Synlett 2020; 31(17): 1707-1712
DOI: 10.1055/s-0040-1706413
letter
© Georg Thieme Verlag Stuttgart · New York

Chiral Brønsted Acids Catalyze Asymmetric Additions to Substrates that Are Already Protonated: Highly Enantioselective Disulfonimide-Catalyzed Hantzsch Ester Reductions of NH–Imine Hydrochloride Salts

Vijay N. Wakchaure
,
Carla Obradors
,


Generous support from the Max-Planck-Gesellschaft, the Deutsche Forschungsgemeinschaft (Leibniz Award to B.L. and Cluster of Excellence RESOLV, Grant No. EXC 1069), and the European Research Council (Advanced Grant ‘C–H Acids for Organic Synthesis, CHAOS’) are gratefully acknowledged. C.O. also acknowledges Alexander von Humboldt Foundation and Bayer Science & Education Foundation for the Humboldt-Bayer Fellowship for Postdoctoral Researchers.
Further Information

Publication History

Received: 19 June 2020

Accepted after revision: 13 July 2020

Publication Date:
14 August 2020 (online)


Abstract

While imines are frequently used substrates in asymmetric Brønsted acid catalysis, their corresponding salts are generally considered unsuitable reaction partners. Such processes are challenging because they require the successful competition of a catalytic amount of a chiral anion with a stoichiometric amount of an achiral one. We now show that enantiopure disulfonimides enable the asymmetric reduction of N–H imine hydrochloride salts using Hantzsch esters as hydrogen source. Our scalable reaction delivers crystalline primary amine salts in great efficiency and enantioselectivity and the discovery suggests potential of this approach in other Brønsted acid catalyzed transformations of achiral iminium salts. Kinetic studies and acidity data suggest a bifunctional catalytic activation mode.

Supporting Information

 
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  • 15 General Procedure for the Asymmetric Reduction of N–H Imine Hydrochloride Salts An oven-dried 10 mL vial was charged with the hydrochloride salt of imine 1 (0.25 mmol), Hantzsch ester 2 (108.3 mg, 0.35 mmol, 1.4 equiv), disulfonimide DSI-3c, freshly activated MS 5Å (250 mg), and a magnetic stirring bar at RT. Then 7.5 mL (0.033 M) of MTBE–MeCy (MTBE–CHCl3 in case of 1l) was added under an argon atmosphere. The mixture was then subjected to the appropriate reaction time and temperature. The reaction mixture was filtered over Celite, washed with isohexane (40 mL), and isohexane–MTBE (1:1, 40 mL) to remove the neutral compounds. The hydrochloride salt of the desired amine product 4 was then collected in >99% purity (by 1H NMR analysis) by washing with 3% MeOH in CH2Cl2 (60 mL) and evaporating the filtrate under reduced pressure. The enantiomeric ratio of products 4 was determined by HPLC after benzoylation following a standard procedure. Crude enantiomeric ratios were determined after subjecting the reaction mixture with sat. NaHCO3 solution, extracting the free amine product with MTBE, followed by benzoylation and HPLC analysis. (S)-1-[4-(tert-Butyl)phenyl]ethan-1-aminium Chloride (4b) Prepared according to the general procedure using DSI-3c (7.98 mg, 2.0 mol%, 0.02 equiv) in MTBE–MeCy (1:1) at RT for 24 h and obtained as colorless solid (43.25 mg, 81%, e.r. = 99.5:0.5, crude reaction e.r. = 99.5:0.5). 1H NMR (500 MHz, CDCl3): δ = 8.58 (br s, 3 H), 7.46–7.27 (m, 4 H), 4.30–4.20 (m, 1 H), 1.55 (d, J = 6.8 Hz, 3 H), 1.21 (s, 9 H). 13C NMR (126 MHz, CDCl3): δ = 151.8, 135.4, 126.8, 126.0, 51.5, 34.7, 31.4, 20.8. HRMS (ESI): m/z calcd for C12H20N [M – Cl]+: 178.159060; found: 178.159024. The enantiomeric ratio was determined by derivatization to the corresponding benzamide by HPLC analysis using Daicel Chiralpak OD-3, n-heptane–IPA = 80:20, flow rate = 1.0 mL/min, 25 °C, λ = 220 nm, t R = 3.13 min (minor) and t R = 4.60 min (major). [α]D 25 –16.0° (c 0.63, CH2Cl2).
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  • 18 See the Supporting Information for NMR studies on the speciation of the catalyst with the substrates and the products under the reaction conditions.