Diastereoselective Synthesis of 1,3-syn-Oxazines via a Tandem Hemiaminalization and Tsuji–Trost Reaction

Abstract

A novel domino sequence for the rapid assembly of 1,3-syn-substituted oxazines is reported. Mechanistically, the one-pot procedure is based on a three-step sequential process involving a hemiaminalization and Tsuji–Trost reaction. The process generates up to two new stereogenic centers in a concise and convergent fashion from simple and readily available starting materials.

Key words

synthetic methodology - tandem reaction - catalysis - allylic substitution - oxazines

• References and Notes

• 1 Present address: University of Basel, Switzerland.
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• 11 In all cases, stereochemical assignment was based on NMR methods. Scheme 4 shows an example.
• 12 A yield of 56% was obtained in the absence of base for the analogous reaction described in entry 5 (Table 2).
• 13 Experimental Procedure: Under an argon atmosphere, imine 10 (62.2 mg, 0.24 mmol), allylpalladium(II) chloride dimer (7.3 mg, 10 mol%) and triphenylphosphine (15.8 mg, 30 mol%) were added to a well-dried Schlenk flask. Then, a solution of the respective carbonate (0.2 mmol) in anhyd toluene (0.33 M, 0.61 mL) was added to the flask and stirred until all solids were dissolved. After cooling to –78 °C, the potassium bis(trimethylsilyl)amide solution (0.5 M in toluene) was added dropwise (40 μL, 10 mol%). After 15 min the reaction mixture was warmed to r.t. and stirred at this temperature until complete conversion. After addition of a sat. aq solution of NH₄Cl (2 mL), the mixture was extracted with EtOAc (3 ×), washed with H₂O and brine and dried over Na₂SO₄. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with EtOAc–hexane (1:16) as eluent to afford the oxazines with the indicated yields and selectivities.
• 14 All new compounds had spectroscopic data in support of the assigned structures. Oxazine 11a: ¹H NMR (500.13 MHz, CDCl₃): δ = 7.97 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H) 7.63 (d, J = 8.2 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 1 H), 7.29–7.42 (m, 5 H), 7.12–7.19 (m, 2 H), 7.07 (d, J = 7.9 Hz, 1 H), 7.00 (d, J = 7.9 Hz, 1 H), 6.75 (s, 1 H), 5.78 (ddd, J = 17.3, 10.4, 7.7 Hz, 1 H), 5.02 (d, J = 17.3 Hz, 1 H), 4.96 (d, J = 10.3 Hz, 1 H), 4.40 (ddd, J = 8.5, 8.2, 7.7 Hz, 1 H), 3.86 (dd, J = 10.2, 4.7 Hz, 1 H), 2.50 (s, 3 H), 2.35 (s, 3 H), 1.93 (ddd, J = 13.7, 10.2, 8.2 Hz, 1 H), 1.54 (ddd, J = 13.7, 8.5, 4.7 Hz, 1 H). ¹³C NMR (125.76 MHz, CDCl₃): δ = 143.93, 141.52, 139.12, 137.74, 137.48, 137.36, 129.78, 129.19, 129.14, 128.27, 128.02, 127.82, 127.63, 127.29, 126.81, 126.17, 125.71, 115.73, 83.83, 73.15, 56.10, 33.62, 21.58, 21.08. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₈NO₃S: 434.17844; found: 434.17839. Oxazine 12a: ¹H NMR (500.13 MHz, CDCl₃): δ = 7.91–7.96 (m, 4 H), 7.71 (d, J = 7.7 Hz, 2 H), 7.50 (d, J = 7.7 Hz, 2 H), 7.32–7.40 (m, 5 H), 6.73 (s, 1 H), 5.78 (ddd, J = 17.3, 10.4, 6.6 Hz, 1 H), 5.02 (d, J = 17.3 Hz, 1 H), 4.94 (d, J = 10.4 Hz, 1 H), 4.50 (ddd, J = 8.2, 8.0, 6.6 Hz, 1 H), 4.34 (dd, J = 11.5, 2.2 Hz, 1 H), 3.71 (s, 3 H), 2.48 (s, 3 H), 2.07 (ddd, J = 13.7, 8.0, 2.2 Hz, 1 H), 1.82 (ddd, J = 13.7, 11.5, 8.0 Hz, 1 H). ¹³C NMR (125.77 MHz, CDCl₃): δ = 155.85, 143.35, 141.45, 139.34, 131.19, 129.72, 129.06, 128.57, 128.00, 127.90, 127.65, 126.89, 126.29, 120.62, 115.46, 110.29, 84.36, 68.03, 55.78, 55.09, 33.19, 21.54. HRMS (ESI): m/z [M + K]⁺ calcd for C₂₆H₂₇NO₄SK: 488.12924; found: 488.12948.
• 15 For a more detailed mechanistic discussion of a related cyclization, see ref. 4d.