Reaction of 2-alkylthio-6-amino-pyrimidin-4(3H)-ones with ethyl bromopyruvate. Synthesis of furo-[2,3-d]-pyrimidine and furo[3,2-e]imidazo-[1,2-c]pyrimidine carboxylates

Abstract

Recently we showed that esters of thieno[2,3-d]pyrimidine-6-carboxylic acids are useful precursors for the synthesis of analogues of folic acid and other 6-(arylamino)methylthieno[2,3-d]pyrimidines -potential inhibitors of dihydrofolate reductase [1,2]. Continuing our work on the synthesis of fused heterocycles with anticipated biological and pharmaceutical activities we present herein some findings on the synthesis of 2-alkylthio-4-aminofuro[2,3-d]pyrimidine-5-carboxylates by the reaction of 2-alkylthio-6-aminopyrimidin-4(3H)-ones (1) with ethyl bromopyruvate. There are only few examples of such an approach to furo-[2,3-d]pyrimidine-5-carboxylates [3,4] in the literature and they show that such a cyclocondensation reaction can be performed under basic conditions. However, attempts to apply the described procedures for the synthesis of 3a,b, using triethylamine or K 2 CO 3 as basic reagents, failed. Nevertheless, it was found that the cyclocondensation reaction of 1a,b with an equivalent amount of ethyl bromopyruvate proceeds under neutral or acidic conditions to give furopyrimidines 2a,b in good yields. Formation of the corresponding pyrrolo-[2,3-d]pyrimidines was not observed. When an excess of ethyl bromopyruvate was used and the reaction was carried out at room temperature together with furopyrimidines 2, formation of furo[3,2-e]imidazo[1,2-c]pyrimidines 3 was also observed. For example, 3b was isolated as a side product (0.4%) from the reaction of 1b with 2 eq. of ethyl bromopyruvate.

4-Amino-5-(arylaminomethyl)-2-(methylthio)furo[2,3-d]pyrimidines via Mitsunobu Reaction of 4-Amino-5-(hydroxymethyl)-2-(methylthio)furo[2,3-d]pyrimidine with N-Mesyl- and N-Nosylarylamines

“…Some properties of the 4-amino-5-(arylaminomethyl)-2-(methylthio)furo [2,3-d]pyrimidines were also studied. Initially, 4-amino-5-(hydroxymethyl)-2-(methylthio)furo [2,3-d]pyrimidine (2) was obtained in 72% yield by reduction of ethyl 4-amino-2-(methylthio)furo [2,3d]pyrimidine-5-carboxylate 8 (1) with lithium aluminum hydride in tetrahydrofuran (Scheme 1). Problems with the isolation of 5-(hydroxymethyl)furo [2,3-d]pyrimidine 2 from the reaction mixture were solved by using saturated ammonium chloride solution for neutralization of the reaction mixture.…”