Synthesis of New 3-[(Alkylthio)methyl]-1-hydroxy-2-phenylindoles

Abstract

The syntheses of new 3-[(alkylthio)methyl]-1-hydroxy-2-phenylindoles are presented. The substrates, obtained by efficient three-step synthesis, were treated with various thiol nucleophiles in the presence of SnCl2·2H2O to provide target compounds, through the consecutive processes of reduction, condensation, and addition in one pot. The mechanistic studies on reaction pathways and the involved intermediates are described.

Synthesis of new 3-[(alkylthio)methyl]-1-hydroxy-2-(4'-substituted phenyl)indoles and their mechanistic studies on substituent effects

“…Substrates 2 were prepared according to analogous procedures 21 with minor modification, through three step synthetic sequences (3 → 5 → 6 → 2). Nitro alcohols (5).…”

“…In particular, we attempted to elucidate the effect of substituent X on this reaction. Based on our previous studies, 21,22 we recognized that the conjugate nitrone 8 could serve as a critical intermediate and hence influence results. Therefore, we considered that the steric effect of X in 8 was probably negligible, but that its electronic effect would be significant.…”

“…SnCl 2 ·2H 2 O was used as an appropriate reducing agent, according to previous procedures. 21,24 After pretreatment of SnCl2·2H2O (3.3 equiv) and thiol nucleophiles (5.0 eq) with 4Å molecular sieves in dimethoxyethane (DME), substrates 2 were added to produce 3-[(alkylthio)methyl]-1-hydroxy-2-(4'-substituted phenyl)indoles 1, as depicted in Scheme 2. We employed substrates 2 containing an electron-withdrawing p-substituent (X) in phenyl ring at C(1) and thiol nucleophiles to give 1 (Table 1).…”

“…Thus, we believed that the interference of another p-nitro group in different phenyl ring would not much affect the reaction results. Significantly, in order to further examine the effects of substituent X on reaction mechanism we compared the results of formation of 1z (X= H), 21,22 1x (X= Cl), and 1y (X= NO2) from substrates 2z, 2x, and 2y, respectively, and seven thiol nucleophiles ( Table 2). Analysis showed substrate 2x provided best results and substrate 2y worst results, and this was consistently observed for all seven nucleophiles.…”

“…Recently, we reported the synthesis of 1-hydroxyindole-2-carboxylates, [16][17][18][19][20] and 1-hydroxy-2-phenylindoles 21,22 with a limited number of derivatives. These initial successes prompted us to expand our studies for the construction of diverse derivatives.…”