NPTEL – Chemistry – Principles of Organic Synthesis
Lecture 1 Base Catalyzed Reactions I
1.1 Principles
The base catalyzed carbon-carbon bond formation is closely related to the carbon-carbon
bond formation from organometallic reagents. In both methods, the negatively polarized
carbon reacts with electrophilic carbon of carbonyl groups and related compounds.
The scope of the base-catalyzed reactions depends on three facts: (i) a wide range of
organic compounds is able to form carbanions, (ii) these carbanions undergo reaction
with electrophilic carbon in a variety of environments, and (iii) the basicity of the reagent
used to abstract the proton may be widely varied.
1.2 Reactions of Enolates with Carbonyl Compounds
1.2.1 Reactions with Aldehydes and Ketones
1.2.1.1 Aldol Condensation
The reaction has become one of the most important methods for carbon-carbon bond
formation. It consists of the reaction between two molecules of aldehydes or ketones that
may be same or different. One of the reactants is converted into a nucleophile by forming
its enolate in the presence of base and the second acts as an electrophile (Scheme 1).
O
O
R''
R'
R'
+ '"R
Base
R''
R
HO R' O
R''
Acid
R"
R' R R"'
R'
If R = H R''
O
R"
R'
R"'
Scheme 1
The geometry ((Z)- or (E)) of the enolate depends on the reaction conditions and the
nature of the substituents. Strong base (e.g. LDA), low temperature and short reaction
time lead to kinetic enolate, while weak base (e.g. hydroxide ion), high temperature and
longer reaction time favour the formation of thermodynamic enolate (Scheme 2)
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O
O
Base
R
R
Me
CH2
"Kinetic enolate"
O
R
O
R
Me
H
R
CH2
"Kinetic enolate"
O
O
+
Me
R
Me
"Thermodynamic
enolate"
Scheme 2
If the reactants are not the same, they can lead to the formation of diastereoisomers and
their distribution depends on the reaction conditions and the nature of the substituents
(Scheme 3).
O
OH
R" +
R'
R
O
R'
O
OH
R'
R"
R
syn
R + R"CHO Base
O
OH
O
OH
R" + R'
R'
R
anti
R"
R
Scheme 3
Under thermodynamic control, the (Z)- and (E)-forms of the enolates are in rapid
equilibrium, and the product distribution is determined by the relative stabilities of the
six-membered chair-shaped cyclic transition states that includes the metal counter-ion
(Scheme 4). Transition sate that leads to the syn product has R in the less stable axial
position, whereas in that leading to anti product both R and R’ are in the more stable
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equatorial position. The latter is therefore of lower energy, leading to a major anti
product.
R'
Base
R
O
R"CHO
R'
Z O M
R
R'
M
O
R"
O
R'
E
R"CHO
R
O M
O
R"
R'
R"
syn / erythro
R'
M
O
O M
R
R
R'
R
Base
O M
R"
R'
R
O
O
O
O
R
O M
R"
O M
R'
R"
R
anti /threo
Scheme 4
In contrast, under kinetic control, the (Z) and (E) enolates are formed rapidly and
irreversibly, and their relative amounts determine the product distribution (Scheme 5).
For examples, for ketone CH3CH3COt-Bu, the (Z)-enolate is normally formed to afford
the syn diasteroisomer as a
O
Me
LDA
OLi
Me
-78 oC
o
-78 C
O
Me
LDA
-78 oC
PhCHO
OLi
Me
PhCHO
O
OLi
Ph
Me
> 98%
O
OLi
Ph +
-78 oC
Me
4
O
OLi
Ph
Me
1
Scheme 5
major product. But, the selectivity falls to 4:1 (syn:anti) when the size of the R is reduced
from t-Bu to isopropyl. This is presumably because of the difference in steric repulsion of
the methyl group with t-butyl and isopropyl groups.
However, there is a general technique to increase the degree of diastereoselectivity. The
enolate can be converted into silyl enol ethers that can be separated by distillation. The
separated silyl enol ethers can then be converted into pure (Z)- or (E)-enoate by treatment
with fluoride ion (Scheme 6).
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R
Me
Base
Me
TMSCl
R
Me
OTMS
O M
Me
R
R
O
Base
Me
R
R + TMSF
O
OTMS
Me
TMSCl
Me
F
R
O M
OTMS
Scheme 6
Asymmetric version of this reaction has also been well explored. For examples, chiral
auxiliaries and chiral catalysts have been used as chiral source for asymmetric aldol
reactions (Scheme 7).
Me
N
S
OH O
S
O
S
TiCl4, TMEDA
Ph
N
S
Me
PhCHO
S
OH O
+ Ph
N
S
Me
97:3
M. T. Crimmins, K. Chaudhary, Org. Lett. 2000, 2, 775.
OHC
+
OHC
OH
L-Proline (catalyst)
OHC
TBS-OTf
Me
P. M. Pihko, A. Erkkila, Tetrahedron Lett. 2003, 44, 7607.
Scheme 7
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Examples:
NaOH
CHO
Me
CHO
Me
H2O Me
86%
M. Haussermann, Helvetica Chimica Acta 1951, 34, 1482.
O
O
O
2% NaOH
Me
Me
Me EtOH
O
+
Me
Me
94
P. M. McCurry, Jr., R. K. Singh, J. Org. Chem. 1974, 39, 2316.
6
1.2.1.2 The Reformatsky Reaction
The enolate generated from an-bromo ester with zinc reacts with an aldehyde or ketone
to give an aldol-type product in diethyl ether (Scheme 8).
O
O
RO
Br
Me Me
Me
OMe Me
RO
OH
Me Me
Me
Zn
Mechanism
O
Br
RO
Me Me
O
Zn
ZnBr
RO
Me Me
RO
Br
O Zn
Me
Me
O
Me
Me
O Me Me
RO
OZnBr
Me Me
H
OMe Me
RO
OH
Me Me
Scheme 8
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Examples:
OH
OEt
Br
CHO
CO2Et
(Other metals can also be used)
O
MeO
MeO
Mn2+, THF
OMe
OMe
79%
Y. S. Suh, R. D. Rieke, D. Reuben, Tetrahedron Lett. 2004, 45, 180.
Me Me
O
OEt
Br
O
O
O
Zn Powder, THF
Ph
Me +
Ph Me
Me Me
HO
CO2Et
Ph Ph
49%
9%
H. Schick, R. Ludwig, K.-H. Schwarz, K. Kleiner, A. Kunath, J. Org. Chem. 1994, 59, 3161.
1.2.1.3 The Perkin Reaction
This process consists of the condensation of an acid anhydride with an aromatic aldehyde
using carboxylate ion (Scheme 9).
O
Me
O
O
Me + ArCHO
i. NaOAc
ii. NaOH
iii. H
COOH
Ar
Mechanism
O
O
O
Me
O
H
O
O
OAc
Me
O
Ar
Me
O
Me
O
O
O
Me
O
Me
Ar
-OAc
O
O
O
O
H
O
O
O
O
Me
Ar
O
OH
Me
O
O
O
Me
O O
-OAc
Ar
Me O
H
O
OH
Ar
HO
-OAc
Scheme 9
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Ar
NPTEL – Chemistry – Principles of Organic Synthesis
1.2.1.4 The Stobbe Condensation
The Stobbe condensation leads to attachment of three carbon chain to a ketonic carbon
atom (Scheme 10).
O
RO2C
O
OR + R
RO2C
Base
R
Acid
CO2H
R
R
Mechanism
H
RO
Base
OR
O
O
O
O
RO
OR
R
RO2C
R
O
O
R
R
O
-OR
OR
RO2C
H
R
O
O
R
Base
RO2C
R
O
R
OH
H
RO2C
R
O
R
O
Scheme 10
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NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
CO2Me
CHO MeO2C
MeO
CO2H
MeO
MeO, MeOH
OH
CO2Me
OH
68%
J. D. White, P. Hrnelar, F. Stappenbeck, J. Org. Chem. 1999, 64, 7871.
CO2Et
EtO2C
CHO
Me Me
CO2Et
t-BuO, t-BuOH
Me Me
COEt
68%
R. Baker, B. H. Briner, D. A. Evans, Chem. Commun. 1978, 410.
1.2.1.5 The Darzen Reaction
The base-catalyzed condensation between an-halo ester and an aldehyde or ketone
affords glycidic ester (Scheme 11).
O
O
O
RO
H
+
X
R'
H Base
X
R'
RO
R"'
"R
O
O
O
O
RO
R"
Base
X
RO
R"
R'
R"' RO
R"
R'"
R'
O
R"'
O
X R'
-X
O
RO
"R
R'
O
R"'
Scheme 11
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NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
O
O
CO2Et
ClCH2-CO2Et
KOtBu, tBuOH
95%
R. Hunt, L. Chinn, W. Johnson, Org. Synth. CV4, 459.
O
O
Br
EtO
O
Me
EtO
O
LDA, THF, HMPA, hexane
70%
F. E. Anderson, H. Luna, T. Hudlicky, L. Radesca, J. Org. Chem. 1986, 51, 4746.
1.2.1.6 The Knoevenagel Reaction
The condensation of methylene group bonded with two electron withdrawing groups with
aldehydes or ketones using weak base is known as the Knoevenagel reaction (Scheme
12). The reaction is more useful with aromatic than with aliphatic aldehydes.
EWG H
+ O
EWG H
R
RNH2
H
R
EWG H RNH2
EWG H
EWG
EWG H
O
H
EWG
EWG
R
EWG
H
R O
EWG H
H
RNH3
EWG
R
R OH
EWG H
EWG
H RNH2
EWG
Scheme 12
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NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
CHO
CN
CH2(CN)2
CN
KOH, bmim PF6
96%
P. Formentin, H. Garcia, A. Leyva, J. Mol. Catal. A: Chem. 2004, 214, 137.
O
H
CH2(CO2H)2
Pyridine
CO2H
46%
P. J. Jessup, C. B. Petty, J. Roos, L. E. Overman, Org. Synth. CV6, 95.
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NPTEL – Chemistry – Principles of Organic Synthesis
Problems:
What products would you expect from the following reactions? Provide mechanism.
CH2(CO2Me)2
1.
OHC
piperidine
Me
CHO CH (CO H)
2
2 2
2.
pyridine
OMe
CO2Me
CO2Me
3.
MeO
CHO
t-BuO
t-BuOH
CHO
CO2Et
4.
CO2Et
cat.
O
OHC
5.
NaH, Ph-H
Hydrolysiis
N
H
Me
+ H
Me
TBS-OTf
Me
O
CHO
CO2H
O
O
6.
EtCO2Na
CF3
7.
F3C
O
O
O
O
AcO2Na
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Text Books:
R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New
York, 2009.
B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic
Synthesis, Wiley Interscience, New Jersey, 2005.
J. March, Advanced Organic Chemistry, 4th ed, Wiley Interscience, Yew York, 1992.
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NPTEL – Chemistry – Principles of Organic Synthesis
Lecture 2 Base Catalyzed Reactions II
1.2.2 Reactions with Esters and Analogues
1.2.2.1 The Claisen Condensation
The condensation of between esters is known as the Claisen condensation. It is important
to note that an equivalent amount of base must be employed for this reaction (Scheme 1).
i. Base
O
O
R
ii. R"
O
OR"'
iii. H
H
OR'
R"
R
OR'
R" = a group that can not form an enolate
O
Mechanism
O
O
R
H
Base
OR'
H
O
R
R"
O
OR"'
OR'
H
O
R
OR'
H
R"
R'"O O
R
OR"' + H
OR'
R"
O
-R"'OH
*The reaction with a mixtue of esters each of which
contains-hdyrogen may yield four products
O
O
R
OR'
R"
H
O
workup R
OR'
R"
O
Scheme 1
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NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
CO2Et +
EtO2C
CO2Et
CO2Et
O
NaOEt
Toluene, Et2O
L. Friedman, E. Kosower, Org. Synth. CV3, 510.
CO2Et
CO2Et
CO2Et
91%
O
Me
MeO
MeO OMe
O
MeO
O
MeO
Me
O
O
O
Me
Me Conc. HCl MeO
MeO OMe
O
NaOMe
A. G. Cameron, A. T. Hewson, M. I. Osammur, Tetrahedron Lett. 1984, 25, 2267.
1.2.2.2 Dieckmann Condensation
Condensation of the diesters of having C6 and C7 can be accomplished to afford five and
six membered cyclic -ketoesters (Scheme 2). The diesters of short-chain do not show
cyclization, while diesters with C8 and C9 provide the cyclized products in fewer yields.
Base
H
O
H
OR RO
O
O
O
RO
Mechanism
H
O
H
OR RO
Base
O
H
O
H
O
ORRO
O
RO
H
O +
OR
O
O
RO
RO
Scheme 2
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O
O
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NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
Me
NaH, cat. EtOH
benzene
Hydrolysis
EtO2C
Me
77%
Me
EtO2C
Me
O
D. P. Provencal, J. W. Leahy, J. Org. Chem. 1994, 59, 5496.
O
Na, Cat. EtOH
CO2Et Toluene
EtO2C
CO2Et
H
P. S. Pinkney, Org. Synth. CV2, 116.
81%
1.2.2.2 The Thorpe-Ziegler Reaction
The cyclization of dinitriles using base can be accomplished (Scheme 3). Although it is
similar to the Dieckmann reaction, the former is often better compared to the latter.
Base
H
H CN
NC
H
NC
H CN
Base
H
H
C
N
CN
H2N
C
N
N
CN
HN
H
CN
H2N
Scheme 3
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CN
NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
CN
NaH
CN
CN
NH2
J. J. Bloomfield, P. V. Fennessey, Tetrahedron Lett. 1964, 5, 2273.
Me
CN
CN
S
Me
EtO
DMSO
CN
S
NH2
Me
Me
G. Seitz, H. Monnighoff, Tetrahedron Lett. 1971, 12, 4889.
1.2.2.3 Enamines
The reaction of secondary amine with aldehyde or ketone that contains an -hydrogen
atom affords enamine (Scheme 4). The process is driven to right by removing the water
as it is formed, either by azotropic distillation or with molecular sieves.
O
R
R
+ R"2NH
R'
NR"2
HO NR"2
R
R'
RH
RH
-H2O
R'
R
Scheme 4
Similar to the enolates derived from ketones, enamines react with acid chlorides to give
imine derivative that could be hydrolyzed to -diketones (Scheme 5).
R2N:
R2N
O
Cl
R2N
O Cl
-Cl
O
O
O
H2O, H+
-R2NH
Scheme 5
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NPTEL – Chemistry – Principles of Organic Synthesis
In case of unsymmetrical ketones, less substituted enanime forms as a major product
(Scheme 6).
N
N
O
-H2O
+
+
N
H
10%
90%
Scheme 6
1.3 The Alkylation of Enolates
Enolates, like other nucleophiles, also undergo reaction with alkyl halides and sulfonates
with the formation of carbon-carbon bonds. Depending on the reaction conditions and
nature of the substrates, the reaction can occur either at oxygen atom or carbon atom of
enolate (Scheme 7).
CH3 X
O
O
CH3
-X
Et
COEt
O
Base
COEt
COEt
O
O
EtI
CO2Et
CO2Et +
O
71%
OEt
13%
Scheme 7
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NPTEL – Chemistry – Principles of Organic Synthesis
1.3.1 Alkylation of Monofunctional Compounds
Depends on the reaction conditions (kinetic vs thermodynamic control), enolate can be
selectively alkylated (Scheme 8).
O
Me
O
Me
O
Me
LDA
MeI
Me
Me
t
BuO
MeI
Scheme 8
Kinetic control with LDA: Proton abstraction takes place at less hindered -CH position
and the reaction is faster and essentially irreversible.
Thermodynamic control with tBuOK: equilibration takes place between the two enolates
and the methyl-substituted one, being the more stable, is present in high concentration.
However, when the highly substituted position is strongly sterically hindered, alkylation
with tBuOK occurs at the less sterically substituted carbon (Scheme 9).
O
O
t
BuOK
Me
MeI
Scheme 9
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NPTEL – Chemistry – Principles of Organic Synthesis
1.3.2 Alkylation of Bifunctional Compounds
A C-H bond adjacent to two electron withdrawing groups is more acidic than that
adjacent to one electron withdrawing group and the alkylation could be carried out in
milder conditions (Scheme 10).
CO2Et
CO2Et
EtO
Br
CO2Et
CO2Et
CO2Et
CO2Et
-EtOH
KOH, H
CO2H
180 oC
CO2H
CO2H
-CO2
Scheme 10
1.4 Addition of Enolates to Activated Alkenes
Enolates undergo addition to alkenes that are activated by conjugation to carbonyl, ester,
nitro and nitril groups (Scheme 11). These reactions are usually referred to as Michael
addition.
CO2Et
CO2Et
+ Ph
OEt
CO2Et
EtO
Ph
O
CH3NO2 + Ph
OEt
EtOC
OEt
O
EtO
OEt
O2N
Ph
O
O
Scheme 11
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NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
O
O
O
NaH
O
DMF
O
55%
O
D. M. Gordon, S. J. Danishefsky, G. K. Schulte, J. Org. Chem. 1992, 57, 7052.
CO2Et
CO2Et
NaH
EtOH
H2C
O
O 76%
Me
Me
S. Nara, t. Toshima, A. Ichihara, Tetrahedron 1997, 53, 9509.
1.5.1 Reactions Involving Alkynes
Acetylene and its monosubstituted derivatives are more acidic than alkenes and alkanes
and take part in reactions with both carbonyl-containing compounds and alkyl halides in
the presence of base (Scheme 12).
H
H
Na-NH3
Br
H
-Br
O
H
H
Na-NH3
H
Me
H
Me
O
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H
H
OH
Page 20 of 25
NPTEL – Chemistry – Principles of Organic Synthesis
Application
Cl
+
H
NaNH2
Cl
-NaI
I
KCN
CO2H
H
reduction
CO2H
Oleic Acid
Scheme 12
1.5.2 Reactions of Cyanides with Alkyl Halides and Sulfonates
HCN, like acetylene, is a weak acid whose anion may be generated by base and is
reactive towards primary and secondary alkyl halides and sulfonates to give the
corresponding nitriles. It is more convenient to introduce the cyanide as cyanide ion (e.g.
NaCN, TMSCN) rather than as HCN. These reactions provide a way of extending
aliphatic carbon chains by one carbon atom. Scheme 13 summarizes some of the useful
transformations.
Cl
OH
Cl
CN
CO2
CO2H
Br
CuCN/Pyridine
Heat
CO2
N
CN
SnCl2-HCl
H2O
Ca2+
OH
O2C
CHO
CO2
O2C
CO2
-CaCl2 2HCl
HO2C
CO2H
Reduction
NH2
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Ca2+
NPTEL – Chemistry – Principles of Organic Synthesis
Mechanism for Stephen Aldehyde Synthesis (Stephen Reduction)
R
Cl
HCl
N:
R
N H + Cl
R
HCl Cl
..
N
H
H
N Cl
H
R
H
SnCl2
H
N
2SnCl4
H
R
H2O
RCHO
H
H N H
proton
H .. H
N
R
transfer
R
O
H
H
H
H
O
H
Scheme 13
1.2.2.5.2.2 Reactions of Cyanides with Carbonyl Compounds
Cyanide ion adds to aldehydes and ketones to give cyanohydrins that can be hydrolyzed
to-hydroxy acids (Scheme 14).
O
R
CN
R
OH
O
R
R
H
CN
R
R
H
CN
OH
R
R
COOH
Scheme 14
Asymmetric version of the process is also well explored. For example, chiral main chain
polymer having Ti(VI) has been found to be an effective recyclable catalyst to obtain the
cyanohydrin with up to 88% ee (Scheme 15).
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O
R
H
OH
2 equiv TMSCN
R * CN
OH
OH
95%, ee 60%
n = 15
OH
OH
CN
OCH3
OC2H5
OC3H5
95%, ee 88%
91%, ee 78%
90%, ee 75%
OH
OH
OH
CN
Br
CN
90%, ee 75%
OH
CN
CN
n
OC8H17
Ti* R' = -(CH2)4-
CN
Cl
3HCO
OH
CN
CN
17HO8C
N Ti N
O
O
O
Yield 90-97%
ee 55-88%
R = alkyl, aryl
O R'
R'
1 mol % Ti*
CHCl3, 0 °C, 48 h
CN
3HC
OH
3HC
CN
3HC
93%, ee 66%
90%, ee 55%
90, ee 74%
97%, ee 68%
97%, ee 78%
S. Sakthivel, T. Punniyamurthy, Tetrahedron: Asymmetry 2010, 21, 2834
Scheme 15
Imine that can be prepared from amine and aldehyde readily undergoes reaction with
cyanide ion to give -amino nitrile which can be hydrolyzed to amino acid (Strecker
synthesis) (Scheme 16).
O
R
+ HCN
H + R'NH2
AcOH
R'
HN
O
OH
R
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NPTEL – Chemistry – Principles of Organic Synthesis
Mechanism
:O:
R
OH
R"NH
.. 2
H
R
H
H
OH
H
"RH2N R
..
"RHN
OH2
H
R
"R
-H2O
CN
H
N
H
H
R"
N
R
N:
R
H
R"
N
H
H
O
NH2
R
R"
N
OH
H
N
H
R
R"
N
OH2
H
N
H
R
R
H2O
N
H
H
R"
N
N
H
R
H2O
H
R"
N
H
H
R"
N
H
H
R"
N
H
H
O
NH2
R
R
OH
NH2
OH2
R"
N
H
H
R
OH
NH3
OH
-NH3
H
R"
N
O
OH
R
Scheme 16
Example:
O
H
N
HN
Ph
NH
NH2
N
NH
HN
O 2 mol%
N
OMe
CN
OMe
HCN, MeOH
M. S. Iyer, K. M. Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem. Soc. 1996, 118, 4910.
Problems:
A. How would you use base-catalyzed reactions in the synthesis of the following compounds?
CN
1
O
CO2H
3
O
O
2
CO2Et
4
O
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Page 24 of 25
NPTEL – Chemistry – Principles of Organic Synthesis
B. Rationalize the following reactions.
Me
O
Me
1.
i. NaNH2, C6H6
OEt
O
MeO
CO2Et
MeO
ii.
iii. Hydrolysis
2.
O
EtO2C
EtO2C
NaOEt
CO2Et
C6H6
S
OMe
S
CO2Me
MeO
3.
+
NaH/THF
O
NC
CN
Text Books:
R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New
York, 2009.
B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic
Synthesis, Wiley Interscience, New Jersey, 2005.
J. March, Advanced Organic Chemistry, 4th ed, Wiley Interscience, Yew York, 1992.
Joint initiative of IITs and IISc – Funded by MHRD
Page 25 of 25