Copper(I) iodide-catalyzed synthesis of 1-benzothiophen-2-amines from 4-(2-bromophenyl)-1,2,3-thiadiazole

Abstract

2-Dimethylamino-1-benzothiophen-6-ol is the key intermediate product in the synthesis of the known selective estrogen receptor modulator Raloxifene and its analogs [1, 2]. However, procedures for the synthesis of 2-amino-1-benzothiophenes have been poorly explored. Nowadays, three methods for the preparation of 2-amino-1-benzothiophene are known: (1) five-step synthesis from thiosalicylic acid [3], (2) from 1-benzothiophen-2-ylmagnesium chloride [4], and (3) reaction of (2-bromophenyl)acetonitrile with Na2S2O3 in the presence of palladium catalyst [5]. 2-(Morpholin-4-yl)1-benzothiophene was synthesized by addition of morpholine to the C–C bond of 1-benzothiophene with subsequent aromatization by the action of sulfur [6]. 2-(Piperidin-1-yl)-1-benzothiophene was prepared by heating a mixture of 2-bromo-1-benzothiophene with piperidine in a sealed ampule [7]. 6-Benzyloxy-N,N-dimethyl-1-benzothiophen-2-amine was obtained in two steps by treatment of a mixture of 4-benzyloxybenzaldehyde and N,N-dimethylthioformamide with lithium diisopropylamide, followed by cycloaromatization with methanesulfonic acid [8].