Synthesis of Pyrrolo[1,2-c]pyrimidines

Abstract

The synthesis of several new pyrrolo [1,2-c]pyrimidines from the base-induced condensation of pyrrolo-2-carbaldehydes with either TosMIC (toluenesulfonylmethyl isocyanide) or ethyl isocyanoacetate is described, along with the preparation of novel bis(pyrrolo[1,2-c]pyrimidines).The pyrrolo[1,2-c]pyrimidine ring system has an interesting history. In 1949 Herz inadvertently synthesized 1-phenylpyrrolo[1,2-c]pyrimidine-3-carboxylic acid (1), the first example of this ring system, in a reinvestigation of the reaction between pyrrole-2-carbaldehyde and hippuric acid. 1 In 1963 Boekelheide achieved the first targeted synthesis of this ring system with the preparation of 3-methyl-6-phenylpyrrolo[1,2-c]pyrimidine (2) via a classical Chichibabin reaction. 2 The parent molecule 3, which was found to be aromatic though oxidatively labile, was prepared by Rapoport in 1965 via the cyclization of 3-(4-pyrimidyl)-1-propanol (or its tosylate) and subsequent dehydrogenation. 3 Rapoport also isolated 3-methyl-6,7-dihydro-5H-pyrrolo[1,2-c]pyrimidin-1-one (4) as a chemical degradation product of the toxic shellfish poison, saxitoxin. 4 More recently, variants of Boekelheide's Chichibabin approach to pyrrolo[1,2-c]pyrimidine 2 have been implemented in syntheses of this ring system, 5 and the synthesis of all of the isomeric pyrrolopyrimidines has been reviewed. 6