Highly Enantioselective Synthesis of Chiral 3-Substituted Indolines by Catalytic Asymmetric Hydrogenation of Indoles

Abstract

[reaction: see text] N-Tosyl 3-substituted indoles were hydrogenated with high enantioselectivities (95-98% ee) by use of a trans-chelating chiral bisphosphine, (S,S)-(R,R)-PhTRAP ligand. The chiral catalyst, which was generated in situ from [Rh(nbd)(2)]SbF(6), PhTRAP, and Cs(2)CO(3), is useful for enantioselectively synthesizing a range of diverse optically active indolines possessing a chiral carbon at the 3-position.

Asymmetric Hydrogenation of Heteroaromatic Compounds

“…Using Ts as the protecting group, the indole derivatives underwent hydrogenation satisfactorily (high conversion and 95-98% ee). 26 Ru-catalyzed asymmetric hydrogenation of N-Boc indoles using a readily prepared catalyst, [RuCl(p-cymene)-RhTRAP]Cl, was developed by the same group in 2006 with 90-95% ee (Scheme 13). 27 2,3-Disubstituted indoles only furnished moderate enantioselectivity (72% ee).…”

Catalytic Asymmetric Hydrogenation of 3-Substituted Benzisoxazoles

“…A small amount of 1a reacted with hydrogen, but no saturation of the C-N double bond was observed in either reaction, which afforded only the achiral imine 3a, formed through the hydrogenolytic cleavage of the N-O bond of 1a [49,50]. The ruthenium catalyst failed to reduce the C-N double bond even in the presence of N,N,N',N'-tetramethylguanidine (TMG) (entries 3 and 4), even though in our previous reports the base additive brought about a remarkable acceleration of hydrogenations of heteroaromatics [22][23][24][25]28,30,31]. We were pleased that the hydrogenation of the benzisoxazole was accompanied by the reduction of the C-N double bond in the presence of stoichiometric Boc 2 O, which afforded N-Boc-protected (R)-1-(2-hydroxyphenyl)-1-propylamine 4a with 25% ee (entry 5).…”

“…In a series of our studies, a trans-chelating chiral bisphosphine, PhTRAP (Figure 1) [20,21], was mainly used as the chiral ligand. PhTRAP-rhodium or ruthenium complex allowed indoles [22][23][24][25][26][27] and pyrroles [28,29] to be reduced with hydrogen to the corresponding chiral indolines and pyrrolidines with high enantiomeric excesses, respectively. Moreover, the chiral ruthenium catalyst recently proved to be useful for the asymmetric hydrogenation of imidazoles and oxazoles, which contain two heteroatoms in their aromatic rings [30,31].…”

Highly Enantioselective Hydrogenation of Quinoline and Pyridine Derivatives with Iridium‐(P‐Phos) Catalyst

“…[1a,b] Asymmetric homogeneous hydrogenation of heteroaromatic compounds to chiral heterocycles using inexpensive molecular hydrogen and a small amount of chiral transition metal catalyst is perhaps the most straightforward, efficient and atom-economic method, and has been widely employed in the reduction of a series of heteroaryl compounds. [2][3][4][5][6][7][8][9][10][11] Zhou and coworkers first reported the Ir-catalyzed asymmetric hydrogenation of 2,6-substituted quinolines with (R)-MeO-BIPHEP [6,6'-dimethoxy-2,2'-bis(diphenylphosphino)-1,1'-biphenyl] as the ligand to produce chiral tetrahydroquinolines with up to 96% ee.…”