1 chapter 5 formatio of carbon-carbon bonds: the use of stabilized carbanions and related...
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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 phos
phorous or sulfur
5.4 Nucleophilic acylation
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5.1 Carbanions stabilized by two –M groups
5.1.1 Alkylation
5.1.2 Hydrolysis of the alkylated products: a route to carboxyl
ic acids and ketones
5.1.3 Acylation
5.1.4 Condensation reaction
5.1.5 The Michael reaction
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X CH2 Y Na+ -OR X -CH YNa+ ROH
X CH2 Y X -CH YNH
NH2
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5.1.1 Alkylation• Monoalkylation
– Appropriate base
EtO OEt
O OEtONa
EtOH EtO OEt
O O
Na
Br
EtO OEt
O O
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OEt
O OEtONa
EtOH OEt
O O
Na
Br
EtO OEt
O O
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O OK2CO3
CH3COCH3
O O
K
I
O O
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• Dialkylation
– If the two alkyl groups are identical, ‘one pot’ reaction may be a choice.
EtO OEt
O O2EtONa
EtO OEt
O O
I
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2NaH
Ph BrNC CN
NC CN
PhPh
OEt
O O
NaH
CH3I OEt
O O
OEt
O O
NaH
CH3I
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• Dialkylation– If two different alkyl groups, they may be introduced in ste
pwise manner:• Smaller group first, then bulky group.• The group having lesser electron-repelling effect first.
OEt
O OEtONa
OEt
O O
EtO OEt
O O
Br
I
OEt
O O
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R
O O2NaNH2
NH3 liqR1
R2
R
O O
R1
R2
R3X
R
O O
R1
R2
R3
O O1) NaNH2
2) PHCH2Cl
O O
Ph
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5.1.2 Hydrolysis of the alkylated products: a route to carboxylic acids and ketones
O
O
O
HO
-CO2
HO OH
CH2
HO O
CH3
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• A method for the conversion of halides into carboxylic acids or ketones
RXNa+-CH(CO2C2H5)2 RCH(CO2C2H5)2
hydrolysis RCH(CO2H)2-CO2 RCHCO2H
R1XNa+-CR(CO2C2H5)2 RR1C(CO2C2H5)2
hydrolysis RR1C(CO2H)2-CO2 RR1CCO2H
R1XNa+-CHCO2C2H5 hydrolysis -CO2 R1CH2COR
COR
R1 CH
COR
CO2C2H5
R1 CH
COR
CO2H
R2XNa+-CR1CO2C2H5 hydrolysis -CO2 R1R2CHCOR
COR
C
COR
CO2C2H5
C
COR
CO2H
R1
R2
R1
R2
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R OR
O O
R1
R1
OH-
OH-
R OR
O- O
R1
R1
OHRCOOH2 R1
2COOR
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NaOEt
CH3IOEt
O O
OEt
O O
?
?
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5.1.3 Acylation
• A method for the conversion of RCOCl to RCOCH3
RCOCl + Na+-HCCO2C2H5
CO2C2H5
H+
H2ORCOCH(CO2H)2
-CO2
RCOCH2COOH-CO2RCOCH3
RCOCH(CO2C2H5)2
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COClC2H5OMg
-CH(COOC2H5)2
COCH(COOC2H5)2H2SO4
H2OCOCH3
COCl
NO2
C2H5OMg
-CH(COOC2H5)2
COCH(COOC2H5)2
NO2
COCH3
NO2
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Preparation of ß-keto-ester
H+
H2OHCRCOCH(CO2C2H5)2
CO2H
CO2C2H5
RCO-CO2 RCOCH2COOC2H5
CH3COCH2CO2C2H5(1) Na, benzene
(2) PhCOClCHCO2C2H5
H3COC
PhOC
NH3, H2O NH4+Cl-
PhCOCH2CO2C2H5
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5.1.4 Condensation reaction
• Knoevenagel condensations
XCH2Y + B-(or B..) XCHY + BH(or BH+)RCOR'
CR O-
R' CHXY
CR OH
R' CHXY
-H2OC
R
R'CXY
Addition of a catalytic amount of
organic acid or an ammonium salt
(usually the acetate) used as catalyst
increase the yield.
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EtO OEt
O OPhCHO
EtO OEt
O O
Ph
piperidine
CHO
CH2(CN)2PhCH2NH2
CH
C(CN)2
OEt
O O
Opiperidine
OEt
O O
• Aldehyde
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•Ketone
O CH2(CN)2
CN
CN
NCCH2COOC2H5
O
CN
COOC2H5
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•Variant of Knoevenagel condensations
R
R'O + XCHCO2H pyridine
CR CHX
R' OH
CO
O-
heat
CR
R'CHX
E-isomer is usually formed
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O
HO OH
O O
OH
O
HO OH
O O
N
CHO
N
OH
O
N
NCCH2COOH
CHO
N
OH
O
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5.1.5 The Michael reaction
EtO OEt
O O
EtO OEt
O O
O 2
OEtEtO
OO
EtO OEt
O O
EtO OEt
O O
O 2
OEt
EtO
O
O
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C C
O
R2
R1
R3 R4+ XCH2Y
baseC CH
O
R2
R1
R3 R4
CHXY
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O
OEt
O O
OEt
O O
O
CN EtO OEt
O O
EtO OEt
O O
NC
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α,β-unsaturated aldehydes may undergo a Knoevenagel-type conde
nsation or a Michael reaction or (in some cases) both.
HO OH
O O
O
HO OH
O O
HO OH
O O
O
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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
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5.2.1 Alkylation
• Where the stabilizing –M group is a cyano or an ester group, the reactions
are staightforward.
CN Br
CCN
OEt
O
LDA
CH3CH2I OEt
O
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• Where the stabilizing –M group is ketonic or aldehydic, serious complications may arise.
– For aldehydes or ketones having only one type α-hydrogen, the pr
oblem can be solved experimently.
O
H
KH
BrCH2CH=C(CH3)2
O
O
C2H5Br
Ph3CNa
O
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Choice of experimental conditions:
in an aprotic solvent, by slow addition of the ketone or a
ldehyde to a solution of the base (i.e. the base is always in exce
ss) and then an excess (up to tenfold) of the alkylating agent mu
st be added rapidly (i.e. so that alkylation is kinetically the most
favoured process).
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For ketones possessing α-hydrogens on both sides of carbonyl group, indirect routes may be a good choice.
PhCH2Br
LDA
OO
O
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Nitroalkanes usually react at oxygen rather than at carbon.
NO2
NaOC2H5
CH2Br
ON+
O-
OH-
O
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5.2.2 Acylation
• Claisen ester condensation
2RCH2CO2R1 NaOR1
RCH2CO(R)CHCO2R1-R1OH
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OC2H5
O
OC2H5
ONaOEt
OC2H5
O O
OC2H5
O
Ph
ONaOEt
O
Ph
O
OCH3
O
NaOMe
O
CNCN
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RCHCO2R1
ORH2C
R1OC
RH2C CH
R1O O
R
CO2R1
C
O
R
CO2R1
HRH2C
+ -OR1
C
O
R
CO2R1RH2C
+ HOR1
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–The reaction is fail with esters of the type R2CHCO2R1.
CO
RCO2R1
RR2H2C + -OR1
CO
RCO2R
1R2H2C
+ HOR1
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– Unsymmetrical ketones with α-hydrogenon both sides of the carbonyl group are acylated, almost exclusively, at the less-substituted carbon
OC2H5
O ONaNH2
O O
O O
H OC2H5
O
NaOMe
O
O
CHO
O
OHC
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5.2.3 Indirect routes to α-alkylated aldehydes and ketones
5.2.3.1 Routes to α-alkylated aldehydes
– Making use of immines
RCH2CHOR1NH2 RCH2CH=NR1 C2H5MgBr
or LDARCHCH=NR1
R2X
RCH
R2CH
NR1H+, H2ORCHCHO
R2
R1=(CH3)3C, (CH3)2N, cyclohexyl
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– Making use of dihydro-1,3-oxazines
RCH2CN +CH3
HO
CH3HOCH3
conc. H2SO4CH3
O
CH3NCH3
RH2C
R=H: 65% yield;R=Ph:50%)
n-BuLi, THF, -78oC
CH3
O
CH3NCH3
RHC
Li
R'X
CH3
O
CH3NCH3
CHR
R'
NaBH4
CH3
O
CH3NH
CH3CH
R
R'
H+,H2O
CHR
R'CHO +
CH3
HO
CH3H2NCH3
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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
R1CH2COCH2CO2R (1)NaH(2)n-BuLi R1CHCOCHCO2R R2X
R1CHCOCHCO2R
R2
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• α,β-unsaturated ketone as starting material
O
R
R1
R2
R3
Li,NH3
R5OH(1mol) O-Li+
R
H
R2
R3R1
O
R
H
R2
R3
R2CuLi
R4X
O
R
H
R2
R3R1
R4
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5.2.4 Condensation reactions
• 5.2.4.1 Self-condensation of aldehydes and ketones
RCH2COR1 baseC C
HO
RH2CR1
R
H
COR1 -H2ORCH2CR1=C(R)COR1
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ONaOH
CHO
PhO
(C2H5)2NHPh Ph
CHO
OBa(OH)2
OH O O
O
NaOC2H5
O
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CH3CH2CH2CHONaOH
EtherCH3CH2CH2CHCHCHO
OH
C2H5
NaBH4 CH3CH2CH2CHCHCH2OH
OH
C2H5
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5.2.4.2 Mixed condensation
RO
R1
Obase
R CHO
R
R1 CHO
R1
R CHO
R1
R1 CHO
R
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• 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-CO-
Order of the acidity of α-hydrogens is inverse.
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• Making use of compounds having no α-hydrogen as o
ne of the reactant. Aromatic (and heteroaromatic) ald
ehydes are particularly useful.
• Another methods
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CHO O
base
O
O CHO
O
base
O
O
CHO
base OC2H5
O
OC2H5
O
CHO
baseOH
O
O
O
O2N
O
O2N
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• 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
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Making use of ethoxyethyne
HC C OC2H5C2H5MgBr
BrMgC C OC2H5(CH3)2CO
C C OC2H5C
HO
H3C
CH3
H2, Pd
(H3C)2C OC2H5
HH
OH
H+, H2O(H3C)2C OC2H5
HH
OH2
OH2
(H3C)2C CH
C H
OC2H5
OH
(H3C)2C CH
CHOBrMgC C OC2H5(CH3)2CO
(H3C)2C CH
CHO
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5.3 Carbanions stabillized by neighbouring phosphorus or sulfur
• 5.3.1 Phosphonium ylides (the Wittig reaction)
R
CHBr
R1
+ PPh3
R
CH
R1
PPh3Brbase
R
C
R1
PPh3
R
C
R1
PPh3
R
C
R1
PPh3 +
R2 R3
O
R
R1
R2
R3
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– Non-stabilized ylides (R, R1= hydrogen or simply alkyl,
a mixture of E- and Z-isomers)
CH3BrPPh3
[-CH2----P+Ph3]
NaHCH3P
+Ph3Br-
CH2
O
CH3BrPPh3
[-CH2----P+Ph3]
NaNH2 NH3CH3P+Ph3Br-
CHO
CHO
CH2
CH2
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Stabilized ylides (R1 = -M group, e.g. an ester. E-isomer usually predominates.
BrCH2COOC2H5PPh3
NaOH
Ph3P+----CHCOOC2H5
or NaOC2H5
Ph3P+CH2COOC2H5Br-
PhCHO
N
O
O
OC2H5
O
N
OC2H5
O
OC2H5
O
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5.3.1.3 Steric control in the Wittig reaction
• The ‘salt-Free’ wittig reaction of non-stabilized ylides gives t
he 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.
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In this modification, the ylide is
prepared by using PhLi and the
addition to the aldehyde is carrie
d out at –78oC. Then a second m
ol. PhLi is added.
O-
R2
PPh3
H R1
H
O-
R2
PPh3
R1H
H
R2
R1
H
H
R2
H
H
R1
R1CH2PPh3BrPhLi R2CHO
-78oC +
PhLi
O-
R2
PPh3
R1
H
O-
R2
PPh3
R1
H
PhLi HX
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5.3.2 Sulfonium ylides
(CH3)2 + CH3OHH2SO4 (CH3)3S+HSO4
- KOH
(CH3)3OH(CH3)2S+-CH2
RCOR'
R
R'O(H3C)2S
O
R
R'+(CH3)2S
(CH3)3S+HSO4- KOH PhCHO
O
Ph
H
(CH3)3S+HSO4- NaH Ph2CO
O
Ph
Ph
(CH3)3S+HSO4- NaH Ph2CS
S
Ph
Ph
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5.4 Nucleophilic acylation
• 5.4.1 The benzoin reaction (condensation)– KCN or NaCN as the catalyst.
– Catalysed by N-substituted thiazolium salts.
ArCHOKCNC2H5OH
OH
HAr
Ar
O
N
S
R
H
base N
S
R
R1CHON
S
R
O-
R1
H
N
S
R
OH
R1
N
S
R
OH
R1
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Summary
1,3-Dicarbony compounds undergo essentially complete monodeprotonatio
n at C-2 using bases such as sodium alkoxides. The resulting carbanions, stabliz
ed by both electron-accepting (-M) groups, readily undergo alkylation and acyla
tion.
Hydrolysis of β-keto-esters and malonate esters may be followed by decarbo
xylation, so that, for example, diethyl malonate and ethyl acetoacetate are synth
etic equivalents of the synthons –CH2CO2H and –CH2COCH3 , respectively.
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Alkylation and acylation of carbanions require stoichiometric quantities of the
base, whereas condensation reaction require the base only as a catalyst. A wea
ker base may be used for condensations and for conjugate additions (Michael a
ddition) than for alkylations or acylations.
The formation of carbanions stabilized by only one –M group requires the us
e of much stronger bases. Deprotonation jof unsymmetrical ketones may give
a mixture of two carbanions (enolates), but methods for the generation of speci
fic enolates have been divised. Alkylation and acylation of these carbanions is
achievable;
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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 ket
one. α-alkylate aldehydes are best prepared by indirect methods, since self-cond
ensation of aldehydes occurs readily in basic media. ‘Mixed’ condensations are
synthetically useful only where one reactant contains the most reactive electrop
hile in the system and the other contains the most acidic hydrogen
The wittig reaction, involving the reaction of and aldehyde with a triphenyph
osphonium ylide (or phosphorane), gives an alkene and triphenyphosphine oxid
e. The stereoselectivety in this reaction can be manipulated by variation of the r
eaction conditions.
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Sulonium ylides react in a different way with aldehydes and ketones, the p
roducts being oxiranes (epoxide).
Aldehydes and ketones are readily convertible into 1,3-dithianes, the carban
ions 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.
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Enols, enamines, arenes and heteroarenes also react as nucleophiles: the electr
ophiles with which they react include aldehydes, ketones, carbenes and iminium
salts.
Some rules for the disconnection of target molecules, tabulated lists of synth
etic equivalents for various synthons and some worked examples are included at
the end of the chapter.