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

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.

Key words

Brønsted acids - N–H imine hydrochloride salt - primary amine - disulfonimide (DSI) - organocatalytic reduction

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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).
• 16 Additionally, when imine salt 1a was dissolved in CHCl₃ and filtered through an HPLC filter to ensure complete absence of insoluble salt, reduction under completely homogeneous conditions proceeded efficiently and with high enantioselectivity (e.r. = 93:7).
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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.