Quantum-chemical study of the electronic structure and reactivity of 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester

Abstract

We have used the MNDO approximation to carry out a quantum-chemical study showing that the selectivity of acylation of 2-methyl- 4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester under Friedel-Crafts reaction conditions in the presence of AlCl 3 depends more on the electron density distribution in the complexes than on the structure parameters.Thienopyrroles are analogs of indoles and so are of significant interest in synthesis of various bioactive substances. Considerable attention has been focused on designing physiologically active compounds based onConsidering the electron-rich nature of thienopyrroles, electrophilic processes are generally used to modify them. An attractive method for adding functional groups to thienopyrroles is to introduce acyl groups which then can be converted to various functional groups, including heterocyclic moieties. However, a serious and poorly studied problem is how to carry out regioselective reactions with thienopyrroles having free positions on both the thiophene ring and the pyrrole ring.Earlier we showed that in the presence of a two-fold excess of AlCl 3 , acylation of 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic methyl ester (1) occurs regioselectively at the 3 position of the diheterocycle, yielding the product 2, while when equimolar amounts of AlCl 3 and thienopyrrole are used, a mixture of 3-and 6-acyl derivatives 2 and 3 is formed (Scheme 1) [4].With the aim of estimating the effect of structural and electronic factors on the selectivity of acylation, in this paper we compare the calculated heats of reaction and the experimentally established percentages of isomers formed, and also the calculated electron density distributions in complexes of thienopyrrole with AlCl 3 and possible routes for electrophilic attack in nonpolar and polar solvents.The calculations were performed using the MOPAC program [5] by the standard semiempirical quantum-chemical method MNDO with full optimization of the geometry for the molecules of thienopyrrole 1, monoketones 2, 3, complexes with aluminum chloride 4-8, and σ-complexes 9, 10 (Scheme 2).

Development of quantum-chemical investigations of heterocycles at the Institute of Organic Chemistry, Russian Academy of Sciences (review)

“…A quantum-chemical investigation of the electronic structure and reactivity of methyl 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate [76] was undertaken in order to interpret the previously discovered [77] change in the direction of acetylation of this compound; the reaction with acetyl chloride in the presence of 2 equiv. of AlCl 3 leads to the 3-acetyl-substituted compound, while the reaction with 1 equiv.…”