Synthesis of a Novel Disubstituted Indole†

Abstract

In continuation of our interest to functionalize selectively the indole-2,3 positions, we now describe the synthesis of 2-bromo-1-(phenylsulfonyl)-1H-indol-3-yl trifluoromethanesulfonate (1) as a potentially useful precursor for the selective functionalization of the indole positions. Our synthesis of 1 is shown in Scheme 1. Following the conversion of commercially available 2-aminoacetophenone (2) to sulfonamide 3, the four subsequent reactions to give 1 were performed with only one intermediate purification due to the presumed formation of indigo by-products (blue-purple discoloration), and the possible lachymatory effects of bromide 4. Bromination of 3 to 4 was subject to capricious reaction times, but we found that the addition of catalytic amounts of concentrated HBr eliminated this phenomenon, presumably by supplying sufficient HBr to the mixture to initiate formation of Br2. Over-bromination of 3 was minimized by exclusion of air. The mixture of 4, containing some ketone and dibromoketone, was converted to indolin-3-one 5 in 60% yield after purification. Subsequent bromination to 6 and triflate formation to 1 proceeded in 54% yield for the two steps. Attempts to brominate (NBS, Br2) the known 1-(phenylsulfonyl)-1H-indol-3-yl trifluoromethanesulfonate to afford 1 were not successful. In summary, we disclose a straightforward synthesis of compound 1 from 2-aminoacetophenone. This new 2,3-unsymmetrically-disubstituted indole should find utility in the synthesis of a wide range of indoles in contrast to, for example, 2,3-dihaloindoles for which regioselective reactions have proven difficult.