N-Heterocyclic Carbene Catalyzed Enantioselective Annulation of Benzothiazolyl Ethyl Acetates with 2-Bromoenals

Abstract

An N-heterocyclic carbene catalyzed enantioselective [3+3] annulation of benzothiazolyl acetates with 2-bromoenals has been developed. The protocol provides a direct asymmetric synthesis of dihydro-1H-benzothiazolopyridinones in good to very good yields and medium ee values. In many cases, the virtually enantiopure heterocycles are available through a single recrystallization (99% ee).

Key words

asymmetric synthesis - N-heterocyclic carbene - organocatalysis - annulation - dihydrobenzothiazolopyridinones

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• 16 General Procedure for the Synthesis of Dihydro-1H-benzothiazolopyridinones 3a–k To an oven-dried and argon-filled Schlenk tube was added 2-substituted benzo[d]thiazole component 1 (0.5 mmol), 2-bromoenal 2 (0.75 mmol, 1.5 equiv), triazolium salt C (0.05 mmol, 10 mol%), and DIPEA (0.6 mmol, 1.2 equiv) in toluene (5 mL). The mixture was stirred at r.t. and monitored by TLC until completion of the reaction. The residue was purified by flash chromatography on silica gel [n-pentane–Et₂O (10:1) or n-pentane–CH₂Cl₂ (1:1 to 1:2)] to afford the products 3a–k as orange or yellow solids. Ethyl (S)-1-Oxo-3-phenyl-2,3-dihydro-1H-benzo[4,5]thiazolo-[3,2-a]pyridine-4-carboxylate (3a)Yield: 135.6 mg (77%), mp 125–127 °C. The ee (65%, 99% after recrystallization) was measured by HPLC using a chiral stationary phase [Daicel IC, n-heptane–EtOH = 7:3, 0.7 mL/min), t _R = 4.53 min (major), 5.35 min (minor)]. [α]_D ²³ = +236.9 (c 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 8.44 (d, J = 8.4 Hz, 1 H), 7.45 (dd, J = 7.2, 1.2 Hz, 1 H), 7.30–7.18 (m, 7 H), 4.33–4.32 (m, 1 H), 4.28–4.16 (m, 2 H), 3.24 (dd, J = 16.2, 8.4 Hz, 1 H), 3.02 (dd, J = 16.2, 1.8 Hz, 1 H), 1.23 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 168.2, 166.6, 152.3, 141.4, 136.8, 128.9 (2 C), 127.2, 127.0, 126.5 (2 C), 126.5, 125.5, 121.4, 117.4, 100.4, 60.7, 40.1, 36.8, 14.3. MS (EI, 70 eV): m/z (%) = 351 (100) [M⁺], 322 (36), 278 (40), 249 (44), 236 (71), 115 (19), 77 (17). IR (ATR): 3851, 3613, 3401, 3060, 2980, 2921, 2645, 2325, 2037, 1903, 1803, 1707, 1660, 1556, 1455, 1359, 1305, 1263, 1194, 1146, 1106, 1034, 939, 906, 853, 795, 748, 697 cm^–1. ESI-HRMS: m/z calcd for C₂₀H₁₇NO₃S [M]⁺: 351.0924; found: 351.0933.
• 17 CCDC 1056458 contains the supplementary crystallographic data for the compound 3b reported in this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.