Palladium‐Catalyzed Synthesis of 3‐Substituted Indoles from 2‐Iodoaniline and Aldehydes.

Abstract

It is known that many indole containing compounds exhibit a wide spectrum of pharmacological and biological activities. Thus, besides conventional named routes, homogeneous transition metal-catalyzed synthetic methods have also been developed as alternative methods for the construction of indole framework because of the wide availability of substrates. We have also reported on ruthenium-catalyzed synthesis of indoles via an alkanol group transfer from alkanolamines to anilines (amine exchange reaction) and ring-opening of epoxides by anilines. In connection with this report, palladium-catalyzed direct or step-by-step annulation of 2-haloanilines with carbonyl compounds such as ketones, 1,3-diketones and α-keto esters also give access to a variety of indoles. However, in contrast to the annulation with such carbonyl compounds, there is no precedent on the similar annulation of 2-haloanilines with aldehydes leading to indoles. Under these circumstances, herein we report on palladium-catalyzed synthesis of 3substituted indoles from 2-iodoaniline and aldehydes. Based on our recent report on palladium-catalyzed synthesis of indoles from 2-iodoaniline (1) and ketones, several annulations between 1 and octanal (2a) are attempted (Eq. 1 and Table 1). Treatment of equimolar amounts of 1 and 2a in the presence of a catalytic amount of Pd(dba)2 (dba = dibenzylideneacetone) and 1,1'-bis(di-iso-propylphosphino)ferrocene (dipf) along with NaOBu in DMF at 120 C for 40 h afforded 3-hexylindole (3a) in 35% yield (25% for 20 h). A slight increase in the yield of 3a was observed with the molar ratio of [2a]/[1] = 2 (44% yield; 31% for 20 h). The addition of molecular sieves, 4A as dehydrating agent did not give any significant change under the employed conditions and lower reaction temperature (80 C) resulted in a lower yield of 3a (24% for 20 h). Among examined solvents (for 20 h) DMF was revealed to be the solvent of choice (23% in MeCN; 12% in dioxane; 10% in toluene).