Oxidative Routes to the Heterocyclic Cores of Benzothiazole Natural Products

Dedicated to Professor Steve Ley FRS in celebration of his 70^th birthday, and of his many outstanding contributions to organic synthesis

Abstract

Methyl 6-(2-acetylaminoethyl)-4-hydroxy-benzothiazole-2-carboxylate, the benzothiazole core of the natural product violatinctamine, was prepared in a biomimetic oxidative route from N-acetyldopamine and cysteine methyl ester. In an alternative oxidative cyclization, ethyl 6-benzyloxy-5-methoxybenzo[d]thiazole-2-carboxylate, the heterocyclic core of erythrazole A, was also prepared.

Key words

heterocycles - natural products - amino acids - quinones - oxidation

• References and Notes

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• 9 Methyl 6-(2-Acetylaminoethyl)-4-hydroxy-benzothiazole-2-carboxylate (9) Ag₂O (256 mg, 1.1 mmol) and Na₂SO₄ (251 mg, 1.8 mmol) were added to a solution of N-acetyldopamine (8, 60 mg, 0.3 mmol) and formic acid (42 μL, 1.1 mmol) in MeOH (4 mL), and the black suspension was stirred for 15 min in the dark at r.t. then filtered through a pad of Celite^®. The filter cake was washed with MeOH (2 × 6 mL), and the combined red filtrates were immediately added dropwise to a solution of cysteine methyl ester hydrochloride (57 mg, 0.3 mmol) in MeOH (2 mL). After addition had completed the pale green solution was concentrated to give the cysteine adduct as a pale yellow–green foam that was used directly without purification {HRMS: m/z calcd for C₁₄H₂₁N₂O₅S⁺: 329.1166; found [M + H⁺]: 329.1160}. The above foam was dissolved in H₂O (0.7 mL) and a solution of FeCl₃·6H₂O (442 mg, 1.6 mmol) in H₂O (1.8 mL) was slowly added dropwise with vigorous stirring. The mixture was stirred for 72 h at r.t., then diluted with H₂O (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with H₂O (30 mL) and brine (30 mL), dried (Na₂SO₄), and concentrated. The residue was subjected to flash column chromatography on silica gel, eluting with EtOH–AcOH (1:9) to give the title compound as yellow solid (34 mg, 37% over two steps); mp 143–144 °C. HRMS: m/z calcd for C₁₃H₁₅N₂O₄S⁺: 295.0747; found [M + H⁺]: 295.0742. IR (CHCl₃): ν_max = 3522, 3011, 2414, 1722, 1603, 1497, 1192 cm^–1. UV-Vis (MeCN): λ_max = 264 (log ε 3.15), 312 (log ε 3.58) nm. ¹H NMR (400 MHz, acetone-d ₆): δ = 9.44 (1 H, br s), 7.79 (1 H, br s), 7.46 (1 H, s), 6.94 (1 H, s), 4.01 (3 H, s), 3.57–3.53 (2 H, m), 2.96–2.93 (2 H, m), 2.02 (3 H, s). ¹³C NMR (100 MHz, acetone-d ₆): δ = 172.8 (C), 161.5 (C), 155.5 (C), 153.7 (C), 143.0 (C), 124.9 (C), 139.1 (C), 113.9 (CH), 113.6 (CH), 53.7 (Me), 41.8 (CH₂), 36.4 (CH₂), 20.9 (Me).
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• 13 Ethyl 6-Benzyloxy-5-methoxybenzo[d]thiazole-2-carboxylate (20) To a solution of ethyl 2-(4-benzyloxy-3-methoxyphenyl)amino)-2-thioxoacetate (19, 2.5 g, 7.2 mmol) in MeCN (175 mL) at 0 °C was added CAN (9.86 g, 18 mmol) in H₂O (175 mL). The reaction mixture was stirred for 1.5 h, then diluted with H₂O (200 mL) and extracted with EtOAc (3 × 100 mL). The organic extracts were combine, washed with brine (2 × 200 mL), then dried over MgSO₄ to give the title compound as a beige solid (1.28 g, 52%); mp 116 °C. HRMS: m/z calcd for C₁₈H₁₈NO₄S: 344.0951; found [M + H]⁺: 344.0961. IR (CHCl₃): ν_max = 3009, 1714, 1607, 1497 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (1 H, s), 7.45–7.31 (6 H, m), 5.24 (2 H, s), 4.52 (2 H, q, J = 7.1 Hz), 3.97 (3 H, s), 1.47 (3 H, t). ¹³C NMR (100 MHz, CHCl₃): δ = 160.7 (C), 156.2 (C), 150.9 (C), 149.9 (C), 148.2 (C), 136.1 (C), 129.8 (C), 128.7 (CH), 128.2 (CH), 127.3 (CH), 106.0 (CH), 104.1 (CH), 71.3 (CH₂), 62.8 (CH₂), 56.2 (Me), 14.3 (Me).