Nucleophilic Addition of Hetaryllithium Compounds to 3-Nitro-1-(phenylsulfonyl)indole: Synthesis of Tetracyclic Thieno[3,2-c]-δ-carbolines

Abstract

3-Nitro-1-(phenylsulfonyl)indole undergoes addition of aryl-and hetaryllithium nucleophiles to produce 2-substituted-3-nitroindoles.Mild reductive-acylation provides excellent access to 3-amido-2-hetarylindoles from which new thieno[3,2-c]--carbolines are synthesized by cyclodehydration.The biochemical ubiquity and medicinal success of the indole motif has earned this substructure 'privileged' status in drug discovery and a deep history of investigation stretching well over a century. 1 Typical of -excessive heteroaromatics, the literature of indole is characterized by electrophilic substitution. 2Reversal of this traditional reactivity offers an opposite and complementary utility; the conception of electrophilic indole has captured the imagination of several groups. 3Early pioneers employed a complicit leaving group at N-1 to facilitate a formal S N 2' by attack at C-3. 4 The chemistry of 1-hydroxyindole has proven to be a versatile methodology 4b that continues to yield new applications, 4c though the substitution itself remains particularly specialized.Arylsulfonyl groups provide a flexible 5 and accessible alternative in exchange for greatly attenuated reactivity.Although 1-(phenylsulfonyl)indole does not engage in S N Ar, if augmented with powerful withdrawing groups, the polarizable indole double bond becomes receptive to a variety of nucleophiles. 61 Scheme 1. 3-Nitro-1-(phenylsulfonyl)indole as a Michael acceptor