Chapter 5 Formatio of carbon-carbon bonds:
the use of stabilized carbanions and related
nucleophiles
5.1 Carbanions stabilized by two –M groups
5.2 Carbanions stabilized by one –M groups
5.3 Carbanions stabilized by neibouring
phosphorous or sulfur
5.4 Nucleophilic acylation
1
5.1 Carbanions stabilized by two –M groups
5.1.1
Alkylation
5.1.2
Hydrolysis of the alkylated products: a route to carboxylic
acids and ketones
5.1.3 Acylation
5.1.4
Condensation reaction
5.1.5
The Michael reaction
2
X
CH2 Y
X
Na+ -OR
CH2 Y
X
X
N
H
-
CH YNa+
ROH
-
CH Y
N
H2
3
5.1.1 Alkylation
• Monoalkylation
– Appropriate base
O
EtO
O
O
OEt
EtONa
EtOH
O
EtO
OEt
Na
Br
O
EtO
O
OEt
4
O
O
O
O
EtONa
OEt
EtOH
OEt
Na
Br
O
EtO
O
OEt
5
O
O
O
O
K2 CO3
CH3COCH3
K
I
O
O
6
• Dialkylation
– If the two alkyl groups are identical, ‘one pot’ reaction
may be a choice.
O
O
O
O
2EtONa
EtO
OEt
I
EtO
OEt
7
2NaH
NC
CN
Ph
O
Ph
Br
NC
O
O
OEt
NaH
CH3I
Ph
CN
O
O
OEt
NaH
CH3 I
O
OEt
8
• Dialkylation
– If two different alkyl groups, they may be introduced in
stepwise manner:
• Smaller group first, then bulky group.
• The group having lesser electron-repelling effect first.
O
O
O
O
EtONa
OEt
O
OEt
Br
O
OEt
I
O
EtO
O
OEt
9
O
R
O
O
2NaNH2
1
R
O
R3 X
R1
NH3 liq
R2
R3
1) NaNH2
R
R
R2
O
O
O
R1
R2
O
O
O
Ph
2) PHCH2Cl
10
5.1.2 Hydrolysis of the alkylated products: a
route to carboxylic acids and ketones
O
CH2
O
-CO2
H
HO
HO
O
CH3
O
HO
O
11
• A method for the conversion of halides into carboxylic acids
or ketones
RX
Na+-CH(CO2C2H5)2
1
RX
Na+-CR(CO2C2H5)2
RCH(CO2C2H5)2
1
RR C(CO2C2H5)2
COR
1
RX
Na+-CHCO2C2H5
R1
COR
R2 X
Na+-CR1CO2C2H5
R1
R2
COR
CH
CO2C2H5
COR
C
CO2C2H5
hydrolysis
hydrolysis
hydrolysis
hydrolysis
-CO2
RCH(CO2H)2
RR1C(CO2H)2
R1
R1
R2
-CO2
COR
-CO2
CH
CO2H
COR
C
-CO2
RCHCO2H
RR1CCO2H
R1CH2COR
R1R2CHCOR
CO2H
12
O
O-
O
R1
R
OR
OHR1
R1
-
OH
O
R
OR
OH
RCOOH2
R12COOR
R1
13
?
O
O
O
O
NaOEt
OEt
CH3I
OEt
?
14
5.1.3 Acylation
• A method for the conversion of RCOCl to RCOCH3
CO2C2H5
RCOCl
+
+-
Na HC
CO2C2H5
+
RCOCH(CO2C2H5)2 H
H2O
RCOCH(CO2H)2
-CO2
RCOCH3
-CO2
RCOCH2COOH
15
COCl
C2H5OMg
-CH(COOC2H5)2
COCl
COCH(COOC2H5)2
COCH(COOC2H5)2
C2H5OMg
H2SO4
H2O
COCH3
COCH3
-CH(COOC2H5)2
NO2
NO2
NO2
16
Preparation of ß-keto-ester
+
RCOCH(CO2C2H5)2 H
H2O
CH3COCH2CO2C2H5
CO2H
-CO2
RCOHC
RCOCH2COOC2H5
CO2C2H5
(1) Na, benzene
(2) PhCOCl
H3COC
CHCO2C2H5
PhOC
NH3, H2O NH4+Cl-
PhCOCH2CO2C2H5
17
5.1.4 Condensation reaction
• Knoevenagel condensations
XCH2Y + B-(or B..)
XCHY + BH(or BH+)
RCOR'
R OC
R' CHXY
-H2O
R OH
C
R' CHXY
Addition of a catalytic amount of
organic acid or an ammonium salt
(usually the acetate) used as catalyst
increase the yield.
R
R'
C CXY
18
• Aldehyde
O
O
O
piperidine
O
PhCHO
EtO
EtO
OEt
OEt
Ph
PhCH2NH2
CH2(CN)2
CHO
C
H
O
O
O
C(CN)2
O
O
piperidine
OEt
OEt
19
•Ketone
CN
O
CH2(CN)2
CN
O
CN
NCCH2COOC2H 5
COOC2H5
20
•Variant of Knoevenagel condensations
O
R
O
+
XCHCO2H
R'
pyridine
R
R'
CHX
C
C
OH
O-
heat
E-isomer is usually formed
R
R'
C
CHX
21
O
O
O
OH
HO
OH
O
O
O
CHO
O
OH
HO
OH
N
N
OH
CHO
O
NCCH2COOH
N
N
22
5.1.5 The Michael reaction
O
O
O
2 EtO
O O
OEt
OEt
EtO
EtO
OEt
O
O
O
2 EtO
O
O
O O
OEt
OEt
EtO
OEt
O
EtO
O
23
R2
R2
O
1
R
3
R
C
C
+
4
R
XCH2Y
base
O
R1
3
R
C
CH
CHXY
R4
24
O
O
O O
O
OEt
O
OEt
O
CN
EtO
O
O
OEt
EtO
O
OEt
NC
25
α,β-unsaturated aldehydes may undergo a Knoevenagel-type
condensation or a Michael reaction or (in some cases) both.
O
O
HO
O
O
HO
OH
O
OH
O
HO
O
OH
O
26
5.2 Carbanions stabilized by one –M group
5.2.1 Alkylation
5.2.2 Acylation
5.2.3 Indirect routes to α-alkylated aldehydes and
ketones
5.2.4 Condensation reaction
5.2.5 The Michael reaction
27
5.2.1 Alkylation
• Where the stabilizing –M group is a cyano or an ester group, the reactions
are staightforward.
CN
Br
CCN
O
O
LDA
OEt
CH3CH2I
OEt
28
• Where the stabilizing –M group is ketonic or aldehydic, serious
complications may arise.
– For aldehydes or ketones having only one type α-hydrogen, the
problem can be solved experimently.
O
O
KH
BrCH2CH=C(CH3)2
H
O
O
Ph3CNa
C 2H5Br
29
Choice of experimental conditions:
in an aprotic solvent, by slow addition of the ketone or
aldehyde to a solution of the base (i.e. the base is always in
excess) and then an excess (up to tenfold) of the alkylating
agent must be added rapidly (i.e. so that alkylation is kinetically
the most favoured process).
30
For ketones possessing α-hydrogens on both sides of carbonyl group,
indirect routes may be a good choice.
O
O
O
LDA
PhCH2Br
31
Nitroalkanes usually react at oxygen rather than at carbon.
ONaOC2H5
NO2
O
N+
CH2Br
OH-
O
32
5.2.2 Acylation
• Claisen ester condensation
1
2RCH2CO2R
NaOR1
1
-R OH
RCH2CO(R)CHCO2R1
33
O
O
O
O
NaOEt
OC2H5
OC2H5
OC2H5
O
O
O
O
NaOEt
OC 2H5
Ph
Ph
O
O
CN
OCH3
CN
NaOMe
34
RCHCO2R1
RH2C
R1O
O
R
RH2C CH CO2R1
C
R1O
O
R
CO2R1
RH2C C
H
+
-
OR1
O
R
RH2C C
CO2R1
+
HOR1
O
35
–The reaction is fail with esters of the type R2CHCO2R1.
R
R 2H 2C C
R
O
CO2R1
-OR1
+
R
R 2H 2C C
O
CO 2R 1
+ HOR1
36
– Unsymmetrical ketones with α-hydrogenon both sides of the carbonyl
group are acylated, almost exclusively, at the less-substituted carbon
O
O
O
O
NaNH2
O
OC2H5
O
O
CHO
O
O
NaOMe
H
OC2H5
O
OHC
37
5.2.3 Indirect routes to α-alkylated aldehydes and ketones
5.2.3.1 Routes to α-alkylated aldehydes
– Making use of immines
RCH2CHO
R1NH2
RCH2CH=NR1
C2H5MgBr
or LDA
RCHCH=NR1
R2X
R1=(CH3)3C, (CH3)2N, cyclohexyl
R
R2
CHCHO
H+, H2O R
CH C NR1
H
R2
38
– Making use of dihydro-1,3-oxazines
CH3
RCH2CN + HO
CH3
conc. H2SO4
O
CH3
CH3
HO
RH2C
N
CH3
CH3
R=H: 65% yield;
R=Ph:50%)
n-BuLi, THF, -78oC
CH3
R
CH
R'
O
N
H
CH3
CH3 NaBH4 R
CH3
CH
R'
CH3
O
N
CH3
CH3
R'X
O
RHC
N
CH3
CH3
Li
H+,H2O
CH3
R
CH CHO
R'
+
HO
H2N
CH3
CH3
39
5.2.3.2 Routes to α-alkylated ketones:
‘specific enolates
• Ketone may be converted to α,β-keto-aldehyde.
• β -keto-ester used as starting material
2
(1)NaH
R
X
1
R CH2COCH2CO2R (2)n-BuLi R CHCOCHCO2R
1
R2
R1CHCOCHCO2R
40
• α,β-unsaturated ketone as starting material
R
R2
R1
Li,NH3
O
R3
R5OH(1mol)
R2
R
H
3
R2
R
H
R1
R3
R4X
O-Li+
R2 R4
R
H
R1
O
3
R
R2CuLi
O
R
41
5.2.4 Condensation reactions
• 5.2.4.1
Self-condensation of aldehydes and ketones
HO
1 base
RCH2COR
R
C
RH2C
R1
COR1
C
-H2O
RCH2CR1=C(R)COR1
H
42
NaOH
O
CHO
Ph
Ph
Ph
(C2H5)2NH
O
CHO
OH
O
O
O
Ba(OH)2
O
O
NaOC2 H5
43
OH
OH
CH3CH2CH2CHO
NaOH
Ether
CH3CH2CH2CHCHCHO
C2H5
NaBH4
CH3CH2CH2CHCHCH2OH
C2H5
44
5.2.4.2
Mixed condensation
R1
R
base
O
O
R
CHO
R1
R
CHO
R1
R
CHO
R1
R1
CHO
R
45
• One method
one of the reactants contains the most acidic hydrogen and
the other contains the most electrophilic carbonyl group.
Order of electrophilicity of carbonyl compounds:
aldehyde > ketone > ester
alkyl-CO- > aryl-COOrder of the acidity of α-hydrogens is inverse.
46
• Another methods
• Making use of compounds having no α-hydrogen as
one of the reactant. Aromatic (and heteroaromatic)
aldehydes are particularly useful.
47
O
O
CHO
base
base
O
CHO
O
O
O
O
CHO
O
C2 H 5
O
base
C 2H 5
O
O
CHO
O
O
OH
base
O2 N
O
O2N
48
• Some indirect methods to prepare R2C=CHCHO or
R2C=C(R1)CHO
– Making use of immines
– Making use of dihydro-1,3-oxazines
– Making use of ethoxyethyne
49
 Making use of ethoxyethyne
HO
HC
C
OC2H5
C2H5MgBr
BrMgC
C
OC2H5
(CH3)2CO
C
C
C
OC2H5
H3C
CH3
H2, Pd
OH2
OC2H5
(H3C)2C
C
H
C
(H3C)2C
BrMgC
C
H
C
OC2H5
H+, H2O
H
OH
(H3C)2C
OH
H
H
(H3C)2C
OH2
H
OC2H5
H
CHO
OC2H5
(CH3)2CO
(H3C)2C
C
H
CHO
50
5.3 Carbanions stabillized by neighbouring
phosphorus or sulfur
• 5.3.1
Phosphonium ylides (the Wittig reaction)
R
R
CHBr + PPh3
CH
R1
PPh3Br
base
R2
R3
R
PPh3
R
C
PPh3
R1
R1
C
R
C
PPh3
R1
R
R2
R1
R3
+
R1
O
51
– Non-stabilized ylides (R, R1= hydrogen or simply alkyl,
a mixture of E- and Z-isomers)
CH3Br
PPh3
CH3P +Ph3Br-
NaH
[-CH2----P+Ph3]
O
CH 2
CH3Br
PPh3
CH3P +Ph3Br-
NaNH2 NH3
[-CH2----P +Ph3]
CHO
CHO
CH2
CH2
52
Stabilized ylides (R1 = -M group, e.g. an ester. E-isomer
usually predominates.
BrCH 2COOC2H5
PPh3
Ph3P +CH2COOC2H5BrNaOH
or NaOC2H5
Ph3P+----CHCOOC 2H5
O
O
PhCHO
O
OC 2H 5
N
O
O
OC2H5
OC 2H 5
N
53
5.3.1.3 Steric control in the Wittig reaction
• The ‘salt-Free’ wittig reaction of non-stabilized ylides gives
the Z-alkene as the major product.
– If the aldehyde contains α-substituents, Z-isomer increase.
– Replacement of one of the P-pheny groups by isopropyl, can alter the
steroselectivity, gives the E-isomer as the major product.
• Wittig reaction of non-stabilized ylides may also be modified
to yield predominantely E-alkene.
54
In this modification, the ylide is
prepared by using PhLi and the
O-
O-
PPh3
addition to the aldehyde is
PPh3
R2
carried out at –78oC. Then a
R2
H
R1
second mol. PhLi is added.
H
R1
PhLi
PhLi
HX
O-
OPPh3
PPh3
R1CH2PPh3Br
PhLi
R2CHO
-78oC
R2
H
H
R1
R2
+
R1
H
R2
H
R1
H
H
H
R2
R1
H
55
5.3.2 Sulfonium ylides
(CH3)2 + CH3OH
H2SO4
(CH3)3S+HSO4-
KOH
(CH3)3OH
(CH3)2S+-CH2
RCOR'
R
R
(CH3)2S
R'
+
(H3C)2S
O
R'
O
Ph
(CH3)3S+HSO4-
KOH
PhCHO
H
O
Ph
(CH3)3S+HSO4-
NaH
Ph2CO
Ph
O
Ph
(CH3)3S+HSO4-
NaH
Ph2CS
Ph
S
56
5.4 Nucleophilic acylation
• 5.4.1
The benzoin reaction (condensation)
– KCN or NaCN as the catalyst.
OH
O
KCN
C2H5OH
ArCHO
Ar
Ar
H
– Catalysed by N-substituted thiazolium salts.
R
R
R
R
N
N
base
N
R1CHO
O-
N
OH
S
H
S
S
H
1
S
R
R1
R
N
OH
S
R1
57
Summary

1,3-Dicarbony compounds undergo essentially complete
monodeprotonation at C-2 using bases such as sodium alkoxides. The resulting
carbanions, stablized by both electron-accepting (-M) groups, readily undergo
alkylation and acylation.
 Hydrolysis of β-keto-esters and malonate esters may be followed by
decarboxylation, so that, for example, diethyl malonate and ethyl acetoacetate
are synthetic equivalents of the synthons –CH2CO2H and –CH2COCH3 ,
respectively.
58
 Alkylation and acylation of carbanions require stoichiometric quantities of the
base, whereas condensation reaction require the base only as a catalyst. A
weaker base may be used for condensations and for conjugate additions
(Michael addition) than for alkylations or acylations.
 The formation of carbanions stabilized by only one –M group requires the
use of much stronger bases. Deprotonation jof unsymmetrical ketones may
give a mixture of two carbanions (enolates), but methods for the generation of
specific enolates have been divised. Alkylation and acylation of these
carbanions is achievable;
59
The mechanism of the acylation process (Claisen acylation) permits the use of a
weaker base (a sodium alkoxide) than is predicted in terms of the pKa of the
ketone. α-alkylate aldehydes are best prepared by indirect methods, since selfcondensation of aldehydes occurs readily in basic media. ‘Mixed’ condensations
are synthetically useful only where one reactant contains the most reactive
electrophile in the system and the other contains the most acidic hydrogen
The wittig reaction, involving the reaction of and aldehyde with a
triphenyphosphonium ylide (or phosphorane), gives an alkene and
triphenyphosphine oxide. The stereoselectivety in this reaction can be
manipulated by variation of the reaction conditions.
60
 Sulonium ylides react in a different way with aldehydes and ketones, the
products being oxiranes (epoxide).
Aldehydes and ketones are readily convertible into 1,3-dithianes, the
carbanions derived from these may then be alkylated and hydrolysis of the
alkylated species regenerates the carbonyl group. This sequence involves the
Umpolung (reversal of polarity) of the C=O carbon and the process is one of
nucleophilic acylation. Nucleophilic acylating agents are also involved in the
dimerization of aromatic aldehydes to acyloins and in the Stetter reaction.
61
Enols, enamines, arenes and heteroarenes also react as nucleophiles: the
electrophiles with which they react include aldehydes, ketones, carbenes and
iminium salts.
 Some rules for the disconnection of target molecules, tabulated lists of
synthetic equivalents for various synthons and some worked examples are
included at the end of the chapter.
62