Chiral Indolizidine Synthesis through the Ir-Catalyzed Asymmetric Hydrogenation of Cyclic Pyridinium Salts

Abstract

The Ir-catalyzed asymmetric hydrogenation of cyclic pyridinium salts is presented as a new strategy for the convenient and efficient synthesis of chiral indolizidines. The asymmetric hydrogenation of cyclic pyridinium salts derived from 2-(2-acylphenyl)pyridines proceeded smoothly in the presence of [Ir(cod)Cl] 2 and (R)-DM-SegPhos to provide the desired chiral 7,8-benzoindolizidines 6 in high to excellent yields with moderate enantioselectivity (up to 86:14 er) and excellent diastereoselectivity (>20:1 dr). The enantiomeric purity of 6j was increased to 92:8 through recrystallization.

Ruthenium(II)-Catalyzed Grignard-Type Nucleophilic Addition of C(sp2)–H Bonds to Unactivated Aldehydes

“…To demonstrate the practicality of this reaction, a gram scale experiment of 1a with 2a was performed, and product 3aa was obtained in 73% yield (Scheme 4). The alcohol products 3 can be further transformed to the cyclic pyridinium salts 4 in high yields by reaction with hydrochloric acid, 10 indicating the applicability of this reaction in organic synthesis.…”

“…Derivatization Reactions of Alcohol. 10 The alcohol product (2 mmol) was dissolved in AcOH (1 mL), and then reacted with 4 mol/ L of HCl in dioxane (1 equiv) at 90 °C (oil bath) for 3 h. The mixture was concentrated in a vacuum to give the crude cyclic pyridinium salts. Purification of the crude product was carried out by washing three times with ether.…”

“…6-(p-Tolyl)-6H-pyrido[2,1-a]isoindol-5-ium Chloride (4a). 10 White solid, 91% yield (469.8 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (d, J = 6.1 Hz, 1H), 8.74 (d,J = 8.0 Hz,1H),8.51 (t,J = 7.7 Hz,1H),1H),8.13 (s,1H),7.74 (t,J = 6.8 Hz,1H),2H),1H),2H),7.18 (d,J = 7.8 Hz,2H), 2.34 (s, 3H).…”

“…3,145.9,143.7,142.1,140.8,133.8,131.0,130.5,130.13,130.10,129.1,124.7,124.4,123.8,120.6,75.7,isoindol-5-ium chloride (4b). 10 White solid (550.2 mg, 89%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (d, J = 5.9 Hz, 1H), 8.67 (d, J = 7.9 Hz, 1H), 8.43 (t, J = 7.7 Hz, 1H), 8.29 (d, J = 6.8 Hz, 1H), 8.10 (s, 1H), 7.67 (t, J = 6.2 Hz, 1H), 7.58 (m, 2H), 7.41−7.33 (m, 3H), 6.83 (d,J = 8.3 Hz,2H), 3.73 (s, 3H).…”

Recent developments in enantio- and diastereoselective hydrogenation of N-heteroaromatic compounds

“…In 2021, Zhang et al established the synthesis of chiral indolizidine by EH of cyclic pyridinium salts using an Ir– L 15 catalytic system. 74 Initially, cyclic pyridinium salts were accessed by reducing 2-(2-acylphenyl)pyridines using NaBH 4 followed by the cyclization using HBr/HCl. The counteranion exchange reaction was carried out with the corresponding silver salts to access other counterions of cyclic pyridinium salts.…”