Asymmetric Hydrogenation of Indoles

With the addition of base, high activity and enantioselectivity were achieved (full conversion and up to 94% ee) (Table 10.10). Then, the effect of base and pressure of H2 was examined with [Rh(nbd)2]SbF6/PhTRAP as the catalyst. The reactions were carried out in 2 propanol at 60 °C under 5.0 MpaofH2 for 2 h. EtjN and CS2CO3 were effective in view of the reactivity and the enantioselectivity (entries 2 and 3). 

The reaction can also be carried out at slightly lower pressure (entry 6). When the hydrogen pressure is increased to 10.0 Mpa, increasing the substrate to catalyst ratio to 1000/1, the reaction can also proceed smoothly without loss of enantioselectivity (entry 7). 

Based on the above results, asymmetric hydrogenation of indoles provides a 

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Table 2.5 Asymmetric hydrogenation of indoles using (S,S)-(I ,I )-PhTRAP-rhodium complex as catalyst...

Asymmetric Hydrogenation of Indoles 325 Table 10.12 Asymmetric hydrogenation of N tosylindoles (24a 24f). 

Scheme 10.31 Pathway of asymmetric hydrogenation of indoles (34a 34i) by Kuwano.

Kuwano, R. Kashiwabara, M. Sato, K. Ito, T. Kaneda, K. Ito, Y. Catalytic asymmetric hydrogenation of indoles using a rhodium complex with a chiral bisphosphine ligand PhTRAP. Tetrahedron Asymmetry 2006,17,521-535. 

The scope of the method was later extended to indoHnes [121] however, as the previous optimized conditions failed to afford any acylated product, a fine-tuning of both the nucleophilic catalyst and the acyl donor appeared to be necessary. After intensive screening, the use of a bulkier cyclopentadienyl-derived catalyst such as 113 in conjunction with 0-acetylated azlactone 111 led to a more effective catalytic system, allowing the resolution of various indo lines with useful levels of selectivity ranging from s = 9.5 to 31 (Scheme 41.45). Most importantly, 2,3-disubstituted indolines, which are usually difficult to obtain in high ee by other methods such as the asymmetric hydrogenation of indoles, were also shown to be suitable substrates. 

Kuwano R, Kaneda K, Ito T, Sato K, Kurokawa T, Ito Y (2004) Highly enantioselective synthesis of chiral 3-substituted indolines by catalytic asymmetric hydrogenation of indoles. Org Lett 6 2213-2215... 

M., Humphrey, G.R. et al. on the long term factory process for the production of a prostaglandin D2 receptor antagonist - unprecedented asymmetric hydrogenation of an indole Fxo-Cyclic Trisubstituted a,(i-Unsaturated Acid. 

Kuwano, R. and Kashiwahara, M. Ruthenium-catalyzed Asymmetric Hydrogenation of N-Boc-Indoles. Org. Lett. 2006, 8, 2653-2655. 

CATALYTIC ASYMMETRIC HYDROGENATION OF 3-METHYL-A-(E-TOLUENESULFONYL)INDOLE... 

Asymmetric hydrogenation of alkenes is efficiently catalysed by rhodium complexes with chiral diphosphite and diphosphoramidite ligands derived from BINOL or diphenylprolinol. Choice of a proper achiral backbone is crucial.341 Highly enantioselective hydrogenation of A-protected indoles was successfully achieved by use of the rhodium catalyst generated in situ from [Rh(nbd)2]SbF6 (nbd = norborna-2,5-diene)... 

The asymmetric hydrogenations of N acetyl, N carbamate, and N sufonyl indoles are asymmetric hydrogenations of enamides. not imines, and will therefore not be covered here. For reports of this reaction, see (a) Kuwano, R. and Kashiwabara. M., (2006) Org. Lett., 8,... 

This method was successfully applied to the total synthesis of chiral indoline alkaloid 2Sh, which is Wierenga s synthetic intermediate for the left hand segment of the antitumor agent ( + ) CC 1065. As shown in Scheme 10.28, the asymmetric hydrogenation of N methanesulfonyl indole (24g) to the corresponding indoline (25g) with 93% ee was the key step. 

Scheme 10.29 Asymmetric hydrogenation of 3 substituted and 2,3 disubstituted indole...

Chiral indolines represent useful building blocks in pharmaceuticals, herbicides and insecticides. Asymmetric hydrogenation of unprotected indoles with molecular hydrogen represents the most straightforward and atom-economy method to produce these compounds.Although the asymmetric (up to 98% ee) hydrogenation of N-protected or N-Ts indoles with is known since 2000 (R. Kuwano, Kyushu... 

Baeza, A. Pfaltz, A. Iridium-catalyzed asymmetric hydrogenation of N-protected indoles. Chem. - Eur.. 2010,16,2036-2039. 

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