Flow synthesis of polysubstituted pyrroles via a Vilsmeier–chloroacrolein strategy
- 1Department of Chemistry 138 Ur Drive, University of Richmond Virginia 23173 USA [email protected] [email protected].
Abstract
A library of twelve polysubstituted pyrroles was synthesized using a flow chemistry (CFC) strategy based on a Vilsmeier-chloroacrolein intermediate. Each step of the multistep sequence was optimized by systematic variation of residence time, temperature, and reactant concentration. The Vilsmeier-mediated formation of chloroacroleins was achieved in 98-100% conversion and 87-99% isolated yield under optimized conditions. The subsequent ring-closing step was investigated using sarcosine ethyl ester hydrochloride (for the N-methyl pyrroles) and glycine methyl ester hydrochloride (for the N-H pyrroles). Addition of Hunig's base significantly enhanced solubility and accelerated cyclization, allowing shorter residence times and improved isolated yields. The optimized flow protocol compared to the previously reported batch synthesis reduces time across the entire four-step synthetic sequence from several days to approximately four hours, improves yield and purity, and minimizes solvent consumption. Notably, synthesis of compound 3,4-bis(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester constitutes a formal synthesis of lukianol A and lamellarin O methyl ether.
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BibTeX
@article{dwomoh2026flow,
title = {{Flow synthesis of polysubstituted pyrroles via a Vilsmeier–chloroacrolein strategy}},
author = {Kingsley Dwomoh and Evelyn Ramirez and Felix Minami and Carlos Perez Mandry and Ariana Kim and Edward Chandler and Joe West and Daniel Fisher and Raymond N Dominey and Emma W Goldman},
journal = {RSC advances},
year = {2026},
month = nov,
doi = {10.1039/d6ra08430c},
url = {https://europepmc.org/article/PMC/PMC13726717},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Flow synthesis of polysubstituted pyrroles via a Vilsmeier–chloroacrolein strategy
AU - Kingsley Dwomoh
AU - Evelyn Ramirez
AU - Felix Minami
AU - Carlos Perez Mandry
AU - Ariana Kim
AU - Edward Chandler
AU - Joe West
AU - Daniel Fisher
AU - Raymond N Dominey
AU - Emma W Goldman
PY - 2026
DA - 2026/11/02
JO - RSC advances
DO - 10.1039/d6ra08430c
UR - https://europepmc.org/article/PMC/PMC13726717
AB - A library of twelve polysubstituted pyrroles was synthesized using a flow chemistry (CFC) strategy based on a Vilsmeier-chloroacrolein intermediate. Each step of the multistep sequence was optimized by systematic variation of residence time, temperature, and reactant concentration. The Vilsmeier-mediated formation of chloroacroleins was achieved in 98-100% conversion and 87-99% isolated yield under optimized conditions. The subsequent ring-closing step was investigated using sarcosine ethyl ester hydrochloride (for the N-methyl pyrroles) and glycine methyl ester hydrochloride (for the N-H pyrroles). Addition of Hunig's base significantly enhanced solubility and accelerated cyclization, allowing shorter residence times and improved isolated yields. The optimized flow protocol compared to the previously reported batch synthesis reduces time across the entire four-step synthetic sequence from several days to approximately four hours, improves yield and purity, and minimizes solvent consumption. Notably, synthesis of compound 3,4-bis(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester constitutes a formal synthesis of lukianol A and lamellarin O methyl ether.
SN - 2046-2069
ER -