Rhodium(II)-Catalyzed Enantioselective C−H Functionalization of Indoles

Abstract

A catalytic, enantioselective method for the C-H functionalization of indoles by diazo compounds has been achieved. With catalytic amounts of Rh 2 (S-NTTL) 4 , the putative Rh-carbene intermediates from α-alkyl-α-diazoesters react with indoles at C(3) to provide α-alkyl-α-indolylacetates in high yield and enantioselectivity. From DFT calculations, a mechanism is proposed that involves a Rh-ylide intermediate with oxocarbenium character.Indoles are important structural motifs in a myriad of biologically interesting natural products and pharmaceutical targets. 1 Accordingly, several methods have been developed for the generation of highly functionalized indoles. 2 Among these strategies is the selective functionalization by metal carbenes derived from α-diazocarbonyl compounds, 3 a reactivity pattern that has been utilized in various total syntheses 4 as well as selective tryptophan modification in peptides and proteins. 5 However, the only catalytic enantioselective reaction of indoles and transient metal carbenes is Davies' [3+2] annulation of indoles with styryldiazoacetates (eq. 1). 6 While indol-3-yl acetate derivatives with stereogenic centers positioned α-to C-3 have high medicinal value, 1e,f only one example of an enantioselective C-H functionalization reaction of an indole has been reported, and the ee was < 5%. 6 Described herein is a general Rh-catalyzed method for enantioselective C-H functionalization of indoles by carbenoids derived from α-alkyl-α-diazoesters (eq. 2).(1) (2) jmfox@udel.edu . Supporting Information Available: Full experimental details, 1 H and 13 C-NMR spectra, stereochemical assignments, computational details and crystallographic (CIF) data are provided. This material is available free of charge via the Internet at http://pubs.acs.org. 4 ]. 10,11 Models for asymmetric induction based on chiral crown conformations have been proposed 7a,9 and debated, 12 and factors that create bias for the chiral crown configuration over competing conformations have been discussed. 7a,9,10 With this foundation, we hypothesized that enantioselective reactions between indoles and α-alkyl-α-diazoesters could be catalyzed by Rh-complexes proposed to adopt chiral crown conformations. NIH Public AccessWe began our investigation with the reaction of 1,2-dimethylindole with a 2-fold excess of ethyl 2-diazohexanoate (Table 1). A variety of Rh-complexes derived from t-leucine were screened, as were Rh 2 (S-DOSP) 4 and Rh 2 (S-PTAD) 4 . While many of the catalysts screened gave 1 with good enantioselectivity, it was found that Rh 2 (S-NTTL) 4 in toluene at −78 °C was optimal both in terms of yield and enantioselectivity, as 1 was formed in 95% yield and 95% ee. In line with our previous observations, 7 the use of low temperature was critical to the success of the reaction: the analogous reaction at higher temperature (0 °C) gave 1 in only 36% yield and 85% ee (entry 7).With the optimized reaction conditions in hand, the scope of this transformation was then explored, and the results are summarized in T...

Optimizing dirhodium(ii) tetrakiscarboxylates as chiral NMR auxiliaries

“…3c). Coordination of methanol at this site is clearly feasible (as indeed related complexes have featured, acetonitrile, ethyl acetate and tetrahydrofuran, for example [13][14][15] ).…”

DFT Study on the Rhodium(II)-Catalyzed C–H Functionalization of Indoles: Enol versus Oxocarbenium Ylide

“…21 Fox and co-workers found that the reactions of the α-alkyl-α-diazoesters with indoles catalyzed by the Rh 2 (S-NTTL) 4 could afford the C−H insertion products with high yield and enantioselectivity (ee value up to 99%). 16 Apparently, this cannot be explained by the mechanism proposed by Davies. 14 By contrast, Fox suggested that the nucleophilic attack of indole at carbene should involve the concerted formations of C−C and C−O bonds first to give oxocarbenium ylide 8 followed by a [1,2]-H shift to complete the catalytic cycle.…”

“…16−20 For instance, Davies's [3 + 2] annulation of indoles with styryldiazoacetates could give the fused indolines with an ee value up to 98%; 14 Barluenga et al reported an asymmetric C2−C3 cyclopentannulation of 2-substituted indoles with Fischer carbenes; 15 Fox et al described a general Rh-catalyzed method for the enantioselective C−H insertion of indole into the α-alkyl-α-diazoesters. 16 However, despite the great successes in this field, the related reaction mechanisms are not quite clear, especially, for the Rh(II)-catalyzed C−H insertion reaction of indole. The reason could be partly attributed to the difficulties in determining the active intermediates experimentally.…”

Iron‐Catalyzed CH Fuctionalization of Indoles

“…Although several catalysts including rhodium, copper, and ruthenium have been developed for the C À H functionalization of indoles in the past decades, [7] only quite recently was a highly enantioselective C À H functionalization of indoles disclosed by Fox and co-workers. [8] With catalytic amounts of [Rh 2 A C H T U N G T R E N N U N G (S-NTTL) 4 ] {dirhodium(II) tetrakis[N-(1,8-naphthaloyl)-(S)-tert-leucinate]}, the aalkyl-a-diazoesters reacted with indoles at C-3 to produce a-alkyl-a-indolylacetates in high yields and high enantioselectivities (79-99% ee). From a synthetic point of view, the indole functionalization with a-aryla-diazoesters is a very useful reaction for the construction of a-aryl-a-indolylacetates, which are key intermediates for the synthesis of a wide range of bioactive compounds.…”