Aza-Wittig Reaction, Carbodiimide-Mediated Ring Closure, and Enol-­Induced Ring Interconversion: A Domino Process for the Synthesis of 4-Methylene-4H-3,1-Benzoxazines

Abstract

4-Methylene-4H-3,1-benzoxazines have been prepared in excellent yields from the reaction of iminophosphorane derived of N-(2-acetylphenyl)-2-azidobenzamide with triphenylphosphine with isocyanates. This transformation involves an initial aza-Wittig reaction to give a carbodiimide, which undergoes ring closure across the enol form of the carboxamide group and eventually an unprecedent imino-benzoxazine-methylene-benzoxazine rearrangement. A slight variation allows the preparation of one analogue of the marine alkaloid rhopaladin D.

iminophosphoranes - aza-Wittig reaction - heterocycles - tandem reactions - multicomponent reactions

References and Notes

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<A NAME="RG07607ST-8">8</A>

N -(2-Acetylphenyl)-2-[(triphenylphosphoranyl-idene)amino]benzamide ( 4)
To a solution of N-(2-acetylphenyl)-2-azidobenzamide (3, 3.5 g, 12.5 mmol) in dry CH₂Cl₂ (70 mL), PPh₃ (3.6 g, 13.6 mmol) in CH₂Cl₂ (70 mL) was added dropwise at 0 °C under N₂. The resultant mixture was stirred at r.t. for 12 h. The solvent was removed under reduced pressure and the residue was recrystallized from CH₂Cl₂-n-hexane (1:1) to give 4 (6.3 g, 98% yield). Yellow prisms, mp 195-196 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.22 (s, 3 H, CH₃CO), 6.46 (dt, 1 H, J = 8.1, 1.0 Hz, H-6), 6.71 (ddd, 1 H, J = 7.2, 7.8, 1.0 Hz, H-4), 6.92 (ddd, 1 H, J = 7.2, 8.1, 2.2 Hz, H-5), 7.08 (ddd, 1 H, J = 7.9, 7.3, 1.1 Hz, H-4′), 7.34-7.39 (m, 6 H, Hm), 7.43-7.51 (m, 4 H, Hp and H-5′), 7.62 (dd, 1 H, J = 7.9, 2.2 Hz, H-3), 7.73-7.51 (m, 6 H, Ho), 8.07 (dt, 1 H, J = 8.3, 1.1 Hz, H-6′), 13.4 (s, 1 H, NH). ¹³C NMR (100 MHz, CDCl₃): δ = 28.5 (CH₃CO), 117.3 (C-5), 122.4 (d, ³ J = 12.0 Hz, C-3), 122.7 (C-4′), 123.9 (C-6′), 126.7 (d, ³ J = 21.9 Hz, C-1), 128.2 (C-2′), 128.7 (d, ³ J = 12.4 Hz, Cm), 129.7 (d, ¹ J = 100.7 Hz, Ci), 129.8 (C-3′), 131.4 (C-4), 131.5 (d, ⁴ J = 2.8 Hz, C-6), 132.0 (d, ⁴ J = 2.9 Hz, Cp), 132.6 (d, ² J = 9.7 Hz, Co); 132.8 (C-5′), 138.6 (C-1′), 150.0 (d, ² J = 1.9 Hz, C-2), 167.5 (d, ⁴ J = 1.1 Hz, CONH), 199.4 (CH₃CO). ³¹P NMR (161.9 MHz, CDCl₃): δ = 7.73. MS-FAB(positive): m/z (%) = 516 (23) [M + 2], 515 (100) [M + 1]. Anal. Calcd for C₃₃H₂₇N₂PO₂: C, 77.04; H, 5.25; N, 5.45. Found: C, 77.01; H, 5.20; N, 5.41.

<A NAME="RG07607ST-9">9</A>

Preparation of 3-[2-(Methylene-4 H -benzo[ d ][1,3]ox-azine-2-yl)phenyl]urea 1-Substituted ( 7) To a solution of N-(2-acetylphenyl)-2-(triphenylphos-phoranylidenamino)benzamide (4, 0.4 g, 0.78 mmol) in dry toluene (40 mL), the corresponding isocyanate (1.56 mmol) was added at r.t. under N₂. The resulting mixture was warmed at reflux temperature for 6-12 h. After removal of the solvent by reduced pressure, the residue was recrystrallized in CH₂Cl₂-n-hexane (1:1).
1-Ethyl-3-[2-(methylene-4 H -benzo[d][1,3]oxazine-2-yl)phenyl]urea ( 7a) Yield 85%, 0.2 g, white prisms, mp 191-192 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.11 (t, 3 H, J = 7.2 Hz, CH ₃CH₂), 3.18 (q, 2 H, J = 7.2, 7.8 Hz, CH₃CH ₂), 4.82 (d, 1 H, J = 2.9 Hz, =CH₂), 5.14 (d, 1 H, J = 2.9 Hz, =CH₂), 7.02 (dd, 1 H, J = 8.2, 7.4 Hz, H-5′), 7.17 (br, 1 H, N₂H), 7.32 (dd, 1 H, J = 7.9, 7.4 Hz, H-6), 7.43-7.49 (m, 2 H, H-4′ and H-7), 7.63 (d, 1 H, J = 8.0 Hz, H-8), 7.72 (d, 1 H, J = 7.9 Hz, H-5), 8.00 (d, 1 H, J = 8.2 Hz, H-6′), 8.39 (d, 1 H, J = 8.7 Hz, H-3′), 11.06 (s, 1 H, N¹H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 15.1 (CH₃CH₂), 34.2 (CH₃ CH₂), 87.2 (C-9), 119.4 (C-3′), 119.7 (C-4a), 120.0 (C-5′), 123.0 (C-5) 126.2 (C-8), 128.1 (C-6), 128.4 (C-6′), 130.9 (C-7), 132.4 (C-4′), 136.8 (C-1′), 141.9 (C-2′), 150.3 (C-4), 154.5 (CO), 154.8 (C-2). MS (EI): m/z (%) = 307 (75) [M⁺], 263 (100), 219 (43). Anal. Calcd for C₁₈H₁₇N₃O₂: C, 70.36; H, 5.54; N, 13.68. Found: C, 70.30; H, 5.48; N, 13.61.
1-(4-Methoxybenzyl)-3-[2-(methylene-4 H -benzo[ d ][1,3]oxazine-2-yl)phenyl]urea ( 7f) Yield 88%, 0.27 g, white prisms, mp 173-175 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.71 (s, 3 H, CH₃O), 4.27 (d, 2 H, J = 5.9 Hz, ArCH ₂), 4.82 (d, 1 H, J = 8.0 Hz, =CH₂), 5.16 (d, 1 H, J = 2.8 Hz, =CH₂), 6.88 (d, 2 H, J = 8.7 Hz, Hm), 7.03 (ddd, 1 H, J = 8.1, 7.3, 1.0 Hz, H-5′), 7.25 (d, 2 H, J = 8.7 Hz, Ho), 7.31 (dt, 1 H, J = 7.9, 1.2 Hz, H-6), 7.43-7.49 (m, 2 H, H-4′ and H-7), 7.67 (d, 1 H, J = 7.9 Hz, H-8), 7.73 (dd, 1 H, J = 7.9 Hz, H-5), 7.82 (t, 1 H, J = 5.9 Hz, N²H), 8.01 (dd, 1 H, J = 8.1, 1.5 Hz, H-6′), 8.39 (dd, 1 H, J = 8.5, 1.0 Hz, H-3′), 11.23 (s, 1 H, N¹H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 42.3 (ArCH₂), 55.0 (CH₃O), 87.4 (C-9), 113.7 (Cm), 114.1 (C-1′), 119.6 (C-3′), 119.8 (C-4a), 120.3 (C-5′), 123.1 (C-5) 126.5 (C-8), 128.2 (C-6), 128.4 (Co), 128.5 (C-6′), 131.0 (C-7), 132.3 (Ci), 132.6 (C-4′), 136.9 (C-8a), 141.9 (C-2′), 150.4 (C-4), 154.7 (CO), 154.8 (C-2), 158.1 (Cp). MS (EI): m/z (%) = 399 (75) [M⁺]. Anal. Calcd for C₂₄H₂₁N₃O₃: C, 72.18; H, 5.26 N, 10.53. Found: C, 71.97; H, 5.01; N, 5.35.

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<A NAME="RG07607ST-13">13</A>

2-(3-Indolecarbonyl)-5-(4-methoxyphenylimino)-4-[(1-methoxymethyl-3-indolyl)methylidene]-5 H -oxazole ( 11) To a solution of α-azidoamide 8 (0.2 g, 0.53 mmol) and 3-indolyloxalyl chloride (0.11 g, 0.53 mmol) in anhyd THF (20 mL), diphenylmethyl phosphine (0.16 g, 0.795 mmol) was added at r.t. under nitrogen. The mixture was stirred for 24 h, then warmed to reflux temperature, and Et₃N (80 mg, 0.11 mL, 0.795 mmol) was added. After that, the mixture was stirred for 1 h, the solvent was eliminated under reduced pressure to give a residue which was purified by column chromatography on silica gel with EtOAc-n-hexane (6:4) as eluent to afford two fractions of the imino-oxazole 10 in 60% yield, corresponding to E (32 mg, 12%) and Z (128 mg, 48%) isomers.
( E )-2-(3-Indolecarbonyl)-5-(4-methoxyphenylimino)-4-[(1-methoxymethyl-3-indolyl)methylidene]-5 H -oxazole R _f = 0.81. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.27 (s, 3 H, CH₃O), 3.82 (s, 3 H, CH₃OAr), 5.74 (s, 2 H, NCH₂O), 7.07 (d, 2 H, J = 9.0 Hz, Hm), 7.26-7.40 (m, 4 H, H-5′, H-6′, H-5′′, H-6′′), 7.56-7.62 (m, 1 H, H-7′′), 7.63 (d, 2 H, J = 9.0 Hz, Ho), 7.72 (d, 1 H, J = 7.3 Hz, H-7′), 8.08 (s, 1 H, H-8′), 8.12 (d, 1 H, J = 8.1 Hz, H-4′), 8.27-8.33 (m, 1 H, H-4′′), 8.98 (s, 1 H, H-2′′), 9.91 (s, 1 H, H-2′), 12.42 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 55.3 (CH₃OAr), 55.9 (CH₃O), 77.7 (NCH₂O), 111.3 (C-7′), 112.0 (C-3′), 112.6 (C-7′′), 113.8 (C-3′′), 114.4 (Cm), 118.8 (C-4′), 121.4 (C-4′′), 121.9 and 122.3 (C-5′ and C-5′′), 123.5 and 123.6 (C-6′ and C-6′′), 125.5 (C-8′), 125.9 (Co), 126.2 (C-3a′), 128.6 (C-3a′′), 134.6 (C-4), 136.1 (C-7a′), 136.4 (C-7a′′), 136.5 (C-2′), 137.8 (C-2′′), 138.1 (Ci), 149.6 (C-5), 154.8 (C-2), 157.2 (Cp), 173.2 (CO).
( Z )-2-(3-Indolecarbonyl)-5-(4-methoxyphenylimino)-4-[(1-methoxymethyl-3-indolyl)methylidene]-5 H -oxazole R _f = 0.64. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.28 (s, 3 H, CH₃O), 3.78 (s, 3 H, CH₃OAr), 5.69 (s, 2 H, NCH₂O), 6.99 (d, 2 H, J = 9.0 Hz, Hm), 7.24-7.38 (m, 4 H, H-5′, H-6′, H-5′′, H-6′′), 7.46 (d, 2 H, J = 9.0 Hz, Ho), 7.54-7.66 (m, 1 H, H-7′′), 7.67 (d, 1 H, J = 8.1 Hz, H-7′), 7.70 (s, 1 H, H-8′), 8.26 (d, 1 H, J = 7.3 Hz, H-4′), 8.28-8.38 (m, 1 H, H-4′′), 8.49 (s, 1 H, H-2′′), 8.89 (s, 1 H, H-2′), 12.47 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 55.7 (CH₃OAr), 55.7 (CH₃O), 77.2 (NCH₂O), 111.2 (C-7′), 112.0 (C-3′), 112.6 (C-7′′), 113.9 (C-3′′), 114.2 (Cm), 120.0 (C-4′), 120.5 (C-8′), 121.4 (C-4′′), 121.8 (C-5′), 122.8 (C-5′′), 123.3 (C-6′), 123.7 (C-6′′), 125.5 (Co), 126.1 (C-3a′), 127.2 (C-3a′′), 133.6 (C-4), 135.2 (C-2′), 136.4 (C-7a′), 136.5 (C-7a′′), 137.8 (C-2′′), 137.8 (Ci), 150.1 (C-5), 156.7 (Cp), 157.2 (C-2), 173.3 (CO). MS-FAB(positive): m/z (%) = 505 (35) [M + H], 504 (30) [M - 1 + H], 460 (5) [M - MOM + H], 360 (10) [M - (indoleCO) + H], 307 (36), 178 (46), 144 (34) [indoleCO]⁺. Anal. Calcd for C₃₀H₂₄N₄O₄ (504.54): C, 71.42; H, 4.79; N, 11.10. Found: C, 71.51; H, 4.90; N, 10.97.

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