57

Barton-Zard Pyrrole Synthesis

(Barton-Zard Pyrrole Condensation;
Barton-Zard Reaction)

A. GENERAL DESCRIPTION OF THE REACTION

This reaction was first reported by Barton and Zard in 1985.1 It is the synthesis of
2-substituted pyrroles (2-pyrrole-carboxylates or 2-sulfonyl pyrroles) via the basic con-
densation between alkyl isocyanoacetate (or tosylmethyl isocyanide) and α,β-unsaturated
nitroalkenes (or β-nitroacetates). Therefore, this reaction is generally known as the Barton-
Zard pyrrole synthesis,2 Barton-Zard pyrrole condensation,3 or the Barton-Zard reaction.4
This reaction is convenient for the synthesis of pyrroles with various substituents at the
β positions (R2 and R3 ) but is not applicable for the synthesis of pyrroles without a sub-
stituent at position 2. The yields of this reaction are generally high (80–90%), however, if
R2 is hydrogen, the yield is moderate. A nonionic strong base, such as DBU and guanidine,
is generally used in this reaction. Currently, this method has been developed for preparing
polypyrroles and porphyrins fused with various aromatic rings or bicyclic frameworks, start-
ing from aromatic nitro compounds and ethyl isocyanoacetate.5 The formed polypyrroles
and porphyrins can be applied as functional dyes. The reaction has been reviewed.6

B. GENERAL REACTION SCHEME

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

Copyright © 2010 John Wiley & Sons, Inc.

254
 CITED EXPERIMENTAL EXAMPLES 255

C. PROPOSED MECHANISMS

The reaction mechanism is shown below.

D. MODIFICATION

A few modifications have been developed for this reaction.7

E. APPLICATIONS

This reaction has been applied for preparing polypyrroles and porphyrins.5 Although
the substituted isoindoles can also be prepared from substituted nitrobenzenes, the simple
isoindole cannot be prepared in this manner because nitrobenzene does not react with ethyl
isocyanoacetate.8

F. RELATED REACTIONS

This reaction is similar to the Leusen Pyrrole Condensation,9 based on the reac-
tion of tosylmethyl isocyanide and electron-deficient alkenes (a toluenesulfinate anion is
eliminated).10 The most important advantage of this reaction is that α-free pyrroles can be
obtained directly.

G. CITED EXPERIMENTAL EXAMPLES

Reference 11.
256 BARTON-ZARD PYRROLE SYNTHESIS

To a stirred solution of 3.04 g (E)-5,9-dimethyl-2-nitrodeca-4,8-dienyl acetate

(11.29 mmol) in 28 mL of a mixed solvent of anhydrous THF/t-BuOH (1:1) were added
1.23 mL ethyl isocyanoacetae (11.29 mmol) and 3.38 mL DBU (22.58 mmol)
dropwise while cooling at 0◦ C. After stirring for 26 h, 30 mL water and 30 mL
EtOAc were added. The mixture was extracted with EtOAc (2 × 20 mL) and the
combined organic layers were washed with water (2 × 20 mL) and 30 mL brine,
dried over Na2 SO4 , and concentrated. The residue was purified by column
chromatography on silica gel (EtOAc/hexane = 1:9) to give 2.36 g ethyl 4-(3,7-
dimethylocta-2,6-dienyl)pyrrole-2-carboxylate as a yellow oil, in a yield of 18%.

Reference 10k.

A solution of 15 g tosylmethyl isocyanide (75 mmol) and 10.0 g ethyl sorbate

(71.3 mmol) in 50 mL dry DMSO and 100 mL ether was added to an ice cold suspen-
sion of 3.6 g NaH (88.5 mmol, 59% dispersion in oil) in 100 mL ether. The mixture was
stirred for 3 h at 20◦ C, poured into 50 mL saturated aqueous NH4 Cl solution, and extracted
with ether (4 × 50 mL). The combined extracts were washed with saturated aqueous NH4 Cl
solution, and dried over MgSO4 . Evaporation of the extract gave 13.0 g of crude ethyl 3-
(4-methyl-3-pyrrolyl)acrylate. Crystallization from EtOH gave 10.6 g of pure product, in a
yield of 80%; m.p. 88–89◦ C.

Other references related to the Barton-Zard pyrrole synthesis are cited in the literature.12

H. REFERENCES

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