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Synlett 2007(10): 1541-1544  
DOI: 10.1055/s-2007-982546
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Pilar M. Fresneda*, Juan Antonio Bleda, Miguel Angel Sanz, Pedro Molina*
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
Fax: +34(968)364149; e-Mail: fresneda@um.es; e-Mail: pmolina@um.es;
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Publication History

Received 13 March 2007
Publication Date:
06 June 2007 (online)

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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.

Key words

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

    References and Notes

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8

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.

9

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.

13

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.