Highly Enantioselective Iridium-Catalyzed Hydrogenation of Heteroaromatic Compounds, Quinolines

Abstract

Catalytic asymmetric hydrogenations of prochiral unsaturated compounds, such as olefin, ketone, and imine, have been intensively studied and are considered as a versatile method of creating a chiral carbon center. 1 However, asymmetric hydrogenation of heteroaromatic compounds is less explored, resonance stability of heteroaromatic compounds might impede the enantioselective hydrogenation. 2 To date, only a few papers on homogeneous asymmetric hydrogenation of heteroaromatic compounds have been reported. Kuwano and co-workers reported a highly effective hydrogenation of N-Boc-or Ac-substituted indoles by application of Rh/Ph-TRAP/Cs 2 CO 3 catalyst, 3 and up to 95% ee was obtained. Bianchini developed an orthometalated dihydride iridium complex for hydrogenation of 2-methylquinoxaline with 90% ee. 4 Studer and co-workers employed Rh(NBD) 2 BF 4 /DIOP as the catalyst for hydrogenation of monosubstituted pyridine and furans with only 24-27% ee. 5a Rh(DIOP)H was used as the catalyst for hydrogenation of 2-methylquinoxaline with only 3% ee. 5b The search for a new catalytic system for asymmetric hydrogenation of heteroaromatic compounds is still a challenge.Direct hydrogenation of easily available quinoline derivatives is the most convenient route to synthesize tetrahydroquinoline derivatives, which are important organic synthetic intermediates 6 and structural units of alkaloids and biologically active compounds. 7 Although many efforts have been made toward development of hydrogenation of quinolines using homogeneous achiral Rh 8 or Ru 9 catalysis, to the best of our knowledge, no report on homogeneous asymmetric hydrogenation of quinolines has appeared in the literature. Therefore, we decided to focus on this reaction. In this communication, we report our preliminary results and describe the first example of highly enantioselective iridium-catalyzed hydrogenation of quinolines.Considering that iridium has been successfully applied to asymmetric hydrogenation of imines and unfunctionalized olefins recently, 1 we first examined the [Ir(COD)Cl] 2 /MeO-Biphep/DCM system for hydrogenation of 2-methylquinoline (1a) (Scheme 1). Unfortunately, it was found that the catalytic activity is very low, and only a trace amount of product with low ee was obtained when the reaction was carried out in methylene chloride at room temperature under 700 psi of hydrogen for 18 h. A number of literature reports have appeared documenting the dramatic impact of additives on catalytic turnover and enantioselectivity. 10 Accordingly, we evaluated a number of additives, such as I 2 11 n-Bu 4 NI, 12,13 BiI 3 , 13 phthalimide, 14 benzylamine, 15 etc., in an attempt to promote reaction turnover. Gratifyingly, iodine proved to be the most efficient additive in this reaction. Chiral iridium complex prepared in situ from [Ir(COD)Cl] 2 and chiral bisphosphine (R)-MeO-Biphep were employed as catalysts, and the reactions were carried out at room temperature under 700 psi of hydrogen with a substrate: [Ir]: ligand:I 2 ratio of 100:0.5:1.1:10. Furt...

Asymmetric Hydrogenation of Heteroaromatic Compounds

“…Using 2-methylquinoline as a model substrate, the reaction proceeded smoothly, affording 2-methyl-1,2,3,4-tetrahydroquinoline with 94% ee (Scheme 4). 11 After screening several other additives, we concluded that only iodine and halogen analogues give excellent conversions and enantioselectivity.…”

“…This methodology can be successfully applied to the asymmetric synthesis of tetrahydroquinoline alkaloids and chiral drugs (Scheme 6). 11,13 For example, the hydrogenation product of 6-fluoro-2-methylquinoline is the key intermediate of the antibacterial agent of Flumequine. N-Methylation of hydrogenation products completed the synthesis of angustrureine, galipinine, and cuspareine in high total yields.…”

Enantioselective Synthesis of Alcohols and Amines by Iridium‐Catalyzed Hydrogenation, Transfer Hydrogenation, and Related Processes

“…Zhou and co-workers reported the first highly enantioselective iridium-catalyzed hydrogenation of quinolines 10 (Scheme 14). [42] The optimal reaction conditions found were [IrClA C H T U N G T R E N N U N G (cod)] 2 together with a ligand possessing axial chirality, (R)-MeO-BiPhep (39), and iodine as the additive. A number of tetrahydroquinolines were prepared with excellent ee values (up to 96 %).…”

“…A number of tetrahydroquinolines were prepared with excellent ee values (up to 96 %). Four products were further transformed into natural alkaloids: galipinine (40), angustureine (41), cuspareine (42), and the antibacterial agent flumequine (43). The catalyst was successfully immobilized on a soluble PEG polymer support by replacing one of the OMe groups by MeO-PEG-(1600).…”

“…[43] The enantioselectivity obtained with the heterogenized catalytic system (S)-MeOBiphep-PEG-(1600) (44) was similar to that obtained under homogenous conditions and 44 could be recycled up to five times with no significant drop in conversion and enantioselectivity. [42] The same group reported that benzyl chloroformate was an excellent imine-activating reagent (Scheme 15a and b). [44] (S)-SegPhos ((S)-45) was the most active among all the ligands tested; several quinolines (10) and isoquinolines (16) activated with chloroformate could be hydrogenated with ee values up to 90 %.…”