A PRIMER TO

Prepared by:

Mr: Mohammed H. Raidah

2008-2009

00972599497541 Brkaa2002@hotmail.com
*Contents:

Introduction to Organic synthesis …………………………………………………3

One group disconnection
disconnection of simple alcohol ………………………………………………….12
disconnection of simple olefins……………………………………………………17
disconnection of aryl ketones…………..………………………………………….18
Two group disconnection ……………………………………………………….21
-Hydroxy carbonyl compounds …………………………………………………21
!- unsaturated carbonyl compounds……………………………………………..23
1,3-dicarbonyl compounds ……………….............................................................24
1,5-dicaronyl compounds…………………………………………………………26
Mannich reaction………………………………………………………………….28
-Hydroxy carbonyl compounds………………………………………………….29
1,2-diol…………………………………………………………………………….33
The Pinacol-Pinacolone rearrangement……………………………………………34
Allan-Robinson reaction…………………………………………………………...36
Bischler-Napieralski reaction………………………………………………………37
Bartoli Indol synthesis…………………………………………………………… .38
Benzilic acid rearrangement……………………………………………………….39
Benzoin condensation……………………………………………………………..39
Birch reduction……………..………………………………………………………40

-2-
 Introduction to Organic synthesis

Synthesis is the process of making a desired compound using chemical reaction. more
often than not, more than one step is involved.

The importance of synthesis :

1. Total synthesis of interesting and/or useful natural products

2. Industrially important compounds
3. Compounds of theoretical interest
4. Structure proof
5. Development of new synthetic methodology
6. Importance to other areas of science and technology

Basic steps of solving synthetic problems :

a. Choice of TARGET MOLECULE (T.M)

b. Consideration of applicable synthetic methodology
c. Design of synthetic pathway
d. Execution of synthesis
-- these steps are highly interactive

Approaching the design of a synthesis (part one)

For simple molecules it can be obvious just by looking at the target structure ,for example:

Br

bromocyclohexane

Bromoalkanes are available from alkenes or from alcohols

Br
HBr

OH Br
PBr3

CO2Me
Esters are available from carboxylic acids by reaction with alcohols
;benzoic acid is available from toluene

methyl benzoate

-3-
 CO2H CO2Me
KMnO4 MeOH
H2SO 4

Approaching the designing of a synthesis (part two)

For more complex molecules , it help to have a formalized , logic-centred approach;

RETROSYNTHETIC ANALYSIS

Retrosynthetic analysis is the process of working backwards from the target molecule to
progressively simpler molecules by means of DISCONNECTIONS and /or
FUNCTIONAL GROUP INTERCONVERSIONS that correspond to know reactions .
When you`ve got to a simple enough starting material (like something you can buy and
usually is cheap) then the synthetic plan is simply to reverse of the analysis . The design
of a synthesis needs to take into account some important factors

1. it hase to actually work

2. In general , it should be as short as possible
3. Each step should be efficient
4. Side products (if formed) and impurities (there always are ) should be easily
separable from the desired product
5. Environmental issues may be relevant
6. There's more than one way to skin a cat

Example retrosynthetic analysis

Target molecule :

OH

Disconnect

B
A

OH OH
SYNTHONS
SYNTHONS

REAGENTS ? ? PhMgBr H
REAGENTS

-4-
 Therefore the target molecule could be synthesized as follows :

OH
Br
i) Mg/Et2O

ii) CHO

What is a synthon?
When we disconnect a bond in target molecule , we are imagining a pair of charged
fragments that we could stick together , like Lego bricks , to make the molecule we
want . these imaginary charged species are called SYNTHONS . When you can
think of a chemical with polarity that matches the synthon , you can consider that a
Synthetic equivalent of the synthon. Thus,

OH O -
+
R H R H

An aldehyde is a synthetic equivalent for the above synthon.

There can be more than one synthetic equivalent for a given synthone, but if you can't
think of one …try a different disconnection.

Always consider alternative strategies.

OH

B
A

OH OH
SYNTHONS
SYNTHONS

Synthetic BrMg
equivalents PhCHO Br Synthetic
?
equivalents

-5-
A second possible synthesis :
OH
Br
i)Mg/Et2O
Ph
ii)PhCHO

similary

OH OH

Ph Ph

O
BrMg
Ph

thus a third possible synthesis is

BrMg
OH
O
Ph
Ph
Besides disconnections , we can also consider functional group interconversion . Our target molecule is
a secondary alcohol ,which could be prepare by reduction of a ketone . this is represented as follows:

OH O
FGI
Ph Ph

DISCONNECT

O Ph

Ph Br

Synthesis number four

O OH
O LiAlH4
i)base
Ph Ph
Ph
ii) Br T.M
Target Molecule
-6-
 Analysis number five :

O
O
Ph
Ph
O

Ph
LiCu 2

Synthesis number five :

O OH
O
t-Bu2CuLi NaBH4 Ph
Ph
Ph
T.M

Disconnecting heteroatoms can also be a good idea:

OH OH H2O

Ph Ph Ph

6th approach :
OH
i) Hg(OAc)2
Ph Ph
ii) NaBH4

There are other possibilities , but let's not bother with any more.

How do you choose which method?

Personal choice .If you have a favourite reagent, or if you are familiar with a
particular reaction (or if you have a strong aversion to a reaction/reagent) then this
will affect your choice .Also you need to bear in mind the efficiency of the reaction
involved, and any potential side reactions (for example ,self- condensation of
PhCOMe in method 4 ).

-7-
 DEFINITIONS
TARGET MOLECULE (T.M) What you need to make
RETROSYNTHETIC ANALYSIS The process of deconstructing the T.M
by breaking it into simpler molecules
until you get to a recognizable SM
STARTING MATERIAL (SM) An available chemical that you can
arrive at by retrosynthetic analysis and
thus probably convert into the target
molecule
DISCONNECTION Taking apart a bond in the T.M to see if
it gives a pair of reagents
FUNCTIONAL GROUP Changing a group in the T.M into a
INTERCONVERSION (FGI) different one to see if it gives accessible
intermediate
FUNCTIONAL GROUP ADDITION Add a functional group to facilitate bond
(FGA) formation ,FGA especially applies in the
case of molecule containing no reactive
functional group
SYNTHON Conceptual fragment that arise from
disconnection
SYNTHETIC EQUIVALENT Chemical that reacts as if it was a
synthon

-8-
Some synthons and synthetic equivalents:

synthon equivalent(s)

RCl ,RBr , RI , ROMs , ROTs

R only when R= alkyl

OH O

R R R R

OH O OH
Br
R R

O O

R R

O O O O
O
R OEt R Cl R O R
R

R RMgBr , RLi , R2CuLi , other organometallic reagents

(alkyl ; NOT"RH+base")

O O O
CO2Et
R R R

make sure you don't lose CH2 group if you represent eg. RCH2 as R
( viz. make sure the product hase the right number of carbon atoms)

-9-
Latent Polarity

Think about some of the reaction we've looked at for carbonyl compounds:

O OH O
A Nu
+
Nu

O
O
B H base
E
O
+
O
E

O O
C Nu
Nu
E
O
+ +
O

Nu
E

ie O
+ + + +

these polarities apply quite generally:

OH Br

+ + + + + +

NR NHR
+ + +
+ + +

- 10 -
 The partial positive and negative charges indicate the latent polarity of the bonds in
a molecule. They help us choose the synthons for key disconnections in a
retrosynthetic analysis . viz.

OH OH
+

Equivalents for synthons with reversed polarity

synthon equivalent(s)

OH O OH
,or Br
R R R R

O O
O O
Br
R R ,or Br
R

O
OEt
Me + sec-BuLi

OEt OEt E OEt

s-BuLi
Li E
(VERY strong base)
ethoxy vinillithium H3O+
EVL
similary from acetylene:
OH O
E
i) base H3O + tautom.
E E
ii) E HgO

- 11 -
 1.One group disconnection

** disconnection of simple alcohol:

disconnection
connection
A + B C A + B

Example.1.1

disconnection
Me OH
+ CN
Me CN OH

Synthesis Me OH
NaCN
O + H + Me CN

T.M
mechanism O + H OH

CN

Example.1.2

Ph
OH Ph
C CH
Me C OH +
CH Me

Synthesis
Ph Ph
base OH
O + H + HC CH
Me Me C
CH

mechanism Ph
HC CH base HC C OH T.M
Me

- 12 -
Example.1.3
Ph
OH
Me Et OH + H3C CH2

Synthesis
Mg/Et2O EtMgBr
EtBr

Ph Ph
OH
O + H + EtMgBr
Me Me Et

mechanism

Ph
T.M
O + H OH
Me

Et MgBr

Example.1.4

Me Me O
C OEt
OH + 2MeMgBr

Synthesis Me Me
O
C OEt OH
+ 2MeMgBr

mechanism
O O
O C OEt C Me T.M
C OEt +
+
Me MgBr Me MgBr

- 13 -
 Alkylhalids
Ketones
Compounds derived from alcohols
Esters

alcohol

Aldehydes Olefins
Example.1.5

OH
OAc FGI
Ph Ph
Ph Ph

O
OH
+ HC OEt
2 Ph
Ph Ph

Synthesis: OH
O
MgBr
2 Ph + HC OEt Ph Ph

mechanism: OH
O
O
Ph H Ph Ph
HC OEt
MgBr
Ph
MgBr
Ph

OAc
OH
Ph Ph
Ph Ph + CH3COOH
T.M

Rem inder:

O O O
SOCl2 R`OH
R C OH R C Cl R C OR`

- 14 -
Example.1.6
OH O
BrMg
H + Ph
Ph

O FGI H OH O
Br
H H + H C H
formaldehyde
cyclopentanecarbaldehyde cyclopentylmethanol

(aldehyde) (alcohol)

Synthesis

Br Mg/Et2O MgBr
O
O H OH
MgBr oxidation H
H C H H

OH
O
BrMg Ph
H + Ph

- 15 -
Example.1.7

Me O
Me O

OH2 O
H OH HO
Me HO + Me
Me O Me
O HO
Me
Me O
H
O
HO 2 H H + H C C H
HO

Synthesis:
O
O Me O
HO Me Me
Me O
H +
2 H C C H HO
H

mechanism: O
O HO
H H HO BaSO4 HO
H C C H H C C HO reduction HO
O Me OH
O Me O
HO Me
Me Me O
HO Me HO

- 16 -
 **disconnection of simple olefins:

Example.1.8

O
Ph FGI OH
Ph + PhMgBr
a
cyclohexanone
b FGI

Ph
no helpful disconnection
OH

Example.1.9

O Ph
FGI Ph
Ph + BrMg
a OH
FGI b

Ph H
Ph
+ BrMg
OH O

another analysis for synthesis:

in example 1.9 the pathway (a) use Wittig reaction instead of Grinard.

Ph Ph Ph
base
Br Ph3P H Ph3P
Ph3P

O PPh3 O PPh3 Ph
+ O PPh3

Ph Ph
R e m in d e r

OH H H
a c id

- 17 -
Example.1.10
OH O
FGI Ph Ph +
Ph H Ph3P
a

b
FGI

Ph H
Ph PPh3 +
O
OH

**disconnection of aryl ketones:

Example.1.11

O O
+
Cl
MeO
MeO

Synthesis: O
O
+ AlCl3
Cl
MeO MeO

mechanism: O
O
O
H
Cl
MeO MeO MeO

- 18 -
 Example.1.12

O O
O
+
O Cl
O
O

OH2
O
HO
H O + H C H
H HO
O

Synthesis

HO O O
+ H C H + H
HO O
O
O O AlCl3 O
+
O Cl
O

Example.1.13

Me Me NO2
NO2
+ Cl
a
O
a b
MeO O MeO

Pathway (b) not occur because NO2 group is electrons withdraw

Example.1.14

O O O
FGI a b
CH + Me I

b
a

O O
CH
+ BrMg + HC CH
Br
COOEt

- 19 -
Example.1.15

N
+ HO CO2 +
NH BrMg
O
O

Example.1.16
OH O
R2 R2 R2 + R2
R1 R1 R1 R1 H BrMg

Example.1.17

MgBr O

OH
+

Synthesis

Br
i) Mg/Et2O i) H3PO4
OH
O ii) H2/Pd
ii)

T.M

Reminder:

acid + H2O
C C
heat
H OH

heat + H2
C C
H H

LiAlH4
O C OH
H

- 20 -
 One group disconnections sum m ary

1. alcohols
R1 R2
R2 OH R 1 MgBr + O
R3 R3

2. O lefins

PPh 3 + O

3. acids
O
R C OH RMgBr + CO 2

4. carbonyl com pounds

O O
Ar C OR ArH + Cl R
O
O
O Et
R CH 2 C R RBr +
R
O

2.Two group disconnection

** -Hydroxy carbonyl compounds

Example.2.1
O O
OH O
+ H
H H

Synthesis:
O

H O
O O O OH O
H Base H H
H H H

- 21 -
Example.2.2

O
O OH
O Ph
+ Ph
Ph O
Ph OH

Synthesis:
O
OH O
O Ph
Ph Ph OH
Ph
O

Reminder:

O
the C group is attached to a carbon atom that has at least one H substituent
(e.g.-CHCHO,-CHCOR, -CHCO2Et ),then electron-withdrawal by the O group
results in such H atom being acidic: C

HO
H OH
C C O C C O
C C O
H2 O H H
H

- 22 -
 ** - unsaturated carbonyl compounds
Example.2.3
O O
O OH O
H + H3C H
H H

Synthesis: O OH O
O O
Base H O H
H3C H H2C H
H2C H

O
OH O
acid H
H heat
T.M

Example.2.4
O OH O O O
+ H3C CO2H
Ph CO2H Ph CO2H Ph H

Synthesis:
O O
O O OH O
base Ph H acid
Ph CO2H heat Ph CO2H
H3C CO2H H2C CO2H
T.M

Example.2.5
O
HO O
O O +
R R
R

Synthesis:
O OH
base O O acid O
O
R heat
R R
R
Exam ple.2.6
OH O

O O O
- 23 -
 ** 1,3-dicarbonyl compounds

O O

+ +
Example.2.7

O O O O O O

Ph Ph Ph
+
Ph Ph OEt Ph

Synthesis:
O O O
O
O Base Ph OEt
Ph Ph Ph
Ph NaOEt
T.M

Example.2.8

Ph Ph
a b b
OEt OEt
Ph + Ph
O O O O
a Ph
EtO OEt
Ph Ph
O O
Ph OEt
O
+
O
Ph
OEt
Ph OEt
O
O
Example.2.9
O O
OEt Ph
Ph OEt + OEt
OEt O
O

Ph O
OEt
EtO OEt
O
- 24 -
Example.2.10

Ph Ph
+ Ph C OEt
Br
O
Ph C OEt
O
Synthesis:
Ph
Base T.M
+ Ph C OEt
Br
O
mechanism:
Ph
T.M
Ph C OEt Br
O

Example.2.11
O
O
O O Me
+
Me H
+ H

O O
Me
EtO H
Synthesis:
O
O
Me base
+ EtO H NaOEt
T.M

- 25 -
 ** 1,5-dicaronyl compounds:
O O

+ + +
Michael addition
O O
O Ph
EtO Ph H 2 Ph
Ph Ph 1 H
Ph
H + 5
O 3
O
H 4
O

Example.2.12

O O O O O O
a b b
R R` R + R` R + R`
H
a

O O

R + R`

Example.2.13
O
O
O O O O
CO2Et
CO Et CO2Et
1 2
3 5 + +
2 4
H

Example.2.14
CN CN
CN
a b b EtO EtO
EtO +
H +
O Ph O O Ph O
O Ph O

a
CN CN
EtO EtO
+ Ph O
+ Ph O
O O

- 26 -
Example.2.15
O O O
CO2Et CO2Et O O
O
5 4 CO2Et
HO CO2Et
Ph Ph 1
3
+ Ph
Ph Ph 2 Ph

Example.2.16
O O O
3 4
1 2
5
O +
O O
O O

Example.2.17
OMe OMe
O
+
O O O
3
1 5
2 4

Example.2.18

O
O O H
H + O
O

- 27 -
Mannich reaction:
O
O O
H R'
R CH3
+ H C H + R'2NH R N
formaldehyde R'

mechanism:
H R'
H R'
R'2NH H N CH2
H O N CH2 OH2
R' R'
O
I Me R CH2
R' O
N CH2 CH2 C R
R'

R' Me H O
R
N CH2 CH C R
R' O

R' Me
I Me was attacked by N thus N bearing +ve charge make easy remove N
R'

Application for mannich reaction

O O O

H N R'
+ CH2O + R'2NH
R'
mechanism:
H R'
H R'
R'2NH H N CH2
H O N CH2 OH2
R' R'
O

I Me
O
R'
N CH2
R'
O
R' Me H O
N CH2
R'

- 28 -
 Example.2.19
O O
O O
Ph 1 2
O Ph Ph +
4 3
5

O O

+ CH2O

remember Mannich reaction

Example.2.20
O O
O
O
NR3
NR2 + CH2 NR2 + CH2 NR2

OH

O O O
H
+ HO CH2 NR2 + HO CH2 NHR2 + CH2O + R2NH

** -Hydroxy carbonyl compounds

Ph OH Ph
O + COOH
C OH
Ph
Ph O or CN

Synthesis:
O Ph OH
CN Ph NaOH
OH C OH
Ph Me H2O
H Ph CN Ph O
T.M

- 29 -
Example.2.21

OH O O
O COOH
2
1 H + + H
C OH or CN C
3
C EtO O
EtO2C O
EtO

C
O
+ EtO H
EtO

Br
EtO
C
O + CH2COOEt

Synthesis:

O O O
C OEt C OEt O C OEt
OEt
H2C OEt
H2C OEt
+ H2C
C C EtO OEt
O O OEt

O O
H
O OEt H C OEt H
C OEt Br
CO2Et CO2Et CO2Et
H2C

OH CN
O
C OH HO/H2O
EtO2C

- 30 -
 Example.2.22

Ph OH O
OH OH + 2PhMgBr
Ph EtO
OH OH

H OH + CN

O
Synthesis:
O
CH2 O CN OH OH
OH CN HO/H2O HO
C
K2CO3 OH
CHO H C H
HO
O
O
OH OH
Ph 2PhMgBr EtO EtOH/H
OH
Ph OH
OH
T.M

Example.2.23

+ CN
HOOC NH H NH
H

+ NH3
H O

Reminder:

NH2 NH2
NH3
RCHO R C CN R C COOH
CN H H

mechanism:

O OH H
CN H HO/H2O
NH3
R C H R C CN R C COOH
R C H R C H
NH NH2 NH2
NH3 NH2

- 31 -
Example.2.24
Ph
Ph Ph
Ph Ph Ph O
O
HO + O
Ph O
Ph Ph
Ph HO Ph
Ph
FGI

Ph
O

2PhCH2MgBr + EtO H OH

Ph
Synthesis:
O OH Ph OH Ph O
CN Ph MgBr CrO3
Ph C H Ph C H
HO/H2O
Ph O O
O OH Ph

Ph
O Ph
+ 2PhCH2MgBr CrO3
H C OEt OH
O
Ph
Ph

Ph H Ph Ph
Ph Ph
Ph O
HO acid
O
+ O
heat
O Ph Ph
Ph Ph
Ph HO Ph
T.M

Reminder:

O OH
LiAlH4
C H

- 32 -
 ** 1,2-diol

Reminder:
HO OH
KMnO4
or OsO4

hydration OH
OH

OH Al2O3
OH

One useful radical reaction is the pinacol reduction:

HO OH
Mg - Hg
O
benzene

HO OH O PPh3
FGI
+
remember Witting reaction

Example.2.25
OH OH
Ph3P
O +
Ph Ph
Ph

Example.2.26

H O H
O CO2Me CO2Me CO2Me
HO CO2Me
+ +
O HO
H H
unsaturated carbonyl

- 33 -
 Example.2.27

O
CO2H
C H + Ph3P CH2 CO2H

O
FG + C H
I

OH
OH

** The Pinacol-Pinacolone rearrangement

HO OH O R4
R1 R4 H
R3
R2 R3 R1 R2

mechanism:

HO OH2 HO O R4
H R1 R4
HO OH R1 R4
R1 R4 R3
R2 R3 R2 R3 R1 R2
R2 R3

Example.2.28

O O
reverse -pinacol OH OH pinacol
2
reduction
rearrangement

Synthesis:

OH OH OH2 OH
Mg - Hg OH
O H+
benzene T.M

- 34 -
A closely allied reductive linking of carbonyl groups is an intramolecular
version with esters, called the acyloin reaction, which again gives
a 1,2-dioxygenated skeleton:

C O
CO2Et
Na
(CH2)n (CH2)n
Xylene
CO2Et CHOH

Example.2.29

CO2Et
CO2Et
O acyloin Diels–Alder
2 +
OH CO2Et
CO2Et

- 35 -
Example.2.30

CO2Et

C
CO2Et CO2Et
+
C
CO2Et CO2Et
CO2Et

OMe OMe OMe

Ph CH2Br

+
HO C
O H
OH

OMe OMe

Synthesis:
Ph3P O
CH3 CH2Br CH2Br
HC C
Br2/light Me2SO4 i) Ph3P H
ii) Base
CHO Ph
iii) Ph
OH OH OMe
OMe

CO2Et OMe
CO2Et
C

C CO2Et

CO2Et

OMe OMe
T.M

- 36 -
 Example.2.31
CO2Et
CO2Et CO2Et
C
O O O +
CO2Et C
CO2Et
CO2Et
Synthesis:
CO2Et
CO2Et
C O
O
C CO2Et

CO2Et T.M

** Allan-Robinson reaction:

Synthesis of flavones

O O
O R'
OH
R' O R
R'CO2Na R
R
O
O

mechanism:

OH O O
H OH OH HO
R'CO2Na
R' R R' O
O R'
R O H
O R
O R R
O O

O R'

R
O

- 37 -
 ** Bischler-Napieralski reaction

Synthesis of dihydro isoquinoline from -phenylethylamide using phosphorus oxychloride.

POCl3
HN N
O R
R

mechanism:

O
HN Cl2P Cl HN N H
N H
O OPOCl2 H
R R R OPOCl2 R OPOCl2

R
Example.2.32

H2C H3C O
OH
FGI
+ Ph3P CH2

Synthesis:

i) Ph3P
Br CH3 Ph3P CH2
ii)base

O PPh3 O PPh3
CH2 CH2

- 38 -
 Example.2.33

O H
N
N N
OH +
H

Synthesis:

O H N N
OH acid
N H heat
+

** Bartoli Indol synthesis

Synthesis of 7-substituted indol from Ortho-substituted nitro benzene and vinyl Grignard
reagent.

i) MgBr

NO2 ii) H3O N

R H

mechanism:

MgBr

O O MgBr
N N N O
N
O
O MgBr O MgBr

H H
H HO H
O MgBr
O
N N N
H H MgBr

- 39 -
 ** Benzilic acid rearrangement

Rearrangment of Benzil to Benzilic acid via aryl migration.

O O
KOH Ar
Ar C OH
C Ar Ar
O OH
Benzil Benzilic

mechanism:
Ar O O O
O OH
Ar Ar Ar Ar
Ar
Ar
C O C OH C O acidic C OH
C Ar Ar workup Ar
O O OH OH
O OH
a proton transfer leads to formation of carboxylate anion

** Benzoin condensation
It's a cyanide-catalyzed condensation of aryl aldehyde to Benzoin.

OH
Ar H CN Ar
Ar
O O
aryl aldehyde Benzoin

mechanism:
O
Ar H CN CN CN CN
-H O Ar
+H Ar
Ar H Ar H Ar
O CN O OH OH Ar H OH

OH OH
CN Proton
Ar Ar
Ar Ar transfer
Reminder: O O

CN
such H bond to Carbon connect with two electron withdrawal groups
Ar H thus this H is Acidic.

OH

- 40 -
 ** Birch reduction

The reduction of aromatic substrates with alkali metal, alcohol in liquid ammonia
, known as “Birch reduction”

1) Benzene ring with an electron donating substituent.

X X
Na,liq,NH3
ROH

X=OR,R,NH2

X X X
X
H
Single Electron Transfere H H
H OR
SET

H H
Radical anion
X X
H
+e- H

H
H OR

2) Benzene ring with an electron withdrawing substituent:

W W

Na,liq,NH3

W=CO2H,CO2R,COR,CONR2,CN,Ar

W W W
W
+e-
+e-

H NH2 H H
H
Radical anion
W W
H NH2

H H

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References:

1) Stuart G. Warren; designing organic synthesis , John Wiley,1978

2) CM3001 Dr.Alan Ford (lab 415) ,text :Willis&Wills organic Synthesis (OUP)

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