Synthesis of alkylpyrroles by use of a vinamidinium salt

Abstract

The synthesis of alkyl-substituted 2-pyrrolecarboxylate esters has been accomplished by the condensation reaction of a symmetrical vinamidinium salt and glycine ester derivatives.

Introduction

Symmetrical vinamidinium salts undergo condensation reactions, similar to malonaldehyde derivatives, with bifunctional nucleophiles to form heterocycles. These organic salts have been used to prepare many different monocyclic heterocycles including isoxazoles,¹ pyrazoles,¹ pyrimidines,¹ and pyrroles.² Most of these studies have used an aryl vinamidinium salt to synthesize an aryl-appended heterocycle. Aryl vinamidinium salts are easily prepared under Vilsmeier–Haack conditions from the corresponding aryl acetic acid.1, 2 Using alkyl acetic acids to synthesize alkyl vinamidinium salts does not work effectively. Davies has reported that alkyl vinamidinium salts could be prepared from alkyl acetic acids in low yield.³ Other methods to prepare alkyl vinamidinium salts usually involve multiple steps and start with material other than carboxylic acids.4, 5, 6 Because of the more involved procedures to make alkyl vinamidinium salts these compounds are not typically used in synthetic studies.

Two examples that use a condensation reaction to produce alkyl pyrroles have been reported by Walizei⁷ and Barton.⁸ In the report by Walizei⁷ 2-carboxy-4-alkyl-substituted pyrroles have been prepared in average yield by the condensation of 3-alkoxyacroleins with glycine derivatives; sacrosine derivatives will produce an N-methylpyrrole. In the report by Barton⁸ the procedure involves the condensation of an α-isocyanoester and a nitroolefin. By the nature of the traditional Barton–Zard procedure, the product will be an N–H pyrrole. The Barton–Zard method gives pyrroles that are 2,3,4-trisubstituted with a carbonyl at the 2-position in the form of an ester, but the carbonyl group could also belong to an amide. The substituents on pyrrole in the Barton–Zard reaction at the 3- and 4-position are typically alkyl or aryl groups, but it is possible for the 3-position to be unsubstituted.

Alkyl pyrroles have some important uses in organic chemistry. Some examples of their utility include, but are not limited to the following: used as building blocks preparing the pharmaceutically important pyrrolo[1,2-a]quinoxalines⁹ structural core; compound 3f has been used to prepare intermediates for compounds tested to treat multiple sclerosis;¹⁰ compound 3b has been used to prepare pyrazolylpyrrole ERK inhibitors.¹¹ Pyrroles 3a and 3b have been used to prepare ring-annulated pyrroles.¹² Pyrrole 3e is an ant trail pheromone of Atta Texana and was first reported by Tumlinson in 1971.13, 14 Most of these simple alkyl pyrroles were synthesized starting with the pyrrole ring already present. Because of the limited use of alkyl vinamidinium salts and the fact that alkyl pyrroles can be important synthetic building blocks a new synthesis of alkyl pyrroles was explored by using alkyl vinamidinium salts. This route is expected to complement the existing procedures by Walizei and Barton.