Synthesis of Indoles from o-Haloanilines

Abstract

A convenient method for the synthesis of indoles has been developed by the sequential orchestration of the cross-coupling reaction of o-haloaniline and PIFA oxidation of the resulting 2-alkenylanilines. A highlight of this two-step indole synthesis is a modular strategy which is applicable to both acyclic and cyclic starting materials. Particularly noteworthy is the regiochemistry that is complementary to the Fischer indole synthesis and related variants. Direct preparation of N–H indoles with no N-protecting group is also advantageous.

A Cascade Synthesis of Indoles

“…Our previously reported synthesis of indoles proceeded in good overall yields . Clean regioselectivity was observed in favor of the 2-alkenylanilines at the less substituted α-carbon (e.g., a methylene or methyl position in preference to the methine), when the starting N -tosylhydrazones are substituted at the α position.…”

“…α-Acetoxy- N -tosylhydrazone 1 (prepared from the known acetate of propioin) and o -bromoaniline ( 2 ) were subjected to the Barluenga reaction under Houpis–Chen’s modified conditions [Pd­(OAc) 2 , tBu 2 MeP·HBF 4 , and K 2 CO 3 in DMA] . The desired indole 3 was obtained in 48% yield, together with 2-(4-methylphenyl)­aniline (19%): , the preliminary (unoptimized) result gave a modest yield, in part due to the known formation of the latter side-product. However, the formation of 3 as a single regioisomer was notable (Scheme ).…”

“…This cascade variant can be carried out in good to excellent yields without isolating reaction intermediates. Advantages over our previous synthesis (involving the Barluenga reaction and subsequent PIFA oxidation) are the predetermined regiochemistry, especially regarding unsymmetrical N -tosylhydrazone substrates having no alpha-substituents (e.g., having two different methylene groups); and the absence of the 2-(4-methylphenyl)­aniline side-product derived from the toluenesulfonyl fragment, obviating the use of the nitrobenzenesulfonyl hydrazones . Both synthetic methods utilize the identical ketone starting materials (as the corresponding N -tosylhydrazones), which are regioisomers of those required for the Fischer indole synthesis and its variants.…”

“…Of burgeoning interest are inherently advantageous cascade reactions that allow indole synthesis in a single operation from simple starting materials . We recently described indole synthesis by the sequential implementation of Pd-catalyzed cross-coupling of o -haloanilines with N -tosylhydrazones and oxidative cyclization of the resulting 2-alkenylanilines (Scheme A) . We report a variant for the convenient construction of mono- and disubstituted indoles with predetermined regiochemistry (Scheme B).…”

Phenyliodine bis(trifluoroacetate) as a sustainable reagent: exploring its significance in organic synthesis

“…Chebieb et al 94 have introduced an efficient method for synthesizing indoles 80 by orchestrating a two-step process that involves the cross-coupling reaction of o -haloanilines 76 and the PIFA oxidation of the resulting 2-alkenylanilines 78 . A notable feature of this sequential approach is its modular strategy, which is applicable to both acyclic and cyclic starting materials.…”