2-Aminobenzimidazole Organocatalyzed Asymmetric Amination of Cyclic 1,3-Dicarbonyl Compounds

Dedicated to the memory of Prof. Carlos F. Barbas III

Abstract

The use of a trans-cyclohexanediamine benzimidazole derivative as a hydrogen-bond catalyst for the electrophilic amination of cyclic 1,3-dicarbonyl compounds is herein presented. High yields and enantioselectivities varying from moderate to excellent are generally obtained using mild reaction conditions and as low as 1 mol% of catalyst loading.

Key words

organocatalysis - electrophilic amination - asymmetric catalysis - dicarbonyl compounds - benzimidazole

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• 10 General Procedure for the Asymmetric Amination of Cyclic 1,3-Dicarbonyl Compounds: In a tube, open to the atmosphere, in a thermostated bath (25 °C) the requisite 1,3-dicarbonyl compound (0.2 mmol) was added to a solution of organocatalyst II (0.002 mmol, 1 mol%) in Et₂O (1 mL). After 5 min, di-tert-butylazodicarboxylate (2a; 0.21 mmol, 1.05 equiv) was added in one portion and the reaction was then allowed to react for 10 h. After this time, H₂O (5 mL) and EtOAc were added, and then the aqueous layer was re-extracted with EtOAc (2 × 5 mL). The combined organic phases were dried (MgSO₄), filtered and the solvent was evaporated under reduced pressure. Finally, the crude product was purified by flash chromatography using hexanes–EtOAc mixtures as eluent.Physical and spectroscopic data given below are for compound 3da and may be taken as representative. For further details; see Supporting Information. Di-tert-butyl 1-[2-(Ethoxycarbonyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl]hydrazine-1,2-dicarboxylate (3da) ^8b Slightly yellow viscous oil (88 mg, 98% yield, 91% ee); [α]_D ²⁸ +23.3 (c = 2.0, CHCl₃). ¹H NMR (300 MHz): δ = 1.33 (br m, 21 H), 2.67 (m, 1 H), 2.95 (m, 2 H), 3.44 (br m, 1 H), 4.31 (q, J = 7.0 Hz, 2 H), 6.23 (m, 1 H), 7.25 (m, 2 H), 7.46 (m, 1 H), 7.95 (dd, J = 28.0, 7.2 Hz, 1 H). ¹³C NMR (75 MHz): δ = 14.1, 25.6, 27.7, 28.0, 31.1, 60.3, 61.9, 80.8, 82.7, 126.4, 127.7, 128.5, 131.7, 133.4, 154.4, 155.5, 169.5, 191.0. MS (IE): m/z (%) = 348 (6.5) [M⁺ – Boc], 292 (47), 219 (100), 175 (86), 158 (30). Chiral HPLC analysis: Chiralcel IA column, hexane–i-PrOH (85:15), flow rate = 1 mL/min, λ = 254 nm, retention times: t_R = 8.0, 11.5 min.
• 11 (S)-3aa [α]_D ²⁹ +3.8 (c = 1, CHCl₃, 92% ee). Reported value in ref. 5b for R-enantiomer: [α]_D ³² –3.47 (c = 1.09, CHCl₃, 97% ee). See Supporting Information for further details.