Highly Enantioselective Partial Hydrogenation of Simple Pyrroles: A Facile Access to Chiral 1-Pyrrolines

Abstract

A highly enantioselective Pd-catalyzed partial hydrogenation of simple 2,5-disubstituted pyrroles with a Brønsted acid as an activator has been successfully developed, providing chiral 2,5-disubstituted 1-pyrrolines with up to 92% ee.T he asymmetric hydrogenation of aromatic compounds offers straightforward access to chiral molecules with cyclic skeletons and has received much attention over the past decades. 1 Some bicyclic heteroaromatic substrates have been successfully hydrogenated because of their relatively low aromaticity (quinolines, isoquinolines, quinoxalines, indoles, and benzofurans). 2À6 This process is much more difficult for single-ring heteroaromatic compounds, although hitherto, special activated pyridines 7 and furans 6 have been successfully hydrogenated, and a single elegant example of asymmetric hydrogenation of N-Boc-protected pyrroles using a chiral Ru catalyst was reported by Kuwano and coworkers. 8 To the best of our knowledge, no report on the asymmetric hydrogenation of simple pyrroles has appeared, despite its potential usefulness. 9 Thus, the exploration of a new strategy for hydrogenation of simple pyrroles is urgently needed and of great significance.Very recently, we disclosed the Brønsted acid-activated asymmetric hydrogenation of simple indoles 5h,i using a homogeneous palladium catalyst. 10,11 As part of our ongoing effort to develop new strategies for asymmetric hydrogenation of heteroaromatic compounds and considering the similarity of pyrroles and indoles, we envisioned that electron-enriched pyrroles could be protonated in the presence of strong Brønsted acids, which would destroy their aromaticity thus be suitable for facilitating hydrogenation. Herein we report the results of our preliminary investigation of asymmetric hydrogenation of simple 2,5-disubstituted pyrroles, wherein partially hydrogenated 1-pyrrolines were obtained with up to 92% ee.Initially, 2-methyl-5-phenylpyrrole (1a) was selected as a model substrate for optimization of the reaction conditions. Pd(OCOCF 3 ) 2 /(R)-BINAP was employed as the catalyst with ethylsulfonic acid (EtSO 3 H) as the activator. When the reaction was carried out at 60°C, it proceeded smoothly, affording the unexpected product 5-methyl-2-phenyl-1-pyrroline (2a) in 70% yield with 71% ee; no pyrrolidine was detected in the reaction mixture (Table 1, entry 1). It is noteworthy that this is the first example of asymmetric hydrogenation of a pyrrole to obtain a

Asymmetric Hydrogenation of Isoxazolium Triflates with a Chiral Iridium Catalyst

“…No change of the enantioselectivity was observed when K 2 CO 3 was used as the base in place of KHCO 3 (Table 3, entry 2v ersus 1), but the base did affect the efficiency of the iridiumc atalyst (Table 3, entries [1][2][3][4][5][6]. No significant decrease in the stereoselectivity was observede ven in the reactionu sing KOAc (Table 3, entry 6).…”

Asymmetric Hydrogenation of Imines

“…Later, it was reported that the introduction of an acid activator could be achieved by preforming iminium type substrates such as N-H imines [43,119], or by the addition of the acid activator in situ [120,121]. Following that strategic breakthrough, groundbreaking works of Pd-catalyzed asymmetric hydrogenation of heteroaromatics, such as unprotected indoles by Zhou et al, and pyrroles by Zhou, Fan et al were recently published [115,122,123].…”

Catalytic Asymmetric Hydrogenation of 3-Substituted Benzisoxazoles

“…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].…”