Catalytic Asymmetric Hydrogenation of Heteroaromatic Compounds, Indoles

Abstract

Catalytic asymmetric hydrogenations of prochiral unsaturated compounds, 1 olefin, 2 ketone, 3 and imine, 4 have been intensively studied and are considered as a versatile method of creating a chiral carbon center. 5 However, no highly enantioselective hydrogenation of heteroaromatic groups has so far been reported except that of 2-methylquinoxaline to our knowledge. 6 Resonance stability of heteroaromatic compounds might impede the enantioselective hydrogenation, 7 which may find potentially wide applicability in stereoselective organic synthesis. 8,9 Herein, we describe the highly enantioselective hydrogenation of heteroaromatic compounds, indoles.We recently disclosed that the rhodium complex generated from Rh(acac)(cod) and PPh 3 is a good catalyst for the hydrogenation of five-membered heteroaromatic compounds. 10 Thus chiral rhodium complexes prepared in situ from Rh(acac)(cod) and various commercially available chiral bisphosphines (1 mol %) were examined for asymmetric hydrogenation of N-acetyl-2-butylindole (1a) at 60°C for 2 h with 5.0 MPa of H 2 in 2-propanol (eq 1), resulting in non-enantioselective hydrogenation (0-1% ee). 11 Fortunately, the successful asymmetric hydrogenation has been achieved by use of a trans-chelating chiral bisphosphine ligand, (S,S)-(R,R)-PhTRAP, 12,13 giving (R)-N-acetyl-2-butylindoline (2a) with 85% ee (77% conversion). No reduction of the fused aromatic ring of 1a was observed.On further investigation into the asymmetric hydrogenation, [Rh(nbd) 2 ]SbF 6 was found to be superior to Rh(acac)(cod) as catalyst precursor (Table 1). It is noted that addition of base is necessary for achievement of high enantioselectivity as well as high catalytic activity. The [Rh(nbd) 2 ]SbF 6 -(S,S)-(R,R)-PhTRAP catalyst scarcely promoted the hydrogenation in the absence of base, giving a trace of 2a with only 7% ee (S) (entry 1). Addition of 10 mol % of Et 3 N or Cs 2 CO 3 brought remarkable improvement of the enantioselectivity and catalytic activity (100% conversion, 94% ee (R)) (entries 2 and 3). 14 Both the enantioselectivity and catalytic activity were significantly dependent upon base: K 2 -CO 3 gave (R)-2a with 76% ee, and pyridine did not activate the cationic PhTRAP-rhodium complex at all (entries 4 and 5). The amount of Cs 2 CO 3 did not affect the selectivity: 20 mol %, 94% ee; 1 mol %, 93% ee. It is possible to carry out the asymmetric hydrogenation at lower pressure (1.0 MPa) without significant decrease of the selectivity and reaction rate (entry 6). The amount of PhTRAP-rhodium complex can be reduced to 0.1 mol %, and the reaction was completed within 20 h to give (R)-2a of 93% ee in 92% isolated yield (entry 7).Although 2-propanol has frequently been used as a hydrogen source in the transfer hydrogenation of unsaturated compounds (1) For reviews, see: (a) Takaya, H.; Ohta, T.; Noyori, R. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York

Asymmetric hydrogenation of 2-substituted N-protected-indoles catalyzed by rhodium complexes of BINOL-derived phosphoramidites

“…As reported by Ito, the addition of a base seems to be crucial in these hydrogenations. 8 Indeed, when 10 mol % of cesium carbonate was added to the hydrogenation of 1a, full conversion and ee's up to 74% were obtained (entries 3-7). Further experiments established that 40°C is optimal, pressure has no influence and other bases gave much poorer results.…”

“…8 They found that the base has an important role in obtaining both good catalytic activity and enantioselectivity. Later, Kuwano et al reported the Rh-catalyzed asymmetric hydrogenation of N-tosyl-3-substitued indoles 9 and the Ru-catalyzed hydrogenation of N-protected-2-and 3-substituted indoles with excellent enantioselectivities and conversions using the same Ph-TRAP ligand.…”

Rhodium Phosphine–Phosphite Catalysts in the Hydrogenation of Challenging N-(3,4-dihydronaphthalen-2-yl) Amide Derivatives

“…It produces an important, particularly for catalyst based on 4a, increase in conversion, although racemic products were unexpectedly obtained (entries 8-10). [18][19] It is noteworthy that catalysts with different phosphine groups and dynamic properties give null enantioselectivity, pointing to a general effect of the additive. It looks therefore apparent that the addition of base leads to an alternative catalyst.…”

Copper(I)-catalyzed Diastereoselective Dearomative Carboborylation of Indoles

“…5,6 Dearomatization reaction of indoles is a powerful and attractive approach for the direct preparation of indoline derivatives, which has been extensively studied over the past decade. 710 Recently, we reported the first CB bond-forming dearomatization of indoles using a chiral copper(I) catalyst to give the corresponding optically active 3-borylindolines.…”