Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles Activated by Brønsted Acids

Abstract

Chiral indolines are ubiquitous structural motifs in naturally occurring alkaloids and many biological active molecules. 1 Some catalytic methods have been developed to obtain such molecules on the basis of the kinetic resolution. 2 Asymmetric hydrogenation of indoles is the most straight and powerful approach to make chiral indolines in terms of simplicity and atom efficiency. Despite the progress achieved in asymmetric hydrogenation of indoles and other heteroaromatic compounds in the past decade, 3 efficient hydrogenation of simple unprotected indoles remains a great challenge in organic synthesis. Kuwano and Ito developed the first highly effective hydrogenation of a series of N-protected indoles by application of a Rh or Ru complex. 4a-d Feringa and co-workers reported Rh-catalyzed hydrogenation of 2-substituted N-protected indoles with moderate enantioselectivity. 4e Very recently, the Pfaltz group revealed Ir/N,P-catalyzed hydrogenation of N-protected indoles with high ee but low reactivity. 4f To the best of our knowledge, no report on asymmetric hydrogenation of unprotected indoles has appeared despite the operational simplicity. 5 Herein, we describe a new strategy for highly enantioselective Pd-catalyzed hydrogenation of unprotected indoles with a Brønsted acid as the activator with up to 96% ee.For the asymmetric hydrogenation of aromatics, the main challenge is the low reactivity. 3 Recently, our group developed two kinds of substrate activation strategies for the asymmetric hydrogenation of six-membered heteroaromatics with a Brønsted acid and chloroformate as activators, respectively. 6 Another breakthrough in hydrogenation of imines is through formation of iminium by addition of a Brønsted acid. 7 We envision that in searching hydrogenation of five-membered heteroaromatic unprotected indoles, development of a new activation strategy is highly desirable. Considering that the simple unprotected indoles can react with a strong Brønsted acid to form the iminium salt by protonation of the carbon-carbon double bond, 8 and the aromaticity of indole is destroyed, the in situ formed iminium salts would be prone to be hydrogenated (Scheme 1).Initially, 2-methylindole was selected as a model substrate for optimization of the conditions. Recently, chiral palladium complexes have been successfully applied to asymmetric hydrogenation of activated imines by us 9 and other groups, 10 due to similarity between iminium salt and activated imine, and thus Pd(OCOCF 3 ) 2 /(R)-SegPhos was used as the catalyst. In a control experiment, without the addition of a Brønsted acid, the reaction did not occur. When the stoichiometric amount of trifluoroacetic acid was added, the reaction proceeded smoothly to give the expected 2a with full conversion and 8% ee. Screening of different acids found that L-camphorsulfonic acid (L-CSA) gave the best result (Table 1, entry 1). 11,12 Solvent experiments showed that mixture solvent DCM/TFE was the best choice (entry 8, 85% ee). Subsequently, various commercially available chiral b...

Asymmetric trapping of zwitterionic intermediates by sulphur ylides in a palladium-catalysed decarboxylation-cycloaddition sequence

“…More significantly, via this approach, an important indoline core that is ubiquitous in many biologically active natural and synthetic chemicals could be conveniently constructed in a highly enantioselective and diastereoselective manner [31][32][33] . The method described here is a complement to previous efficient protocols including kinetic resolutions of racemic indolines 34 , catalytic asymmetric hydrogenation of indoles 35 and de nevo construction of chiral indolines via formal [3 þ 2] cycoloaddions of anilines and olefins 36 .…”

Chiral 2,3‐Disubstituted Indolines from Indoles and Aldehydes by Organocatalyzed Tandem Synthesis Involving Reduction by Trichlorosilane

“…Recently, Zhou and co-workers reported an efficient method for the highly stereoselective reduction of a broad range of substituted indoles via chiral transition metal complex-catalyzed hydrogenation. [10] Later on, we developed an organocatalytic method for the same transformation using the Lewis base/HSiCl 3 system, which also afforded high stereoselectivities and exhibited good substrate generality. [6e] However, this approach suffers from an apparent drawback that certainly limits its application.…”

Palladium‐Catalyzed Asymmetric Hydrogenation of Simple Ketimines Using a Brønsted Acid as Activator

“…Most recently, an efficient Pd-catalyzed asymmetric hydrogenation of simple indoles was developed by us with a Brønsted acid as activator. [15] Although much effort has been successfully made in the asymmetric hydrogenation of functionalized ketones and activated imines, there is no report on the highly enantioselective, Pd-catalyzed hydrogenation of simple ketimines due to the low activity of simple ketimines. Accordingly, Ru-, Rh-and Ir-catalyzed asymmetric hydrogenations of quinolines [17] and imines [6] revealed that the addition of a Brønsted acid is one of the key factors for both high reactivity and enantioselectivity.…”

“…MeOH and CH 2 Cl 2 led to very low reactivity (entries 13 and 14); TFE was found to be the optimal solvent, which is in accordance with the Pd-catalyzed hydrogenation of ketones and activated imines in the literature. [8][9][10][11][12][13][14][15][16] Subsequently, some commercially available bisphosphine ligands were examined under the above conditions. The results showed that axial chiral bidentate bisphosphine ligands L1-L4 and L6-L8 (Table 2, entries 1-4 and 6-8) gave full conversions with 58-75% ee.…”

“…Interestingly, this catalytic system is particularly effective for the asymmetric hydrogenation of cyclic ketA C H T U N G T R E N N U N G imines 1j-1o derived from the cyclic ketone, 1-tetralone, 88-95% ees were achieved (Table 3, en- tries [10][11][12][13][14][15]. For the cyclic imines 2p-2s derived from 4-chromanone, 86-93% ee were obtained under the standard conditions (entries [16][17][18][19].…”