by BH,.Me,S takes place on the ester group [FC2]
(Figure 3.63).
BH,.Me,S or amine-boranes induce the same reductions of acids to alcohols;
linear anhydrides are reduced by Ph,NH.BH, in THF to alcohols, while succinic
and phthalic anhydrides remain intact [Cull.
The special reactivity of carboxylic acids allows the following selective reduc-
tions shown in Figure 3.63:
P-Chloropropionic acid is reduced by AlH, in Et20 to P-chloropropanol

[BK5].
The nonracemic hemiester 3.175, obtained by the action of pig liver esterase
(PLE) on the corresponding dimethyl diester, may be transformed into two
nonracemic enantiomeric lactones. This occurs either through reduction of the
methyl ester by LiBH,, which leaves the carboxylic acid group unattacked, or
else through action of BH,.THF, or, better, via transformation of the acid group
to the mixed carboxylic-carbonic anhydride followed by reduction by NaBH,,
which does not reduce the ester [BG2] (Figure 3.63).
Thioacids are also reduced to thiols by BH,.Me2S [JS4].

Me*
T O 1 ~ COOH
cOOMe
BH3*Me2S-THF,
* To1~cH20H
Me'* COOH
3.174 r.t. then H+
89% *
I 1- ClCOOEt
COOMe
COOMe
Figure 3.63
3.2.7 Acid Chlorides: RCOCl

The reduction of acid chlorides is particularly easy; however, by carefully adjusting
the reaction conditions, the reduction process can be controlled. Starting from acid
chlorides, aldehydes can be obtained by four different methods [C5, M3]:
aBy the action of LTBA or Na(t-BuO),AlH in diglyme at -7SoC, the aldehyde

formed is not reduced. Due to the basicity of the reaction medium, the yields
are good only if the aldehydes are not easily enolized. Aromatic or
a,@-unsaturatedacid chlorides are good substrates; however, Na(t-BuO),AlH
reduces some aliphatic acid chlorides [BK3, CB6] (Figure 3.64). The method is
compatible with ester, nitrile, and nitro groups, and it has been applied to the
transformation of N-protected amino acid chlorides 3.176 into the correspond-
ing aldehydes [Zl] (Figure 3.64).
* By the action of NaBH, in DMF-THF in the presence of pyridine at 0°C [Bl].
This reduction generates borane, which coordinates to pyridine, forming a
complex that precipitates under these conditions (Figure 3.64). The reduction
leaves the halide functional group intact (Figure 3.64).
* By the action of NaBH, in the presence of CdCI, in DMF. This method is
compatible with aliphatic chlorides, esters, nitriles, NO, groups, and double
bonds [EB3].
* By the action of complex borohydrides (Ph,P),CuBH, [DFl,W4] or
(Ph,P),CuCNBH, [HM2]. These reductions take at room temperature in
acetone, and only acid chlorides are sensitive under these conditions.
ArCOCl * ArCHO+LiCI+Al(O ~ - B u ) ~
LTBA-diglyme, -78°C or NaCl
or N~(~-BuO)~AJH
70 - 90%
RCOCl
Na(t-BuO)AH,
* RCHO
60%
R ~ c o C 1 LTBA-THF, -78°C
NHBOC NHBOC
.*74 - 77%
el Q
RCOCl + NaBH4 + - RCHO + NaCl +
DMF-THF,
oOC BH3
COCl &H
77% CI
0°C
90 10
Figure 3-64
Other reducing reagents transform acid chlorides into corresponding alcohols.

These include: LAH or SAH in THF, on silica gel or complexed to amines [BK5,
CB5, FS1, KH21, AlH, in Et,O, A1H3.Et3N [BK5, CB7, MP21, DIBAH [YGl],
NaBH,, and LiBH, in THF, dioxane, DME, or on alumina or in the presence of
polyethylene glycol [BK5, PSI, SF21, lithium arninoborohydrides [FH5], n-Bu,NBH,
in CH,Cl,, (i-PrO),TiBH, in CH,Cl, [RC2], Zn(BH,),-TMEDA in Et20 [KU3],
9-BBN in the cold [PSI]. The reductions by BH,.THF and Sia,BH are nevertheless
relatively slow [BK5].
The selective reduction of acid chlorides in the presence of esters by 9-BBN in
cold THF is possible because esters are reduced only under reflux in this solvent
[PSI]. Reduction by Zn(BH4)2-TMEDA in Et,O leaves C1, NO,, ester groups, and
conjugated double bonds unchanged [KU3].
3.2.8 Amides and Imides: RCONR,', (RCO),NR'

The attack of the amide carbonyl group by a hydride occurs through a tetracoordi-
nated intermediate, which can proceed either by the breaking of the C-N bond
Figure 3.65
(path a), leading thus to an aldehyde (which can eventually be reduced to an

alcohol), or by the breaking of the C-0 bond (path b), producing an iminium salt
(which is the precursor of an amine) (Figure 3.65). Depending on the nature of the
reducing agent and the nitrogen substituents, the reaction follows one pathway or
the other.
Path a: Access to aldehydes and alcohols.
N-Dimethylamides 3.177 are transformed into aldehydes by reaction of 0.25
equivalent of SAH in THF at O°C [CB5], by one equivalent of Na di-
ethylpiperidinoaluminate in THF-toluene at 0°C [YA2], or by the ate complex
DIBAH-n-BuLi in THF-hexane at the same temperature [KAl] (Figure 3.66).
The synthesis of aldehydes [C5] can also be accomplished by controlled reduc-
tion of acylaziridines 3.178 [BK5] or of acylimidazoles 3.179 [W3] by LAH in Et20
at - I O°C, by LTBA or by Red-A1 in C,H, [H3, M3]: R can be aliphatic or aromatic
(Figure 3.66). The N-methoxy-N-methylcarboxamides 3.180 are also cleanly re-
duced to aldehydes by LAH in excess in THF at low temperature or by DIBAH in
THF at 0°C. In many cases, the latter reagent does not lead to formation of alcohols
as byproducts resulting from a subsequent reduction of the aldehyde [NWl]. This
behavior can be understood by the stabilization through chelation of the lithium or
aluminum intermediate (Figure 3.66). a$-Unsaturated aldehydes may also be pre-
pared by this method, using DIBAH in THF [BS8, NBl].
The method can be applied to N-protected amino acid derivatives 3.181 or to
peptides 3.182 [FC 1, FH3] without racemization (Figure 3.67).
LTBA or, better, LTEA in Et,O, reduces all tertiary amides to aldehydes at O°C.
Tertiary amides coordinate the Li cation better because their carbonyl is more basic
[BK5, C5, M31 (Figure 3.68). The reduction of precursors of chiral aldehydes 3.183
by LTEA does not cause any epimerization [MY21 (Figure 3.68). Treatment of
tertiary amides by LiEt,BH in THF at 0°C leads, via triethylborates, to aldehydes,
which can be reduced to alcohols by an excess of reagent [BK3, BK51 (Figure 3.68).
N-Dimethylamides react with EtOTf to give iminium salts, which can be selec-
tively reduced to aldehydes by Li(s-Bu),BH in THF at -78OC [TR2]. This method
can be applied to a$-unsaturated amides and is compatible with isolated double
bonds, nitriles, and esters.
The other alkylborohydrides, 9-BBN and Sia2BH, also transform tertiary amides
to alcohols [BK5, PSI]. Alcohols are obtained via the action of LiBH, in MeOH-
hot diglyme on some tertiary amides [SO31 or by the controlled reduction with Li
pyrrolidinoborohydride in THF [FFl] (Figure 3.69). This latter method, however,
has some limitations. The reduction of 3.183 by Li pyrrolidinoborohydride or better
by LiNH2BH, obtained from boranemnmonia and n-BuLi does not promote any
racemization [MY2, MY41 (Figure 3.69).
96 - 99%
RCONMez ) RCHO
3.177 0.25SAH or 1.1 Na c N E t 2 A E I
THF,0°C
R = n-C6H11, Ph, 4-NO2C&
RCO-~3
-
3.178
67 81%
0.25 LAH-Et 20,
s RCHO
-10°C
RCO-Nd
0.25 LAH-Et20
-
R = n-CSHll, t-Bu,
RCHO
0 71 - 74%
h.0Me lo\
RCH @i-Buz -RCHO
I DIBAH-THF, \ I
Me 0 or -78OC N-d,
3.180 Me' Me
excess DIBAH -THF,

0°C
Figure 3.66
,OMe
RCH-CON,
I
NHBOC
Me
3.181
R = Me, Ph, i-Bu, PhCH2, s-Bu
1excess LAH-Et @, o0c
Figure 3.67
75 - 82%
RC0NK2 * RCHO
LTEA(1equiv.)-Et 20,0°C
3.183
R or R'= Me, PhCH2, n-Bu, Ph
excess
Figure 3.68
71% * n-C7H15CHzOH
Li c N * H , -
THF, 25°C
Li ~ B H ~
THF, 25°C
R = Me, Et, i-Pr
3.183 THF,25°C
Figure 3.69
-
75 85% + RuCH20q
aq. LiBH4-THF ,. p
or Et20, r.t. or O°C
P~C!H~
R = Et, n-Pr, i-Pr, R'= PhS
R = Ph3C,Ph2MeC, PMle2C, R'= N3
RvCI-I,OH +
aq. NaBH4-THF,
R'= H, i-Pr, COOMe R = n-C5H11,n-CgH17,PhCH=CH, Ph or chmd residue
3.186
R = Me, i-Pr, Ph
Figure 3.70
Secondary amides remain intact in the presence of LiBH,-MeOH [S03], while

at lower temperature or in the absence of MeOH, reduction of tertiary arnides
seldom takes place. However, an exception has been found with fused xanthines
[CK4].
The reductive cleavage of the amide residue of many chiral auxiliaries is recom-
mended for recovery of c h i d compounds and auxiliary regeneration [S3]. Evans's
acyloxazolidinones 3.184 have been transformed into aldehydes by DIBAH or Red-
A1 at low temperature [CW2, EBS, MS81, but in the case of R1=SPh, some
epimerization occurs (Figure 3.70). DIBAH has also been proposed to transform
N-acylthiazolidinthiones 3.185 [NKl] into the c o ~ ~ e s p o n d haldehydes
g (Figure
3.70). Related chiral auxiliaries [AM41 suffer the same transformations. If the
reductive cleavage of 3.184 is carried out with LAH in Et,O, LiBH, in THF [EG2,
EE1, EG3, ES21, or, better, LiBH, in the presence of water [CW2, DN 1, IA1, PDl],
alcohols are formed. When R' = PhS, N,, or CF,Br, no racemization is observed
[CW2, DN1, IAl] (Figure 3.70). From 3.185, NaBH, in aqueous THF gives the best
results [NKl] (Figure 3.70). Similar reductive cleavage of unsymmetrically substi-
tuted chiral amides by LAH or LiBH, in EtOH without racemization have been
described [AM4, DD41. Chiral sultams 3.186 can be cleaved in the same fashion
[OB2] (Figure 3.70).
Path b: Access to amines.
LAH in ethers (Et20, THF), as well as its complex with N-methylpyrrolidine,
Red-A1 in C6H6, AlH, in Et20, AlH3.Et3N, BH,.THF, or BH3.SMe2reduce most
types of amides to amines at room temperature. Primary amides, however, are
reduced by BH,-THF only under reflux in THF [BCl 1, BH 1, BK5, BN2, CB7, FS 1,
L2, M3, PSI]. Borane can be generated in situ from NaBH, and I, in THF [BB7], or
in the presence of Me3SiC1 [GS2]. Since BH,.THF does not reduce esters, nitro
derivatives, or nitriles under these conditions, selective reductions can be run [BK5]
(Figure 3.71). Selective reductions of tertiary amides to amines in the presence of
secondary amides can be carried out when the secondary amides are protected as
lactim ethers [WB2]. Sulfonamides are reduced by BH3.Me2S only in refluxing
THF [BF2]. Tertiary amides are reduced to amines by BH,.aminoethanol [IWl], but
no reduction takes place if the aminoalcohol is grafted onto a polymeric support
[IW 11.
DIBAH reduces tertiary amides well and appears to be more selective than LAH
with a$-unsaturated derivatives. LAH in Et,O induces the partial reduction of the
double bond of 3.187 [Wl] (Section 3.2.9) (Figure 3.71). The reduction of amides
by LAH in Et,O is compatible with the presence of an SePh group in the molecule,
as shown in the case of 3.188 [TTl] (Figure 3.71).
The alkali borohydrides in an ether medium do not reduce amides at room
temperature [BIG], but under reflux of THF secondary and tertiary amides are
reduced to amines [PSI]. Lithium diisopropylaminoborohydride in THF reduces
aliphatic and aromatic N,N-dialkylamides to the corresponding amines [FFl] (Fig-
ure 3.72). NaBH,-ZrCl, reduces PhCONMe, to the corresponding amine [ISl],
while NaBH,-TiCl, in DME reduces all amides and lactams to the corresponding
amines [KT2]. Tertiary mides are transformed into the corresponding amines by
n-Bu,NBH, in refluxing CH2C12 [WIl] or by NaBH, in refluxing pyridine [KIl]. In
the presence of an organic acid and under reflux, NaBH, reduces all amides to
amines [GN 1, UIl]. Under these conditions, a diarylketone can remain unaffected,
as shown in the reaction of 3.189 (Figure 3.72).
The activation of NaBH, by ethanedithiol allows access to primary amines with
nitriles remaining intact [GEl]. The same reduction can be accomplished either by
LiBH,-diglyme-hot MeOH starting from primary aliphatic and aromatic amides
[SO31 or by NaBH, in an alcohol medium in the presence of CuCl, (for aromatic
amides only) [W4]. (CF,COO),BH leaves the amides unchanged [MMl].
An alkylation method for primary and secondary amines consists of treating them
3.2 CARBON-OXYGENDOUBLE BONDS 105
PhSet,,,,, ,dEt Phse~,,,~.
Ph 0
I
n-Bu
0
O0C
56%
LAH-Et 20,
C
Ph Q I
n-Bu
,,&t
3.188
Figure 3.71
R = n-C7H15,n-C9H19, Ph, 3-MeC6H4,
R' = Et, i-Pr,(CH2),

Q'
NHCOCF3
AX
C1
3.189
coph NaBH4-CF3COOH-
toluene, 40°C
CI
Figure 3.72
Figure 3.73
with NaBH, in an organic acid medium. In the cold, monoalkylation of primary

amines occurs, while at high temperature, the secondary amines are further alky-
lated. The mechanism of this reaction has not been elucidated [GNI]. The reaction
is better with aromatic amines and is compatible with OH, COOEt and CONR,
groups, and heterocycles (Figure 3.73). With formic acid, the reaction is not always
easy to run. In the presence of CF,COOH, or if NaBH, is replaced by NaCNBH3,
this alkylation does not take place (Section 3.3.1).
Another facile method of methylation of amines consists of their transformation
into carbamates, which are reduced in situ either by LAH [REI] or by NaBH, in the
presence of AcOH or CF,COOH in dioxane or THF [GNl]. However, under the
latter conditions, the t-butyl carbamates react poorly (Figure 3.74).
Lactams such as 3.190 or 3.191 are reduced under the same conditions as linear
amides, as shown in Figure 3.75 [BK5, BM6, LH1, WM2]. However, LAH on silica
gel reduces esters, but it does not reduce lactams (Figure 3.75). Under suitable
conditions with LAH, it is possible selectively to reduce a lactam bearing a sulfone
group that remains unchanged [TGl]. The reduction of the lactams 3.192 to cyclic
tertiary amines has been accomplished through reaction with NaBH, in refluxing
t-BuOH in the presence of MeOH added dropwise [MGI, MG2] (Figure 3.75).
Partial reduction of carbamate-protected five-membered lactams such as 3.193 to
hemiaminals can be performed with DIBAH or LiEt,BH [KN3, LAl, PEI] (Figure
3.75). The stepwise reduction of lactams such as 3.194 into hemiaminals followed
by dehydratation to iminium salts, which suffer a second reduction, gives better
79% global
as above
-
dioxane
Figure 3-74
yields in the expected pyrrolidine than the one-step reduction by BH,.Me,S [LR2,
PEl] (Figure 3.75). Esters are not affected under such conditions. 2-Pyrrolidinone
3.195 (X = H) as well as its N-carbamoyl derivative 3.195 (X = CONH,) remain
unchanged in the presence of NaBH, in MeOH [KM3]. However, an amino alcohol
3.196 (X = Ts) is obtained from 3.195 (X = Ts) under these conditions, probably
via the corresponding hemiaminal. Ring opening takes place from 3.195 (X =
CONH,) only in the presence of K2C0, [KM3] (Figure 3.75).
A problem that has received some attention in relation to the chemistry of
p-lactam antibiotics is the reduction of the azetidin-Zones 3.197 [Y02]. While AlH,
or LAH in Et,O and BH,.THF cleave the N-alkylazetidinones to 3-aminopropanols,
cis-3-benzyloxy-l,4-diphenylazetidinone 3.198 is cleaved only by LAH or lithium
trialkylborohydrides in THF (Figure 3.76). The reduction of 3.198 by DIBAH in a
hexane-THF mixture under reflux or better by AlH,Cl or AlHC1, in Et,O preserves
the heterocycle and selectively provides the substituted azetidine 3.199 (Figure
3.76). When the p-lactam carries a methyl ketone functional group at the 3-position,
such as 3.200, the selective reduction of the ketone group by NaBH, in THF,
Zn(BH,), in Et20, or Li and K(s-Bu),BH in THF leaves the p-lactam unchanged
[PAl] (Section 3.2.2) (Figure 3.76).
Cyclic imides undergo a reduction with a regioselectivity that is comparable to
that of cyclic anhydrides (Section 3.2.6). NaBH, in EtOH in the presence of HC1 or
in MeOH partially reduces the imides to a'-hydroxyamides, the carbonyl adjacent to
the most substituted carbon being preferentially reduced [PSI, SH2] (Figure 3.77).
The reduction of bicyclic imides bearing CN or COOEt groups must be performed
with NaBH,-CeCl, in order to prevent overreduction [DR2]. Chelation can direct
the reduction of one carbonyl, as in the case of 3.201 [GK2] (Figure 3.77). DIBAH
in toluene at low temperature also brings about this reduction [HT2, SH2, Wl], but
108 REDUCTION O F DOUBLE BONDS
04
COOMe
BH3*THF * d I
COOMe
.:
k ~ ~ ~ h CHzPh
3.190
. . , d ' ~
-
LAH
86 95%
0
3.191
70%
N~BH~-~-BUOH~
MeOH, reflux
C2H5
t-BuOCOCH~ t-BuOCOCH~
.A& C00CH2Ph 1- DIBAKhexaoz

82% ~ C O O C H 2 P h
~ O O M ~ 2- TsOH, MeOH ~ O O M ~
Figure 3.75
+ CH2-CH2
AH3-Et20 or LAH-Et20 I
HOCHz NHR
I
or BH3-THF
LAH-THF or LiEt 3BH-

THF CH20H NHPh
3,200
Figure 3.76
the regioselectivity is inverted. Asymmetric reduction of meso imides by boranes

associated to chiral co-reagents has been described [KL4, RR2].
The reduction of N-methylglutarimide to the corresponding lactamol by DIBAH
gives very poor yields, but this transformation can easily be performed with
LiEt3BH in CH2C12 at low temperature [TRl]. The reduction of chiral N-(1-phe-
nethy1)glutarimide with LiEt3BH is highly stereoselective [PB3]. This is also the
best reagent to reduce pyrrolizinediones 3.202 to the corresponding lactamols [TRl]
because NaBH, in acidic conditions induces ring cleavage and Zn(BH,), gives
lower yields (Figure 3.78). The highly stereoselective formation of cis-substituted
a'-hydroxylactams via the auxiliary controlled reduction of imides has been carried
out from chiral imides 3.203 [MC3]. Reduction of the free alcohol 3.203 (R = H) by
Me,N(AcO),BH or of the related silyl ether 3.203 (R = %Me2-t-Bu) by Li-Se-
lectride selectively gives each cis enantiomer (Figure 3.78). Red-A1 is the most
efficient reagent to perform the selective reduction of chiral imide 3.204 derived
from meso cis-caronic anhydride [MY31 (Figure 3.78).
Red-A1 reduces N-methylsuccinimide to N-methylpyrrolidone [H3] (Figure
3.78). Reduction of succinimides to pyrrolidines can be carried out by NaBH,-
Figure 3.77
BF,.Et,O in diglyme [MS2]. Thioamides are reduced to mines by BH,-Me$

[JS4].
3.2.9 a$-Ethylenic Carbonyl Compounds: a$-Ethylenic Aldehydes,

Ketones, Esters, and Amides: RCH=CHCOY (Y = H, R', ORf, NRfR")
Reduction of a$-ethylenic aldehydes and ketones can lead to three compounds
(Figure 3.79):
Allylic alcohols resulting from attack on the carbonyl;

Saturated aldehydes and ketones resulting from attack on the double bond;
Saturated alcohols resulting from the subsequent reduction of intermediate
saturated aldehydes and ketones. This is generally observed in the presence of
proton donors (most frequently the solvent).
The regioselectivity of these reductions depends on the structure of the starting

compound: Aldehydes are more sensitive to the attack at the carbonyl than ketones.
Other things being equal, the reduction of the carbonyl group becomes predominant
when the double bond is sterically hindered. The regioselectivity also depends on
the type of reducing agent and the medium. The more important the electrophilic
Figure 3.78
assistance by a protic solvent, by the cation associated with the reagent, by the
reagent itself, or by an added Lewis acid, the easier the attack on the carbonyl [LL3,
LS1, S2]. In contrast, the reduction of the double bond is more prevalent if the
reducing agent is bulkier or if it is associated with a cation such as ammonium, not
able to induce electrophilic assistance [S2], or with a transition metal such as
copper. Aprotic media strongly solvate alkaline cations, and this also favors double-
bond reduction. Similar trends are found in the reduction of a$-ethylenic esters and
lactones either to allylic alcohols or to saturated esters and lactones.
Thus the attack on the carbonyl group of a-enones or a,P-ethylenic aldehydes is
preferred when one uses LAH in Et,O [LS 1, PR51, AlH, in Et20 [E2, MI], DIBAH in
hexane [CG3, PR5, Wl], DIBAH-n-BuLi ate complex [KAI], LiAl(OMe),H in
Et20 [MI, M31, Red-A1 in C,H, [MI], NaBH, in aqueous glycosidic media [DL2],
112 REDUCTION OFDOUBLE BONDS
Figure 3.79
borohydride exchange resin in MeOH [SJ3], Li aminoborohydrides [FF2, FS21,

diisopropoxytitanium tetrahydroborate [RB3], Zn(BH,), or NaCNBH,-ZnCl, in
Et20 [ILI, KOI, VM1, YLl], Zn(BH,), on SiO, [R3], BH,.Me,S [HCI], or
BH,.THF in the presence of LiBH, [AHI], LiBuBH, in Et,O [KMI], 9-BBN in THF
[ B U , KB2, PS 11, Na(AcO)BH, in THF [NB3], and NaBH,-CeCl, in MeOH [EHl,
GLl, KK12, W4]. This latter reduction can also be carried out in CH,CI,-EtOH and
is compatible with SePh groups [DDl]. With the last two reagents, ester, nitrile,
carbamate, and NO, groups are unchanged. a$-Unsaturated aldehydes can be
selectively reduced to primary allylic alcohols by NaBH,-MeOH-CH,Cl, at -78OC,
leaving a-enones unchanged [WRI]. Moreover, benzalacetone PhCH=CHCOCH,
is overreduced by AlH, to 1-phenyl-1-butene PhCH=CHCH,CH, [E2]. In the pres-
ence of nickelocene, LAH reduces the C=C bond of a-enones [CC2]. NaCNBH,-
BF,.Et,O in THF promotes the overreduction of a-enones to alkenes [SVl].
BH,.THF generally attacks the carbonyl group and the double bond [PS 11.
In contrast, in the presence of copper salts, LiAl(OMe),H, Red-A1 in THF [CL3,
M1, M3, SSl], or borohydride exchange resin [YSI], various complexes of CuH
with organolithiums [BM4, MBI], the complex (Ph,PCuH), [MB2, MS61, DIBAH
in THF-HMPA sometimes in the presence of MeCu [THI], LAH in the presence of
cuprates [ALl], n-Bu,NBH, in THF [IL2], and Li and K(s-Bu),BH in THF [CRl,
GI, KH3, OM21 or KPh,BH [KP2] favor the reduction of the double bond of
a-enones (Figure 3.80). When the carbonyl group is precoordinated to a bulky
Lewis acid such as aluminum tris(2,6-diphenylphenoxide), 19-reduction of
a$-unsaturated aldehydes and of a-enones can be performed with n-BuLi-DIBAH
complex at -78OC [SY6]. Catecholborane promotes the conjugate reduction of
a-enones, which can lie under the s-cis conformation, even when sterically hindered
[EF2]. The 1,4-reduction by LiAl(OMe),H,-CuBr in the presence of BH,.Et,O is
compatible with the N-COO-t-Bu group [CL3]. The mechanism of the reduction is a
conjugate addition of hydride; the enolate formed can then be trapped by an electro-
phile [CNI, CS 1, G1, KSI, MB2, OM21 (Figure 3.80).
The reduction of a$-unsaturated aldehydes to saturated aldehydes can be carried
out by (Ph,PCuH),.Me,SiCl in C,H,. When the reaction is run in wet THF without
Me,SiCl, saturated alcohols are formed [BS3].
The conjugate addition of Li and K(s-Bu),BH in THF to a-enones is sensitive to
Figure 3.80
steric hindrance of the double bond; 3-methylcyclohexenone gives a mixture of

ketone and allylic alcohol [Gl]. LTBA in THF [Ml] and LiEt,BH [BK6, CL3, Gl],
although less bulky, often give rise to mixtures. Similarly, 201-fluoro-A-4-an-
drosten-3,17-dione is reduced by K (s-Bu),BH to the 3-01-01 [GMl]. However, in the
presence of MAD [aluminum bis(2,6-di-t-butyl-4-methyl)phenoxide], Li n-Bu
i-Bu,AlH [NM2], LiEt,BH, or Li(s-Bu),BH [CL3] give I$-reduction of sterically
hindered a-enones.
Cyclopentenones, which are particularly prone to conjugate addition, are reduced
by LTBA to the corresponding cyclopentanones [Ml], while the 3-substituted cyclo-
hexenones give mainly allylic alcohols [BGI, G l ] (see above). The complexes of
copper hydrides or DIBAH-MeCu are much less sensitive to steric hindrance [LUl,
MB1, MB2, THl]. Indeed, progesterone 3.205 is selectively reduced to pro-
gestanone under these conditions (Figure 3.81). Likewise, bicyclic ketones 3.206
and 3.207 are reduced at the ring junction in a stereoselective fashion (Figure 3.81).
With regard to the reactions with DIBAH-MeCu, trapping of the aluminum
2- MeLi
3- e B r
Figure 3.81
enolates obtained with alkyl halides requires their transformation into an -ate com-
plex by reaction with MeLi [TS 11 or t-BuLi [DKI]. In the latter case, trapping of the
A1 enolate can be carried out with aldehydes or acyl chlorides; ketones, esters,
methyl vinyl ketone or methyl acrylate, MeI, tosylates, and methyl chloroformate do
not react. Polyalkylation reactions are thus avoided (Figure 3.81).
The reduction of a-enones by the alkaline borohydrides in alcohols or THF in the
presence of a protic solvent most often gives mixtures in proportions that depend on
the solvent and on the structure of the substrate [EHl, PSI, VKl]. Aldehydes
principally lead to allylic alcohols, as do some linear ketones (Figure 3.82). When
N&H4-EtOH aq.
X/ CH20H
Me*~H~ * M e * ~ ~ 2 0+~CH3CH2CH2CH20H
as above
85 15
Figure 3.82
starting from cyclic a-enones, one obtains saturated alcohols, the intermediate enol-
ate being protonated to give a saturated ketone, which is then reduced (Figure 3.82).
Vinyl ketones are reduced to saturated ketones by NaBH, on resin in dioxane, but
a,@-unsaturatedaldehydes give saturated alcohols under the same conditions [NS11.
Sodium borohydride reductions of enones in the presence of micelles, in microemul-
sions, or in the presence of polyethyleneglycol methyl ether also give mixtures
[BK8, FR2, LS7, NS41.
Cyanoborohydrides in the presence of acid in MeOH or HMPA most often lead
to allylic alcohols from linear a-enones or a$-unsaturated aldehydes and to mix-
tures from cyclic a-enones [HK2], even though some of the steroid ketones could
have been reduced to allylic alcohols [VMl].
The relative reactivity of the a-enones and ketones towards different reducing
agents has been examined [S2]. When electrophilic assistance is important, the more
basic saturated ketone is selectively reduced. This is the case with LTBA in THF
[Ml], Zn(BH,),.l.S DMF in MeCN [HJl], NaBH,, and BH,.NH, in MeOH [Al,
IL1, TK21. Provided that steric hindrance does not intervene, the reactivity order
with NaBH, in MeOH-CH2C12 at -78°C is as follows [WMI, WRl, WR41:
a-enones < ketones < a$-unsaturated aldehydes < aldehydes
It is therefore possible selectively to reduce ketones in the presence of a-enones

using this reagent-solvent mixture. When an a-enone and a saturated ketone are
present in the same molecule, such as in androst-3-enone 3.208 or Wieland-Mis-
chler ketone 3.207, one obtains the corresponding secondary alcohol [WRl, WR2]
(Figure 3.83). A similar selectivity is observed when performing the reduction of
3.207 with NaBH, in EtOH at - 10°C [IT3, TUl]. Curiously, Zn(BH4)2 in Et20
does not appear to be very selective toward progesterone 3.205 [ILl]. However, in
DME, this reagent reduces saturated ketones, leaving a-enones untouched [SD2]. At
-7S°C, 3.207 is selectively reduced to 3.209 (Figure 3.83). NaBH,-CeC1, in
MeOH [GLl] reduces the a-enone moiety of progesterone 3.205 to allylic alcohol,
but with a low selectivity, while n-Bu,NBH, in THF leads to a mixture of 20-
keto-3-01s 3.210 [ILl] (Figure 3.83). The reduction of steroidal diketones 3.205 and
3.208 with Selectrides is poorly selective [WDl].
The presence of a hydroxy group at the a position may direct the double-bond
reduction of 3.211 to the face bearing this group [SJ2] (Figure 3.83). Enarninones
RCOC(R')=CHNMe, are reduced by LAH in Et20 to P-aminoketones
RCOCH(Rf)CH2NMe2[SEI 1.
As previously mentioned (Section 3.2.2), axial attack is more favored for cyclic
a-enones than for saturated cyclanones [CG7, N2, WH31. Therefore, highly stereo-
selective reductions of enones are expected. Indeed, the reductions of steroids such
as 3.212 or 3.213 by various borohydrides [RB3, VMl] or of 3.214 and of tes-
tosterone 3.215 by NaBH,-CeC1, in MeOH [GLI, KA2] give rise to equatorial
allylic alcohols (Figure 3.84). The reduction of pulegone 3.216 by ami-
noborohydrides [FF2, FS21, diisopropoxytitanium tetrahydroborate [RB3], or
NaBH,-CeCl, in MeOH [GLl] is also highly stereoselective (Figure 3.84).
Other related examples are provided in the literature [KY3, NS5, SM8, TH2,
WKl, YK61. The reductions of substituted cyclopentenones, functionalized vi-
nylketones, and carbacyclin precursors by NaBH,-CeC1, in MeOH have also pro-
vided interesting stereoselectivities [BA4, GLl, J1, MH5, SG31. The asymmetric
reduction of a-enones by oxazaborolidines-BH, has been described in Section
3.2.3.
In the case of a,@-ethylenicesters, DIBAH in toluene at -70°C and its ate
complex with n-BuLi [AH2, KA1, TR3] are the reagents of choice to access allylic
alcohols [YGl], the E or Z configuration of the double bond being retained [DD2,
MT4] (Figure 3.85). The selective reduction of an ester group may be performed in
the presence of a carboxylic acid such as 3.217 [TR3] (Figure 3.85). With LiEt,BH,
isolated benzoate esters may be preserved in sugar derivatives, while they are
reduced by DIBAH [DD2]. LAH in THF, Et20, or C,H, can also induce this
reduction when one adds the ester to a cold solution of LAH, but the results are often
unsatisfying. When the a,@-unsaturatedester bears an acylamino group, the yield of
Figure 3.83
the reduction is higher if one begins by adding BF,-Et,O to prevent the complexa-
tion of the reagent to the nitrogen site of 3.218 [MH3) (Figure 3.85). A sto-
ichiometric amount of Red-A1 in C,H, can give access to allylic alcohols [H3].
Red-A1 or LiAl(OMe),H in the presence of CuBr in THF-2-butanol leads to
saturated esters or lactones [M3, SS I], as does LiEt,BH in THF-t-BuOH [Gl]. The
role of the alcohol here is to protonate the enolate formed, thus avoiding side
condensations. As shown in Figure 3.86, the nonconjugated double bond of 3.219
7 I @ >90%
____c &I7
\ \
PhCOO PhCOO ;
0 OH
3.212
NaBH4-THF-MeOH de 88%
NaCNBH3-THF-HCl de > 99%
ZII(BH~)~-E~~O de > 99%
NaBH4-dioxane mixture of 1,2 and 1,4
3.213 R = C8HI7,COOMe de > 99%
P
NaBH4-CeC13-
PhCOO MeOH PhCOO
Qo - 75 - 95%
(see text)
3.216 de > 95%
Figure 3.84
remains untouched [BS2]. DIBAH-MeCu also gives access to saturated esters

[THl]. Just as in the case of a-enones, trapping of the enolates formed by reaction
with an alkyl halide requires an intermediate ate complex [TSl] (Figure 3.86).
Catecholborane also reduces a,@-unsaturatedesters into saturated esters, but only
under Rh(PPh,),Cl catalysis [EF2] (Figure 3.86).
M H 2 ~ cMe0OEt DIBAH-toluene, -70°C * M H 2 ~ C HMe

20H
or LAH-THF
LAH-THF
DIBAH-toluene
CH20H
OMe ?Me
H
R F C O O E t 1- BF3*Et20-CH2C12
* R Hv C H 2 0 H
NHBO C 2- DIBAH-toluene NHBO C
3.218
Figure 3.85
In dioxane solution, NaBH, on a resin reduces a,@-ethylenicesters to saturated

esters [NS I], as do NaBH,-Cu2C12 in MeOH at 0°C [NH I] and NaBH,-BiCI, in
EtOH [RP3]. Disubstituted isolated double bonds remain unchanged [NHI].
Alkaline borohydrides in alcoholic media or in THF-MeOH [SO31 most often
give mixtures, while NaBH,-LiCI in THF-EtOH leads to saturated alcohols [JDI].
However, gemdiesters 3.220 or a,@-unsaturatedlactone-esters are reduced to satu-
rated esters by NaBH, or NaCNBH, in alcoholic media [HRI, PSI, SS3] (Figure
3.86). In some cases, BH3.Me2NH may be preferred, as shown in the reduction of
3.221 [HS2] (Figure 3.86). NaCNBH, in an alcoholic medium at pH 3-4 reduces
unsaturated gem-ketoesters or the nitrile-esters 3.222 to saturated derivatives with-
out modifying other functional groups [HRI], while NaBH, reduces the nitrile-
esters to alcohols in the same medium [MR4], unless NaBH, is fixed on a resin
[NSI] (Figure 3.86). The reduction can be stereoselective, as shown in the case of
3.223 [BJ3] (Figure 3.86).
AlH, reduces a,@-unsaturated amides to allylic amines [BK5] (Figure 3.87).
a,@-Unsaturatedamides and related compounds such as 3.224 are reduced to satu-
rated amides by Li or K(s-Bu),BH [GI, GL71. Trapping by alkyl halides has been
described in many cases, such as 3.225 [KS I] (Figure 3.87). Conjugate reduction of
1- DIBAH-MeCu-TKF-HMPA b
2-MeLi
3- m B r
"#"
R' COOEt NaCNBH3-EtOH-H+
- R\
qc-(H
Rl
CN
COOEt
Fu 0
CO OEt
Figure 3.86
OH SMe
95% Et SMe
Me
OH SMe
Me
3.227 LAH-THF,
98Xreflux E"tSMe G~
Figure 3.87
a$-unsaturated amides or imides can be performed with catecholborane under

Rh(PPh3),Cl catalysis [EF2]. NaCNBH, also reduces a$-ethylenic amides that are
geminally substituted by another electron-withdrawing group to saturated com-
pounds [HRl]. a$-Unsaturated lactams can be reduced to saturated cyclic m i n e s
by LAH or alkoxyaluminohydrides in ether media, but the results are often disap-
pointing [H3].
The asymmetric reduction of prochiral P,P-disubstituted a$-unsaturated esters
and amides can be performed with NaBH, in the presence of catalytic amounts of
CoCl, and a semicomn at r.t. in protic solvents [MP4, P31. Chiral a$-unsaturated
sultams 3.226 are reduced by LAH-CoCl, in suspension in THF or Et,O to satu-

rated derivatives [OM3]; the stereoselectivity is inverted depending on the nature of
the solvent (Figure 3.87). Li(s-Bu),BH also promotes such conjugate reduction
[OP2].
The transformation of the a-oxoketene dithioketals 3.227 is especially interest-
ing. Reduction by LAH in THF at room temperature leads to allylic alcohols, while
under reflux, the hydroalumination of the double bond also takes place. This reac-
tion can be stereoselective [GB2, RCl] (Figure 3.87). NaBH, in MeOH gives allylic
alcohols, while DIBAH leads to the corresponding saturated ketones [RCl].
3.3 CARBON-NITROGEN DOUBLE BONDS: X=N-

+
3.3.1 lmines and lminium Salts: )C=NR, )C=NRR'
Imines and iminium salts are easily reduced to amines by LAH in THF or Et,O,
Red-A1 in C6H6 at room temperature [H3, M3, PSI], alkaline borohydrides in
alcoholic medium or in AcOH [GNl], or else in the presence of Co or NiCl, in
THF-MeOH [PD2], Zn(BH,), in Et,O [KY2], NaBH,-ZrCl, in THF [ISl], alkyl
borohydrides in THF [WGl], BH3.THF [L2], (CF,COO),BH.THF [NMl], or arn-
ine-boranes in acid media in CH,Cl, [PSI]. In the case of N-triphenylmethyl-
imines, NaBH, in AcOH must be used because LAH induces unwanted bond
cleavage [PR6]. Nevertheless, the common reductions are those run with the cya-
noborohydrides at pH 6-8 [Ll]. Indeed, under these conditions, ketones and al-
dehydes are reduced much more slowly. It is then possible to carry out "one-flask"
reductive amination of carbonyl compounds by reaction of a primary or secondary
amine in the presence of cyanoborohydrides in aqueous MeCN or in MeOH at
controlled pH [KOl, L1, PSI]. NaBH, in the presence of H,SO, [GC2, VGl],
NaBH,, and cyanoborohydrides in AcOH or CF3COOH [GNI], NaCNBH, in tri-
methylorthoformate [SB5], preformed Na(AcO),BH in THF, MeCN, or better
ClCH,CH,Cl [AC5, AMl, RJ2, YH3] are also valuable reagents. With the last
reagent, aromatic and a$-unsaturated ketones react slowly [AC5]. When using
NaBH, in AcOH, one can still observe the side reaction of alkylation (Section 3.2.8)
[GJ2, GNl]. In the presence of Ti(0-i-Pr),, reductive amination either with NaBH,
[AC5, B4, B5, BClO] or with NaCNBH, [MPl] takes place under mild conditions
in diglyme or in EtOH. Hindered amines can also be used provided that the imine is
pregenerated in CH,Cl, eventually in the presence of TiC1, and EtN-i-Pr,; reduction
is then performed with NaCNBH, in MeOH [BH5, RK31. This reaction can also be
carried out with a phase-transfer catalyst [HMl, HN3, YK51 or in the presence of
pyridine-borane eventually on solid phase [BC9, KA5, KS8, M7, PR21.
Na(AcO),BH is the most efficient reagent to perform reductive aminations with
weakly basic amines even from aldehydes [AC5]. Primary amines and NH, give
imines, which are then reduced [H3] (Figure 3.88). In acid media, secondary arnines
are converted to iminium salts, which also undergo reduction (Figure 3.88).
3.3 CARBON-NITROGEN DOUBLE BONDS 123
R'
++ R"
H~N:X-
R"'
- R
R'
)=N:
R"
X-
R"'
- R\
R"
CH-N:
R
R'"
PhCHO + EtNHz
Figure 3.88
The following examples show the compatibility of the reaction with the presence
of various functional groups [B4, L l ] (Figure 3.89). Nitroimidazoles remain un-
changed [YH3]. No epimerization takes place when chiral amino esters are used
[SS9], but in the presence of water, some esters can be hydrolyzed [Ll]. The
methodology involving Ti(0-i-Pr), and NaCNBH, [MPI] leaves acid-sensitive
groups such as acetals, carbamates, ureas, esters, and amides unchanged. Similarly,
a-ketoesters suffer reductive amination with Na(AcO),BH in ClCH,CH,Cl, leading
to N-substituted a-amino esters [AC5]. It is possible to obtain amino acids from
ketoacids by using LiCNBH, in MeOH under a careful control of the reaction pH,
although only moderate yields result [BBl].
The application in the N-methylation of alkaloids has been published [SH3]. The
N-methylation of amines by paraformaldehyde-NaBH, in CF3COOH in the pres-
ence or absence of THF or by CH,O-NaCNBH, in AcOH has also been recom-
mended [GN3]. However, this method is limited because it is not possible to make
monomethylated amines from primary amines; the transformation of the intermedi-
ate secondary amine to tertiary amine is very rapid [AC5]. The best way to prepare
monomethylated amines is then via the carbamates (Section 3.2.8).
Reductive amination can also be accomplished in an intramolecular fashion
[BMB, VOl], as shown in Figure 3.90. One predominant stereoisomer 3.228 is
formed when generating six-membered rings [AOl]. The stereoselectivity of the
formation of pyrrolidines is lower [BM8]. Finally, one can couple the reductive
amination and alkylation with an acid (Section 3.2.8) by raising the temperature
[GNl] (Figure 3.90). a-Amino esters can easily be obtained from N-silyl-iminoes-
ters 3.229 with NaCNBH, in MeOH, NaBH, in MeOH, or Me,NH.BH, in MeOH
[MT5], while LAH converts them to amino alcohols [MT5] (Figure 3.90). Reduc-
tive amination can be carried out from acetals [M8].
The stereoselectivity of the reduction of the six-membered cyclic imines has been
CH20 aq.with excess

NaCNBH3-MeCNaq. pH 6-8
COFHCH2COOMe
96%
CHzO aq.4
thexcess
NaCNBH3-MeCNaq. pH 6-8
CHO
I y32NM"2
I then NaBH4, r.t. I

X X
X = C1, NHAc, CN
Figure 3.89
examined [HS I, M3, PD2, WGI, ZHl]. The results are comparable to those ob-
tained with the cyclic ketones, as shown in Figure 3.9 1. One nevertheless observes
less axial attack by slightly hindered reagents than with the corresponding ketones
[HSI]. A suggested variant involving N-diphenylphosphinylimines such as 3.230
allows the preparation of axial primary amines with an excellent stereoselectivity
[HA2, HR2, ZHl] by the action of Li(s-Bu),BH followed by treatment in an acid
medium (Figure 3.9 1). These observations were extended to other substituted cyclo-
hexyl, cyclopentyl, and bicyclic derivatives. On the other hand, reduction of 3.230
with t-BuNH,.BH, in MeOH gives predominantly the equatorial m i n e [HA21
(Figure 3.91). Other reducing agents are less stereoselective. The stereoselective
reductive amination of substituted cyclohexanones and of tropinone has been real-
ized using in situ generated acyloxyborohydrides [AC5, ML31. The stereoselective
reduction of bicyclic N-silyliminocyclopentenes with Red-A1 has been recently
published [HB I],
Asymmetric reductive amination can be carried out on chiral ketones able to
form an intermediate imine such as 3.231 or 3.232 [BW 1, MNl, PP4] (Figure 3.92).
According to the structure of the substrates, NaBH,, NaCNBH,, or Me,N(AcO),BH
are the reducing agents that give the best yields or selectivities.
Another way to obtain achiral or chiral P-aminoalcohol derivatives stereoselec-
tively is to use NaBH, or Zn(BH,), to reduce a-hydroxyimines 3.233 or cu-trimethyl-
N'~~e3 [ R$HCH@H
LAH-THF NH2
3.229
silyloxy-N-magnesioimines 3.234. The latter intermediates are formed by a Grignard

reaction with the corresponding protected cyanohydrin [JJ I , KJ I, UA 1, ZH I] (Fig-
ure 3.92). NaBH, gives poorer stereoselectivity except when using 0SiMe2-b-Bu
ethers, which are subsequently cleaved by HF to avoid racemization; syn isomers
are predominant in this case [BDl]. y-Amino alcohols have also been obtained in a
stereoselective fashion by DIBAH reduction of iminoalcoholates 3.235 [TVl] (Fig-
ure 3.92). Chiral @-iminosulfoxidesalso suffer stereoselective reductions by DI-
BAH-ZnBr, or by Li (s-Bu),BH, each reagent giving predominantly one isomer or
the other [GL8].
Chiral substituents may also be introduced on the nitrogen of the imine [HM6,
ZHl]. The reductions of imines of (S)- 1-phenethylamineeither with NaBH,-CoC12
or with LiEt2NBH3[FB 11 do not give high stereoselectivities, except with imines of
t-BuCOMe. The reduction of a chiral sulfilimine 3.236 by 9-BBN in THF gives a
single diastereoisomer, precursor of (R)-alanine ethyl ester [HL3] (Figure 3.93).
LAH or DIBAH is more or less stereoselective [HM6].
Reduction of prochiral imines with chiral reducing reagents has also been exam-
ined [NNl, ZHl]. Binal reduces phosphinylimines with a high enantioselectivity,
but in a low chemical yield [HA3]. Itsuno's reagent (borane plus amino alcohol 3.69
in THF) allows the enantioselective reduction of N-phenylarylimines 3.237 with a
good selectivity [CC9] (Figure 3.93). CBS reagents are sometimes less efficient
[CC9, SY71. The asymmetric reduction of dialkylarylimines, iminoesters, or -sul-
famides under similar conditions [CC9, CG8, SY5] also gives moderate or poor
126 REDUCTiON OF DOUBLE BONDS
Figure 3.91
enantioselectivities (up to 70%). Oxazaphospholidine-borane reagents are also

poorly enantioselective (up to 63% ee) [BB9]. A peculiar reaction leading to nitro-
alkenes has been observed when reacting 2-nitroimines 3.238 with NaBH,-CeCl,
[DS3] (Figure 3.93).
Iminium salts can also be formed by cleavage of the C-CN bond of ami-
nonitriles either in alcoholic media or in the presence of a cation having sufficient
Lewis acid properties. The intermediates are then transformed in situ into amines
(Figure 3.94). Aminonitriles are thus reduced to arnines by LAH in Et,O [CTl],
AlH, in Et20 [E21, NaBH, in alcoholic medium [GRl, MR2, YRl] or in diglyrne
[YAl], Zn(BH,), in ether medium; sometimes the presence of AgBF, or Hg(OTf)2
is required [FDl, GR1, GR2, S71 (Figure 3.94). The reduction is inhibited if the
carbon is too sterically hindered [BM2]. This reductive decyanation can be stereo-
3.3 CARBON-NITROGENDOUBLE BONDS 127
*
Zn(BH4),-Et20, -78OC
then H 3 0 +
C
Z I @ H ~ ) ~ - E ~ ~-78OC
O,
OTMS
then H 3 0 +
3.234
DIBAH-hexane-THF, -78OC
then H 3 0 +
Figure 3.92
selective in cyclic systems, as shown with 3.239 [BRl] (Figure 3.94). In noncyclic
molecules, the stereoselectivity is even lower [MR2].
Another way to produce iminium salts is to reduce aminals with LAH, AlH,,
DIBAH, NaCNBH, in AcOH [GRl, MR2, WR31, or NaBH, in EtOH (Figure 3.95).
Cyclic aminals 3.240 are converted to amino alcohols [GRI, MR2] (Figure 3.95).
However, six-membered tetrahydro-l,3-oxazines 3.241 are not reduced by NaBH,.
LAH in Et,O converts aminals such as 3.241 by C - 0 bond cleavage to y-amino
alcohols, and their corresponding methiodides are converted by C-N bond cleav-
age to alkyl N-methyl-3-aminopropylethers [AAl] (Figure 3.95). Stereoselective
reductions can be observed as with 3.242 [MQl] (Figure 3.95). The reduction of the
five-membered analogues in bicyclic derivatives 3.243 (n = 1 or 2) can be per-
formed either with AlH, (n = 1) at low temperature or with Red-A1 in refluxing
THF (n = 2). The lactam carbonyl is simultaneously reduced in both cases [BM7,
MM91 (Figure 3.95). This method provides the route to nonracemic Zalkylpyr-
rolidines or piperidines.
THF,r.t. 3.69
R = Et, n-Pr
NO 2 yo 2
3.238
R = Me, n-Bu, CH2=CHCH2
Figure 3.93
Figure 3.94
de 84 - 95%
3242 R = Me, Ph
R
1
Me0
Me0
R
yeH
> 95%
NaBH4-MeOH, -78OC
t
MeO
R H
3.244
Figure 3.95
Similarly, chiral iminium salts such as 3.244 can be reduced in a diastereoselec-

tive fashion by NaBH, in MeOH at -78°C [PKl] (Figure 3.95). The highest
stereoselectivity is observed when the aryl group is 2,6-dichlorophenyl. The bifunc-
tional derivatives can undergo two successive reductions [MR2].
R = H, Me, Ph R' = H,Me, Et R = i-Pr, c-C6Hll,t-Bu
3.245
Figure 3.96
a,@-Unsaturated imines are converted into the corresponding unsaturated sec-

ondary amines by NaBH, in MeOH or EtOH [DS2] (Figure 3.96). Allylic amines
can be obtained from 6aminoazadienes 3.245 and AlH, or DIBAH [BA2] (Figure
3.96). If R' is ally1 or benzyl, saturated imines are predominantly formed, but
sequential treatment of these azadienes by DIBAH and NaBH, in MeOH leads to
allylic amines.
3.3.2 Enamines: )c=c(

NR2
The reduction of enamines occurs after their protonation and the tautomerism of the
protonated enamine to an iminium salt. Substrates will be accordingly reduced only
in the presence of sufficiently strong acids or in protic media. LAH in THF does not
reduce enamines. Enamines are transformed into saturated amines by AlH, in Et20
[H3] and by NaBH, in alcoholic media [BBI], in THF-AcOH [GNl], in the
presence of CF,COOH [GNl] or, better yet, by Zn(CNBH,), in MeOH [KO11 and
NaCNBH, in THF-MeOH [BB 11 (Figure 3.97). Since cyanoborohydrides do not
reduce esters, p-enaminoesters can be transformed into p-aminoesters with
NaCNBH, in THF-MeOH [BBI]. The stereoselectivity of the reduction of cyclic
enamines such as 3.246 and 3.247 has been examined. Reaction with NaCNBH, in
AcOH or BH,.NH, in AcOH provides predominantly the axial saturated amines
[HSl] (Figure 3.97). In heterocyclic systems such as alkaloids, highly stereoselec-
tive reductions can be observed; however, stereoselectivities are highly dependent
on both substituents and conformation [WFI]. Substituted P-enaminoesters suffer
diastereoselective C=N reduction with Na(AcO),BH in AcOH-MeCN [CP5].
3.3.3 Nitrogen Heterocycles

lndoles Indoles can be viewed as cyclic enamines. here fore, they are reduced to
indolines in acid medium by BH,.THF in CF,COOH [LOl, MMl], pyridine-
NaBH4-THF
hot HOAc
I
COOMe benzene
NR'R" NR'R"
I 1
3.246 de 80%
R = Me. t-Bu
Figure 3.97
borane in CF,COOH [K3], and NaCNBH, in CF,COOH [GNl, GN2, KL21. The
use of NaBH, in AcOH is unsuitable because there may be concurrent N-acylations
[GNl, GN2, GJl]. However, if the indole carries a COMe or COEt substituent, it is
reduced by NaCNBH, in CF,COOH to a CH2Me or CH2Et group [KL2]. It is
interesting to note that NaBH, in CF,COOH does not lead to indolines with
NS02Ph derivatives [KLl], while NaCNBH, in CF,COOH does [KL2]. These
reductions are compatible with ester and nitrile substituents. The reduction by
NaBH, in CF,COOH is compatible with halides and ester groups, and it can be
stereoselective, as shown in the reduction of 3.248 [GNl] (Figure 3.98). Zn(BH,),
reduces 2,3-dimethylindole into the trans-2,3-indoline [DG2].
The reduction of indoles by pyridine-borane in CF,COOH [K3] or BH,.THF in
CF,COOH [MMl] is compatible with amide, nitrile, or ester groups. It is interesting
to emphasize that LAH in ether media reduces these groups without affecting the
k
70-80%
NaBH4-CF3COOH
20°C
"w AH
3.248 R = F, C1, Br, COOEt
3.250
Figure 3.98
indole heterocyclic double bond. The formation of a compound with a trans ring
junction can be realized starting from an indole ring fused to a nitrogen heterocycle
3.249 by preforming the corresponding amine-borane. This leads to the trans-
indoline in an intramolecular fashion [EGl] (Figure 3.98). A similar stereoselec-
tivity is observed in the reduction of 2-phenyl-3-dimethylaminomethyl-N-methylin-
dole 3.250 by BH, in THF [DG2] (Figure 3.98).
Heterocyclic lmines and lminium Salts Heterocyclic imines are reduced

under the same conditions as linear ones. This reduction is compatible with the same
functional groups, as shown in the case of 3.251 [GNl] (Figure 3.99). Moreover, if
the acid used is chiral, one can observe an asymmetric induction [GNl] (Figure
3.99). In the reduction of compound 3.252. the presence of the secondary amine in
the six-membered ring prevents the subsequent reduction of the indole, which is not
protonated under these conditions (Figure 3.99). 2,6-Dialkylpiperideines or 23-
dialkylpyrrolines 3.253 can be stereoselectively reduced to cis- or trans-disubsti-
tuted piperidines or pyrrolidines by using either DIBAH or LAH-Me,Al [BC8,
MM.51, the other reagents being less stereoselective (Figure 3.99). The reduction of
2-phenyl-3-alkyl-A-1-pyrrolines 3.254 by NaCNBH,-AcOH at low temperature is
highly diastereoselective towards the cis-2,3-disubstituted pyrrolidine [PB2]. At
higher temperature, the stereoselectivity decreases, except when R = i-Pr (Figure
or -78°C k
de 98%
R = Me, Et, n-Pr,i-Pr, Ph n = 1,2
COOMe
H
CHzCOOMe
H
90%
Na(0Ac) 3BH
AcOH-MeCN
~ c o o c H 2 p h
Figure 3.99
3.99). Cyclic N-oxides (nitrones) are reduced with NaCNBH, in MeOH to the
corresponding oximes [OB3].
The reduction of the bicyclic iminium salts having the nitrogen at the ring
junction can be very stereoselective. The hydride enters preferentially on the axial
face antiperiplanar to the developing lone pair on nitrogen [D2, HL4, M3, NS3]
(Figure 3.99). LTBA or Na(AcO),BH can be more stereoselective than NaBH, or
NaCNBH, [HL4, M3], and the nature of the substituents in the 6-position of 3.255
has a strong influence on the stereoselectivity of the reaction [HH5, HL4] (Figure
3.99). When the nitrogen atom is not at the ring junction, the reduction is often less
stereoselective [BB4, SM51.
Isoxazolidines, Isoxazolines, Oxazolines, and Oxazines Isoxazolidines,

easily obtained by cycloaddition of nitrones to olefins, are reduced to 1,3-amino
alcohols by reaction with LAH in ether media. The synthesis of racemic sedridine
from 3.256 is illustrative [TA2] (Figure 3.100).
Quaternary ammonium salts derived from isoxazolidines are also reduced by
LAH. Depending on the nature of the substituents, hydride attack takes place a to
the oxygen, as previously from 3.257, or a to the nitrogen from 3.258. One can then
obtain either a 1,3-amino alcohol [TA2] or a substituted hydroxylamine [LS3]
(Figure 3.100).
Isoxazolines 3.259 are obtained by cycloaddition of nitrile-oxides to olefins.
Their reduction by LAH in Et,O leads to 1,3-amino alcohols, the syn isomer gener-
ally being largely predominant [JS2, WPl]. This constitutes an interesting synthetic
method (Figure 3.100). When R is a latent carboxyl group such as p-anisyl or
a-furyl, a-hydroxy amino acids can be obtained in a highly stereoselective fashion
[JGl]. Such methodology can also be applied to the synthesis of amino sugars [JGl,
JM21. However, NaCNBH, in the presence of HCI reduces only the C=N bond and
converts the isoxazolines to the corresponding isoxazolidines [JB I], which can be
further reduced by LAH-NiCl, [G02]. In some cases, NaBH,-NiCI, in MeOH
gives better results than LAH [AC4]. 5,6-Dihydro-1,2-oxazines3.260 can be re-
duced by NaCNBH3 in AcOH into the corresponding tetrahydro-l,2-oxazines with a
good stereoselectivity [ZAl] (Figure 3.100). Other ethers give similar results. How-
ever, if the EtO group is replaced by Me,SiO, this latter group is removed under
these conditions.
The reduction of aryloxazolines 3.261 to 1,2-amino alcohols is carried out by
DIBAH in EtzO or in hexane at O°C [MHl], and is compatible with a halogen
substituent on the aromatic ring (Figure 3.101). Quaternarization of chiral ox-
azolines with MeOTf followed by treatment with NaBH, generates the correspond-
ing aldehydes [GM4]. 2-Aminosubstituted phenols can also be prepared by reduc-
tion of the oxazoline 3.262 by NaBH, in THF in the presence of AcOH [YL3]
(Figure 3.101). This method leaves the ester groups unchanged, while nitriles suffer
some reduction to amines. The N-oxides of chiral oxazoline 3.263 also suffer
reduction by NaBH, in MeOH to the saturated hydroxylamine [DBl] (Figure
3.101).
The stereoselective synthesis of 1,3-amino alcohols having three or four chiral
3.3 CARBON-NITROGENDOUBLE BONDS 135
mixture of stereoisomers 78 22
N-0 LAH-Et 2 0 NH2 OH

+ NH2 OH
3.259
major
72 - 87%
Eto QR
3.260
N-,AH
,* Eto
-
de 86 92%
Figure 3.100
centers can be carried out by LAH reduction of 1,3-oxazines 3.264 [BJ4] (Figure
3.101). However, NaBH, in THF-EtOH can only reduce the C=N bond of 3.265.
This leads to arninals, which are hydrolyzed under acidic conditions to aldehydes
[PHI] (Figure 3.101). The reduction of cyclic arninals is described in Section 3.3.1.
Pyridines, Quinolines, and Analogues Pyridines are not reduced by the

alumino- and borohydrides unless they carry electron-withdrawing groups at the 3-
and 5-positions. In this case, they are converted into the corresponding 14-dihy-
dropyridines by NaCNBH, in AcOH [GNl]; the use of NaBH, leads to mixtures
& _Nb o r n R 74 - 90%

NaBH4-m- ArcH2NH
3.262 AcOH, r.t.
Figure 3.101
(Figure 3.102). LAH in pyridine functions as a reducing agent [LLl]. l-Methyl-4-

phenyl-33-dihydro-2-pyridone 3.265a can be reduced by hydrides. Among them, Li
(s-Bu),BH in THF gives selectively the 3-unsaturated pyridone, while LAH-TiC1,
leads to the 4-unsaturated pyridine [MC4] (Figure 3.102).
Pyridinium quaternary salts 3.266 are, on the other hand, easily reduced by AlH,
or LAH in ether media, Red-A1 in C,H,, or alkaline borohydrides in alcoholic
media, leading to the 1,2,3,4-tetrahydro-N-alkylpyridines. If diastereoisomers can
be generated, the stereoselectivity is usually poor [DG2]. When the pyridinium salt
65%
2.
3 eq. LTBA
I
CO OCHzPh 4.4 eq. CuBr-THF COOCHzPh
3.267
X = Me, C1, COOMe
*
NaBH4-MeOH or LTBA-THF,
QX CICOOCHzPh I
COOCHlPh
X = Me, Et, MeO, MeS, C1, Br >95%
Figure 3.102
bears a substituent at the 3-position, one of the regioisomers is selectively formed

(Figure 3.102). Acylpyridinium salts are converted to mixtures by reaction with
NaBH, or NaCNBH,, or with LBTA or Red-Al-CuBr under standard conditions
[SS I]. A specific method provides the obtaining of N-acyl- 1A-dihydropyridines
3.267 with a high regioselectivity through the reaction with LTBA-CuBr in THE
Under these conditions, chlorides and esters remain intact [CAI] (Figure 3.102). It
is possible to reduce regioselectively some 3-alkylpyridines with NaBH, in MeOH
or LTBA in THF into N-carbamoyl-l,2-dihydropyridine 3.267a by performing the
addition of chloroformate esters at - 7 8 T to a mixture of the pyridine and the
reducing reagent. The regioselectivity is high provided that X is neither too bulky
nor an electron-withdrawing group [SH8] (Figure 3.102).
Quinolines and isoquinolines are more easily reduced than pyridines. Alumi-
nohydrides or BH,.THF in CF,COOH [MMl] leave them intact, but NaBH, or
NaCNBH, in AcOH [GNl], NaCNBH,-BF,.Et,O in refluxing MeOH [SR2], pyri-
dine-borane in AcOH [H3] and NaBH,-NiCl, in MeOH [GO21 reduce them to
tetrahydroquinolines or isoquinolines (Figure 3.103). With NaBH, in a hot organic
acid medium, one can carry out a subsequent N-alkylation as from 3.268 (Section
3.2.8) [GNl] (Figure 3.103). However, NaBH, in CF,COOH leads to mixtures. In
the presence of a ketone, it is possible to form an N-alkylated amine 3.269 by
reduction followed by reductive amination (Section 3.3.1) [GN I] (Figure 3.103).
The treatment of the nitroquinolines 3.270 by NaBH, in AcOH at 5OC leads to
the reduced compounds 3.271, the NO, functional group being retained [GNI]. On
heating, the corresponding N-ethylamine 3.272 (Section 3.2.8) [GNl] is obtained
(Figure 3.103). Quinoxalines and quinazolines 3.273 or acridine show the same kind
of reactivity: NaBH, in AcOH or CF,COOH in the cold leads to cyclic secondary
diamines, while in hot AcOH, the corresponding bis-N-ethylamines (Section 3.2.8)
[GNI] are obtained (Figure 3.103).
3.3.4 Oximes and Hydrazones: )C=NOH, )C=NNR,
Oximes are reduced to amines by LAH or SAH in THF or in Et,O [CB5, H3].
LAH-N-methylpyrrolidine or AlH3-Et3N complexes also reduce oximes to amines
[CB7, FSl]. Oximes are inert in the presence of LTBA or NaBH, (unless NiCl, in
MeOH is added to the latter) [GO21 (Figure 3.104), ion-exchange borohydride in the
presence of Ni(OAc), [BKIO], TiCl, in DME [KT2, ZHl], or ZrC1, in THF [ISI].
They also are inert towards diisopropoxytitanium tetrahydroborate [RC2]. When
using NaBH,-NiCl, in MeOH, a$-ethylenic oximes 3.274 are reduced to saturated
amines. In the presence of MOO,, the double bond is preserved [GO21 (Figure
3.104). The reduction by DIBAH induces some rearrangements [SM4], while, in
some cases, reductions b) LAH in Et,O or Red-A1 in C,H, can give mixtures of
primary and secondary amines, or even aziridines [GW1, M3, PP 1, ZH 1] (Figure
3.104). The stereoselectivity of the reduction of substituted cyclohexyloximes is
poor [ZHl]. However, some chiral oximes have been reduced with good stereo-
selectivity using NaCNBH,-TiCl, [ZHl].
The reduction of a-alkoxyoximes 3.275 by LAH or AlH, is also poorly stereo-
selective [IY2] (Figure 3.105).
Oximes are reduced to the corresponding hydroxylamines by BH,.THF, BH, in
CF,COOH, amine-boranes [KKl I], NaBH,, or NaCNBH, in AcOH in the cold.
On warming, NaBH, in organic acids leads to N-alkylhydroxylamines [GN1, MM 11
NIBHI-RCOOH, 500;
mN-CH2R
wN * a
3.268 R = H, Me, Et
NaBH4-AcOH-
Me2C0, 50°C 3.269 I
i-Pr
R = H, Me, Et
Figure 3.103
Ph$Me 72% + PhCHMe + PhNHCH2Me

NOH LAH-Et20-reflux I
NH2
77 23
Figure 3.104
(Figure 3.105). Heating in the presence of CF,COOH provides primary arnines

[GNl].
Ketoxime ethers are reduced under similar conditions to ketoximes. A high
stereoselectivity can be obtained when reducing syn P-hydroxyoxime ether 3.276 by
LAH in THF, while reduction of dnti isomer 3.277 requires the presence of MeONa
[LYl, NY1, ZHl] (Figure 3.106). Reduction of 3.278 with tetramethylammonium
triacetoxyborohydride in AcOH-MeCN also gives interesting stereoselectivities
towards syn a-hydroxy-N-benzyloxyamines,precursors of the syn 1,2-amino alco-
hols [WOI] (Figure 3.106). The reduction of chiral N-methoxy-a-sulfinyl ketoxime
3.279 by Li(s-Bu),BH is also highly stereoselective [MT7] (Figure 3.106). Other
reducing agents give lower yields.
Asymmetric reduction of ketoxime 0-alkylethers to chiral primary arnines can be
carried out with a high enantiomeric excess by borane or better by NaBH,-ZrCI, in
THF in the presence of a chiral amino alcohol [IS2, WM2, ZHI].
* +
LAH or AlH 3-
OMEM OMEM
Et20
NaBH4-CF3COOH-
*
Ph
k' Me
diglyme
Figure 3.105
Oxime esters 3.280 can be reduced to acyloxyamines by NaCNBH, in AcOH

[GNl, SJl] (Figure 3.106). On the other hand, BH3.THF or NaBH,-I, converts
oxime ethers to amines and to the corresponding alcohols [BC 11, H3]. NaCNBH3-
TiCI, in aqueous MeOH converts oximes into amines; this reduction is compatible
with ketones, esters, acetals, and isolated double bonds [LK2].
Moreover, a-oximinoesters can be reduced to a-amino acid esters by
NaCNBH3-TiCl, in aqueous MeOH in buffered conditions. Tartaric acid is the best
buffer, although no asymmetric induction is observed [HT3].
Hydrazones are reduced to hydrazines by LAH in ether, but some exceptions are
met [EKl], or by BH,.THF. Whereas dialkylhydrazones are resistant to reduction
with NaBH,, a-nitrohydrazones such as 3.281 are reduced extremely rapidly in
EtOH IDS31 (Figure 3.107).
The most interesting reduction is that of tosylhydrazones, due to the presence of
the leaving group, which, in a basic medium, converts the tosylhydrazine that is
formed into saturated hydrocarbons and nitrogen (Figure 3.107). This reduction can
be accomplished with NaBH, in EtOH [PSI], BH,-PhCOOH, BH3-CF,COOH in
THF [KB4, MMI] catecholborane [KB7], but, above all, by NaCNBH, in DMF in
the presence of acid or NaBH, in organic acid media [HNl, L1, MYl]. NaCNBH3-
ZnC1, in refluxing MeOH has also been used. Under these conditions, epimerization
,OCHzPh
N OH
NH2 OH
n-Buun-Bu 87% B.
LAH-THF n-Buun-Bu
3.276 de 90%
76 99% -
R ~ OH
' " ~ MeCN
~ ~ ( ~,BH-*COB
~ ~ )
OH
3'278 R = Me, i-Bu R'= Ph, Me de ,95%
3.279 de 90 - 94%
R = Me, Et, n-Pr, n-Bu, 4-MeOC6H4CH2,PhCHz
3.280
Figure 3,106
of the carbon cr to the tosylhydrazone moiety is avoided [SH5]. The reaction can be
run in "one-flask fashion starting from the ketone. This is a modification of the
Wolff-Kishner reaction that is compatible with ester and nitrile functional groups,
as shown in Figure 3.107 [ITl, Ll]. Indeed, while reduction of tosylhydrazone
3.282 with NaBH, in refluxing THF or MeOH promotes the transformation of the
ester groups into the corresponding alcohols, the use of NaBH, in AcOH leaves
them unchanged. When starting from tosylhydrazones derived from arylketones, the
transformation to hydrocarbons requires warming in the presence of base. The
limitation of the method is the migration of the double bond during the reduction of
tosylhydrazones of a-enones [Ll] (Figure 3.107).
Figure 3.107
3.284 -
de 86 94%
R = Me, Ph R'= Me, i-Pr, CH20CH2Ph
Figure 3.108
(Ph,P),CuBH, in hot CHC1, reduces tosylhydrazones of aldehydes or aliphatic

or alicyclic ketones to hydrocarbons [FH2], but leaves the tosylhydrazones of aro-
matic or a$-unsaturated ketones and aldehydes unperturbed. This method has been
applied to the selective reduction of the tosylhydrazone of a multifunctional al-
dehyde 3.283 [GL3], carrying an a-enone, an epoxide, and a lactone, all of which
remain unchanged (Figure 3.108). Pyridine-borane reduces tosylhydrazones to
tosylhydrazines, even in the aromatic series [KK8]. In the presence of base and with
heating, these tosylhydrazines can be converted to the corresponding hydrocarbons.
Hydrazonium ions can be reduced by various reducing agents. The reduction of
chiral substrates 3.284 is highly stereoselective, NaBH, in MeOH giving the best
chemical yields [SA3]. The asymmetric reduction of a benzodiazepine with borane
in the presence of (R)-or (S)-diphenylleucinol in CH,Cl, gives a good enantioselec-
tivity (86%) [LP2].
Chapter 4
Reduction of Triple Bonds
4.1 CARBON-CARBON TRIPLE BONDS: -CzC-
Carbon-carbon triple bonds undergo facile hydroboration [PS 1, HH 11 and hydro-

alumination [HHI, HH3, W 11 at room temperature. Therefore, boranes and DIBAH
are not used, except for special cases, in the selective reduction of other functional
groups. Alkynes can undergo selective monohydroboration by using relatively
bulky boranes such as Sia2BH or (c-C,H, ,),BH. The stereospecific cleavage of the
C-B bond of the resulting cis-alkenylboranes by an organic acid or by MeOH in
the presence of catalytic quantities of organic acid [BM3] is a frequently used
method for the synthesis of terminal or 1,2-disubstituted Z-alkenes. There are nu-
merous applications of these transformations in the synthesis of pheromones (Figure
4.1).
Reaction with LAH in THF or hot diglyme converts disubstituted alkynes to
trans-alkenes [DMl, H3, HHI] (Figure 4.1). However, at room temperature, iso-
lated triple bonds are not attacked by LAH, LTBA, AIH,, or Red-Al [HHl] or by the
alkaline borohydrides, except in the presence of Lewis acids, which induce the
formation of diborane. In the presence of transition metal salts (PdCl,, COX,, Nix,),
NaBH, in alcoholic media reduces alkynes to alkenes or to saturated hydrocarbons,
depending on the conditions [G02, SK3, W4].
Propargylic amines 4.1 and alcohols 4.2, 4.3, and 4.4 are reduced to allylic
amines and alcohols by LAH in ethers or by Red-Al in ether or toluene [HH 1, HH3,
JD2, MI]. With LAH, the reduction is stereoselective only if the solvent is basic
enough (THF or DME) [DJI, DM1, KJ2, Ml]. E-Isomers are obtained, and a
mechanism involving an intramolecular regioselective transfer of hydride is sup-
ported by trapping of the adduct by D,O (Figure 4.2). Although some authors have
pointed out that the reaction leads to allenes if R = H [HH3], propargylic alcohol
145
146 REDUCTION OF TRIPLE BONDS
RCZCH RCH=CH2
1- Sia2BH
2- MeOH, R"C0OH cat.
RC-R
1- SiazBH H H
2-AcOH or MeOH,
RTOOH cat.
Figure 4.1
RC=YHRt
NR"2
4.1
R e d 4 or LAH-THF
e
H"xH YHR'
NR'I2
RCXCHOHR'
4.2
Red-Al or LAH-THF
+ RxH
H CHOHR'
n-C4H9CWCH20H
I- LAH-THF n ' c 4DH 9 ~CHzOH
H
4.3 2- D20
HC=CCH20H +
1- LW4-THF, 0"
then 20°C
Me3si\=;\ CHOHMe
4.5 Me3Si CHOHMe

LAH in Et 20-solution Ld
Figure 4.2
4.1 CARBON-CARBON TRIPLE BONDS 147
R
Ri /
R4-C=C-C-R w
k I
OH
LAH
)~--CH=CH-C=CH LAH
w
Me OH
R = n-Pr, n-Bu, n-C5H11,MesSi

Figure 4.3
has been selectively reduced to the trans-dideuterated alcohol by precisely master-

ing the experimental conditions [BB2] (Figure 4.2). Starting from silyl derivatives
4.5, it is possible to obtain selectively the E- or Z-allylic alcohol [MH2] (Figure 4.2).
A suspension of LAH in Et20 gives a mixture of E- and Z-isomers. The reduction of
Me,SiC=CCH,OH follows the same trends, but is less stereoselective [KJ2] unless
it is performed with Red-A1 in ether-toluene [OCl].
The reduction of 4-aryl-3-butyn-1-01s 4.6 is stereoselective towards the E-a,@-
unsaturated alcohol only in Et,O. In THF, a mixture of E- and Z-isomers is formed
[KJ2] (Figure 4.3). The presence of a leaving group a' to the triple bond induces the
formation of a-allenic alcohols 4.7 [HH3] (Figure 4.3). An allenic alcohol is also
formed from conjugated allylic alcohol 4.8 (Figure 4.3).
I-Alkynylsulfides such as 4.9 are reduced to I-alkenylsulfides. Depending on the

reagent, E- or Z-isomers are formed: Li(MeO),AIH or LAH in THF lead to E-iso-
mers, while Li(MeO),AIH-CuBr gives 2-isomers [M3, NK2] (Figure 4.3). Chiral
a-acetylenic sulfoxides 4.10 are converted to E-a$-unsaturated analogues by
DIBAH or, better, by LAH in THF at low temperature [KKIO] (Figure 4.3).
4.2 a,P-ACETYLENE KETONES AND ESTERS:

RC=CCOY (Y = R', OR')
The alkoxyaluminohydrides or LAH modified by amines or aminoalcohols [GHI,

MI], DIBAH, and cyanoborohydrides in acid media [HK2] reduce the a-ynones to
propargylic alcohols. The use of chiral ligands can give high asymmetric induction
[GHI, MI, MS5] (Section 3.2.3). Asymmetric reduction of a-ynones to optically
active propargylic alcohols can also be carried out via acetals formed from chiral
1,3-diols (Section 2.4.3). The reduction of 4.11 shows that LTBA selectively re-
duces the ketone and leaves the triple bond untouched, in spite of the presence of the
alcoholic functional group [SAl] (Figure 4.4).
The selective reduction of the a,P-acetylenic ketones such as 4.12 to
a$-ethylenic ketones is accomplished by reaction with DIBAH in THF-HMPA
[TY2]. In the presence of a catalytic quantity of MeCu, the reduction is faster and
the stereoselectivity is modified (Figure 4.4). Nevertheless, the stereoselectivity is
never very high [TY2]. The reagent does not reduce the isolated triple bond of 4.13
(Figure 4.4).
MeCO MeCHOH
H
,,,,,Me
+
LTBA or LAH-THF
n-Bu +n-Buw COi-Pr

n-BuCWCOi-Pr >99% +
4.12 DIBAH-THF-HMPA, COi-Pr
0°C 79 21
94% + 40 60
DIBAH-THF-HMPA,
+ MeCu
MeC-"C(CH2)4CrCCOi-Pr P MeCW(CH2)4CH=CHCOi-Pr
DIBAH-M&u-
4.13 THF-HMPA, -50°C E-Z = 42-58
Figure 4.4
4.3 CARBON-NITROGEN TRIPLE BONDS 149
Me(CH2)4CH=CHCOOMe
Z +E mixture
82%
* PhCH=CH-COOMe
Red-Al-CuBr-THF- Z +E mixture
2-&OH
Figure 4.5
a,@-Acetylenic esters are reduced to E-allylic alcohols by LAH in Et,O [DMI]

(Figure 4.5). Reduction of these esters by DIBAH in THF-HMPA takes place only
if the alkyne contains HCEC residue such as 4.14; the adduct thus formed may then
be trapped by an allylic bromide [TYl] (Figure 4.5). Substituted a,@-acetylenic
esters 4.15 are reduced only in the presence of MeCu (Figure 4.5). They are also
reduced to a,@-ethylenicesters by Red-Al-CuBr in the presence of 2-butanol. In all
these cases, the reaction leads to a mixture of Z- and E-a,@-unsaturatedesters [SS I]
(Figure 4.5).
4.3 CARBON-NITROGEN TRIPLE BONDS: NITRILES RCsN
The reduction of nitriles occurs in two stages:
Formation of an imine, which can be hydrolyzed to an aldehyde;

Double reduction to an arnine.
Depending on the reagents and experimental conditions, either process may be

observed [C5, HH3] (Figure 4.6).
Nitriles are not reduced by LAH on SiO, [KH2], alkaline borohydrides in alcohol
media or in ethers at room temperature [BK5, PSI], (CF,COO),BH [MMl], cya-
noborohydrides [GNl, Ll], or diisopropoxytitanium tetrahydroborate [RC2]. Nev-
ertheless, the 2-cyano- or 4-cyanopyridines are reduced to amines by NaBH, in
EtOH under reflux [HH3, KK21.
1.0'
RCHO
Figure 4.6
A few reducing agents lead to the imines and, after hydrolysis, to the aldehydes.
Such is the case of trialkoxyaluminohydrides. Among these, Li(EtO),AlH in THF
proves to be the best, while LTBA is unreactive [BKS, C5, H3, M3] (Figure 4.7).
The intermediate RCH=NAl(OEt), can be trapped by Me,SiCI, and this leads to
N-trimethylsilylimines [AC2]. However, the initial configuration of nitriles that are
substituted at the a-position is not always retained. For example, starting with a pure
Z-nitrile 4.16, a mixture of stereoisomeric aldehydes is produced IPS21 (Figure 4.7).
Catecholalane, generated from catechol and allows the reduction of aromatic,
a$-unsaturated and aliphatic nitriles into the corresponding aldehydes in THF at r.t.
[CClO].
6 76%
as above
C
6
60%
).
70 30
Me as above
4.16
Figure 4.7
4.3 CARBON-NITROGEN TRIPLE BONDS 151
DIBAH
*
1.0.
RCH=N-Ali-Bu2
RCHO
PhCHzOCHzQCHO
Boc
%.-CHzCH21 *
DIBAH-THF,
4.16 -78 to +25"C
2- LDA-Et 20-HMPA,
-10°C
3- C5HlIBr, then H ~ O '
46% *
Me 1- LDA-THF
4.18 2- DIBAH or LAH-THF,
-78°C then AcOH
Figure 4.8
If employed in the cold and in stoichiometric quantities, DIBAH leads to the

iminoaluminate, which is hydrolyzed to aldehyde [K2, W1, YGl] (Figure 4.8).
Toluene or hexane are usually the best solvents for this transformation. The reaction
proceeds with aliphatic, aromatic, a,&unsaturated (see Section 4.4), or cyclo-
propane nitriles [HH3, WY 11 and is compatible with N-BOC groups [KN3] (Figure
4.8). The iminoaluminate thus formed can undergo an intramolecular alkylation, as
toluene
2- aq.NH4CIor MeOH
3- H2S04 IN
CHO
R(H p~t
0-c,H
RCHO -+ - CN
RqH ,OEt
0-c,H
Me
H.01
RCHOHCHO
Me
Figure 4.9
shown with compounds 4.16 [OBI] (Figure 4.8). The deprotonation at the a-position
of the iminoaluminate by reaction with LDA, followed by alkylation, allows access
to the branched aldehyde 4.17 [GTl] (Figure 4.8). As in the case of ketoesters,
selective reduction of the ketonitriles 4.18 in which the CN is located on a tertiary
carbon can be carried out provided that the ketone enolate is preformed [KF2]
(Figure 4.8). a-Trimethylsilyloxynitriles 4.19 (R = Me), easily obtained from ke-
tones, are transformed into the a-hydroxyaldehydes by DIBAH at 0°C followed by
subsequent hydrolysis of the imine and the silylether [HY 11. When starting from
aldehydes, t-butyldimethylsilyloxynitriles 4.19 (R, = t-BuMe,, R' = H) suffer the
same transformation at low temperature without racemization when chiral [HYI]
(Figure 4.9).
Starting from aldehydes, which are converted into cyanohydrins whose hydroxyl
group is protected as an acetal, one can also obtain a-hydroxyaldehydes by reaction
with Red-A1 or a-hydroxyamines via reduction by LAH [SB 11 (Figure 4.9).
The use of NaEt,AlH, in the presence of a Lewis acid for converting aliphatic
nitriles to aldehydes has also been described [YK2]. Sodium triaminoaluminohy-
drides or diethylpiperidinoaluminohydride reacts with aromatic nitriles in THF at
r.t., allowing their transformation into the corresponding aldehydes [CJl, YA21.
The reduction of nitriles to arnines can be carried out by LAH or SAH in an ether
medium, LAH-N-methylpyrrolidine complex, AlH, in Et,O or AlH,-Et,N [BKS,
CB5, CB7, E2, FS1, H3, L2, M3, MC1, MP2, PSI]. Li(MeO),AlH or Red-A1 at
80°C reduces aromatic nitriles, while aliphatic nitriles remain untouched [M3]. This
transformation can also be accomplished with BH,.THF or aminoboranes under
4.3 CARBON-NITROGEN TRIPLE BONDS
83% w CH2=CHCH2CH2NH2
AM3, 25OC
6
CHzNHz
COOMe
NaBH4-CF3COOH-
THF, 20°C
*
0 COOMe
*
NaBH4-CF3COOH-
THF, 20°C or
n-Bu4NBH4-CH2C12
reflux
Figure 4.10
warming or NaBH,-I, [BB7], Na or LiBH,-Me,SiCl in THF [GS2], NaBH,-

ZrC1, in THF [ISI], NaBH,-CoCl, in MeOH [G02, W4], NaBH, in CF,COOH-
THF [GNI], n-Bu,NBH, under reflux of CH,Cl, [WIl], or LiBH, in diglyme-hot
MeOH [S03], LiBH,-(MeO),B in Et,O at 25OC [BN3]. With the last reagent,
sulfones, sulfoxides, NO, groups, and pyridine rings remain unchanged. Therefore,
it is possible to perform a number of selective reductions [GNl, GO21 (Figure 4.10)
with NaBH,-CoCl, [PFl] or BH,.THF in the presence of NiCl, [LM2].
Trialkylborohydrides also reduce nitriles to amines [BK5]. An exception is Li
(s-Bu),BH, which leaves aliphatic and aromatic nitriles intact unless the latter are
para-s"bstituted by an electron-donating group [SMl]. An aldehyde is then obtained
(Figure 4.1 1). Whereas thexylborane and 9-BBN react slowly with nitriles [PSI],
thexylchloroborane reduces aliphatic nitriles into corresponding amines [BN5]. Sur-
prisingly, gem-dicyanoepoxides 4.20 are reduced to a-cyano a-epoxymethyl amines
by NaBH, in aqueous THF [MR4] (Figure 4.11). The reductions of chiral nitriles
such as 4.21 or 4.22 by LAH or AlH, take place without epimerization [CLI 1, RK2]
(Figure 4.1 1).
A C-CN bond cleavage has been observed in the reduction of 5-cyano-5-
isopropylsulfonylnorbom-2-ene with LAH in THF, likely via a SET process in the
propagation chain [MS lo].
4.4 a$-UNSATURATED NITRILES: RCH=CH-CN
a$-Ethylenic nitriles are reduced to a$-unsaturated aldehydes by DIBAH in

toluene at low temperature [K2, TK3] (Figure 4.12). The presence of an acetal group
that can coordinate to DIBAH decreases the extent of the reduction. But the addition
of a Lewis acid such as Et,AlCl solves this problem, and the formation of the
aldehyde from compound 4.23 is carried out in a satisfying yield [TT2] (Figure
4.12).
DIBAH-toluene,
-78°C
@ '""'Me OW); 73% @ """Me

1- DIBAH 1.5 eq.-
Me Et2AlCl 1.5 eq.- Me
Me Me
EtzO-toluene, -78
4.23
to 40°C
2- HCI-THF
~ C N
CHO
Meh N
4.24
NaBH,-CoC1, in MeOH also reduces a$-unsaturated nitriles without affecting

the double bond, but one obtains an a$-ethylenic amine [GO21 (Figure 4.12).
However, if the double bond is conjugated either to another double bond or to an
aldehyde such as 4.24, the totally reduced product is obtained [GO21 (Figure 4.12).
LAH reduces a,P-unsaturated nitriles to saturated amines [H3]. The formation of
an alcoholate in a suitable position, followed by an intramolecular hydride transfer,
allows the stereoselective reduction of an a$-unsaturated nitrile to the saturated
nitrile by reaction with LAH [LMl, LVl] or even with LiBH, in THF under reflux
[LV I] (Figure 4.13).
Reduction of a$-unsaturated nitriles to saturated nitriles is generally carried out
with Semmelhack's system [M3, SSl]. This involves reduction with Red-A1 in the
presence of CuBr in THF-hexane-2-BuOH, as shown in Figure 4.13 [OPI]. Alka-
line borohydrides in alcoholic media do not reduce the a,P-ethylenic nitriles. How-
ever, NaBH, in MeOH-pyridine under reflux [RB2] and NaBH, in EtOH do work
in some cases [KS6, UCI]. On the other hand, if the double bond is activated by
another electron-withdrawing group, reduction to the saturated compound takes
place [MC2, MR4]. If the experimental conditions are appropriate, the functional
groups remain unchanged (Figure 4.13).
156 REDUCTlON OF TRIPLE BONDS
Figure 4.13
The reduction of a,@-acetylenicnitriles to E-a,@-ethylenicnitriles by 0.5 equiva-

lents of LAH in Et,O under reflux [VK4] or NaBH, in EtOH [KS6] has been
described.
Chapter 5
Other Derivatives
5.1 NITRO AND NITROSO DERIVATIVES: RNO,, RNO
Nitro and nitroso compounds are among the most difficult to reduce using alumino-
and borohydrides.
LAH and SAH in an ether medium and Li(MeO),AlH reduce aromatic nitro and
nitroso derivatives to azo compounds, ArN=NAr, as does Red-A1 [CB5, CB7, FS1,
H3, M3]. When an excess of SAH is used, PhNHNHPh is obtained [CB5]. On the
other hand, nitro derivatives are untouched by AlH, in Et,O [BK5, E2] or by LAH
on SiO, [KH2]. Borohydrides and boranes leave nitro groups unchanged under the
usual conditions (ether or alcohol solvent) [L2, PSI, NM3, R3] or in acid media
[MM 11. However, 4-nitroimidazoles, nitropyrazoles, and nitropyridines are reduced
by NaBH4-NaOMe in MeOH [SW 11. The reduction of aliphatic nitro derivatives by
LAH or SAH gives amines [CB5, H3, M31, although some side reactions can be
observed when the reaction is performed with tertiary nitro compounds [WNI].
LiBH, in diglyme-MeOH under reflux allows the reduction of aliphatic and aro-
matic nitro derivatives to the corresponding amines [SO31 (Figure 5.1). In the
presence of transition metal derivatives (SnCl,, Cu(acac),, CuBrSMe,, CuSO,,
(Ph,P),Ni, NiCl,, Ni(OAc),, CoCl,, BiCl,), reduction of aromatic nitro derivatives
to amines by NaBH, takes place in ether, dioxane, or alcohols [DGl, G02, PVl,
RP3, W4, YC2, YL51. Under these conditions, halogen or acid groups remain
unchanged. In the presence of SnCl,, Cu(acac),, or Ni(OAc),, reduction can also be
compatible with ketone, ester, amide, and nitrile groups [C4, W4, YC2] (Figure 5.1).
Similarly, reduction of aromatic nitro compounds to amines by KBH4-Cu,Cl, in
MeOH is compatible with bromide and ester substituents, but iodides are reduced
[HZl]. The NaBH,-CuSO, system in alcoholic medium also reduces aliphatic nitro
compounds, but more slowly than aromatic ones [YL5]. Ketones are reduced faster
158 OTHER DERIVATIVES
Figure 5.1
than nitro groups, but esters and nitriles can remain untouched [YL5]. The bor-
ohydride exchange resin (BER)-Ni(OAc), reagent in MeOH rapidly reduces alipha-
tic nitro compounds at r.t. [YC2] (Figure 5.1).
Primary and secondary aliphatic or aromatic nitro derivatives can also be reduced
to amines by NaBH, in THF in the presence of palladium on charcoal [PBl]. The
reduction is compatible with ester and nitrile groups and also with chlorides, but aryl
bromides are reduced under these conditions (Figure 5.1 ).
5.1 NlTRO AND NlTROSO DERlVATlVES 159
R,
CHCOR"
R"
$ o q ~ e
NaBH4-EtOHaq.
+ +P;oM~
No2 O°C =
- NO2
5.2
RCH=CHN02 *
LAH or BH3-THF-
N&H4 cat.
Me0 kNo2OMe LAH-THF, 25OC
Figure 5.2
m
a$-Ethylenic nitro derivatives 5.1 are converted to saturated nitro compounds by

reaction with NaBH,, NaCNBH,, borohydride-ion-exchange-resin reagent in alco-
hol media or in THF-MeOH [GW3, VK31, or with Li(s-Bu),BH or LiEt,BH in
THF [MVl]. Treatment in an acid medium allows access to the corresponding
ketones (Figure 5.2). In the case of nitrostyrenes, polymeric products are also
obtained, but the formation of these byproducts is avoided if the reaction is carried
out on SiO, in CHC1,-i-PrOH [SB2]. The reduction can be stereoselective as shown
in the case of compound 5.2 [NS2] (Figure 5.2).
It is possible to trap in situ the carbanion formed during the reduction of
a$-ethylenic nitro derivatives by an acrylate; y-nitroesters 5.3 are thus obtained
(Figure 5.2). Reduction of the same compounds by LAH or BH,-THF in the pres-
ence of catalytic amounts of NaBH, leads, on the other hand, to saturated primary
amines or to saturated hydroxylamines [MV2, MV4, VK2J (Figure 5.2). Similarly,

LAH in THF [KS4] or NaBH,-Me,SiCl in THF [GS2] effects the reduction of an
a$-ethylenic aromatic nitro derivative to saturated amine (Figure 5.2). However,
reduction of conjugated nitroalkenes with Zn(BH,), in DME can lead either to
saturated nitro derivatives or to saturated oximes depending upon the substituents
[W.
5.2 AZIDES: RN,, ArN,
The RN, and ArN, derivatives are reduced to amines by LAH in ether media [Sl].
NaBH, in alcohol or in THF reduces azides with difficulty, except for certain
sugars [S I] and for ArOSO,N,, which gives sulfoxamides ArOS02NH2 [HGI].
(i-PrO),TiBH, leaves azides untouched [RC2]. Nevertheless, under phase-transfer
conditions, reduction of the aryl azides by NaBH, takes place at room temperature,
and alkyl azides are reduced at 80°C [Rl] (Figure 5.3). These reductions can be
carried out with borohydride supported on an ion-exchange resin or by Zn(BH,), in
DME under sonication [KW2, RSl]. In a similar fashion, arylsulfonylazides are
converted into arylsulfonamides [KW2, R S l j (Figure 5.3).
Zn(BH4)2-DME,sonication
ArS02N3 * ArS02NH2
BER- or Zn(BH4)2-DME
Figure 5.3
5.3 ORGANOMETALLICS 161
NaBH, in THF under reflux in the presence of MeOH also reduces the primary
aliphatic or aromatic azides to amines. The reduction is compatible with C1 and NO,
substituents on the aromatic ring, which remain unchanged [SY3]. Aliphatic sec-
ondary azides are not reduced under these conditions. Aminoborohydrides [AFl,
FF2] and borohydride-exchange resin-Ni(OAc), [YC3] reduce primary and sec-
ondary azides and aromatic azides in high yields. The latter reagent is compatible
with chlorides and esters (Figure 5.3). Dichloroborane reduces all azides to amines,
leaving bromides, nitro groups, esters, and nitriles untouched [SB3] (Figure 5.3).
Aroylazides when substituted by an electron-donating group are transformed by
NaBH,-CF, COOH into trifluoroethylanilines [KS7].
5.3 ORGANOMETALLICS
Reduction by hydrides of two types of organometallic compounds has received

some synthetic applications; so only these cases will be discussed.
5.3.1 Organomercurials: RHgX

Solvomercuration reactions of unsaturated compounds have been the topic of many
studies. Organomercurials thus formed, when treated by alkali borohydrides in
alcoholic media or better in PTC conditions [BEI] or by LAH in ether, are reduced
to saturated functionalized compounds [R2, W5] (Figure 5.4). The proposed mecha-
nism for the reduction involves the formation of an intermediate mercury hydride
5.4, which undergoes homolytic cleavage and starts a chain reaction (Figure 5.4).
Recently, alkylmercury hydrides 5.4 have been prepared from RHgCl and LAH or
NaBH, [BG6]. The mercury hydride formed during reductions can be trapped by
a$-unsaturated compounds [BG6, G2, RL2] in an intra- or intermolecular fashion
(Figure 5.4). Alkylmercurials can also be generated from cyclopropanes. These
reductions are compatible with P(O)(OEt),, COOEt CN, SO,Ph, and SiPh, groups
[RJl, RL21. Vinylmercurials can be reduced to alkenes, but a mixture of Z- and
E-isomers is obtained [RJl].
Aminomercuration leads to substituted organomercurials 5.5, which also suffer
demercuration with sodium borohydride, preferentially under PTC conditions [BE 1,
EB4] (Figure 5.5). The mechanism proposed for this reduction in protic solvents is
an ionic one, implying the intermediate formation of aziridinium salt [L3]. This
method has been applied to the synthesis of cyclic amines from a#-ethylenic
precursors 5.6 [EB4] (Figure 5.5). When the reduction in run in alcohol or water,
mixtures of five- and six-membered cyclic arnines are obtained from each precursor
5.6 (n = 1 or 2).
5.3.2 Palladium Complexes

Complexes of IT-allylpalladium formed by reaction with Pd(0) complexes with
allylic derivatives (acetates, ethers, thioethers, and sulfones) can be reduced in a
Figure 5.4
R-
NRR'
M
,'R 'R'
Figure 5.5
5.3 ORGANOMETALLICS 163
MeOCO MeOCO
'0 1
OAc
1- Pd(0)
2- NaBD4
Lr
2- L&~BH-THF
X = OPh 97
OMe 94
SPh 94
S02Ph 86
OSiMezt-Bu 98
90%
RNHCOOCH2CH=CH2 C
as above
5.8
Figure 5.6
regio- and stereoselective fashion by NaBH, or LiEt,BH in THF to the correspond-

ing internal alkene derivatives, as shown in Figure 5.6 [HLI, KR1, MEI, TM31.
Reductions in which X is a different group can be less selective (Figure 5.6), as can
reactions performed with LAH or NaCNBH, [HLI, TM31. The method preserves
the isolated double bonds (Figure 5.6). On the other hand, reduction of these T-ally1
complexes by ammonium formate gives terminal olefins [TM3]. An interesting
application is the Pd(0)-catalyzed deprotection of ally1 aryl ethers 5.7 and carba-
. .-
I THF-i-PrOH selectivity 92%
selectivity 80%
COOMe (Ph3P),Pd
5.11 NaCNBH3
Figure 5.7
mates 5.8 [BBIO, BN7], which are, respectively, transformed into propene and
phenols or amines (Figure 5.6). This methodology is compatible with NO, groups,
acids, nitriles, and arnides. When performing the reaction in the presence of BOC
anhydride, protected amines such as 5.9 are formed (Figure 5.6). Peptide coupling
can also be realized under these conditions [BN7].
Allylic nitro derivatives such as 5.10 can also suffer similar reductions via n-ally1
complexes (TM31 (Figure 5.7). Tertiary allylic atnines such as 5.11 can be trans-
formed into secondary amines via n-allylpalladium complexes that are reduced with
NaCNBH, [TM3] (Figure 5.7).
Terminal propargylic bromides 5.12, mesylates, and phosphates are also trans-
formed into palladium complexes that are hydrogenolyzed to allenes with a high
regioselectivity. LiEt,BH is the best reagent for this reaction [MT3] (Figure 5.7).
However, 1,2-disubstituted alkynes lead to mixtures [MT3].
5.4 SULFIDES, THIOETHERS, SULFOXIDES, SULFONES,

AND AMINE-OXIDES: RSR', RSOR', OR RSO,R1
Sulfoxides and sulfones are reduced to sulfides by LAH or AlH, in an ether medium
(H3, HL51, LAH-TiCl, in THF [ A M ] , NaBH,-Me3SiC1 in THF [GS2], and
DIBAH [HL5]. Sulfamides are reduced to amines by Red-A1 in refluxing toluene
[GB9, RG31. SAH, LAH, and AlH, reduce disulfides to thiols [BYl, CB5, CB7, H3,
5.4 SULFIDES, THIOETHERS, SULFOXIDES, SULFONES, AND AMINE-OXIDES 165
RSOR'
-
87 96%
NaBH4-EtOH-Fe3+,
- RSR'
-
co2% ~ i ~ + s a l t s
RSOR' * RS+(OM~)R' RSR'

NaCNBH3-MeOH,
0°C
R. ,SR"
C RCH2R'
R' 'SF NaBH4-Ni2+ salts
5.14
5.15
/-7
/Me
0 N-0
w
5.16
Figure 5.8
M41, as do DIBAH in hot toluene [H3, M3, M4, YGl], nickelocene-LAH, and
NiC1,-PPh,-LAH [CC2]. Diary1 or dialkyldisulfides are converted to thiols by
LTBA in THF at room temperature [KA3, M3]. This reduction is faster with diary1
compounds such as 5.13 and is compatible with MeO, C1, and CN substituents
(Figure 5.8). In the presence of copper salts, desulfurization takes place upon heat-
ing, and the corresponding hydrocarbons are obtained [GO21 (Figure 5.8). Total
reduction also takes place in the presence of NiC1,-PPh, [HL2] (Figure 5.8).
Sulfones and sulfoxides are not affected by borohydrides in alcohol media [RJI]
except in the presence of transition metal salts such as FeCI,, CoCI,, or TiCI, [CH3,
G02, KT2, LZ1, W4] (Figure 5.8). The sulfides obtained are not reduced under
these conditions but are desulfurized in the presence of the Ni2+ salts [G02].
Another possibility is to treat the sulfoxides with NaCNBH, in MeOH. This reduc-
tion takes place via the sulfoxonium salt [PSI] (Figure 5.8).
Reductive desulfurization of the dithioketals 5.14 and 5.15 is performed under
the same conditions as for thioethers [G02]: LAH in the presence of copper salts or
borohydrides in the presence of nickel salts (Figure 5.8). The deoxygenation of
tertiary amine-oxides such as 5.16 and 5.17 can be performed with borohydride
exchange resin-copper sulfate in methanol at room temperature or under reflux.
This reaction tolerates other functional groups such as carbon-carbon double bonds,
chlorides, epoxides, esters, amides, nitriles, sulfoxides, and sulfones [SA4] (Figure
5.8).
5.5 PHOSPHINE OXIDES AND PHOSPHATES:

R3P0 AND ROP(OR'),
Phosphine oxides remain untouched by LAH [NW2] or borohydrides [EWl, HJ51.

They are reduced to corresponding phosphines by LAH-CeCI, in THF [GO21 or in
a few cases by LAH in hot THF [TA4] (Figure 5.9). Phosphates are cleaved by LAH
in THF to corresponding alcohols [JFI], while en01 phosphates 5.18 are converted
into carbonyl compounds. However, by using LAH-CuBr, or DIBAH [IK3], it is
\
-Si-X
/ LAH-AH3 or DIBAH * 3si-H
X = F, C1, Br, I, OR, SR
Figure 5.9
5.7 BORON DERIVATIVES 167
possible in some cases to generate the corresponding aluminum enolates 5.19 (Fig-
ure 5.9). These enolates can suffer in situ condensation with aldehydes [IK3] (Figure
5.9).
5.6 SlLYL DERIVATIVES: R,SiX
The silicon-halogen, silicon-oxygen, and silicon-sulfur bonds of the halogenosil-

anes, silyl ethers, and silyl thioethers are cleaved by reaction with LAH, AlH,, or
DIBAH, and the corresponding silyl hydrides are obtained [CGl, CG21. Ultrasound
activation can be applied (LC21 (Figure 5.9). Anionic pentacoordinated silicon
compounds are reduced to hydrogenosilanes by LAH or DIBAH [BC6].
A study focusing on the stereochemistry of reduction has been carried out on
molecules chiral at silicon. Depending on the Lewis acid character of the reducing
agent and the nature of the X group, one observes more or less retention or inversion
of configuration at the silicon atom. For a given leaving group, the amount of
retention increases as the Lewis acid character of the reducing reagent increases:
DIBAH in hexane > DIBAH in Et20 > DIBAH in THF > AlH, in Et20 >
LAH in Et,O > LAH in THF > LAH in THF-(2.1.11
For a given reducing agent, the degree of retention of configuration becomes

higher as the X group becomes harder: RO > F, RS > C1,Br. A theoretical inter-
pretation of these results has been suggested [CGl, CG21.
5.7 BORON DERIVATIVES
B-Cl and B-Br bonds are converted to B-H bonds by LAH in stoichiometric
amounts or by K(i-PrO),BH (BC3, DK41. LAH also converts boronates RB(OR1),
into ate complexes Li+RBH,-, which are cleaved to give the corresponding al-
kylboranes by Me,SiCl [BJ51. If the R alkyl group is chiral, its configuration is
retained, opening a route to asymmetric hydroboration reactions [S3].
Synoptic Tables
170 SYNOPTIC TABLES
Products Substrates Section Reagents
\
Alcohols -y2-OH
H
R~HOHR' cyclic 1,2-diol sulfates 52.2 NaBH,; NaCNBH,
52.3 IAH; IAH.R,N;

AIH,; AIH,.Et,N; DIBAH
H OH R' 0 R"' NaCNBH,-BF,;
LiBH,-BEt,; BH3-BF,;
LiEt,BH; Li 9-BBNH
Zn(BH4)2-Si0,
R' -++
R
H
R"
OH
CHOHR"'
Red-Al; IAH; DIBAH
LiBH,-Ti salt
R R" R' 0 CHOHR"'
ROH IAH; LiAI(OR),.,H,;

MBH,; DIBAH
AIH,; BH,.THF;
NaCNBH,-BF,
AIH,
RCHO IAH: LiAI(OR),.,H,; SAH;

AIH,; Red-Al; MR,BH;
BH3.R3N, THF or Me,S
arninoborohydrides; MBH,;
MCNBH,-acid; M(AcO),BH;
(Ph,P),CuBH,-acid
NaBH,-alcohols; I A H
MCNBH,-acid; AIH,;
DIBAH; Red-Al; BHM
; eS
,
RCOSEt rrBu,NBH, under heating
RCOOR' or lactones IAH; IAH.R,N; SAH;

AIH,; DIBAH-rrBuLi;
LiBH, under heating;
LiR,BH; NaBH,-MeOH or
other additives; BH3.Me2S
under heating; 9-BBN and
ThexBHCl under heating;
Li 9-BBNH; Ca(BH,),
RCH=CHCH,OH RCH=CHCOOR' 53.2.9 DIBAH; IAH-Et,O;

AIH,; DIBAH-rrBuLi
(continued)
SYNOPTIC TABLES 171

RCH=CHCH,OH
RCHOHCHOHR' RCH -CHR' 52.4.4 IAH; NaBH,;

I I BH,Me,S
0\o/O
53.2.9 IAH-THF
RCOOH or (RCO),O 53.2.6 IAH; SAH; AIH,; Red-AI

(under heating); LiBH,-hot
MeOH; BH,.THF or NR,;
NaBH,-ZnCI, or TiCI,;
(kPrO),TiBH,; in situ gener-
ated borane
53.2.6 NaBH,
33.2.6
33.2.7 IAH; SAH; AIH,; DIBAH;

(kPrO),TiBH,; MBH,;
9-BBN; aminoborohydrides;
Zn(BH4)2
RCH,OH RCONR; 33.2.8 LiR,BH; 9-BBN; Sia2BH;

LiBH4-hot MeOH; Li pyrro-
lidinoborohydride
RCHOHR' RCOR' 53.2.1 IAH; LAi I(OR),H,;

33.2.2 AIH,; Red-Al;
(stereo- MBH,; BH,.THF,
selectivity) RN
, or Me$; MR,BH;
53.2.3 MCNBH,-acid;
(asymmetric NaBH,-CeCI,-MeOH
reductions)
33.2.9 IAH-Et20; AIH,;

53.2.3 DIBAH; DIBAH-nBuLi;
(asymmetric LiAI(OMe),H; Red-A1 in
reductions) benzene; NaCNBH,-ZnCI,;
BH,.Me2S; 9-BBN;
NaBH,-CeCI,-MeOH;
(kPrO),TiBH,; Li amino-
borohydrides; Zn(BH,),
33.2.3 IAH; LA
i I(OR),H,;
(asymmetric DIBAH; MCNBH,-acid;
reductions) IAH + ligand
9.2
(continued)
172 SYNOPTIC TABLES
I
RCHOHCO OR' 53.2.2 BH,-t-BuNH,; DIBAH;
53.2.4 tiAI(E$CO),H; M-S-Bu,BH;
NR; (stereo- Red-Al; LAH; Zn(BH,),;
selectivity) NaBH,-CaCI,; LiEt,BH;
RCHOHCHCO I OR' LiBH,-LiBr
R R 53.2.2 Zn(BH,),; MBH,;

NaBH,-CeCI, or
t7\
0 CHOHR'
'Yn
0 COR'
53.2.4
(stereo- CaCI,
selectivity)
R'CHCHOHR" R'CHCOR" 53.2.4 Zn(BH,),; LAH; Red-Al;

I I (stereo- LTBA; DIBAH; Ms-Bu,BH;
(H0)RO (H0)RO
selectivity) BR, or MeOBR,-Na or
LiBH,; catecholborane;
R'CHCHCHOHR" R'CHCHCOR"
I I I I TIC\,-Et,NCNBH,;
(H0)RO R"' (H0)RO R'" R,NB(OAc),H
RCHOHCHCHOHR' RCOCHCOR' 53.2.4 LTBA; LTBA-TiCI,;

I I (stereo- NaBH,-CeCI,;
R" R"
selectivity) LiEt,BH
53.2.4
(stereo-
selectivity)
53.2.4 DIBAH; DIBAH-ZnCI,; LAH

(stereo-
selectivity)
53.2.4
(stereo-
selectivity)
R'CHCHOHR" R'CHCOR" 53.2.4 LAH; LAH-TiCI,; LTBA;

I I (stereo- DIBAH-ZnCI,; MBH,
R2N '38 selectivity)
R'CHCHCHOHR" R'CHCHCOR"
I I I I
RN
, R'" RN
, R"'
RCHCH,OH RCCOOR' 53.3.1 LAH

I I\
"4% NSiMe,
RCHCH,OH R~HCOOH 53.2.6 in situ generated borane

I I
NH, NH,
R~HCH,OH RCHCOOH 53.2.6 in situ generated borane

I I
NHEt NHCOMe
R~HCH,OH R~HCOOH 53.2.6 in situ generated borane;

I I (CPrO),TIBH,
NMBOC NHBOC
SYNOPTIC TABLES 173
RCHCHOHAr RCCHOHAr 93.3.1 Zn(BH4),

I I1 (stereo-
NHR' NR'
selectivity)
R'CHCH,CHOHR" R'
I
NHR 93.3.3 LAH; LAH-NiCI,
ALDEHYDES RCHO
RCHO RCOOPh 93.2.5 LTBA
RCHO RCOOEt 93.2.5 DIBAH; Na(Et,N),AIH;

piperazinoalurninohydride
RCHO RCOSEt 93.2.5 DIBAH
RCH=CHCHO RCH=CHCOOU 93.2.5
RCHO RCOOH 53.2.6 piperazinoalurninohydride;

ThexBHCl
RCHO LTBA; DIBAH;

NaBH,-CdCI,-DMF;
(Ph,P),CuBH,;
(Ph,P),CuCNBH,
RCHO R C O N ~RCON
, 93.2.8 LAH; Red-Al
/OMe
RCHO RCON 53.2.8 LAH; DIBAH
h e
DIBAH
RCHO RCONR; 93.2.8 LTEA; SAH; DIBAH-

n-BuLi; LiR,BH
(continued)
174 SYNOPTIC TABLES

RCHO RCN 94.3 LTEA; DIBAH; Na amino-
aluminohydride; NaEt2AIH,-
Lewis acid; catecholborane
RR'R"CCH0 RR'CHCN 54.3 DIBAH-LDA-R"X
RCH=CHCHO RCH=CHCN 94.4 DlBAH
AMINES (Amlno Alcohols: e m Alcohole) Primary: R-NH,
RCH2NH2 RCONH, 93.2.8 IAH; AIH,; Red-Al;

BH,.THF; NaBH,-liCI,;
LiBH,-cliglyrne-MeOH;
in situ generated borane
SAH; IAH; NaBH,-NiCI,,

liCI,, or ZrCI,; AIH,.Et,N;
NaBH,-CF,COOH-cli-
glyme (under heating);
NaCNBH,-liCI, or liCI,
RCHNH, %=NOH 53.3.4

I I
COOR' COOR'
RCH=CH-CR' 93.3.4
II
NOH
RCN 94.3 SAH; IAH; AIH,; BH,;

NaBH,-CoCI,; NaBH,-
acid; in situ generated bo-
rane; Red-Al (under heating);
LiBH,-cliglyme-MeOH;
LiEt,BH
IAH
RCHCOOR' RC-COOR' 93.3.1

I II
NH, NSiMe,
IAH: Red-Al
93.3.4 IAH
(stereo-
selectivity)
RCHCHOHR'
I
NHOCH,Ph
(continued)
SYNOPTIC TABLES 175

RNO, 55.1 LiBH,-diglymehot MeOH;
MBH4-transition metal salt
or Pd-C
ArCH,CH,NH, ArCH=CHNO, 55.1 LAH; BH,; CI,BH

RNH, 55.2 LAH; NaBH,-THF-

hot MeOH; NaBH4-PTC;
aminoborohydrides;
Zn(BH,),
Secondary end Tertiary: RNHR' end RNR'R"
RCONR'R" 53.2.8 LAH; AIH,; Red-Al;

DIBAH; LiBH, (under
heating); MBH4-hot acid;
BH,.THF; NaBH,-T,CI,;
RCH=CHCONR'R" 53.2.8 DIBAH; AIH,

53.2.9
$3.3.1 NaBH,-ZrCI,; LAH

(stereo- MBH4-CoCI, or NiCI,
selectivity) Red-Al; MBH4-MeOH;
MR,BH; BH,; MCNBH,;
LiEt,NBH,
RCH=CHNR'R" 53.3.2 AIH,; MBH,-acid;

MCNBH,-acid;
BH,-acid
+
RCHO HNR'R" 53.3.1 MCNBH,; NaBH4-
(reductive amination) acid; Na(AcO),BH;
NaBH, or NaCNBH, +
E(0-LPr),
RNH, 53.2.8 NaBH4-acid
RN(R')COOR" 53.2.8 LAH; NaBH,-acid
RR'C(CN)(NR?, 53.3.1 NaBH4-MeOH; LAH;

Zn(BH,),; AIH,
54.1 LAH; Red-Al
RR'R"N+Me, X- $1.5 LAH; LiEt,BH

(continued)
176 SYNOPTIC TABLES
NITROGEN HETEROCYCLES: see 53.3.3 and 3.2.8
UNSATURATED DERIVATIVES or RC=CH or ArH
LAH; NaBH4-transition
metal salt; LAH + CeCI,
LAH (under heating)
M"
R
LAH, Red-A1
H CHOHR'
LAH; Red-A1
H CHR"
I
NR;
9.2 LAH
54.2 DIBAH-MeCu;
DIBAH-HMPA if R = H
HC=CCOOR 54.2 DIBAH + R'X
RC=CCN 9.3 LAH; NaBH4-MeOH
RC=CS(O)R' 54.1 DIBAH; LAH-THF
RC=CSR' 54.1 LAH; Li(MeO),AIH

with or without CuBr
R
/ 55.3 Pd(0)-LiEt,BH
HC--CCH
'~r
(continued)
SYNOPTIC TABLES in

Red-Al; LAH-CeCI,
Red-Al; LAH; NaBH,-

transition metal salt;
NaBH,-DMF-hv
NaBH4-DMF (X = Br)
Red-Al; LAH
LAH
LAH
I
SATURATED DERIVATIVES:
-7-"
RCH, or RCH,R' RCH,Cl or RR'CHCI 52.1 DIBAH-n-BuLi; LAH;
Red-At; LiEt,BH;
NaCNBH,; LAH-CeCI,
RCH, or RCH,R' LAH; LiBH,; LiEt,BH

DIBAH; NaBH4-hot DMSO
RCH, or RCH,R' LAH; Red-Al; LTBA;

NaBH4-hot DMSO or
DME; LiEt,BH; NaCNBH,
RCH, or RCH,R' RCH,t or RR'CHI 52.1 n-Bu4NCNBH3;LAH;

LiR,NBH,; Red-Al; LTBA;
LiEt,BH; NaCNBH,
n-Bu,NCNBH,; LAH
NaBH,-alcohols; Zn(BH,),;
NaBH,-CuCI,; NaCNBH,-
Znl, or SnCI,; 9-BBN.n-BuLi
LAH; AIH,
ArCH, ArCH,N+Me,, X- 52.5 NaCNBH,

(continued)
178 SYNOPTIC TABLES
R q R '
OR or OCOR
LAH; Red-Al;
NaBH,-alcohols
LAH
NaBH,-acid; AIH,;
NaBH,-AICI,; MBH4-
Ni(OAc),; NaBH,-Znl,;
NaBH,-PdCI,; NaCNBH,-
acid; f-BuNH,+3H3-AICI,
NaBH,-RCOOH or MeOH;
BH,-RCOOH; NaCNBH,-
RCOOH or ZnCI,;
(Ph,P), CuBH, in a few
cases; catecholborane
NaBH,-transition metal salt
Red-Al-CuBr; DIBAH-MeCu;
Li and K s-Bu,BH; LTBA;
LAH-nickelocene;
R,NBH,(resin); (Ph,PCuH),
Red-Al-CuBr: DIBAH-MeCu;
LiAI(OMe),H-CuBr; R,NBH,
(resin); NaBH,-Cu,CI,
Li and K s-Bu,BH; LTBA;

catecholborane-Rhcomplex
NaBH,-Co,CI, semicorrin
SYNOPTIC TABLES 179

I A H in a few cases: Red-Al-
CN
RCH<
COR' or COOR'
CN
RCH<
COR" or COOR'
NaBH,-alcohol; NaCNBH3-
alcohol; LiEt,BH
RSH or RSSR IAH-Cu2+ salts;

MBH,-Ni salts
RHgX NaBH,; NaB(OMe),H

MBH,-PTC
ETHERS
IAH-TiCI,; DIBAH under

R heating; AIH,; BH,; AIBr2H;
\
R'- COW AICI,H; CIBH,.Me,S;
/ NaBH, or NaCNBH,-acid
H
or TiCI,; Zn(BH,),-Me,SiCI
or TiCI,
HYDROXYLAMINES: RNHOH
RCH=NOH 52.3.4 BH,; NaBH,-RCOOk;

NaCNBH,-FiCOOH:
aminoboranes
IAH
HYDRAZINES
RCH=NNHRf 53.3.4 IAH; BH,
RCH=NNHTs 53.3.4 BH,-pyridine
MINES
RCN 54.3 Li(OEt),AIH, then

Me3SiCI
DIBAH-THF
(continued)
180 SYNOPTIC TABLES

LACTOLS, LACTONES; LACTAMS
DIBAH
LAH in calc. amount;

LiBH,; NaBH4-THF-
MeOH or DMF;
MR,BH; DIBAH-mBuLi
NaBH4-acid; DIBAH;
NaBH,-CeCI,
Red-Al
PHENOLS
DIBAH; LiE$BH
ArOH ArOCH,CH=CH, 55.3.2 Pd(0)-NaBH,

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Index
Acetals, 30-34 Aluminum chloro- and bromohydrides, 4

dioxolanes and dioxanes, 3 1-34 Aluminum chloro- and bromohydrides in the re-
regio- and stereoselective reductions of, 32-34 duction of
THP ethers, 3 I acetals, 31 -33
Acid chlorides, 98-99 ketones, 44
Acylboranes, 6 lactarns, 107-109
Acylboranes in the reduction of oxetanes, 27
alcohols, 27 Aluminum hydride, 4
aldehydes, 39 Aluminum hydride in the reduction of
halides, tertiary, 18 acetals, 3 1
imines and iminium salts, 122 acid anhydrides, 92
indoles, 130- 132 acid chlorides, 99
ketones, 39 alcohols, benzyl, 28
propargyl alcohols cobalt complexes, 28 aldehydes, 39
quinolines and isoquinolines, 138 aldehydes, a$-unsaturated, I I I
tosylhydrazones, 141 amides, 104
Acylpyridinium salts, 137-138 amides, a$-unsaturated, 119, 121
Adamantanones, 55 aminals, 127, 129
Alcohols, 27-29 carboxylic acids, 92, 97-98
ally], 27-28 disulfides, 164
benzyl, 27-28 enamines, 50
ferrocenyl, 28 epoxides, 22-23
tertiary, 28-29 esters, 86
Aldehydes, 37-43, 144 fluorides, 15
aryl, 40 halides, 15
asymmetric reductions of, 56, 58-59 ketones, 39-40
chemoselective reductions of, 42, 44 ketones (stereoselectivity), 54
Aldehydes, a,&msaturated, 110-1 15 ketones, aryl, 40
asymmetric reductions of, 58 ketones, a$-unsaturated, I I I
electrophilic assistance in the reduction of, lactams, 106-1 09
110-111 nitriles, 152- 154
regioselective reductions of, 110- 1 15 oxetanes, 27
216 INDEX
Aluminum hydride in the reduction of 9-Borabicyclo[3.3.1]nonanein the reduction of

(Continued) acid chlorides, 99
oximes, 138, 140 aldehydes, 39
pyridiniurn salts, 136 aldehydes, a,P-unsaturated, 1 12
silyl derikatives, 166- 167 amides, 100
sulfones and sulfoxides, 164 esters, 91
Amides, 99- 1 10 ketones, 39
acylaziridines, 100- 101 ketones (stereoseIect~vity),54
acylimidazoles, 100-101 ketones, a$-unsaturated, 1 12
acyloxazolidinones and -thiazolidinthiones, sulfilimines, 125, I28
103-104 Borane, 10
chiral amides and sultams, 100- 104, 121 - 122 Borane as co-reagent in asymmetric reductions,
N-methoxyamides, 100- 101 59
Amides and lactarns, a,P-unsaturated, 104-105, Borane in the reduction of
119-121 acetals, 31
Amineboranes, 1 1 acid chlorides, 99
Amineboranes in the reduction of aldehydes, 39-42
acid anhydrides, 97 aldehydes, a$-unsaturated, 1 12
aldehydes, 39, 42 amides, 104- 105
carboxylic acids, 97 carboxylic acids, 20, 95-97
enamines (stereoselectivity), 130- 131 epoxides, 22-24
esters, 91 esters, 91
gem-diesters, a$-unsaturated, 1 19- 120 hydrazones, 141
imines and iminium salts, 122 hydroxyesters, 90-91
indoles, 13 1-132 hydroxyketones (stereoselectivity), 71
ketones, 39-43 imines and iminium salts, 122
ketones (stereoselectivity), 54 ketoboronates (stereoselect~vity),82, 84
ketones, a$-unsaluraLed, competition with ketones, 39-40
saturated ketones, 115 ketones, a$-unsaturated, 112
n~triles,152 lactarns, 106- 108
oximes, 138 nitriles, 152- I53
tosylhydrazones, 144 nitro derivatives, a$-unsaturated, 159
Amine-oxides, 166 organomercurials, 161
Amino acids and derivatives, 85-88, 94, 96, 98, oximes and derivatives, 138, 141
100-101, 123, 125, 134, 141 ozonides, 34
Aminonitriles, 126 sulfonamides, 104
Ammonium salts, 34-35 tosylhydrazones, 141
Anhydrides, 92-98 Boron derivatives, 167
asymmetric reductions of, 93
mixed carboxylic-carbonic, 94, 97-98 Calcium borohydride, 7
regioselective reductions of, 93-94 Calcium borohydride in the reduction of
Asymmetric reductions of epoxyketones, 67-68
anhydrides (meso), 93 esters, 88-89
benzodiazepine, 144 ketoesters, 70, 82
esters, a$-unsaturated, 121 Carbon-carbon double bonds
imides (meso), 109 conjugated to C=O bonds, 1 1 1 - 122
imines, 125, 128 non-conjugated, 37-38
ketones, saturated and a$-unsaturated, 55-65, Carbon-carbon triple bonds, 145-148
I48 conjugated to C=O bonds, 148-149
Asymmetric reductive amination, 124, 127 of propargyl alcohols and amines, 145-
Azides. 160- 161 147
a-to sulfur, 147- 148
Carboxylic acids, 92-98
Catecholborane, 12
INDEX 217
Catecholborane as co-reagent in asymmetric re- carbamoyl ketones (stereoselectivity), 71

ductions, 59-60, 65 carboxylic acids, 92
Catecholborane in the reduction of disulfides, 165
amides, a,@-unsaturated, 12 1 epoxides, 22-23, 25
carboxylic acids, 95 esters, 84-87
esters, 9 1 esters, a$-unsaturated. 86, 1 16- 120, 149
esters, a,@-unsaturated,1 18, 120 ethers, aryl, 29-30
hydroxyketones (stereoselectivity), 72 halides, 15
ketones, 39 hydroxyketones (stereoselectivity), 7 1-72, 74
ketones, a,@-unsaturated. 1 12 imides, cyclic, 107, 108
tosylhydrazones, 141 imines, 125
CBS reagents, 59-64, 109, 125 imines, heterocyclic, 132- 133
Chelation control, 65-84, 100 ketoamides (stereoselectivity), 7 1
Chiral aluminohydrides and borohydrides, 56- ketones, 39, 44
59, 61 ketones (stereoselectivity), 47, 5 1-55
Chiral boranes, 59, 65 ketones, a,@-unsaturated, 1 1 1 - 1 14, 148
Chirald, 56 ketones a,@-unsaturated(stereoselectivity), 47,
Chloroborane, 12 53
Chloroborane in the reduction of ketosulfoxides (stereoselectivity), 81, 83
acetals, 3 1 lactams, 106- 109
Cram cyclic model, 66 lactones, 86, 88
Cuprous borohydride, bistriphenylphosphine, 8 N-methoxyamides, 100
Cuprous borohydride, bistriphenylphosphine in nitriles, 15 1 - 152
the reduction of nitriles, a,@-unsaturated, 154- 155
acid chlorides, 98 orthoesters, 3 1
aldehydes. 39, 42 oxazolines, 134- 136
tosylhydrazones, 144 oximes, 139- 140
Cyclic ketones, 48-55, 1 16-1 17 phosphates, 166
silyl derivatives, 166- I67
Dichloroborane, 12 thiolesters, 86, 88
Dichloroborane in the reduction of vinylepoxides, 25
azides, 161 Diisopropoxytitanium borohydride, 13
Diisoamylborane, 12 Diisopropoxytitanium borohydride in the reduc-
Diisoamylborane in the reduction of tion of
acid chlorides, 99 acid chlorides, 99
aldehydes, 39 carboxylic acids, 95
amides, 100 ketones (stereoselectivity), 54
ketones, 39 ketones, a,@-unsaturated, 112
ketones (stereoselectivity), 53 ketones, a,@-unsaturated(stereoselectivity),
lactones, 86, 88 116, 118
triple bonds, non-conjugated, 145 Diols cyclic sulfates, 22
Diisobutylaluminum hydride, 4
Diisobutylaluminum hydride in the reduction of Enamines, 130- 131
acetals and ketals, 30, 32-33 stereoselective reductions of, 130- 131
acid anhydrides, 93 Epoxides, 22-27
acid chlorides, 99 regioselective reductions of, 22-24, 27
acyloxazolidinones, 104 stereoselective reductions of, 22-24, 26-27
aldehydes, 39 vinyl, 25-26
aldehydes, a,@-unsaturated, 1 11 - 1 I2 Epoxyalcohols, regio- and stereoselective reduc-
alkoxyketones (stereoselectivity), 66-69, 83, tions of, 25
85 Esters, 20-2 1, 84-92, 142
amides, 100-101, 104- 105 chemoselective reductions of, 89-92
aminals, 127 electrophilic assistance in the reduction of,
aminoketones (stereoselectivity), 77-78 87-88
Esters, a$-unsaturated, 86, 111, 1 16- 120, 149 Hemithioketals, 32
asymmetric reductions of, 121 Houk model, 5 1-54
regioselective reductions of, 116- 120, 149 Hydrazones and tosylhydrazones, 141- 144
Ethers, 29-30
allyl, 30 Imides, 107-1 10
aryl, 29 regioselective reductions of, 107-1 1 1
silyl, 30 stereoselective reductions of, 109, 1 11
THP, 3 1 Imines and iminium salts, heterocyclic, 132-
134
Felkin-Anh model, 45-51, 66, 74, 77, 78, 82 stereoselective reductions of, 132- 133
Fluorides, 15- 16 Imines, 122-1 30
Functionalized esters asymmetric reductions of, 125-126, 128
acid-esters, 88, 91 stereoselective reductions of, 123- 126
epoxyesters, 86, 89, 91 Imines, a$-unsaturated, 130
hydroxyesters, 9 1 Iminium salts, 100, 106, 122, 126-1 30
Functionalized ketones, 48-49, 65-84 Iminium salts, bicyclic, stereoselective reduc-
aminoketones, stereoselective reductions of, tions of, 133- 134
68, 77-78, 82 Indoles, 130- 132
diketones, stereoselective reductions of, 63, Isoxazolidines, isoxazolines, 134- 135
76-77 stereoselective reductions of, 134-1 35
epoxyketones, 42
epoxyketones, stereoselective reductions of, Ketones, 36-55, 122-124, 142-144
66-68 aryl, 38, 40, 44, 142
hydroxyketones, stereoselective reductions of, asymmetric reductions of, 55-65
65-66, 7 1-75 chemoselective reductions of, 42-44, 48
ketoacids, stereoselective reductions of, 80, 82 electrophilic assistance in the reduction of,
ketoamides, 59 38-39, 52
ketoamides, stereoselective reductions of, 70- ferrocenyl, 40, 62
71, 77-82 stereoselective reductions of, 45-55
ketoboronates. stereoselective reductions of. Ketones, a$-unsaturated, 110- 1 18, 142, 148
81 -82, 84 asymmetric reductions of, 56. 59-60, 64
ketoesters and lactones, 41, 59, 86-87, 9 1, 123 competition with saturated ketones, 115-1 18
ketoesters and lactones, stereoselective reduc- electrophilic assistance in the reduction of,
tions of, 70, 77-82 110-111
ketoethers, 59 regioselective reductions of, 1 10- 1 16, 148
ketoethers, stereoselective reductions of, 66- stereoselective reductions of, 47, 53, 116- 1 18
68, 74-76, 79, 83
ketophosphonates and phosphine oxides, 36, Lactams, 104- 109, 127
41, 60 Lactones, 84-91
ketophosphonates and phosphine oxides, ste- Lactones, a$-unsaturated, 1 1 1, 1 17
reoselective reductions of, 68-69 Lithium alkoxyaluminohydrides, 2-3, 56
ketosulfoxides, stereoselective reductions of, Lithium alkoxyaluminohydrides in the reduction
81, 83 of
ketothioethers, stereoselective reductions of, aldehydes, 39
68-69 aldehydes, u,p-unsaturated, I1 I
alkynyl sulfides, 148
Halides amides, 100
acetylenic, 15- 16 bromides, 14
alkyl, 14-17, 38 iodides, 14
allyl, 14, 18-19 ketoesters (stereoselectivity), 70
aryl, 14-18, 158 ketones, 39
benzyl, 14-18 ketones (stereoselectivity), 48, 54
tertiary, 14, 18-19 ketones, a$-unsaturated, 1 1 1 . 148
vinyl, 14-16 lactams, a$-unsaturated. 12 1
INDEX 219
nitriles, 150- 152 oxazines, 135- I36

nitro and nitroso derivatives, 157 oxetanes, 27
Lithium alkoxyaluminohydrides + copper salts oximes, 138, 140-142
in the reduction of ozonides, 34
esters, a,@-unsaturated, 1 17- 120 phosphates, 166
ketones, a,@-unsaturated, 1 12, 128 phosphonium salts, 35
Lithium aluminohydride, 1-2 propargyl alcohols, 145- 146
Lithium aluminohydride in the reduction of propargyl amines, 145- 146
acid anhydrides, 92-94 pyridinium salts, 136
acid chlorides, 99 silyl derivatives, 166-167
acyloxazolidinones, 104 sulfonates, 19-20
aldehydes, 39 sulfones and sulfoxides, 164- 165
aldehydes, a$-unsaturated, 1 1 1 triple bonds, non-conjugated, 145
alkoxy- and silyloxyketones (stereoselectivity), vinylepoxides, 25
67. 76 Lithium aluminohydride on solid support in the
alkynyl sulfides and sulfoxides, 147- I48 reduction of
ally1 phosphonates, 35-36 acid chlorides, 99
amides, 100- 105 aldehydes, 39
amides, a,@-unsaturated, 12 1 esters, 86, 106-108
aminals, 127, 129 ketones, 39
aminoketones (stereoselectivity), 68, 77-78 ketoesters, 42
aminonitriles, 126 Lithium aluminohydride + transition metal salts
ammonium salts, 34 in the reduction of
azides, 160 acetals, 31
boron-halides bonds, 167 ally1 ethers, 30
bromides, 14-15, 19 dithioketals. 165- 166
carbamates, 106 fluorides, 15
carboxylic acids, 92 halides, 15
chlorides, 14, 18 isoxazolidines, 134
disulfides, 164 phosphates, 166
epoxides, 22-24 phosphine oxides, 166
epoxyalcohols, 25 sultams, a,@-unsaturated, 12 1 - 122
epoxyesters, 86 thioethers, 165- 166
esters, 86-89 Lithium aminoborohydrides, 9
esters, a,@-unsaturated, 116, 149 Lilhium aminoborohydrides in the reduction of
ethers, trimethylsilyl, 30 acid chlorides, 99
hydrazones, 141 amides, 100- 102, 104- 105
hydroxyketones (stereoselectivity), 66, 71 azides, 160- 16 1
imines and iminium salts, 122 epoxides, 22
iodides, 14- 15 esters, 89
isoxazolidines and isoxazolines, 134- 135 ketones, a$-unsaturated, 1 12, 116, 1 18
ketoesters, 9 1-92 Lithium 9-Boratabicyclo[3.3.I Jnonane, 12
ketones, 39 Lithium 9-Boratabicyclor3.3.IJnonane in the re-
ketones (stereoselectivity),47-5 1, 54 duction of
ketones, a$-unsaturated, 1 11, 148 epoxides, 23
ketosulfoxides (stereoselectivity), 83 esters, 91
lactams, 106-109 lactones, 91
lactams, a$-unsaturated, 121 Lithium borohydride, 6
nitriles, 152-154 Lithium borohydride in the reduction of
nitriles, a$-unsaturated, 155- 156 acid anhydrides, 93
nitro and nitroso derivatives, 157 acid chlorides, 99
nitro derivatives, a,@-unsaturated, 159 acyloxazolidinones, 103- 104
N-methoxyamides, 100- 101 aldehydes, 39
organomercurials, 161 amides, 100- 104
Lithium borohydride in the reduction of aldehydes, 24, 39, 42
(Continued) amides, 100- 102
carboxylic acids, 95 aminoketones (stereoselectivity), 68
esters, 16, 85-89, 97-98 disulfides, 165
ketoamides (stereoselectivity), 70-71 esters, 84-87
ketoesters (stereoselectivity), 76 iminium salts, bicyclic (stereoselectivity),
ketones, 39, 44 133-134
ketones (stereoselectivity), 54 ketoethers (stereoselectivity), 75
nitriles, a$-unsaturated, 155 ketones, 39, 42-43
nitro derivatives, 157- 158 ketones (stereoselectivity), 49, 52-54
sulfamoylketones (stereoselectivity), 82, 85 ketones, a$-unsaturated, 1 1 1, 1 13, 1 15
sulfonates, 19 ketosulfoxides (stereoselectivity), 81
thiolesters, 92 phosphonates, 36
Lithium borohydride + BEt3 or EtB(OMe), in Lithium triethylborohydride, 9
the reduction of Lithium triethylborohydride in the reduction
epoxides. 22-23 of
esters, 88 acid anhydrides, 93
hydroxyketones (stereoselectivity), 72 aldehydes, 39
nitriles, 153 amides, 100- 102
Lithium cyanoborohydride in reductive amina- ammonium salts, 34
tion, 122-1 23 epoxides, 23-24
Lithium tri(s-butyl)borohydride, 10 esters, 89-90
Lithium tri(s-buty1)borohydridein the reduction esters, a$-unsaturated, 116-1 17
of ethers, 29-30
aldehydes, 39 halides, 16-17
alkoxyketones (stereoselectivity), 66, 75-76 hydroxyketones (stereoselectivity), 75
amides, 100- 102 imides, cyclic, 109, 1 1 l
amides, a,P-unsaturated, 1 19, 121 - 122 imines and iminium salts, 122, 124
ammonium salts, 35 ketoamides (stereoselectivity), 71
anhydrides, 94 ketolactams, 107
arylthioketones (stereoselectivity), 68-69 ketones, 39, 77
esters, 89 ketones, a$-unsaturated, 112, 148
ethers, 2 1 lactams, 106- 109
hydroxyketones (stereoselectivity), 74-75 nitriles, 153
imines and iminium salts, 121 nitro derivatives, a$-unsaturated, 159
imines and iminium salts (stereoselectivity), palladium complexes, 163- 164
124-126 sulfonates, 19
ketoamides (stereoselectivity), 70-71, 80 Lithium and sodium aminoaluminohydrides, 3,
ketoesters (stereoselectivity), 70 56
ketolactones (stereoselectivity), 67, 79, 81 Lithium and sodium aminoalurninohydrides in
ketones, 39 the reduction of
ketones (stereoselectivity), 47-49, 52-54 aldehydes, 39
ketones, a$-unsaturated, 1 12- 1 13 amides, 100- 102
ketones, a$-unsaturated (stereoselectivity), carboxylic acids, 92
47, 53 esters, 84-87
nitriles, 153 ketones, 39
nitro derivatives, a$-unsaturated, 159 ketones, a$-unsaturated, 1 16, 1 18
sulfamoylketones (stereoselectivity), 82, 85 nitriles, 152
suitams, 122
Lithium tri(t-butoxy)aluminohydride, 2 Nitriles, 149- 154
Lithium tri(t-butoxy)aluminohydridein the re- Nitriles, a,P-unsaturated, 151, 154- 156
duction of regioselective reductions of, 154- 156
acid chlorides, 98-99 Nitro and nitroso derivatives, 157-160
acylpyridinium salts, 137 Nitrocompounds, a$-unsaturated, 159- 160
INDEX 221
Organomercurials, 161 - 162 Silyl derivatives, 167

Orthoesters, 3 1 Sodium alkoxyaluminohydrides, 3
Oxazolidines, oxazolines, 134- 136 Sodium alkoxyaluminohydrides in the reduction
stereoselective reductions of, 134- 136 of
Oxetanes, 27 acid chlorides, 98-99
Oxime ethers amides, 100-102
stereoselective reductions of, 140-142 Sodium aluminohydride, 2
Oximes and derivatives, 138-1 42 Sodium aluminohydride in the reduction of
stereoselective reductions of, 138, 140- 142 acid chlorides, 99
Oximes, a$-unsaturated, 138, 140 aldehydes, 39
Ozonides, 34 amides, 100- 102
disulfides, 164
Palladium complexes, 161, 163- I64 esters, 86
regio- and stereoselective reductions of, 163 ketones, 39
Phosphine oxides, phosphates, 166-1 67 nitriles, 152
Phosphorus derivatives, 35-36 nitro and nitroso derivatives, 157
Potassium borohydride. 5-6 oximes, 138
Potassium borohydride in the reduction of Sodium bis(methoxyethoxy)aluminohydride, 3-4
aldehydes, 39 Sodium bis(methoxyethoxy)aluminohydride in
diols cyclic sulfates, 22 the reduction of
ketoamides (stereoselectivity),77 acid anhydrides, 92
ketoesters (stereoselectivity),77 alcohols, 27
ketones, 39 aldehydes, 39
ketones (stereoselectivity),50-5 1 aldehydes, a$-unsaturated, 1 1 1
pyridinium salts, 136-137 alkoxy-.and silyloxyketones (stereoselectivity),
Potassium tri(s-butyl)borohydride, 10 66
Potassium tri(s-buty1)borohydride in the reduc- amides, 100, 104
tion of ammonium salts, 35
aldehydes, 39 carboxylic acids, 92
amides, 100- 102 epoxyalcohols, 22-25
amides, a$-unsaturated, 1 19, 12 1 esters, a,P-unsaturated, 117
anhydrides, 94 ethers, 29
imines and iminiurn salts, 122 fluorides, 15
ketoamides (stereoselectivity),77, 79-80 halides, 14
ketoesters (stereoselectivity),70, 77 imides, cyclic, 109, l l l
ketolactones, 90-9 1 imines and iminium salts, 122
ketones, 39, 43 ketoamides (stereoselectivity), 71
ketones (stereoselectivity),48-49, 54 ketolactones (stereoselectivity), 67
ketones, u,P-unsaturated, 112- 1 13 ketones, 39
Potassium triethylborohydride, 9 ketones, a$-unsaturated, I1 I
Potassium triethylborohydride in the reduc- nitriles, 152- 153
tion of nitro and nitroso derivatives, 157
aldehydes, 39 N-methoxyamides, 100-1 01
esters, 89 propargyl alcohols, 145- 146
ketoamides (stereoselectivity),71 propargyl amines, 145-1 46
ketones, 39 pyridinium salts, 136
Potassium triisopropoxyborohydride, 9 sulfonamides, 164
Potassium triisopropoxyborohydride in the re- Sodium bis(methoxyethoxy)aluminohydride +
duction of copper salts in the reduction of
boron-halides bonds, 167 esters, u,P-unsaturated, 117, 120, 149
Pyridines, quinolines and analogues, 135- 139 ketones, a$-unsaturated, 112
lactones, u,P-unsaturated, I20
Reductive amination, 122-127, 138 nitriles, a$-unsaturated, 155-156
Reductive amination (stereoselectivity), 124- 127 Sodium borohydride, 5-6
222 INDEX
Sodium borohydride in reductive amination, 122, amides, I06

138 carbamates, 106- 107
Sodium borohydride in the reduction of diarylketones, 40
acid anhydrides, 93-94 enamines, 130- 131
acid chlorides, 98-99 imines and iminium salts, 122
aldehydes, 39, 42 imines and iminium salts, heterocyclic, 132-
aldehydes, a,P-unsaturated, 111-1 12 133
allylic ammonium salts, 35 indoles, 131- 132
amides, 104 ketones, 40
aminals, 127 nitriles, 153
aminonitriles, 126-1 28 oxazolines, 134- 136
anhydrides, carboxylic-carbonic, 94 oximes, 138
azides, 160- I6 1 propargyl alcohols, cobalt complexes, 28
enamines, 1 12 quinolines and isoquinolines, 138-139
epoxyketones, 42 quinoxalines and quinazolines, 138-139
esters, 90-9 1 tosylhydrazones, 141
gem-diesters, a$-unsaturated, 1 19- 120 Sodium borohydride + CdC12 in the reduction
halides, aryl, 16 of
halides, primary, 15- 17 acid chlorides, 98-99
halides, tertiary, 18 Sodium borohydride + CeCI, in the reduction of
imides, cyclic, 107, 110 epoxyketones (stereoselectivity), 67-68
imines and iminium salts, 122, 129 imides, cyclic, 107
ketoamides, 40 ketones, 42
ketoamides (stereoselectivity), 62 ketones (stereoselectivity), 54, 77
ketoesters, 40-4 1, 9 1 ketones, a,@-unsaturated, 1 12
ketoesters (stereoselectivity), 70, 82, 85 ketones, a,@-unsaturated (stereoselectivityj,
ketolactams, 107 116-1 17
ketolactones, 42 phosphinyloxyketones (stereoselectivity), 68
ketolactones (stereoselectivity), 67 Sodium borohydride + BEt3 or EtB(OMe)2 in
ketones, 39-44 the reduction of
ketones (stereoselectivity), 49-54 hydroxyketones, 71, 73-75
ketones, aryl, 40 Sodium borohydride + transition metal salts in
ketones, a$-unsaturated, 111- 115 the reduction of
ketones, a$-unsaturated, competition with acetates, 20
saturated ketones, 115-1 17 aldehydes and ketones, 40-42
ketophosphinoxides (stereoselectivity), 69 allyl ethers, 30
ketophosphonates, 36, 40 amides, 104
ketosulfoxides (stereoselectivity), 81 anhydrides, carboxylic-carbonic, 94, 97-
lactams, 106-108 98
nitriles, 149 azides, 160- 161
nitriles, a$-unsaturated, 156 carboxylic acids, 95
nitro derivatives, a$-unsaturated, 159 dithioketals, 143
organomercurials, 161- 162 double bonds, non-conjugated, 37
oxazolines, 134-136 esters, a$-unsaturated, 119
palladium complexes, 163-164 halides, 16, 18
pyridinium salts, 136- 137 imines, 122
sulfonates, 19 ketolactones (stereoselectivity), 79
sulfones and sulfoxides, 164 nitriles, 153
tosylhydrazones, 141-143 nitriles, a$-unsaturated, 155
Sodium borohydride in the presence of organic nitro derivatives, 157-158
acids in the reduction of oximes, 138, 140
acetals, 3 1 quinolines and isoquinolines, 138
alcohols, benzyl, 27 sulfones and sulfoxides, 164- 165
INDEX 223
thioethers, 165 Sulfonamides, 104

triple bonds, non-conjugated, 145 Sulfonates, 19-21, 26
Sodium cyanoborohydride, 7-8 Sulfur derivatives, 164
Sodium cyanoborohydride in reductive amina-
tion, 122-125 Tetrabutyl- and tetraethylammonium cya-
Sodium cyanoborohydride in the reduction of noborohydrides, 7-8
aldehydes, 39 Tetrabutyl- and tetraethylammonium cya-
aldehydes, a,@-unsaturated,1 15 noborohydrides in the reduction of
ammonium salts, 34-35 aldehydes, 39, 42
diols cyclic sulfates, 22 bromides and iodides, primary, 17
enamines, 130- 131 ketoximes ethers (stereoselectivity), 140, 142
epoxides, 22-24 Tetrabutylammonium borohydride, 6-7
halides, 17 Tetrabutylammonium borohydride in the reduc-
imines and iminium salts, 122-124 tion of
isoxazolines, 134 acid chlorides, 99
ketones, 39 aldehydes, 39, 42
ketones, a,@-unsaturated, 1 IS, 148 amides, 104
nitro derivatives, a,@-unsaturated, 159 ketones, 39-41
nitrones, cyclic, 134 ketones, a,@-unsaturated, 112
sulfones and sulfoxides, 166 nitriles, 153
tosylhydrazones, 141-143 thiolesters, 92
Sodium cyanoborohydride in the presence of or- Thexylborane, 12
ganic acids in the reduction of Thexylborane in the reduction of
acetals, 3 1 ketones (stereoselectivity), 54
imines and iminium salts, 122 Thexylchloroborane, 12
imines and iminium salts, heterocyclic, 132- Thexylchloroborane in the reduction of
133 aldehydes, 39
indoles, 131 carboxylic acids, 92
ketones, aryl, 40 esters, 91
oximes and derivatives, 138, 141 ketones, 39
pyridines, 135- 137 ketones (stereoselectivity), 54
quinolines and isoquinolines, 138 nitriles, 153
Sodium cyanoborohydride + transition metal Thiolesters, 86, 92
salts in the reduction of
acetals, 32 Zinc borohydride, 7
alcohols, allyl, benzyl and tertiary, 28 Zinc borohydride in the reduction of
aldehydes, 40 acetals, 32
aldehydes, a,@-unsaturated, 112 acid chlorides, 99
halides, ally], benzyl and tertiary, 18 aldehydes, 39, 42
imines and iminium salts. 123-124 aldehydes, a,@-unsaturated, 1 12
ketones, 40 alkoxyketones (stereoselectivity), 67
ketones, a,@-unsaturated, 1 12 aminonitriles, 126
oximes, 141- 142 arylthioketones (stereoselectivity), 68
tosylhydrazones, 141 azides, 160
Sodium and tetrabutylammonium triacetox- carboxylic acids, 95
yborohydride, 6 epoxides, 22-24
Sodium and tetrabutylammonium triacetox- epoxyketones, 42
yborohydride in the reduction of halides, benzylic and tertiary, 18
aldehydes, 42-44 hydroxyketones (stereoselectivity), 66
enamines, 130 imines, 122- 124. 127
hydroxyketones (stereoselectivity), 73-75 ketoamides (stereoselectivity), 78-79
Steroidal ketones, 41-50, 52-54, 64, 116- ketoesters, 9 1
l I8 ketoesters (stereoselectivity), 78-81
224 INDEX
Zinc borohydride in the reduction of Zinc cyanoborohydride, 8

(Continued) Zinc cyanoborohydride in the reduction of
ketolactarns, 107 enamines, 130-131
ketolactones (stereoselectivity), 67 ketones, 39, 44
ketones, 39, 44
ketones, a,@-unsaturated, 1 12, 1 15
ketosulfoxides (stereoselectivity), 81

Seyden-Penne, J. - Reductions by The Alumino and Borohydrides in Organic Synthesis

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Reductions by the

This book is printed on acid-free paper. @

Copyright O 1997 by Wiley-VCH, Inc. All rights resewed.

Library of Congress Cataloging in Publication Data:

Printed in the United States of America

1. Description and Characteristics of the Main Reagents

Sodium and Tetrabutylamrnonium Cyanoborohydrides:

2. Cleavage of the Carbon-Heteroatom Single Bond

3. Reduction of Double Bonds

3.2.3 Asymmetric Reductions / 55

4. Reduction of Triple Bonds

The present book is organized in the following fashion:

I am particularly grateful to Mr. Fenouil (Lavoisier-Tec-Doc), who allowed me to

1.1 LITHIUM AND SODIUM ALUMINOHYDRIDES:

Lithium aluminohydride (LiAlH,, LAH) is soluble in ethers. In diethylether and

1.2 LITHIUM AND SODIUM ALKOXY- AND

Because of this disproportionation, some solutions of alkoxyaluminohydrides con-

Various sodium aminoaluminohydrides have been proposed for selective reduc-

1.3 SODIUM BIS(METHOXYETH0XY)ALUMINOHYDRIDE:

An interesting feature of sodium bis(methoxyethoxy)aluminohydride is its solubility

1.4 DIISOBUTYL ALUMINUM HYDRIDE: i-Bu,AIH (DIBAH)

1.5 ALUMINUM HYDRIDE (AIH,), AMINOHYDRIDES, AND ALUMINUM

1.6 SODIUM AND POTASSIUM BOROHYDRIDES: NaBH,, KBH4

1.7 LITHIUM BOROHYDRIDE: LiBH,

1.8 TETRABUTYLAMMONIUM BOROHYDRIDE: n-Bu4NBH4

n-Bu4NBH4 is a very mild reducing agent. The reactivity order in CH,Cl, is as

1.9 CALCIUM BOROHYDRIDE

Calcium borohydride is generated in methanol or ethanol from CaCl, and NaBH,

1.10 ZINC BOROHYDRIDE: Zn(BH4),

1.11 SODIUM AND TETRABUTYLAMMONIUM

1.12 ZINC CYANOBOROHYDRIDE

Zinc cyanoborohydride [KOI, LDI] is formed by reaction of ZnC1, in diethylether

1. I 3 CUPROUS BIS(DIPHENYLPH0SPHINE) BOROHYDRIDE

1.14 POTASSIUM TRllSOPROPOXYBOROHYDRIDE: K(i-PrO),BH

This borohydride [BC3], obtained in THF by adding 3 moles of i-PrOH to a solution

1.1 5 LITHIUM AMINOBOROHYDRIDES

Lithium aminoborohydrides are obtained by the reaction of n-BuLi with amine-

1.I6 LITHIUM TRIETHYLBOROHYDRIDE: LiEt,BH (SUPERHYDRIDE)

1.17 LITHIUM AND POTASSIUM TRl(sBUTYL) BOROHYDRIDES

1.18 LITHIUM ALKYLBOROHYDRIDES

These can be easily prepared by reaction of di- or trialkylboranes with lithium

1.19 BORANE: BH,

1.20 AMINE-BORANES: R3NaBH3

1.21 SUBSTITUTED BORANES

Substituted boranes are obtained by hydroboration of relatively hindered olefins

1.22 ALUMINO- AND BOROHYDRIDES IN THE PRESENCE OF

Solutions or suspensions of LAH in diethylether or THF in the presence of iron

The reduction of alkenes with LAH-FeCI,, CoCl,, TiCI, or NiCI,, or NaBH,-

2.1 HALIDES: >c-x

LAH in THF reduces chlorides, bromides, and iodides to hydrocarbons, whatever

cyclopropanes can be selectively reduced to monobromocyclopropanes by heating

R3C-X -----D R~c+- R3C-H

2.2 SULFONATES AND ESTERS:S C - 0 ~ 0 , ~ fC-OCOR

R = H,n-alkyl, Ph R' = COO i-Pr

Cyclic sulfates of 1,2-diols 2.14 are transformed into monoalcohols by

2.3 EPOXIDES: >C,-P(

The cleavage of the C - 0 bond of epoxides requires the electrophilic assistance of a

The regioselectivity of the opening of disymmetrical epoxides depends essen-

with BH, or NaCNBH, in the presence of BF,.Et,O or by Zn(BH,), on SO,. The