Cyclic 1-(Arylamino)carboxylates via Mild Diastereospecific Jocic-Type Reaction with 2,2,2-Trichloromethyl Carbinols and Anilines

Abstract

A mild, practical Jocic-type rearrangement for the synthesis of cyclic 1-(arylamino) carboxylates from readily available 2,2,2-trichloromethyl carbinols and anilines is described. The method demonstrates good scope, with a large variety of anilines providing direct access to several novel cyclic 1-(arylamino) carboxylates. The reaction is robust and has been shown to provide comparable results on kilogram scale. The reaction is diastereospecific, leading to the formation of a single diastereomer when utilizing stereodefined 2,2,2-trichloromethyl carbinol cores.

Key words

Jocic rearrangement - 2,2,2-trichloromethyl carbinols - cyclic 1-(arylamino) carboxylates - diastereospecific - anilines

• References and Notes

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• 14 General Experimental Procedure Preparation of (2S,4R)-1-Benzyl 4-Methyl 4-(3-Cyanophenylamino)-2-methylpiperidine-1,4-dicarboxylate (1d, Table 2, Entry 5) from (2S,4S)-4-Hydroxy-2-methyl-4-(trichloromethyl)piperidine-1-carboxylate (4) To a 20 mL vial equipped with a stir bar was charged with (2S,4S)-benzyl 4-hydroxy-2-methyl-4-(trichloromethyl)piperidine-1-carboxylate (4, 367 mg, 1 mmol), MeOH (2 mL), and 3-aminobenzonitrile (354 mg, 3 mmol). The resulting homogeneous reaction mixture was placed in a precooled plate at 0 °C and was stirred for 10 min. To the cooled reaction mixture was added Cs₂CO₃ (1.2 g, 3.5 mmol) in two portions over a period of about 10 min. The mixture was then warmed to 5 °C and stirred for 42 h. The reaction mixture was removed from the cold bath and was concentrated under reduced pressure in the rotavap to a gum. To the crude reaction mixture was then added MTBE (10 mL) and was transferred to an extraction funnel with MTBE (10 mL). The cloudy solution was washed with 0.5 N HCl (2 × 5 mL) and brine (5 mL). The organic layer was then dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure in the rotovap. The resulting crude material was purified twice by silica gel flash chromatography (isco CombiFlash purification system, 24 g HP silica column, 0–60% EtOAc–heptane) and provided compound 1d as a gum in 64% yield (268 mg). ¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.37 (m, 5 H), 7.17–7.21 (m, 1 H), 7.01–7.03 (m, 1 H), 6.76–6.77 (m, 1 H), 6.73 (ddd, J = 8.0, 2.4, 0.8 Hz, 1 H), 5.14 (s, 2 H), 4.34–4.39 (m, 1 H), 4.21 (s, 1 H), 4.07 (ddd, J = 14.0, 5.6, 2.4 Hz, 1 H), 3.70 (s, 3 H), 3.27 (ddd, J = 14.4, 12.4, 4.0 Hz, 1 H), 2.60–2.64 (m, 1 H), 2.19 (ddd, J = 14.0, 5.6, 1.2 Hz, 1 H), 2.07 (dd, J = 13.6, 6.0 Hz, 1 H), 1.70 (ddd, J = 13.6, 12.4, 5.6 Hz, 1 H), 1.15 (d, J = 6.8 Hz, 3 H). ¹³C (100 MHz, CDCl₃): δ = 174.5, 155.1, 145.4, 136.6, 129.9, 128.4, 128.0, 127.8, 122.3, 119.2, 119.0, 117.6, 112.9, 67.1, 57.5, 52.6, 45.6, 38.6, 36.1, 33.1, 17.7. ESI-HRMS: m/z calcd for C₂₃H₂₅N₃O₄ [M + H]⁺: 408.1918; found: 408.1918