New C2-Fragment for Ruthenium-Catalyzed Synthesis of Indoles

Abstract

It is well known that indole moiety plays an important role as an intermediate for the synthesis of many pharmacologically and biologically active compounds. Thus, besides conventional popular routes, homogeneous transition metalcatalyzed synthetic methods have also been developed for the construction of indole framework because of the wide availability of substrates. In connection with this report, as the part of our ongoing studies on homogeneous ruthenium catalysis, we recently developed on the synthesis of indoles via a ruthenium-catalyzed alkanol group transfer from alkanolamines to N-atom of anilines (amine exchange reaction) (Scheme 1, route a) and ring-opening of epoxides by anilines (Scheme 1, route b). Watanabe et al. have also reported a ruthenium-catalyzed intermolecular cyclization of anilines with ethylene glycols as C2-fragment leading to indoles (Scheme 1, route c). In these regards, it was suggested that theses reactions proceed via a sequence involving an initial formation of 2-anilinoalkanols shown in Scheme 1 and N-alkylation of anilines by 2-anilinoalkanols to form 1,2-dianilinoalkanes. These circumstances led us to seek a new C2-fragment for such an intrinsic formation of 1,2dianilinoalkanes. Herein we report on a ruthenium-catalyzed synthesis of indoles from anilines and 1,2-dibromoethane as C2-fragment. The results of several attempted cyclization between aniline (1a) and 1,2-dibromoethane (2a) are listed in Table 1. When 1a was generally treated with 2a at 180 C in dioxane in the presence of a catalytic amount of a ruthenium catalyst, indole (3a) was produced with concomitant formation of 1,2-dianilinoethane (4). As has been observed in our recent report on ruthenium-catalyzed synthesis of indoles from 1a and trialkanolamines, the yield of 3a was considerably affected by the molar ratio of 1a to 2a. Table 1 shows that the yield of 3a increased as the molar ratio [1a]/[2a] increased, while that of 4 remained nearly constant (entries 1, 2 and 5-7). It was reported by us that the addition of tin(II) chloride or a hydrogen acceptor was necessary for the effective formation of indoles or quinolines via rutheniumcatalyzed amine exchange reaction. However, the present reaction showed no significant change by the addition of either tin(II) chloride or 1-hexene as hydrogen acceptor (entries 3 and 4). Performing the reaction for a longer reaction time (40 h) under RuCl2(PPh3)3 or RuCl3·nH2O/ 3PPh3 did not affect the yield of 3a, whereas the use of a smaller amount of a ruthenium catalyst affected product distribution, resulting in a relatively increased yield of 4