Base-Promoted Internal Redox-Cyclisation Reactions

Abstract

A new internal, base-mediated redox-cyclisation reaction has been discovered and developed. In this transformation, the sacrificial reduction of an alkynyl moiety to an alkene allows direct functionalisation of an α-amino C–H bond. This approach allows the preparation of several 1,3-oxazinane derivatives in an atom-­efficient manner.

Key words

C–H activation - C–H functionalisation - redox - cyclisation - pyrrolidine

• References and Notes

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• 6 The remainder of the mass balance in these reactions was typically composed of a mixture of oligomeric material, decomposition products and (occasionally) small amounts of cyclisation products isomeric or akin to 5a (Scheme 3).
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• 9 Typical Procedure; Synthesis of 1,3-Oxazine 4a: To a solution of amino alcohol 3a (62 mg, 0.22 mmol) in THF (5 mL) was added NaH (60% w/w, 1.0 equiv, 8.8 mg, 0.22 mmol) under argon at room temperature and the mixture was stirred at 50 °C overnight. The reaction mixture was then cooled to room temperature, quenched with sat. aq NH₄Cl, extracted with EtOAc (3×), dried (Na₂SO₄), and concentrated under reduced pressure. Purification by column chromatography (pentane–EtOAc, 9:1) afforded the desired product 1,3-oxazinane 4a. 3a-Styryl-2,3,3a,5-tetrahydro-1H-benzo[d]pyrrolo[2,1-b][1,3]oxazine (4a): Yield: 52%. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.33 (m, 2 H), 7.30–7.27 (m, 2 H), 7.23–7.16 (m, 2 H), 6.88 (d, J = 7.2 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H), 6.71–6.67 (m, 1 H), 6.41 (d, J = 15.7 Hz, 1 H), 6.19 (d, J = 15.7 Hz, 1 H), 4.88 (d, J = 14.6 Hz, 1 H), 4.62 (d, J = 14.6 Hz, 1 H), 3.79 (td, J = 8.9, 1.8 Hz, 1 H), 3.36 (ddd, J = 9.8, 8.8, 6.7 Hz, 1 H), 2.25–2.20 (m, 1 H), 2.16–2.09 (m, 1 H), 2.05–1.91 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 142.4, 136.1, 133.8, 130.4, 128.5, 127.8, 127.7, 126.8, 124.5, 120.1, 116.7, 113.3, 93.6, 63.5, 50.0, 39.3, 21.3. IR (neat): 3024 (w), 2970 (w), 2841 (w), 1881 (w), 1607 (s), 1497 (s), 1361 (s), 1196 (m), 1029 (m), 973 (m), 747 (s) cm^–1. HRMS: m/z calcd for [C₁₉H₁₉NO + H]⁺: 278.1545; found: 278.1539. Typical Procedure; Synthesis of 1,3-Oxazine 4f: To a solution of amino alcohol 3f (50 mg, 0.15 mmol) in THF (4 mL), NaH (60% w/w, 1.0 equiv, 6.2 mg, 0.15 mmol) was added under argon at room temperature and the mixture was stirred at 50 °C overnight. The reaction mixture was cooled to room temperature, quenched with sat. aq NH₄Cl, extracted with EtOAc (3×), dried (Na₂SO₄), and concentrated under reduced pressure. Purification by column chromatography (pentane–EtOAc, 19:1) afforded the desired 1,3-oxazinane 4f. 3a-[4-(tert-Butyl)styryl]-2,3,3a,5-tetrahydro-1H-benzo[d]pyrrolo[2,1-b][1,3]oxazine (3f): Yield: 38%. ¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.25 (m, 4 H), 7.12–7.09 (m, 2 H), 6.81–6.77 (m, 1 H), 6.80 (d, J = 7.6 Hz, 1 H), 6.72 (d, J = 8.2 Hz, 1 H), 6.62–6.59 (m, 1 H), 6.31 (d, J = 15.7 Hz, 1 H), 6.08 (d, J = 15.4 Hz, 1 H), 4.80 (d, J = 14.8 Hz, 1 H), 4.54 (d, J = 15.8 Hz, 1 H), 3.71 (td, J = 8.5 Hz, J = 8.4 Hz, 1 H), 3.36 (m, 1 H), 2.16–2.11 (m, 1 H), 2.08–2.02 (m, 1 H), 1.91–1.95 (m,1 H), 1.89–1.82 (m, 1 H), 1.25–1.22 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 133.6, 133.1, 129.7, 127.8, 126.8, 125.7, 124.5, 120.3, 116.7, 113.2, 96.6, 93.8, 63.5, 50.3, 39.4, 34.6, 30.9, 21.2. IR (neat): 3024 (w), 2970 (w), 2841 (w), 1830 (w), 1698 (s), 1498 (s), 1362 (s), 1263 (m), 1029 (m), 815 (m), 749 (s) cm^–1. HRMS: m/z calcd for [C₂₃H₂₇NO + H]⁺: 334.2167; found: 334.2165.