Ring Enlargement of Enantiopure 1,2-Oxazines to 1,2-Oxazepine Derivatives and Their Palladium-Catalyzed Couplings

Abstract

Phase-transfer-catalyzed cyclopropanation of enantio­pure 1,2-oxazine derivatives anti-1a,b or syn-1 followed by solvo­lysis of the resulting geminal dibromocyclopropane intermediates afforded the expected ring-expanded products, namely 1,2-oxazepines anti-3a,b or syn-3. These heterocycles could be further substituted by use of their bromoalkenyl group employing ­palladium-catalyzed coupling reactions, which smoothly led to new enantiopure 1,2-oxazepine derivatives anti-4-anti-8.

Key words

dibromocyclopropanes - ring enlargement - 1,2-oxazines - 1,2-oxazepines - palladium catalysis

References

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4

Typical Procedure, conversion of anti -1a into anti -3a.
A solution of NaOH (0.60 g) and KF (4.10 g) in H₂O (4.10 mL) was added to a vigorously stirred solution of anti-1a (0.50 g, 1.64 mmol) in CHBr₃ (2.70 mL) containing benzyltriethylammonium chloride (5.5 mg). The biphasic mixture was stirred for 2 d at r.t. and then diluted with H₂O (8 mL) and extracted with Et₂O. The combined ethereal extracts were washed with brine, dried (Na₂SO₄) and concentrated. The excess CHBr₃ was removed in vacuum. The residue was purified by column chromatography (silica gel, hexane-EtOAc, 4:1) to give 2a as colorless liquid (511 mg, 65%, dr 68:32).
Dibromocyclopropane derivative 2a was refluxed for 20 h in a solution of anhyd K₂CO₃ (0.87 g, 6.27 mmol) in MeOH (7 mL) under Ar atmosphere. The mixture was cooled to r.t., diluted with H₂O and extracted with CH₂Cl₂. The combined organic extracts were dried (Na₂SO₄) and concentrated. The product was purified by column chromatography (silica gel, hexane-EtOAc, 9:1) to yield 241 mg (53%) of anti-3a as colorless oil.
Analytical data for (3R,4′S)-2-benzyl-5-bromo-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-4,4-dimethoxy-2,3,4,7-tetrahydro-1,2-oxazepine: [α]_D ²² -84.2 (c 0.45, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.33, 1.36 (2 s, 3 H each, Me), 3.19, 3.29 (2 s, 3 H each, OMe), 3.28 (d, J = 5.6 Hz, 1 H, 3-H), 4.07 (dd, J = 8.4, 8.8 Hz, 1 H, 5′-H), 4.11 (dd, J = 8.0, 8.4 Hz, 1 H, 5′-H), 4.29, 4.34 (2 d, J = 14.0 Hz, 1 H each, NCH₂), 4.31 (m_c, 1 H, 4′-H), 4.37 (dd, J = 1.1, 13.5 Hz, 1 H, 7-H), 4.47 (dd, J = 0.8, 13.5 Hz, 1 H, 7-H), 6.70 (dd, J = 0.8, 1.1 Hz, 1 H, 6-H), 7.24-7.39 (m, 5 H, Ph) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 25.7, 26.3 (2 q, CH₃), 49.0, 49.1 (2 q, OMe), 58.1 (t, NCH₂), 63.6 (t, C-7), 66.7 (d, C-3), 67.2 (t, C-5′), 74.9 (d, C-4′), 99.2 (d, C-2′), 108.5 (d, C-6), 108.9 (s, C-4), 127.1, 128.2, 128.6, 138.0 (3 d, s, Ph), 135.3 (s, C-5) ppm. IR (KBr): ν = 3090-3030 (=C-H), 2985-2845 (C-H), 1635 (C=C) cm^-1. MS (EI, 80 eV, 100 °C): m/z (%) = 429 (1) [M]⁺, 427 (1) [M]⁺, 414 (1) [M - CH₃]⁺, 412 (1) [M - CH₃]⁺, 398 (0.4) [M - OCH₃]⁺, 396 (0.4) [M - OCH₃]⁺, 329 (6) [M - CH₅H₉O₂]⁺, 327 (6) [M - CH₅H₉O₂]⁺, 91 (100) [CH₂Ph]⁺. Anal. Calcd for C₁₉H₂₀BrNO₅ (428.3): C, 53.28; H, 6.12; N, 3.27. Found: C, 53.10; H, 5.91; N, 2.68. HRMS (EI, 80 eV, 100 °C): m/z calcd for C₁₉H₂₀ ⁷⁹BrNO₅: 427.09943; found: 427.09947; m/z calcd for C₁₉H₂₀ ⁸¹BrNO₅: 429.09744; found: 429.09738.