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Chapter-5
Synthesis of highly substituted pyrroles
Ethyl-3-amino-5-phenyl-1H-pyrrol-2-carboxylate found to be a useful
intermediate in the synthesis of other nitrogen heterocycles. 27 However Elliott and coworkers
28-29 have described that condensation of aldehyde with aminomalonate gave
3-substituted enamine, which was cyclized in the presence of sodium methoxide to
give 3-amino-4-benzyl-1H-pyrrol-2-carboxylate (Figure-16).
Figure-16
Using a similar approach toward the synthesis of pyrrole (Figure-17), Ning
Chen, et al. 30
were failed to synthesize 2-substituted enamine intermediate from
benzoyl acetonitrile and diethyl aminomalonate using standard conditions such as
azeotropic removal of water, 31
dehydration with molecular sieves or Lawis acid
catalysis(TiCl 4 32 , BF3.OEt 2 )
NH 2
COOEt
Ph
O
CN
EtOOC
EtOOC
EtOOC
NC
N
H
Ph
EtOOC
H 2 N
N
H
Ph
Figure-17
Considering the lower electrophilicity of the aryl ketone compared to the
aldehyde, an alternative strategy for preparing enamine was examined. Since amines
are known to undergo substitution reactions with chloro- and alkylthio-substituted
olefins to yield enamines 33 , a similar approach was considered and the reaction of p-
toluenesulfonyl enol ester of α-cyano ketone with diethyl aminomalonate was
investigated. Tosylate was prepared by reacting benzoyl acetonitrile with p-
toluenesulfonic anhydride (1.2 eq.) in dichloromethane and triethylamine (1.5 eq.) in
99% yield. When a mixture of tosylate and diethyl aminomalonate hydrochloride (1.2
eq.) were treated with an ethanolic solution of sodium ethoxide (0.2 M, 3.5 eq.), 34 the
pyrrole was directly obtained without isolation of enamine. Addition of the amine,
cyclization and decarboxylation occurred in one-pot at room temperature to give a
46% overall yield of from benzoyl acetonitrile (Figure-18).
Department of Chemistry, Saurashtra University, Rajkot-360005 163