Reduction

General References • Catalytic hydrogenation is used for the reduction of many organic functional groups. The
reaction can be modified with respect to catalyst, hydrogen pressure, solvent, and temperature in
Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry Part B, Plenum Press: New York, order to execute a desired reduction.
1990, p. 615-664.
• A brief list of recommended reaction conditions for catalytic hydrogenations of selected functional
Hudlicky, M. In Reductions in Organic Chemistry 2nd Ed., American Chemical Society groups is given below.
Monograph 188: Washington DC, 1996, p. 19-30.
Catalyst/Compound
Brown, H. C.; Ramachandran, P. V. In Reductions in Organic Synthesis: Recent Advances and Substrate Product Catalyst Ratio (wt%) Pressure (atm)
Practical Applications, Abdel-Magid, A. F. Ed.; American Chemical Society: Washington DC,
1996, p. 1-30. Alkene Alkane 5% Pd/C 5-10% 1-3

Seyden-Penne, J. In Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd Alkyne Alkene 5% Pd(BaSO4) 2% + 2% quinoline 1
Ed., Wiley-VCH: New York, 1997, p. 1-36.
Aldehyde Alcohol PtO2 2-4% 1
Reactivity Trends (Ketone)
• Following are general guidelines concerning the reactivities of various reducing agents.
Halide Alkane 5% Pd/C 1-15%, KOH 1
Substrates, Reduction Products
Nitrile Amine Raney Ni 3-30% 35-70
Iminium Ion Acid Halide Aldehyde Ester Amide Carboxylate Salt Adapted from: Hudlicky, M. In Reductions in Organic Chemistry 2nd Ed., American Chemical
Society Monograph 188: Washington DC, 1996, p. 8.
Hydride Donors
Summary of Reagents for Reductive Functional Group Interconversions:
LiAlH4 Amine Alcohol Alcohol Alcohol Amine Alcohol
Acid Alcohol
DIBAL – Alcohol Alcohol Alcohol or Amine or Alcohol Lithium Aluminum Hydride (LAH) Lithium Borohydride Borane Complexes
Aldehyde Aldehyde
Ester Aldehyde
NaAlH(O-t-Bu)3 – Aldehyde Alcohol Alcohol Amine –
(slow) (slow) Diisobutylaluminum Hydride (DIBAL) Reduction of Acid Chlorides, Amides, and Nitriles
AlH3 – Alcohol Alcohol Alcohol Amine Alcohol Lithium Triethoxyaluminohydride (LTEAH)

** Aldehyde Alcohol
NaBH4 Amine – Alcohol – – –
Reductive Amination Luche Reduction Samarium Iodide
NaCNBH3 Amine – Alcohol – – – Sodium Borohydride Ionic Hydrogenation
(slow)

Na(AcO)3BH Amine – Alcohol Alcohol Amine – Aldehyde Alkane

(slow) (slow) (slow)
Deoxygenation of Tosylhydrazones Desulfurization with Raney Nickel
B2H6 – – Alcohol Alcohol Amine Alcohol
(slow) (slow) Wolff–Kishner Reduction Clemmensen Reduction

Li(Et)3BH – Alcohol Alcohol Alcohol Alcohol – Alcohol Alkane

(tertiary amide)
Barton Deoxygenation Diazene-Mediated Deoxygenation
H2 (catalyst) Amine Alcohol Alcohol Alcohol Amine –
Reduction of Alkyl Tosylates Radical Dehalogenation
** Acid Alkane
α-alkoxy esters are reduced to the corresponding alcohols.

– indicates no reaction or no productive reaction (alcohols are deprotonated in many instances, Barton Decarboxylation
e.g.)
 Acid Alcohol
TESO O CH3 TESO O CH3
O LiAlH4, ether O
CH3O N CH3O N
Lithium Aluminum Hydride (LAH): LiAlH4 H –78 °C H
(CH3)2N OTES N (CH3)2N OTES N
CO2CH3 CH2OH
• LAH is a powerful and rather nonselective hydride-transfer reagent that readily reduces
carboxylic acids, esters, lactones, anhydrides, amides and nitriles to the corresponding 72%
alcohols or amines. In addition, aldehydes, ketones, epoxides, alkyl halides, and many other
functional groups are reduced readily by LAH.

• LAH is commercially available as a dry, grey solid or as a solution in a variety of organic Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453.
solvents, e.g., ethyl ether. Both the solid and solution forms of LAH are highly flammable and
should be stored protected from moisture.

• Several work-up procedures for LAH reductions are available that avoid the difficulties of H H
separating by-products of the reduction. In the Fieser work-up, following reduction with n
grams of LAH, careful successive dropwise addition of n mL of water, n mL of 15% NaOH LiAlH4
solution, and 3n mL of water provides a granular inorganic precipitate that is easy to rinse and N N THF N N
filter. For moisture-sensitive substrates, ethyl acetate can be added to consume any excess H Ts H H
LAH and the reduction product, ethanol, is unlikely to interfere with product isolation. O
88% (+)-aloperine
• Although, in theory, one equivalent of LAH provides four equivalents of hydride, an excess of
the reagent is typically used.

Paquette, L. A. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing

Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, p. Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1999, 121, 700-709.
199-204.

Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis 1967, 581-595.

H H
• Examples O O HO O
LiAlH4
O
O ether HO
N CH3 N CH3
H3C H3C
LiAlH4 CH3 89-95% CH3
CH3O CH3O
H THF H
O O
H H
O 70% OH
Heathcock, C. H.; Ruggeri, R. B.; McClure, K. F. J. Org. Chem. 1992, 57, 2585-2599.
(+)-codeine
• In the following example, rearrangement accompanied reduction.
White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64, 7871-7884.

CH3O2C HOCH2 H H
O C(CH3)3 OH CH3 CH3
CH3O2C HOCH2 H3C H3C
LiAlH4
H CH3 CH3
H O
LiAlH4, THF HH THF HH
reflux CH3 OH
OH
H H TsO 60% H3C
OH
H3C CO2H 72% H3C

Bergner, E. J.; Helmchen, G. J. Org. Chem. 2000, 65, 5072-5074. Bates, R. B.; Büchi, G.; Matsuura, T.; Shaffer, R. R. J. Am. Chem. Soc. 1960, 82, 2327-2337.
Lithium Borohydride: LiBH4 Borane Complexes: BH3•L

• Lithium borohydride is commonly used for the selective reduction of esters and lactones to the • Borane is commonly used for the reduction of carboxylic acids in the presence of esters,
corresponding alcohols in the presence of carboxylic acids, tertiary amides, and nitriles. lactones, amides, halides and other functional groups. In addition, borane rapidly reduces
Aldehydes, ketones, epoxides, and several other functional groups can also be reduced by aldehydes, ketones, and alkenes.
lithium borohydride.
• Borane is commercially available as a neat complex with tetrahydrofuran (THF) or dimethysulfide
• The reactivity of lithium borohydride is dependent on the reaction medium and follows the or in solution. In addition, gaseous diborane (B2H6) is available.
order: ether > THF > 2-propanol. This is attributed to the availability of the lithium counterion
for coordination to the substrate, promoting reduction. • The borane-dimethylsulfide complex exhibits improved stability and solubility compared to the
borane-THF complex.
• Lithium borohydride is commercially available in solid form and as solutions in many organic
solvents, e.g., THF. Both are inflammable and should be stored protected from moisture. • Competing hydroboration of carbon-carbon double bonds can limit the usefulness of borane-THF
as a reducing agent.
Nystrom, R. F.; Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1949, 71, 3245-3246.
Yoon, N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.; Stocky, T. P. J. Org. Chem. 1973, 38,
Banfi, L.; Narisano, E.; Riva, R. In Handbook of Reagents for Organic Synthesis: Oxidizing and 2786-2792.
Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York,
1999, p. 209-212. Lane, C. F. Chem. Rev. 1976, 76, 773-799.

• Examples Brown, H. C.; Stocky, T. P. J. Am. Chem. Soc. 1977, 99, 8218-8226.

• Examples

F O 1. BH3•THF, 0 °C O
O O
O 2N H CH3 2. dihydropyran, THF H CH3
O CO2CH3
H LiBH4, CH3 OH
N OTBS TsOH, 0 °C
N THF, Et2 O, 0 °C Br CO2H Br CH2OTHP
H
O 86%
H3C CH3
83%
Corey, E. J.; Sachdev, H. S. J. Org. Chem. 1975, 40, 579-581.

F
BH3•THF
O 2N OH HO2C HOCH2
O CO2Et 0 → 25 °C CO2Et
H
Laïb, T.; Zhu, J. Synlett. 2000, 1363-1365. N OTBS
N
H 67%
O
H3 C CH3
Kende, A. S.; Fludzinski, P. Org. Synth. 1986, 64, 104-107.

• The combination of boron trifluoride etherate and sodium borohydride has been used to
generate diborane in situ.

HO CH3 LiBH4 HO CH3 CO2H CH2OH

CH3O2C CO2H HOCH2 CO2H NaBH4 , BF3•Et2O

81% THF, 15 °C
HN SO2 HN SO2
95%

Huang, F.-C.; Lee, L. F.; Mittal, R. S. D.; Ravikumar, P. R.; Chan, J. A.; Sih, C. J. J. Am. Chem. Miller, R. A.; Humphrey, G. R.; Lieberman, D. R.; Ceglia, S. S.; Kennedy, D. J.; Grabowski, E. J.
Soc. 1975, 97, 4144-4145. J.; Reider, P. J. J. Org. Chem. 2000, 65, 1399-1406.
 Ester Aldehyde

O OMOM
H
Diisobutylaluminum Hydride (DIBAL): i-Bu2AlH H3C N O
TMS
• At low temperatures, DIBAL reduces esters to the corresponding aldehydes, and lactones O
to lactols. MOMO CH3
H3C CH3 DIBAL, THF
OMOM
O CH3 –100 → –78 °C
• Typically, toluene is used as the reaction solvent, but other solvents have also been OAc OAc O O
employed, including dichloromethane.
Miller, A. E. G.; Biss, J. W.; Schwartzman, L. H. J. Org. Chem. 1959, 24, 627-630. CH3 CH3 CH3 CH 3 CO2CH3
O O
Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 3, 619-620.

• Examples

CO2CH3 CHO
DIBAL, toluene O OMOM
O O H
N –78 °C N H 3C N O
H3C Boc H3C Boc TMS
CH3 CH3
O
76% MOMO CH3
OMOM H3C CH3
(+)-damavaricin D CH 3
O OAc OAc O O
Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18-28.

CH3 CH3 CH3 CH3 R

1. DIBAL, CH2Cl2, –78 °C O O

2. CH3 OH, –80 °C

I CO2Et 3. potassium sodium tartrate I CHO R = CH2OH, 62%
Swern, 82%
R = CHO, 16%

88%

Marek, I.; Meyer, C.; Normant, J.-F. Org. Synth. 1996, 74, 194-204. Roush, W. R.; Coffey, D. S.; Madar, D. J. J. Am. Chem. Soc. 1997, 119, 11331-11332.

• Reduction of N-methoxy-N-methyl amides, also known as Weinreb amides, is one of the • Nitriles are reduced to imines, which hydrolyze upon work-up to furnish aldehydes.
most frequent means of converting a carboxylic acid to an aldehyde.

O O
Cl O Cl O
CH 3 DIBAL, toluene DIBAL, ether
TBSO N TBSO H NC OHC
CH2 Cl2, –78 °C –78 °C
OCH3 HO C(CH3)3 HO C(CH3)3

82% 56%

Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 3542-3545. Crimmins, M. T.; Jung, D. K.; Gray, J. L. J. Am. Chem. Soc. 1993, 115, 3146-3155.
Lithium Triethoxyaluminohydride (LTEAH): Li(EtO)3 AlH Reduction of Acid Chlorides

• LTEAH selectively reduces aromatic and aliphatic nitriles to the corresponding aldehydes • The Rosemund reduction is a classic method for the preparation of aldehydes from carboxylic
(after aqueous workup) in yields of 70-90%. acids by the selective hydrogenation of the corresponding acid chloride.

• Tertiary amides are efficiently reduced to the corresponding aldehydes with LTEAH. • Over-reduction and decarbonylation of the aldehyde product can limit the usefulness of the
Rosemund protocol.
• LTEAH is formed by the reaction of 1 mole of LAH solution in ethyl ether with 3 moles of ethyl
alcohol or 1.5 moles of ethyl acetate. • The reduction is carried out by bubbling hydrogen through a hot solution of the acid chloride in
which the catalyst, usually palladium on barium sulfate, is suspended.
Et2O
LiAlH4 + 3 EtOH Li(EtO)3AlH + 3H2 Rosemund, K. W.; Zetzsche, F. Chem. Ber. 1921, 54, 425-437.
0 °C
Mosetting, E.; Mozingo, R. Org. React. 1948, 4, 362-377.
Et2O
LiAlH4 + 1.5 CH3CO2Et Li(EtO)3AlH • Examples
0 °C
PhtN CO2H PhtN CHO
1. SOCl2
Brown, H. C.; Shoaf, C. J. J. Am. Chem. Soc. 1964, 86, 1079-1085. H H
CH3 2. H2 , Pd/BaSO4 CH3
Brown, H. C.; Garg, C. P. J. Am. Chem. Soc. 1964, 86, 1085-1089.
CH 3 CH3
Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089-1095. 64%

• Examples Johnson, R. L. J. Med. Chem. 1982, 25, 605-610.

CON(CH3)2 CHO O O
Cl Cl H H
1. LTEAH, ether, 0 °C H2, Pd/BaSO4
O COCl O CHO
2. H+ NH NH
F 3C F3C
CF3 CF3
80% 64%

CON(CH3)2 CHO Winkler, D.; Burger, K. Synthesis 1996, 1419-1421.

1. LTEAH, ether, 0 °C • Sodium tri-tert-butoxyaluminohydride (STBA), generated by the reaction of sodium aluminum
2. H+ hydride with 3 equivalents of tert-butyl alcohol, reduces aliphatic and aromatic acid chlorides to
the corresponding aldehydes in high yields.
NO2 NO2
75%
STBA, diglyme
COCl CHO
THF, –78 °C
Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567-607.
100%

1. LTEAH, hexanes, STBA, diglyme

CH3 O O COCl CHO
Bn THF, 0 °C Bn ClOC THF, –78 °C OHC
N H
2. TFA, 1 N HCl
OH CH3 CH 3 CH3
93%

>99% de 77% (94% ee) diglyme = (CH3OCH2CH2)2O

Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Cha, J. S.; Brown, H. C. J. Org. Chem. 1993, 58, 4732-4734.
Chem. Soc. 1997, 119, 6496-6511.
 Aldehyde or Ketone Alkane
• Examples

• In the following example, exchange of the tosylhydrazone N-H proton is evidently faster than
Deoxygenation of Tosylhydrazones reduction and hydride transfer.

• Reduction of tosylhydrazones to hydrocarbons with hydride donors, such as sodium

cyanoborohydride, sodium triacetoxyborohydride, or catecholborane, is a mild and selective
method for carbonyl deoxygenation. H3C CH3 NNHTs H3C CH 3Y X

• Esters, amides, nitriles, nitro groups, and alkyl halides are compatible with the reaction conditions. CH3 CH3

• Most hindered carbonyl groups are readily reduced to the corresponding hydrocarbon. CH3 CH3
Conditions Product (Yield)
• However, electron-poor aryl carbonyls prove to be resistant to reduction. NaBD4 , AcOH X = D, Y = H (75%)
NaBH4 , AcOD X = H, Y = D (72%)
Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am. Chem. Soc. 1973, 95, 3662-3668.
NaBD4 , AcOD X = Y = D (81%)
Kabalka, G. W.; Baker, J. D., Jr. J. Org. Chem. 1975, 40, 1834-1835.

Kabalka, G. W.; Chandler, J. H. Synth. Commun. 1979, 9, 275-279.

Hutchins, R. O.; Natale, N. R. J. Org. Chem. 1978, 43, 2299-2301.
• Two possible mechanisms for reduction of tosylhydrazones by sodium cyanoborohydride have
been suggested. Direct hydride attack by sodium cyanoborohydride on an iminium ion is
proposed in most cases.
OH OH
Ts Ts Ts CH3 CH3
NH + NH NH NH NNHTs
N H+ HN NaBH3CN HN N H H
H H CH3 CH3
R R' R R' R R' –TsH R R' –N2 R R' H ZnCl2, NaBH3CN H
CH3OH, 90 °C
• However, reduction of an azohydrazine is proposed when inductive effects and/or H CH H CH
3 3
conformational constraints favor tautomerization of the hydrazone to an azohydrazine. H H
CH3 ~50% CH3
Ts Ts Ts
NH H + N NH (±)-ceroplastol I
N N NaBH3CN HN
H H
R R' R R' R R'
Boeckman, R. K., Jr.; Arvanitis, A.; Voss, M. E. J. Am. Chem. Soc. 1989, 111, 2737-2739.
Miller, V. P.; Yang, D.-y.; Weigel, T. M.; Han, O.; Liu, H.-w. J. Org. Chem. 1989, 54, 4175-4188.

• α,β-Unsaturated carbonyl compounds are reduced with concomitant migration of the conjugated
alkene.

• The mechanism for this "alkene walk" reaction apparently proceeds through a diazene CH3O2C OAc 1. TsNHNH2, EtOH CH3O2 C OH
intermediate which transfers hydride by 1,5-sigmatropic rearrangement. 2. NaBH3CN
O 3. NaOAc, H 2O, EtOH O
N O
H N H 4. CH3O–Na+, CH3OH
H Ot-Bu Ot-Bu
R R' –N2 R R'
68% overall

Hutchins, R. O.; Kacher, M.; Rua, L. J. Org. Chem. 1975, 40, 923-926.

Kabalka, G. W.; Yang, D. T. C.; Baker, J. D., Jr. J. Org. Chem. 1976, 41, 574-575. Hanessian, S.; Faucher, A.-M. J. Org. Chem. 1991, 56, 2947-2949.
Wolff–Kishner Reduction Desulfurization With Raney Nickel

• The Wolff–Kishner reduction is a classic method for the conversion of the carbonyl group in • Thioacetal (or thioketal) reduction with Raney nickel and hydrogen is a classic method to
aldehydes or ketones to a methylene group. It is conducted by heating the corresponding prepare a methylene group from a carbonyl compound.
hydrazone (or semicarbazone) derivative in the presence of an alkaline catalyst.
• The most common limitation of the desulfurization method is the competitive hydrogenation
• Numerous modified procedures to the classic Wolff–Kishner reduction have been reported. In of alkenes.
general, the improvements have focused on driving hydrazone formation to completion by
removal of water, and by the use of high concentrations of hydrazine. In addition, attempts have Pettit, G. R.; Tamelen, E. E. Org. React. 1962, 12, 356-521.
been made to increase the rate of hydrazone decomposition, in some cases by increasing the
reaction temperature. • Example
• The two principal side reactions associated with the Wolff–Kishner reduction are azine formation OCH3 OCH3
and alcohol formation (proposed to occur by Meerwein–Ponndorf–Verley-like reduction of the
carbonyl compound with sodium alkoxide). N(CHO)CH3 N(CHO)CH3

Todd, D. Org. React. 1948, 4, 378-423. SEt

H SEt Raney Ni, H2 H
Hutchins, R. O.; Hutchins, M. K. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., N N
H H H H
Eds., Pergamon Press: New York, 1991, Vol. 8, p. 327-362.
O O O O
H ~50% H
• Examples

Woodward, R. B.; Brehm, W. J. J. Am. Chem. Soc. 1948, 70, 2107-2115.

diethylene glycol, Na metal Clemmensen Reduction

H2NNH2, 210 °C • The Clemmensen reduction of ketones and aldehydes using zinc and hydrochloric acid
O
is a classic method for converting a carbonyl group into a methylene group.
90%
• Typically, the classic Clemmensen reduction involves refluxing a carbonyl substrate with
40% aqueous hydrochloric acid, amalgamated zinc, and an organic solvent such as
toluene. This reduction is rarely performed on polyfunctional molecules due to the harsh
conditions employed.
Piers, E.; Zbozny, M. Can. J. Chem. 1979, 57, 1064-1074.
• Anhydrous hydrogen chloride and zinc dust in organic solvents has been used as a
milder alternative to the classic Clemmensen reduction conditions.
Vedejs, E. Org. React. 1975, 22, 401-415.
N N
N N Yamamura, S.; Ueda, S.; Hirata, Y. J. Chem. Soc., Chem. Commun. 1967, 1049-1050.
CHO CH 3
N N
Toda, M.; Hayashi, M.; Hirata, Y.; Yamamura, S. Bull. Chem. Soc. Jpn. 1972, 45, 264-266.
O H2NNH2, EtOH; O
Cl NH KOt-Bu, reflux Cl NH • Example
O
Cl Zn(Hg), HCl Cl
91%

Cl Cl
56%

Coffen, D. L.; Fryer, R. I.; Katonak, D. A.; Wong, F. J. Org. Chem. 1975, 40, 894-897. Marchand, A. P.; Weimer, W. R., Jr. J. Org. Chem. 1969, 34, 1109-1112.
 Aldehyde or Ketone Alcohol
Luche Reduction

Sodium Borohydride: NaBH4 • Sodium borohydride in combination with cerium (III) chloride (CeCl3) selectively reduces
α,β-unsaturated carbonyl compounds to the corresponding allylic alcohols.
• Sodium borohydride reduces aldehydes and ketones to the corresponding alcohols at or
near 25 °C. Under these conditions, esters, epoxides, lactones, carboxylic acids, nitro • Typically, a stoichiometric quantity of cerium (III) chloride and sodium borohydride is
groups, and nitriles are not reduced. added to an α,β-unsaturated carbonyl substrate in methanol at 0 °C.
• Sodium borohydride is commercially available as a solid, in powder or pellets, or as a
• Control experiments reveal the dramatic influence of the lanthanide on the regiochemistry
solution in various solvents.
of the reduction.
• Typically, sodium borohydride reductions are performed in ethanol or methanol, often
with an excess of reagent (to counter the consumption of the reagent by its reaction with O OH OH
the solvent).
+
Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1949, 71, 122-125.
Reductant
Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567-607.
NaBH4 51% 49%
• Examples NaBH4, CeCl3 99% trace

I I
O HO
Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
CH3 NaBH4, CH3OH CH3
O 0 °C O • Examples
OPiv OPiv

~100%

N N
Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; N NaBH4, CeCl3 N
Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162-3164. H H H H H H
CH3CN, CH3OH
H H
1. OsO4 (cat), CH3O2C CH3O2C
CH 3 O Ph CH3 O Ph 78%
CH3O CH3O O OH
aq. NMO
O O
O 2. NaIO4 HO O
H H
H 3C H 3C 3. NaBH4 H3C H3C
Binns, F.; Brown, R. T.; Dauda, B. E. N. Tetrahedron Lett. 2000, 41, 5631-5635.
90%

Ireland, R. E.; Armstrong, J. D., III; Lebreton, J.; Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem.
Soc. 1993, 115, 7152-7165. 1. NaBH4,
CH3 CH3
H CeCl3•7H2O H
O TIPSO
CH3O O CH3O OBOM OBOM
O CH3OH, 0 °C
1. NaBH4, CH3OH O O
NEt2 2. TIPSCl, Im
2. 6 M HCl O
CHO 87%
>81%

Wang, X.; de Silva, S. O.; Reed, J. N.; Billadeau, R.; Griffen, E. J.; Chan, A.; Snieckus, V. Org. Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. K.; Danishefsky, S. J.
Synth. 1993, 72, 163-172. J. Am. Chem. Soc. 1997, 119, 10073-10092.
Ionic Hydrogenation Samarium Iodide: SmI2

• Ionic hydrogenation refers to the general class of reactions involving the reduction of a • Samarium iodide effectively reduces aldehydes, ketones, and alkyl halides in the
carbonium ion intermediate, often generated by protonation of a ketone, alkene, or a lactol, presence of carboxylic acids and esters.
with a hydride donor.
• Aldehydes are often reduced much more rapidly than ketones.
• Generally, ionic hydrogenations are conducted with a proton donor in combination with a
hydride donor. These components must react with the substrate faster than with each Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693-2698.
other.
Molander, G. A. Chem. Rev. 1992, 92, 29-68.
• Organosilanes and trifluoroacetic acid have proven to be one of the most useful reagent
combinations for the ionic hydrogenation reaction. Soderquist, J. A. Aldrichimica Acta. 1991, 24, 15-23.

• Examples
• Carboxylic acids, esters, amides, and nitriles do not react with organosilanes and
trifluoroacetic acid. Alcohols, ethers, alkyl halides, and olefins are sometimes reduced.
Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633-651.
H3C HO H3 C
• Examples O SmI2
H
THF, H2O
• The ionic hydrogenation has been used to prepare ethers from the corresponding lactols.
OTBS OTBS
CO2CH3 CO2 CH3
97% (86% de)
H H
O N O N
Et3SiH, CF3CO2H
CH2Cl2, reflux
CH3N CH3N Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc. 1987, 109, 6187-6189.
O O
OH • In the following example, a samarium-catalyzed Meerwein–Ponndorf–Verley reduction
>65% (±)-gelsemine successfully reduced the ketone to the alcohol where many other reductants failed.

Madin, A.; O'Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem., Int.
Ed. Engl. 1999, 38, 2934-2936.
H3 C H3C
• Intramolecular ionic hydrogenation reactions have been used in stereoselective reductions.
DEIPSO DEIPSO
H H
H CH3 CH3
CH 3 CH3 SmI2 H
t-Bu2Si(H)O CF3CO2– t-Bu HO H O H O
H H
H O Si t-Bu PMBO
O
i-PrOH, THF PMBO
O
CF3 CO2H; H H
H3C H
+ –
n-Bu4 N F + CH3 CH3 O 98% CH3 OH
H OCH3
CH3 CH3
65-75% >95% isomeric purity

McCombie, S. W.; Cox, B.; Lin, S.-I.; Ganguly, A. K.; McPhail, A. T. Tetrahedron Lett. 1991, 32, Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112,
2083-2086. 7001-7031.
Reductive Amination
O
• The reductive amination of aldehydes and ketones is an important method for the CH3
synthesis of primary, secondary, and tertiary amines.
CH3 CH2 CHO
• Iminium ions can be reduced selectively in the presence of their carbonyl precursors. H3 C N(CH3)2 NaBH 3CN
O HO
Reductive aminations are often conducted by in situ generation of the imine (iminium ion) HO OCH2 CH3 O O OH
O O CH3 CH3 OH,
intermediate in the presence of a mild acid. OCH3 CH3
CH3O
Et O OH O OH HN O
• Reagents such as sodium cyanoborohydride and sodium triacetoxyborohydride react CH3
selectively with iminium ions and are frequently used for reductive aminations.
Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897-2904. tylosin 79%

Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron 1990, 31, 5595-5598.

Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. O O
1996, 61, 3849-3862. CH3 N

• Examples CH3
H3 C N(CH3)2
O
HO OCH2 CH 3 HO O
O O O CH 3 OH
OCH3 CH3
OTBS CH 3O
Et O OH O OH
AcO CH3 Na(AcO)3BH, Sn(OTf)2 CH3
+ H3 C
O CHO 4 Å MS, ClCH2CH2Cl, 0 °C
N
H H
Matsubara, H.; Inokoshi, J.; Nakagawa, A.; Tanaka, H.; Omura, S. J. Antibiotics 1983, 36,
66% 1713-1721.

OTBS H CO2 Bn H CO2Bn CO2 Bn H CO2 Bn H CO2Bn

AcO CH 3 NaBH3CN
Hosokawa, S.; Sekiguchi, K.; Hayase, K.; Hirukawa, Y.; OHC H
Kobayashi, S. Tetrahedron Lett. 2000, 41, 6435-6439. H3 C N N OTHP N N OTHP
CH3OH
H O CO2t-Bu CO2t-Bu

+ 59%
1. H2, Pd/C, EtOH,
CO2Bn
H H2O, HCl
Ph Ph Ph Ph 2. TFA
O O NH•TFA
NaBH3CN
H CH2O N H
N
H CH3 CH3
H3 C CO2H H CO2H H CO2H
84% H
Ohfune, Y.; Tomita, M.; Nomoto, K. J. Am. Chem. Soc. N N OH
1981, 103, 2409-2410. H

2'-deoxymugineic acid
Jacobsen, E. J.; Levin, J.; Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4329-4336.
 Alcohol Alkane

Barton Deoxygenation O 1. 1,1'-thiocarbonyl-diimidazole, O

PhO N DMAP, CH2Cl2 PhO N

• Radical-induced deoxygenation of O-thiocarbonate derivatives of alcohols in the presence of
O O
hydrogen-atom donors is a versatile and widely-used method for the preparation of an alkane 2. AIBN, Bu3SnH, toluene, 75 °C
from the corresponding alcohol.
OH H
• The Barton deoxygenation is a two-step process. In the initial step, the alcohol is acylated to
75%
generate an O-thiocarbonate derivative, which is then typically reduced by heating in an aprotic
solvent in the presence of a hydrogen-atom donor.

• The method has been adapted for the deoxygenation of primary, secondary, and tertiary Nicolaou, K. C.; Hwang, C.-K.; Smith, A. L.; Wendeborn, S. V. J. Am. Chem. Soc. 1990, 112,
alcohols. In addition, monodeoxygenation of 1,2- and 1,3-diols has been achieved. 7416-7418.

• The accepted mechanism of reduction proceeds by attack of a tin radical on the thiocarbonyl • In the following example, the radical generated during the deoxygenation reaction
sulfur atom. Subsequent fragmentation of this intermediate generates an alkyl radical which
propagates the chain. undergoes 6-exo-trig radical cyclization.

Sn(n-Bu)3 Sn(n-Bu)3
S S S
(n-Bu)3Sn
R +
RO R' RO R' O R'
H3 C CH3 1. 1,1'-thiocarbonyl-diimidazole, H3C H3C
DMAP, CH2Cl2, reflux i-Pr H
Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. I 1975, 1574-1585. OH CH3 +
2. AIBN, Bu3 SnH, toluene, 70 °C H i-Pr
Barton, D. H. R.; Motherwell, W. B.; Stange, A. Synthesis 1981, 743-745. H H H

Barton, D. H. R.; Hartwig, W.; Hay-Motherwell, R. S.; Motherwell, W. B.; Stange, A. Tetrahedron 46% (1 : 1 mixture) β-ylangene β-copaene
Lett. 1982, 23, 2019-2022.

Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675-684.

Barton, D. H. R.; Jaszberenyi, J. C. Tetrahedron Lett. 1989, 30, 2619-2622.

Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron Lett. 1990, 31, 3991-3994. Kulkarni, Y. S.; Niwa, M.; Ron, E.; Snider, B. B. J. Org. Chem. 1987, 52, 1568-1576.

Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron Lett. 1990, 31, 4681-4684.

Barton, D. H. R.; Blundell, P.; Dorchak, J.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron 1991, 47,
8969-8984.
N
• Examples N
S O AIBN, Bu3SnH
OH O S O O
toluene, 90 °C O O
HO O HO C10H21 O O C10H21
AIBN, Bu3SnH
H OH H O Im H
xylenes, 140 °C
HO CO2H O O 91%
O S O
quinic acid 40%

Mills, S.; Desmond, R.; Reamer, R. A.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1988, 29, Avedissian, H.; Sinha, S. C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org.
281-284. Chem. 2000, 65, 6035-6051.
Diazene-Mediated Deoxygenation
• In related studies, it was shown that alkyllithium reagents add to N-tert-butyldimethylsilyl aldehyde
• Deoxygenation proceeds by Mitsunobu displacement of the alcohol with tosylhydrazones at –78 °C and that the resulting adducts can be made to extrude dinitrogen in a
o-nitrobenzenesulfonylhydrazine (NBSH) followed by in situ elimination of o-nitrobenzene sulfinic free-radical process.
acid. The resulting monoalkyl diazene is proposed to decompose by a free-radical mechanism
to form deoxygenated products. t-BuSi(CH3)2 t-BuSi(CH3)2 H
N Li N N
• The deoxygenation is carried out in a single step without using metal hydride reagents. N SO2Ar R'Li N SO2 Ar AcOH, TFE N H H
H H
–78 °C –78 → 23 °C R –N2 R R'
• The method is found to work well for unhindered alcohols, but sterically encumbered and R H R R' R'
β-oxygenated alcohols fail to undergo the Mitsunobu displacement and are recovered
unchanged from the reaction mixture. Ar = 2,4,6-triisopropylbenzene

PPh3 , DEAD, NBSH ≥ 0 °C • Examples 1. TBSOTf, Et3N,

RCH2OH RCH2N(NH2)SO2Ar RCH2 N=NH RCH3 THF, –78 °C
THF, –30 °C –N2 SO2Ar
2. CH 3 CH3 CH3
N CH3 CH 3 CH3
Ar = 2-O2NC6H 4 N H Li Ph
Ph
Ph H Ph
• Examples 3. AcOH, CF3CH2OH, CH3
CH3
–78 → 23 °C
OH
CH3 94%
CH3O CH 3O
CH3 PPh3, DEAD, NBSH CH3 SO2 Ar 1. TBSOTf, Et3N,
N THF, –30 °C N N THF, –78 °C
N H 2. Li CH3
O O O O O CH3
Cl 87% Cl H3 C O H H3 C CH 3 H3 C
H3 C H3 C H3C CH3
O 3. AcOH, CF3CH2 OH, O O
O
• In the following example, the radical generated from decomposition of the diazene intermediate O –78 → 23 °C O
CH3 CH3
underwent a rapid 5-exo-trig radical cyclization. This generated a second radical that was
CH3 CH3
trapped with oxygen to provide the cyclic carbinol shown after work-up with methyl sulfide. 87%

Myers, A. G.; Movassaghi, M. J. Am. Chem. Soc. 1998, 120, 8891-8892.

N N
O CH3 PPh3, DEAD, NBSH, O CH3 1. t-BuLi, ether CH3
2.
THF, –30 °C;
OH OMOM
O2; DMS
CH3 CH3
OH C4 H9
84% I CH3O OCH3

C4 H 9 CH3O OCH3
NN(TBS)Ts
• Monoalkyl diazenes will undergo concerted sigmatropic elimination of dinitrogen in preference to
radical decomposition where this is possible.
CH3O OCH3 3. HCl, CH3OH, THF CH3O OCH3
CH2OH HO
C4 H9 C4 H9
PPh3, DEAD, NBSH 73% CH3
NMM, –35 °C

(–)-cylindrocyclophane F
65%

Myers, A. G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1997, 119, 8572-8573. Smith, A. B., III; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 1999, 121, 7423-7424.
• Reductive 1,3-transposition of allylic alcohols proceeds with excellent regio- and stereochemical Reduction of Alkyl Tosylates
control.
• p-Toluenesulfonate ester derivatives of alcohols are reduced to the corresponding alkanes with
ArSO2NHNH2, H 2N SO2Ar certain powerful metal hydrides.
R4 HO H R4 N
Ph3 P, DEAD H 23 °C
R3 R1 • Among hydride sources, lithium triethylborohydride (Super Hydride, LiEt3BH) has been shown to
–30 °C, 0.5-6 h R3 R1 0.3-2 h rapidly reduce alkyl tosylates efficiently, even thoes derived from hindered alcohols.
R2 R2

OTs OH
H N H
R4 N R4
H H
+ +
R3 R1 –N2 R3 R1
R2 R2 Reductant
LAH 54% 25% 19%
LiEt3BH 80% 20% 0%
• Example

O Ph3P , DEAD O
Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1976, 41, 3064-3066.
HO OH OH
NBSH, NMM
H3C CO2CH3 H3C CO2CH3 • Examples
O O
66%
LiEt3BH, THF;
CH3 CH2OTs CH3 CH3
Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841-4844. H2O2, NaOH (aq)
BnO BnO
• In addition, allenes can be prepared stereospecifically from propargylic alcohols. CH3OH
OH OH

SO2Ar 92%
H OH ArSO2NHNH2 , H2N N H
Ph3P, DEAD 23 °C
R1 R1 Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112,
R2 –15 °C, 1-2 h R2 1-8 h 5290-5313.

• In the following example, selective C-O bond cleavage by LiEt3BH could only be achieved with a
N N H H 2-propanesulfonate ester. The corresponding mesylate and tosylate underwent S-O bond
H cleavage when treated with LiEt3BH.
R1 R2 R1
–N2
R2
H

H3 C HO O
H3C HO O
• Example LiEt3BH, toluene
H 3C 90 °C H3 C

H OH ArSO2NHNH2, H H H
CH3 EtO H OSO 2i-Pr H H
Ph3 P, DEAD CH3 72%
EtO EtO
CH3 –15 °C CH3
OEt H
74% Hua, D. H.; Venkataraman, S.; Ostrander, R. A.; Sinai, G.-Z.; McCann, P. J.; Coulter, M. J.; Xu,
M. R. J. Org. Chem. 1988, 53, 507-515.

Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-4493.

Radical Dehalogenation
• Alkyl bromides and iodides are reduced efficiently to the corresponding alkanes in a free-radical I
O I
chain mechanism with tri-n-butyltin hydride. BzO O
O O
I Bz O
• The reduction of chlorides usually requires more forcing reaction conditions and alkyl fluorides I H3 C O
are practically unreactive. O I
BzO O
O O O
O
• The reactivity of alkyl halides parallels the thermodynamic stability of the radical produced and I Bz
H 3C O I
follows the order: tertiary > secondary > primary.
OTBS
• Triethylboron-oxygen is a highly effective free-radical initiator. Reduction of bromides and
iodides can occur at –78 °C with this initiator. 1. Bu3SnH, Et3B, O2

Neumann, W. P. Synthesis 1987, 665-683. 2. K2 CO3, THF, CH3 OH

3. Bu4N+F–, AcOH, THF
Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn.
1989, 62, 143-147.
61%
OTIPS
I CH 3 H3 C
O H3 C
CH3O HO O
HO Bu3 SnH, AIBN, THF O O
O OTIPS HO
H H PhBr, 80 °C H3 C H3 C O
CH3 O H3 C
TIPSO O HO O
H O O O
70% HO
OPMB H 3C O
OTIPS
Cl OPMB
CH3 OH
CH3O
HO
O OTIPS
H H
CH3 Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 2000, 122, 6124-6125.
TIPSO O
altohyrtin A H
• In the following example, the radical generated during the dehalogenation reaction
OPMB undergoes a tandem radical cyclization.
Cl OPMB

Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y. Angew.
Chem., Int. Ed. Engl. 1998, 37, 187-196. CH3
H3 C H3C CH3
Br H
O O Bu3SnH, AIBN
OAc O OH O
H H benzene, 80 °C
AcO HO H 3C H H3 C H
CH3 CH3
5 5
H Br H
61% (±)-capnellene
O O
1. Bu3 SnH, AIBN, PhCH3
H H
H 2. CH3 OH, CH3COCl H
O O
H 64% H parviflorin Curran, D. E.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991-4994.
H3 C H3 C
OAc OH
7 7

Trost, B. M.; Calkins, T. L.; Bochet, C. G. Angew. Chem., Int. Ed. Engl. 1997, 36, 2632-2635.
 Acid Alkane 1. i-BuOCOCl, NMM
CO2H S
2.
N O–Na+
N O N O
Barton Decarboxylation N N
HH H 3. t-BuSH, hν HH H
CH3 CH3
• O-Esters of thiohydroxamic acids are reduced in a radical chain reaction by tin hydride reagents.
H H
O O
• These are typically prepared by the reaction of commercial N-hydroxypyridine-2-thione with
activated carboxylic esters.

O
N RCO2 + R + (n-Bu)3SnH RH + (n-Bu)3Sn
R O N –CO2 N O
S N
+ SSn(n-Bu)3 H
Martin, S. F.; Clark, C. W.; Corbett, J. W. J. Org. Chem. 1995, HH CH3
Sn(n-Bu) 3 60, 3236-3242.
H
O

Barton, D. H. R.; Circh, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939-941. (–)-tetrahydroalstonine
Barton, D. H. R.; Bridon, D.; Fernandez-Picot, I.; Zard, S. Z. Tetrahedron 1987, 43, 2733-2740.

• Examples
• In the following example, the alkyl radical generated from the decarboxylation reaction was
trapped with an electron-deficient olefin. This produced a second radical intermediate that
S O continued the chain to give the stereoisomeric mixture of products shown.
O N AIBN, Bu3SnH
N O THF, reflux
O S
~100% cubane O O
1. i-BuOCOCl, NMM
NH S NH
2.
H2NOC SPy
N O–Na+
Eaton, P. E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1421-1436. HO2C N O N O
O O
3. hν CONH2 CbzNH
• The Barton decarboxylation is known to be stereoselective in rigid bicycles.
O O H CO2Bn O O

H3C CH3 CbzNH H 3C CH3

1. S
O O
H CO2 Bn
N OH
N N
2. t-BuSH, toluene, 80 °C
COCl H
sinefungin analogs
65%

Diedrichs, N.; Westermann, B. Synlett. 1999, 1127-1129. Barton, D. H. R.; Géro, S. D.; Lawrence, F.; Robert-Gero, M.; Quiclet-Sire, B.; Samadi, M. J. Med.
Chem. 1992, 35, 63-67.