Mendeleev Communications Electronic Version, Issue 4, 2001 (pp. 125–164) Condensation of oxazolidines with 2-hydroxybenzaldehydes Boris F. Kukharev,* Valerii K. Stankevich, Galina R. Klimenko and Victor V. Bayandin A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russian Federation. Fax: +7 3952 39 6046; e-mail: admin@irioch.irk.ru 10.1070/MC2001v011n04ABEH001467 The reaction of N-unsubstituted oxazolidines with 2-hydroxybenzaldehydes resulted in 2,3,5,10b–tetrahydrooxazole[3,2-c][1,3]- benzoxazines.It is known that cyclic O,N-acetal derivatives, oxazolidines, can be involved in the exchange reaction with aldehydes to give new oxazolidines and aldehydes.1 Reactions of oxazolidines with phenols result in N-(2–hydroxyethyl)aminomethylphenols.2 Reactions of N-unsubstituted oxazolidines with aldehydes containing phenyl hydroxyl groups have not been investigated. We found that salicylic and 5-bromosalicylic aldehydes react with 4,4-dimethyl- and 5-methyloxazolidines to give 2,3,5,10btetrahydrooxazole[ 3,2-c][1,3]benzoxazine derivatives 3a–d.The reaction took place under reflux of an equimolecular mixture of an oxazolidine and a corresponding aldehyde in benzene followed by the azeotropic distillation of water.† An attempt to involve the simplest oxazolidine in the reaction was unsuccessful.Probably, this was due to the high rate of oxazolidine trimerization to stable N,N',N''-tris(2-hydroxyethyl)- perhydro-1,3,5-triazine.3 It is likely that oxazolidine, which is a typical secondary amine, forms semi-acetal 4 at the first stage; then, the oxazolidine ring is decomposed with a phenyl hydroxyl group to give benzoxazine 5, which transforms to oxazolobenzoxazine 3 (Scheme 2).The structure of the compounds obtained was confirmed by 1H NMR spectroscopy and elemental analysis. Compounds 3c and 3d (mixtures of diastereomers) were obtained when oxazolidine 1b having an asymmetric carbon atom was involved in the reaction.In 1H NMR spectra, the proton signals of both the methyl groups and the OCNH fragment of the oxazolidine ring of a minor isomer were upfield shifted in comparison with those in the major isomer. The ratio between diastereomers calculated from the integral intensity of the proton signals was approximately 1:1.1 for compounds 3c and 3d.References 1 K. D. Petrov and O. K. Gosteva, in Sbornik statei po obshchei khimii (Collected Articles on General Chemistry), AN SSSR, Moscow– Leningrad, 1953, vol. 2, p. 1352 (in Russian). 2 (a) K. D. Petrov, O. K. Gosteva and V. I. Pukhova, Zh. Obshch. Khim., 1957, 27, 3218 [J. Gen. Chem. USSR (Engl. Transl.), 1957, 27, 1300]; (b) R. A. Fairhurst, H.Heaney, G. Papageorgiou, R. F. Wilkins and S. C. Eyley, Tetrahedron Lett., 1989, 30, 1433. 3 M. Riehl and P. A. Laurent, Bull. Soc. Chim. Fr., 1969, 1223. † A mixture of oxazolidine 1a,b (0.1 mol), aldehyde 2a,b (0.1 mol) and benzene (100 ml) was refluxed with a Dean-Stark condenser trap until water isolation was ceased. The mixture was distilled in a vacuum to give 2,3,5,10b-tetrahydrooxazole[3,2-c][1,3]benzoxazines 3a–d. 1H NMR spectra were measured at 400.13 MHz in CDCl3 solution, standard TMS. 3a: yield 59%, bp 129–131 °C (6 torr), nD 20 1.5466, d4 20 1.1132. 1H NMR, d: 1.24 (s, 3H, Me), 1.31 (s, 3H, Me), 3.67 (d, 1H, OCHAHB, 2JAB 7.8 Hz), 3.71 (d, 1H, OCHAHB, 2JAB 7.8 Hz), 4.85 (d, 1H, NCHAHB, 2JAB 11.0 Hz), 4.93 (d, 1H, NCHAHB, 2JAB 11.0 Hz), 5.87 (s, 1H, OCHN), 6.78 (dd, 1H, 7-HC, 3J7–8 8.2 Hz, 4J7–9 1.1 Hz), 6.94 (ddd, 1H, 9-HC, 3J8–9 7.4 Hz, 3J9–10 7.6 Hz, 4J7–9 1.1 Hz), 7.17 (ddd, 1H, 8-HC, 3J7–8 8.2 Hz, 3J8–9 7.4 Hz, 4J8–10 1.7 Hz), 7.26 (dd, 1H, 10-HC, 3J9–10 7.6 Hz, 4J8–10 1.7 Hz).Found (%): C, 70.03; H, 7.51; N, 6.53. Calc. for C12H15NO2 (%): C, 70.22; H, 7.37; N, 6.82. 3b: yield 65%, bp 170–172 °C (3 torr), mp 43–44 °C. 1HNMR, d: 1.22 (s, 3H, Me), 1.27 (s, 3H, Me), 3.66 (d, 1H, OCHAHB, 2JAB 7.9 Hz), 3.71 (d, 1H, OCHAHB, 2JAB 7.9 Hz), 4.87 (d, 1H, NCHAHB, 2JAB 11.3 Hz), 4.91 (d, 1H, NCHAHB, 2JAB 11.3 Hz), 5.83 (s, 1H, OCHN), 6.64 (d, 1H, 7-HC, 3J7–8 8.8 Hz), 7.25 (dd, 1H, 8-HC, 4J8–10 2.4 Hz, 3J7–8 8.8 Hz), 7.37 (d, 1H, 10-HC, 4J8–10 2.4 Hz). Found (%): C, 50.94; H, 5.06, Br, 28.03; N, 4.77. Calc.for C12H14BrNO2 (%): C, 50.72; H, 4.97; Br, 28.12; N, 4.93. 3c: yield 67%, bp 120–123 °C (4 torr), nD 20 1.5465, d4 20 1.1335. 1H NMR, d: (major) 1.28 (d, 3H, Me, 3J 6.1 Hz), 2.88 (dd, 1H, NCHAHBCHX, 2JAB 9.6 Hz, 3JAX 6.8 Hz), 3.40 (dd, 1H, NCHAHBCHX, 2JAB 9.6 Hz, 3JBX 7.0 Hz), 4.11 (m, 1H, NCHAHBCHXMe), 4.74 (d, 1H, NCHAHBO, 2JAB 9.7 Hz), 4.82 (d, 1H, NCHAHBO, 2JAB 9.7 Hz), 5.75 (s, 1H, OCHN), 6.82 (m, 1H, 7-HC), 6.95 (m, 1H, 9-HC), 7.18 (m, 1H, 8-HC), 7.27 (m, 1H, 10-HC); (minor): 1.22 (d, 3H, Me, 3J 6.1 Hz), 2.80 (t, 1H, NCHAHBCHX, 2JAB 8.9 Hz, 3JAX 8.9 Hz), 3.32 (dd, 1H, NCHAHBCHX, 2JAB 8.9 Hz, 3JBX 5.9 Hz), 4.28 (m, 1H, NCHAHBCHXMe), 4.71 (d, 1H, NCHAHBO, 2JAB 9.6 Hz), 4.76 (d, 1H, NCHAHBO, 2JAB 9.6 Hz), 5.61 (s, 1H, OCHN), 6.82 (m, 1H, 7-HC), 6.95 (m, 1H, 9-HC), 7.18 (m, 1H, 8-HC), 7.27 (m, 1H, 10-HC).Found (%): C, 69.17; H, 6.97; N, 7.11. Calc. for C11H13NO2 (%): C, 69.09; H, 6.85; N, 7.32. O NH R1 R1 R 1a R = H, R1 = Me CHO OH R2 1b R = Me, R1 = H 2a R2 = H 2b R2 = Br O R2 N O R1 R1 R 3a R = R2 = H, R1 = Me 3b R = H, R1 = Me, R2 = Br 3c R = Me, R1 = R2 = H 3d R = Me, R1 = H, R2 = Br Scheme 1 – H2O 1a + 2a OH HO N O O HO N OH – H2O 3a 5 4 Scheme 2 Received: 27th April 2001; Com. 01/1793 3d: yield 57%, bp 158–160 °C (3 torr), mp 61–62 °C. 1H NMR, d: (major): 1.27 (d, 3H, Me, 3J 6.2 Hz), 2.85 (dd, 1H, NCHAHBCHX, 2JAB 9.5 Hz, 3JAX 6.5 Hz), 3.36 (dd, 1H, NCHAHBCHX, 2JAB 9.5 Hz, 3JBX 7.0 Hz), 4.09 (m, 1H, NCHAHBCHXMe), 4.76 (d, 1H, NCHAHBO, 2JAB 10.2 Hz), 4.81 (d, 1H, NCHAHBO, 2JAB 10.2 Hz), 5.72 (s, 1H, OCHN), 6.67 (d, 1H, 7-HC, 3J7–8 8.9 Hz), 7.24 (dd, 1H, 8-HC, 4J8–10 1.8 Hz, 3J7–8 8.9 Hz), 7.37 (d, 1H, 10-HC, 4J8–10 1.8 Hz); (minor): 1.20 (d, 3H, Me, 3J 6.2 Hz), 2.79 (dd, 1H, NCHAHBCHX, 2JAB 8.9 Hz, 3JAX 8.5 Hz), 3.29 (dd, 1H, NCHAHBCHX, 2JAB 8.9 Hz, 3JBX 5.6 Hz), 4.29 (m, 1H, NCHAHBCHXMe), 4.73 (d, 1H, NCHAHBO, 2JAB 9.9 Hz), 4.75 (d, 1H, NCHAHBO, 2JAB 9.9 Hz), 5.61 (s, 1H, OCHN), 6.70 (d, 1H, 7-HC, 3J7–8 8.9 Hz), 7.24 (dd, 1H, 8-HC, 4J8–10 1.8 Hz, 3J7–8 8.9 Hz), 7.38 (d, 1H, 10-HC, 4J8–10 1.8 Hz). Found (%): C, 48.74; H, 4.59; Br, 29.17; N, 5.02. Calc. for C11H12BrNO2 (%): C, 48.91; H, 4.48; Br, 29.58; N, 5.19.