a primer to designing organic synthesis
DESCRIPTION
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 interactiveTRANSCRIPT
محن الرحيممحن الرحيممحن الرحيممحن الرحيمبسم اهللا الربسم اهللا الربسم اهللا الربسم اهللا الر
A PRIMER TO
Prepared by:
Mr. Mohammed H. Raidah
2008-2009
[email protected] 00972599497541
- 2 -
*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
β-Hydroxy carbonyl compounds …………………………………………………21
α-β unsaturated carbonyl compounds……………………………………………..23
1,3-dicarbonyl compounds ……………….............................................................24
1,5-dicaronyl compounds…………………………………………………………26
Mannich reaction………………………………………………………………….28
α-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
- 3 -
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:
Bromoalkanes are available from alkenes or from alcohols
Esters are available from carboxylic acids by reaction with alcohols
;benzoic acid is available from toluene
Br
bromocyclohexane
HBrBr
OHPBr3
Br
CO2Me
methyl benzoate
- 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
AB
OHSYNTHONS
REAGENTS ? ?
OH
PhMgBr
O
H
SYNTHONS
REAGENTS
CO2H CO2Me
KMnO4 MeOH
H2SO4
- 5 -
Therefore the target molecule could be synthesized as follows :
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,
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.
Bri) Mg/Et2O
ii) CHO
OH
R H
O
R H
OH
≡ δ+
δ-
OH
AB
SYNTHONS
Syntheticequivalents
OH
PhCHO BrMg
OH
Br?
SYNTHONS
Syntheticequivalents
- 6 -
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:
Ph
OHFGI
Ph
O
DISCONNECT
Ph
O
Ph
O
Br
Synthesis number four
Ph
Oi)base
ii) Br
Ph
OLiAlH4
Ph
OH
T.M
Target Molecule
A second possible synthesis :
Bri)Mg/Et2O
ii)PhCHOPh
OH
similary
Ph
OH
Ph
OH
≡ ≡
Ph
O
BrMg
thus a third possible synthesis is
Ph
O BrMg
Ph
OH
- 7 -
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 ).
Analysis number five :
Ph
O
Ph
O
Ph
O
LiCu 2
Synthesis number five :
Ph
Ot-Bu2CuLi Ph
O
NaBH4 Ph
OH
T.M
Ph
OH
Disconnecting heteroatoms can also be a good idea:
Ph
OH H2O
Ph
6th approach :
Phi) Hg(OAc)2
ii) NaBH4Ph
OH
- 8 -
DEFI.ITIO.S
What you need to make TARGET MOLECULE (T.M)
The process of deconstructing the T.M
by breaking it into simpler molecules
until you get to a recognizable SM
RETROSYNTHETIC ANALYSIS
An available chemical that you can
arrive at by retrosynthetic analysis and
thus probably convert into the target
molecule
STARTING MATERIAL (SM)
Taking apart a bond in the T.M to see if
it gives a pair of reagents
DISCONNECTION
Changing a group in the T.M into a
different one to see if it gives accessible
intermediate
FUNCTIONAL GROUP
INTERCONVERSION (FGI)
Add a functional group to facilitate bond
formation ,FGA especially applies in the
case of molecule containing no reactive
functional group
FUNCTIONAL GROUP ADDITION
(FGA)
Conceptual fragment that arise from
disconnection
SYNTHON
Chemical that reacts as if it was a
synthon
SYNTHETIC EQUIVALENT
- 9 -
Some synthons and synthetic equivalents:
synthon equivalent(s)
R
R R
OH
R R
O
R
OH OH
R
O
RCl ,RBr , RI , ROMs , ROTsonly when R= alkyl
Br
R
O
R
O
R
O
R OEt
O
R Cl
O
R O
O
R
O
R
(alkyl ; NOT"RH+base")RMgBr , RLi , R2CuLi , other organometallic reagents
R
O
R
O
R
O
CO2Et
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)
- 10 -
Latent Polarity
Think about some of the reaction we've looked at for carbonyl compounds:
AO OH O
OO
O
O
Nu
Nuδ+
δ−
H baseB
E
E
O
δ+
δ−
δ−
C NuNu
O
E
Nu
O
E
O
δ+
δ−
δ−δ+
ie O
δ+ δ+δ+δ+δ− δ−δ−
δ−
these polarities apply quite generally:
OH
δ+δ+δ+δ− δ−δ−
δ−
δ−
Br
δ+δ+δ+δ− δ−δ−
δ−
δ−
NR
δ+δ+δ+δ− δ−δ−
δ−
δ−
NHR
δ+δ+δ+δ− δ−δ−
δ−
δ−
- 11 -
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
δ+
δ−
δ−
OH
Equivalents for synthons with reversed polarity
synthon equivalent(s)
R R
OH
R
O
Me
O
O
R RBr
OH
,or
RBr
O
,or
OO
RBr
OEt
+ sec-BuLi
OEt
(VERY strong base)
OEt
Li
EOEt
E
H3O+
E
O
ethoxy vinillithiumEVL
similary from acetylene:
i) base
ii) E
EH3O
+
HgO E
OHtautom.
s-BuLi
- 12 -
1.One group disconnection
:nection of simple alcoholdiscon **
A + B Cconnection
disconnectionA + B
Me OH
Me CN OH + CN
disconnection
Synthesis
O + +H NaCNMe OH
Me CN
mechanism O + H OH
CN
T.M
Example.1.1
Example.1.2
Me C
OHPh
CH
Ph
Me
OH +C CH
SynthesisPh
Me
O + H + HC CHbase
Me C
OHPh
CH
mechanism
HC CH baseCHC
Ph
Me
OH T.M
- 13 -
Example.1.3
Me Et
OHPh
OH + H3C CH2
Synthesis
EtBrMg/Et2O EtMgBr
Ph
Me
O + EtMgBrMe Et
OHPh
mechanism
O + H
H +
Ph
Me
OH
Et MgBr
T.M
Me Me
OHC
O
OEt+ 2MeMgBr
C
O
OEt+ 2MeMgBr
Me Me
OH
C
O
OEt C
O
Me
Me MgBr Me MgBr
+C
O
OEt+
T.M
Example.1.4
Synthesis
mechanism
- 14 -
Compounds derived from alcohols
alcohol
Esters
OlefinsAldehydes
KetonesAlkylhalids
Example.1.5
Ph Ph
OAc FGI
Ph Ph
OH
Synthesis:
mechanism:
+ HC OEt
Ph Ph
OH
Ph2 + HC OEt
O
PhMgBr
2O
Ph Ph
OH
PhMgBr
HC OEt
O
PhMgBr
Ph H
O
Ph Ph
OH
Ph Ph
OH
+ CH3COOHPh Ph
OAc
T.M
R C
O
OHSOCl2 R C
O
ClR`OH
R C
O
OR`
Reminder:
- 15 -
Example.1.6
Ph
OH O
H +BrMg
Ph
O
H
FGIOH
H
(aldehyde) (alcohol)
Br
+ H C
O
H
cyclopentanecarbaldehydeformaldehyde
Br Mg/Et2O MgBr
Synthesis
MgBrH C
O
H
oxidation
O
H
O
H +BrMg
PhPh
OH
H
cyclopentylmethanol
OH
H
H
- 16 -
O
O
Me
Me
Example.1.7
O
O
Me
Me
OH2H HO
O
Me
Me
OH
H
HO
HO+ Me Me
O
HO
HO
2 H H
O
+ C C HH
Synthesis:
2 H H
O
+ C C HH
HO
HO
Me Me
O
O
O
Me
Me
mechanism:
C CH H H
O
C C
HOH H
O
HO
HO
BaSO4
reduction
HO
HO
HO
HOMe
MeOO
HO
Me
Me
OHO
O
Me
Me
- 17 -
**disconnection of simple olefins:
Ph FGI OHPh
O
cyclohexanone
+ PhMgBr
Example.1.8
FGI
Ph
OH
no helpful disconnection
a
b
Example.1.9
PhFGI
a
Ph
OH
O
+BrMg
Ph
FGI
Ph
OH
H
O+ BrMg
Ph
b
another analysis for synthesis:
in example 1.9 the pathway (a) use Wittig reaction instead of Grinard.
Ph
BrPh3P
Ph
Ph3P H
base Ph
Ph3P
Ph
PPh3O
Ph
PPh3O Ph + PPh3O
R em in d e r
O H H H
a c id
- 18 -
**disconnection of aryl ketones:
Example.1.10
Ph
FGI Ph
OH
Ph
O
H+Ph3Pa
bFGI
Ph
OH
PhPPh3 +
O
H
Example.1.11
O
MeOMeO
+Cl
O
Synthesis:
MeO
+Cl
O
AlCl3
O
MeO
mechanism:
MeOCl
O
MeO
O
H
O
MeO
- 19 -
Example.1.12
O
O
O
O
O
+
O
Cl
O
O
H
H
OH2
HO
HO
+ H C
O
H
Synthesis
HO
HO+ H C
O
H + H
O
O
O
O+
O
Cl
AlCl3
O
O
O
Example.1.13
O
Me
MeO
NO2
a b
a
Me
MeO
+
O
NO2
Cl
Pathway (b) not occur because NO2 group is electrons withdraw
Example.1.14
O FGIO
CH
O
+ Me I
O
Br+ HC CH
O
COOEt
+CH
BrMg
ab
a b
- 20 -
Example.1.15
N
O
NH+
O
HO CO2 +BrMg
Example.1.16
R1R2 R1
R2 R1R2
OH
R1 H
O
R2BrMg+
Example.1.17
OH
MgBr O
Synthesis
+
Br
Mg/Et2Oi)
ii)O
OHH3PO4i)
ii) H2/Pd
T.M
Reminder:
C C
H OH
C C
H H
O
acid
heat
heat
LiAlH4C OH
H
+
+
H2O
H2
- 21 -
2.Two group disconnection
**β-Hydroxy carbonyl compounds
One group disconnections summary
1. alcohols
2. Olefins
3. acids
R1
R3
OHR2 R1 MgBr +R2
R3
O
PPh3 + O
R C
O
OH RMgBr + CO2
4. carbonyl compounds
Ar C OR
O
ArH +Cl R
O
CH2 C
O
RR RBr +
O
OEt
OR
OH O
H
Example.2.1
αβ H
O
+
O
H
Synthesis:
O
HH Base
O
H
O
HH
OH
O
OH O
H
- 22 -
Example.2.2
Ph
OO
Ph OH
αβ
OH
+Ph
Ph
O
O
Synthesis:
OH
PhPh
O
O
Ph
OO
Ph OH
Reminder:
the group is attached to a carbon atom that has at least one H substituent (e.g.-CHCHO,-CHCOR, -CHCO2Et ),then electron-withdrawal by the group results in such H atom being acidic:
C
O
C
O
C C O
H
HHO
OH
H2O
C C O
H
C C O
Hα
- 23 -
** α-β unsaturated carbonyl compounds
H
O
αβ
Example.2.3
H
OOH
H
O
H3C H
O
+
H3C H
OBase
H2C H
O
αH
O
H2C H
O H
OOH
H
OOHacid
heatH
O
αβ
T.M
Synthesis:
Example.2.4
Ph CO2H
Oβ
αPh CO2H
OH O
Ph H
O
+H3C CO2H
O
Synthesis:
H3C CO2H
Obase
H2C CO2H
OPh H
O
Ph CO2H
OH Oacid
heat Ph CO2H
O
T.M
Example.2.5
R
Oβ α
R
OHO
O
+
R
O
Synthesis:
R
Obase
R
O
O
R
OOH
acid
heatR
O
Example.2.6
α
β
O O
OH
O
O
- 24 -
** 1,3-dicarbonyl compounds
O O
δ+ δ−δ−
δ−δ−
δ−δ+
Ph Ph
O O
Example.2.7
Ph
O
Ph
O
Ph
O
Ph
O
OEt+
Synthesis:
O
Ph
O
Ph
Base
NaOEt
Ph
O
OEtPh Ph
O O
T.M
Ph
O O
OEt
Pha b
Ph
O
Ph
O
OEt
+O
OEt
Ph
O
OEt
Ph
a
b
O
OEt+ Ph
O
Ph
O
OEtPh
O
Ph
Example.2.8
EtO
Example.2.9
Ph
O
O
OEt
OEt
Ph
O
OEt + OEt
O
Ph
O
OEtOEt
O
EtO
- 25 -
Example.2.10
Ph
CPh
O
OEt
Ph
Br+ CPh
O
OEt
Synthesis:
Ph
Br+ CPh
O
OEtBase T.M
mechanism:
CPh
O
OEt
Ph
BrT.M
Example.2.11
H
OO
δ+
δ−
Me
O
Me+
H
O
O
MeEtO H
O
Synthesis:
O
Me
EtO H
O
+base
NaOEtT.M
- 26 -
** 1,5-dicaronyl compounds:
O O
δ+δ−δ+ δ+
δ− δ−
δ− δ− δ−
Michael addition
PhPh
O
H
Oβ
αPh 1
2
O
3
4
5
HPh
O
Ph
O
HPh
O
H
+EtO
R R`
OO
Example.2.12
β
α
a b b
R`
O
R
O
H
+ R
O
R`
O
+
a
R
O
R`
O
+
Example.2.13
OCO2Et
O
1
2
3
45
O
CO2Et
+
O
H
O
CO2Et
+
O
Example.2.14
EtO
OO
CN
Ph
a b EtO
O
CN
Ph O+
EtO
O
CN
Ph O+
H
b
a
EtO
O
CN
OPh+
EtO
O
CN
OPh+
- 27 -
Example.2.15
Ph Ph
CO2Et
O
β
α
Ph Ph
CO2Et
O
HO1
2
3
45
Ph
CO2Et
O
OCO2Et
O
+ Ph
O
Example.2.16
O
Oαβ
1 2
3 4
5
O
OO
O
O
+O
12
3
45
OO
OMe
O
OMe
+
O
Example.2.17
Example.2.18
OO
O
H
O
O
H
+
- 28 -
Mannich reaction:
R CH3
O
+ C
O
H H
formaldehyde
+ R'2NHH
R N
O
R'
R'
mechanism:
R'2NH
H
H OH
R'
N
R'
CH2 OH2H
R'
N
R'
CH2
R CH2
O
C
O
RCH2CH2N
R'
R'
I Me
C
O
RCHCH2N
R'
R'
Me HR
O
was attacked by N thus N bearing +ve charge make easy removeI Me N
R'
R'
Me
Application for mannich reaction
O
+ R'2NH+ CH2OH
O
N R'
R'
O
mechanism:
R'2NH
H
H OH
R'
N
R'
CH2 OH2H
R'
N
R'
CH2
O
CH2N
R'
R'
I Me
CH2N
R'
R'
Me
O
OH O
- 29 -
** αααα-Hydroxy carbonyl compounds
Example.2.19
O
Ph 1O
2
345
O
Ph
O
Ph +
O
O O
+ CH2O
remember Mannich reaction
O
NR3
Example.2.20
O
NR2
O
+ NR2CH2
O
+ CH2
OH
CH2 NR2HO
H
CH2 NHR2HO
O
+
O
+
O
+ CH2O + R2NH
NR2
Ph
Ph
C
O
OH
OH
α
Ph
Ph
O + COOH
or CN
Synthesis:
Ph Me
OCN
H
Ph
Ph
OH
CN
NaOH
H2O
Ph
Ph
C
O
OH
OH
T.M
- 30 -
C
EtO2C
OHO
OH1
2
C3
O
H +COOH
or CN
OEtO
O
HCOEtO
COEtO
+
+ EtO H
O
COEtO
Br+ CH2COOEt
Example.2.21
Synthesis:
OEtC
H2CC
O
O
OEt
OEt
C
H2CC
O
O
OEt
OEt
OEt
EtO OEt
O
+C
H2C
OOEt
C
H2C
OOEt Br
CO2Et
H
CO2Et CO2Et
HH C
O
OEt
O
CN
HO/H2OC
EtO2C
OHO
OH
OEt
- 31 -
Example.2.22
PhOH
OH
Ph OH
OH
OH
O
EtO+ 2PhMgBr
OH
O
H + CN
Synthesis:
CHO
CH2 O
C
O
H
OH
K2CO3
CNC
CN OHHO/H2O
HO
OH
OH
O
HO
EtOH/HOH
OH
O
EtO2PhMgBr
PhOH
OH
Ph OH
T.M
H
RCHO R CH
NH2
CN R CH
NH2
COOH
mechanism:
R C HNH3
NH3
R C
OH
H
NH2
R C H
NH
CNR
HC CN
NH2
HO/H2O RHC COOH
NH2
O
NH3
CN
Reminder:
HOOC NH
H
NHH
+ CN
Example.2.23
OH
+ NH3
- 32 -
Reminder:
O
C
OH
HLiAlH4
Example.2.24
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
HO
HO
OPh
Ph O
+
Ph
Ph
OO
FGI
Ph
Ph
OHEtO H
O
+2PhCH2MgBr
Synthesis:
Ph C H
OCN
Ph H
OH
C
OHO
HO/H2O
Ph MgBrOHPh
Ph O
CrO3OPh
Ph O
H C
O
OEt + 2PhCH2MgBr
Ph
Ph
OHCrO3
Ph
Ph
O
OPh
Ph O
Ph
Ph
O
Ph
Ph
Ph
Ph
HO
HO
H
acid
heat
Ph
Ph
Ph
Ph
O
T.M
+
- 33 -
** 1,2-diol
KMnO4
or OsO4
OHHO
hydration
OH
OH
OH
OH Al2O3
Reminder:
One useful radical reaction is the pinacol reduction:
OMg - Hg
benzene
OHHO
OHHO FGIO
+PPh3
remember Witting reaction
Example.2.25
Ph
OHOH
PhO +
Ph3P
Ph
Example.2.26
O
O
H
H
CO2Me OHO
HO
H
H
CO2Me
+
CO2Me CO2Meα
β
α−β unsaturated carbonyl
+
- 34 -
rearrangementPinacolone -** The Pinacol
R1
R2
R4
R3
OHHOH
R1
R4
R3
O
R2
mechanism:
R1
R2
R4
R3
OHHOH
R1
R2
R4
R3
OH2HOR1
R2
R4
R3
HO
R1
R4
R3
O
R2
Example.2.28
OOH OH
OH
reverse -pinacol
rearrangement
pinacol
reduction
2
O
OMg - Hg
benzene
OH OH
H+OH2 OH
Synthesis:
T.M
Example.2.27
CO2H C
O
H + Ph3P CH2 CO2H
+ C
O
Hα
β
OH
OH
FGI
- 35 -
(CH2)n
CO2Et
CO2Et
Na
Xylene(CH2)n
C O
CHOH
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:
Example.2.29
O
OH
CO2Et
CO2Et
2 +
CO2Et
CO2Et
acyloin Diels–Alder
Mechanism of Acyloin Condensation
R OMe
O
2+ 2Na0
R OMe
O
R OMe
O
+OO
R R
OMeMeO-2NaOMe
OO
R R
Na+ Na+ Na+ Na+
OO
R R
2Na0OO
R R
Na+Na+ OO
R R
Na+ Na+ H2O
-2NaOH
OHHO
R R
tautomerismOHO
R R
- 36 -
Example.2.30
OMe
CO2Et
CO2Et
OMe
CO2Et
CO2Et
OMe
+
C
C
CO2Et
CO2Et
Synthesis:
CH3
OH
Br2/light
CH2Br
OH
Me2SO4
CH2Br
OMe
i) Ph3P
ii) Base
iii) PhCHO
HC
OMe
Ph3P
Ph
C
O
H
OMe
OMe
C
C
CO2Et
CO2Et
OMe
CO2Et
CO2Et
T.M
OMe OMe
HO
CH2Br
OH
+
Ph
CO H
- 37 -
:Robinson reaction-** Allan
Synthesis of flavones
Example.2.31
CO2Et
CO2Et
O
CO2Et
CO2Et
O O +C
C
CO2Et
CO2Et
Synthesis:
OC
C
CO2Et
CO2Et
CO2Et
CO2Et
O
T.M
O
OH
R
R' O R
O O
R'CO2Na
O R'
R
O
mechanism:
O
OH
R
H R'CO2Na
O
OH
R
R' O R
O O
O
OH
R
R'
O
O
O
HO
R'
H
R
O
O
R'
R
- 38 -
&apieralski reaction-chler** Bi
Synthesis of dihydro isoquinoline from β-phenylethylamide using phosphorus oxychloride.
HN
RO
POCl3N
R
mechanism:
HN
RO
Cl2P
O
Cl HN
ROPOCl2
N
R OPOCl2
HN
HR OPOCl2
H
N
RExample.2.32
H2C
FGI
H3COH
O
+ Ph3P CH2
Synthesis:
Br CH3i) Ph3P
ii)basePh3P CH2
O PPh3
CH2
O PPh3
CH2
- 39 -
** Bartoli Indol synthesis
Synthesis of 7-substituted indol from Ortho-substituted nitro benzene and vinyl Grignard
reagent.
Example.2.33
N N
HOH
N
O H
+
Synthesis:
N
O H
+
N
HOH acid
heat
N
mechanism:
N
O
O
MgBr
N
O
O
MgBr
N
O
MgBr
NO
MgBr
NO
H
MgBr
NO
H H
H
MgBr
H HO
N
H
NO2
R
N
H
MgBri)
ii) H3O
- 40 -
** Benzilic acid rearrangement
Rearrangment of Benzil to Benzilic acid via aryl migration.
** Benzoin condensation It's a cyanide-catalyzed condensation of aryl aldehyde to Benzoin.
ArC Ar
O
OKOH Ar
C OH
OH
O
Ar
mechanism:
ArC Ar
O
O
OH
ArC O
O
ArOH
ArC OH
O
O
Ar
ArC O
OH
O
Ar
acidic
workup
ArC OH
OH
O
Ar
a proton transfer leads to formation of carboxylate anion
Benzil Benzilic
HAr
O
CN ArAr
O
OH
Benzoinaryl aldehyde
mechanism:
HAr
O CN
Ar
CN
H
O
Ar
CN
HOH
Ar
CN
OH Ar H
O ArAr
O
OH
CN-H+H
Proton
transferAr
Ar
OH
O
CNAr
Ar
O
OH
Reminder:
Ar
CN
H
OH
such H bond to Carbon connect with two electron withdrawal groups thus this H is Acidic.
- 41 -
** Birch reduction
The reduction of aromatic substrates with alkali metal, alcohol in liquid ammonia
, known as “Birch reduction”
.Benzene ring with an electron donating substituent 1)
Benzene ring with an electron withdrawing substituent: 2)
W
W=CO2H,CO2R,COR,CONR2,CN,Ar
Na,liq,NH3
+e-
W W W
HH NH2
W
H H
+e-
W
H H
H NH2
W
Radical anion
W
X
Na,liq,NH3
ROH
X
X=OR,R,NH2
Single Electron Transfere
SET
X X
H
H
Radical anion
H OR
H
H
H
X
+e-
X
H
H
H
X
H OR
X
- 42 -
References:
1) Stuart G. Warren; designing organic synthesis , John Wiley,1978
2) CM3001 Dr.Alan Ford (lab 415) ,text :Willis&Wills organic Synthesis (OUP)