1,3-Oxazines and Related Compounds. XIII.1) Reaction of Acyl Meldrum's. Acids with Schiff Bases Giving 2,3-Disubstituted 5-Acy1-3,4,5,6-

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1 1860 Vol. 35 (1987) Chem. Pharm. Bull. 35( 5 ) (1987). 1,3-Oxazines and Related Compounds. XIII.1) Reaction of Acyl Meldrum's Acids with Schiff Bases Giving 2,3-Disubstituted 5-Acy1-3,4,5,6- tetrahydro-2h-1,3-oxazine-4,6-diones and 2,3,6- Trisubstituted 2,3-Dihydro-1,3-oxazin-4-ones YUTAKA YAMAMOTO,* YUKIYOSHI WATANABE, and SHUHEI OHNISHI Tohoku College of Pharmacy, Komatsushima, Sendai 983, Japan (Received November 17, 1986) The reactions of Schiff bases (2) with various acyl Meldrum's acids (1) were investigated. Refluxing of 1 and 2 in benzene caused an exchange reaction of the acetone moiety of 1 with the Schiff base moiety through the intermediate acylketenes 11 formed in situ from 1 to give 2,3- disubstituted 5-acy1-3,4,5,6-tetrahydro-2H-1,3-oxazine-4,6-diones (3). The oxazindiones 3 underwent thermal conversion to afford 2,3,6-trisubstituted 2,3-dihydro-1,3-oxazin-4-ones (4) in good yield. The intermediates 11 were found to be formed by thermal cleavage of both 1 and 3. Keywords \ acyl Meldrum's acid; Schiff base; 1,3-oxazine-4,6-dione; 1,3-oxazin-4-one; 1,3- oxazine-5-carboxylic acid; acylketene; cycloaddition In recent years, acyl Meldrum's acids (1, 5-acyl-2,2-dimethy1-1,3-dioxane-4,6-diones) have been widely utilized as acylacetylating agents,2) because of the characteristic that 1 loses acetone and carbon dioxide with ease to generate acylketenes (12). An additional unique reactivity of 1 was found by Kato et al., though only one example was described3a); when a solution of acetyl Meldrum's acid (la) and N-benzylidenepropylamine (2a) in toluene was refluxed, exchange reaction between a C-O moiety of the dioxane ring in la and C =N moiety of the Schiff base took place with loss of acetone to produce the 1,3-oxazinedione derivative 3a, without involvement of an acetylketene intermediate, along with a small amount of the oxazin-4-one 4a. la 2a 3a 4a Chart 1 In this series of studies, our interest has been focused on an exploration of such reactivities of acyl Meldrum's acids 1. This paper describes an investigation of the reaction of various acyl Meldrum's acids 1 with Schiff bases 2, including the reaction modes of 1 and the transformation of the products 3 into 4, which would open a way for further synthesis of 1,3- oxazine derivatives. According to the reported method3) except for the use of benzene as a solvent instead of toluene, a solution of acetyl Meldrum's acid la and 2a in benzene was refluxed for 25 min to give the oxazine-4,6-dione 3a as a sole product in good yield. Similarly, the oxazine-4,6-diones 3b-i7) were obtained from la-e(r1: aliphatic) and 2b-e (Table I). In contrast, similar

2 No treatment of acyl Meldrum's acids 1f - i (R1: aromatic) with 2d, e gave rise to 1,3-oxazin-4- one derivatives 4m -t7) instead of the expected 3. Reaction between 2d, e and lj afforded both 3 and 4. In the reactions of la, b with the Schiff bases 2d, e, very small amounts of 1,3-oxazine-5- carboxylic acids 5d, e, i were found to be formed as by-products; they are isomers of the corresponding oxazine-4,6-diones 3d, e, i. The structural assignment of 5 was accomplished on the basis of microanalysis and the spectroscopic data, such as infrared (IR), proton nuclear magnetic resonance (1H-NMR) and mass spectra (MS) (summarized in Table VI). The following reaction provides further evidence for the structure of 5; refluxing a solution of 5d in toluene caused decarboxylation to give 4d, and treatment of 5d with diazomethane gave the corresponding methyl ester (6), the IR spectrum of which showed the characteristic C = 0 band due to the ester group at 1715 cm -1. 2a-e 3a -j, m-v 4a-d, i-v 5d. e. i 4d 5d 6 Chart 2 It was found that the product alternative of 3 or 4 in the reactions depends on the reaction temperature; thus, treatment of lf-j with 2d, e in benzene at 50 C (bath temperature) for 4h gave exclusively the expected diones 3 in satisfactory yields (Table I). Therefore, in order to examine the thermal stability of 3, a solution of 3 in benzene was refluxed. The results obtained are shown in Table II. The diones 3a-c, possessing an aliphatic acyl group, were relatively stable and were mostly recovered unchanged, whereas 3h, i, m, were transformed into 4h, i, m8 with the loss of carbon dioxide, and 3d, e, g were converted into the amide derivatives 7d, e, g8) together with a small amount of the /3-lactams 8.9) The oxazines 4 were also obtained by refluxing a solution of 3a-i in xylene, or by treatment of 1 and 2 in refluxing xylene (Table I). 3a-e,g-i, m 4h, i, m 7d, e, g 8d, e, g Chart 3

3 1862 Vol. 35 (1987) Mechanisms for the formation of 4, 7, and 8 have been proposed by Kato et al.3); the oxazines 4 are formed by 1,4-cycloaddition of acetylketene (12a) across the C = N double bond of the Schiff bases 2, whereas 1,2-cycloaddition of 12a to the C N bond yields the /3- lactams 8, and compounds 7 are produced via pyrimidine derivatives intermediately formed from 1 eq of 12a and 2 eq of the Schiff bases. It is strongly suggested that the transformations of 3 into 4, 7, and 8 each involve generation and addition of acylketenes 12 in the reaction systems, that is, retro Diels-Alder type cleavage of 3 into 2 and 12, followed by decarboxylation of 11 leading to 12. Generation of the important intermediates 11 from 1 by the retro Diels-Alder reaction 10 3d 2e 3i Chart 4 lla 11b 11c (mode A) (mode B) a : R1 =Me 4 (mode C) Chart 5

4 No TABLE I. Reaction of Acyl Meldrum's Acids la-j with Schiff Bases 2a-e

5 1864 Vol. 35 (1987) TABLE I. (continued) TABLE II. Thermal Decomposition of 1,3-Oxazine-4,6-diones 3a-e, g-i, m was proven by means of an interchange reaction of the acetone moiety in la with a cyclohexanone moiety on refluxing la and cyclohexanone (9) in benzene (Chart 4). In addition, the intermediates 11 were found to be formed from 3; when a solution of equimolar

6 No amounts of 3d and 2e in benzene was refluxed for 1 h, exchange reaction between the Schiff bases 2d and 2e took place giving 31 and 3d in 52% and 21% yields, respectively. Meanwhile, 3d and 3i were obtained from 3i and 2d by the same procedure in 32% and 50% yields, respectively. TABLE III. Acyl Meldrum's Acids la-j TABLE IV. Spectral and Analytical Data for Acyl Meldrum's Acids la-j

7 1866 Vol. 35 (1987) In conclusion, the reaction of 1 with 2 proceeds through the three reaction modes A, B, and C as illustrated in Chart 5; acyl Meldrum's acids 1 lose the acetone moiety, generating the intermediates 11, which can be represented by formulae 11a, 11b, and 11c as illustrated in Chart 5. At a relative low temperature, 1,4-cycloadditions of lla and 11c across the C =N bond of 2 proceed leading to the corresponding 3 (mode A) and 5 (mode B) with considerable predomination of mode A over B, whereas at a relative high temperature lla or 11c undergoes decarboxylation, giving the acylketenes 12 and 1,4-addition of 12 to the C = N bond occurs to yield 4 (mode C). Experimental Melting points were determined on a Mel-Temp melting point apparatus with an open capillary tube, and are TABLE V. Spectral Data for 5-Acyl-tetrahydro-1,3-oxazine-4,6-diones 3a-i, m-v

8 No TABLE VI. 1,3-Oxazine-5-carboxylic Acids 5d, e, i TABLE VII. Spectral Data for 2,3-Dihydro-1,3-oxazin-4-ones 4a-d, i-v

9 1868 Vol. 35 (1987) TABLE VIII. Spectral Data for Amide Derivatives 7d, e, g and ƒà-lactams 8d, e, g uncorrected. IR spectra were taken on a Shimadzu IR-430 spectrometer. MS were recorded with a Hitachi RMU- 6MG spectrometer. 11-I-N MR spectra were measured on a JEOL JNM-PMX 60 instrument. Chemical shifts are reported in 6 values downfield relative to internal tetramethylsilane. The following abbreviations are used: s= singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, and dd = double doublet. Preparation. of Acyl Meldrum's Acids (1). General Procedure A solution of an acid chloride (60 mmol) in CHC13 (50 ml) was added dropwise with stirring over a period of 1 h to a solution of Meldrum's acid (7.20 g, 50 mmol) and pyridine (7.9 g, 100 mmol) in CHC13 (150 ml), in an ice-salt bath. The temperature was maintained for an additional 1 h, then the reaction mixture was allowed to stand at room temperature for 1 h. The resulting mixture was washed with 10`) HC1 (3 x 30 ml) and then water (50 ml). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. The resulting crude product was purified by recrystallization from the solvent indicated in Table III. When aroyl chlorides were used as the acid chloride, the use of 4-dimethylaminopyridine instead of pyridine resulted in satisfactory yields. The results and physical data (mp, IR and H-NMR spectra) are summarized in Tables III and IV. Preparation of 3 from 1 and 2. General Procedure A solution of 1 (10 mmol) and 2 (10 mmol) in benzene (50 ml) was refluxed for 25 min, or kept at 50 Ž (bath temperature) for 4 h. After removal of the solvent under reduced pressure, the remaining crude product (3) was purified by recrystallization from the solvent indicated in Table I. The results obtained are summarized in Table I. Reactions of lj with 2d and 2e gave 4u and 4v, respectively, besides 3u and 3v (see Table I). Reaction of la, b with 2d, e to Give 3d, e, i and 5d, e, i Benzene. solutions of la and 2d, lb and 2d, and la and 2e were each refluxed for 25 min. After work-up as described above, a mixture of 3 and 5 was obtained in each case. The products were separated by fractional recrystallization from ether and purified by recrystallization from the solvent shown in Table VI. Table VI also summarizes the results. Decarboxylation of 5d to 4d A solution of 5d (1.19 g, 4.1 mmol) in toluene (30 ml) was refluxed for 10 min, and then washed successively with 10% Na2CO3 aqueous solution (3 x 10 ml) and water (10 ml). The organic layer was separated, dried over anhydrous Na2SO4, and evaporated to give crude 4d. Recrystallization of the crude product from ether-petroleum ether gave 0.1 g (10%) of 4d, mp C. The IR spectrum of this product was identical with that of the sample obtained above. The starting 5d was recovered in 65% yield by acidification of the aqueous layer. Prolonged reflux caused decomposition of 4d. Esterification of 5d to 6 A solution of excess diazomethane (prepared by the general method from p- toluenesulfonyl-n-methylnitrosoamide and KOH aqueous solution) in ether was added dropwise with stirring to a solution of 5d (0.45 g, 1.55 mmol) in ether, with cooling in an ice bath. After completion of the addition, stirring was continued for 30 min. After evaporation of the solvent under reduced pressure, the residue was recrystallized from ether-petroleum ether to give 6, 0.4g (85%), mp C. Anal. Calcd for C N04: C, 67.31; H, 6.98; N, Found: C, 67.50; H, 7.02; N, IR (KBr): 1715, 1650 cm' NMR (CDC13)6 : 1.53 (9H, s), 2.03 (3H, s), 3.73 (3H, s), 6.56 (1H, s), 7.37 (5H, s). MS m/::: 303 (M t). Synthesis of 4. General Procedure i) Reaction of if-i with 2d, e: A solution of if-i (10 mmol) and 2d, e, in benzene (50 ml) was refluxed for 25 min. After work-up as described above, the crude 4m-t obtained was purified by recrystallization from the solvent indicated in Table I. The results are summarized in Table I. ii) Thermal Decomposition of 3h, i, m to 4h, 1, m: A solution of 3h, i, m (5 mmol) in benzene (50 ml) was refluxed for the period shown in Table II, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using hexane-ether (1 : 4) as eluent to give 4h, 1, m. The results are summarized

10 No TABLE IX. Elemental Analyses of Compounds 3-5, 7 and 8 in Table II. Interchange Reaction of 3d and 3i with 2d and 2e A solution of 3d (1.45 g, 5 mmol) and 2e (0.90 g, 5 mmol) in benzene (50 ml) was refluxed for 1 h and the solvent was removed under reduced pressure. The remaining mixture of 3d and 3i was purified by fractional recrystallization from ether to afford 3i (0.8 g, 52%) and 3d (0.3 g, 21%). Similar treatment of 3i (1.55 g, 5 mmol) and 2d (0.81 g, 5 mmol) in benzene (50 ml) gave 3d (0.46 g, 32%) and 3i (0.77 g, 50%). Reaction of la with Cyclohexanone (9) Giving 10 A solution of la (0.93 g, 5 mmol) and 9 (4.9 g, 50 mmol) was refluxed for 1 h, allowed to stand to room temperature, and then extracted with 10% Na2CO3 aqueous solution (3 x 20 ml). The aqueous layer was acidified with 10% HC1 aqueous solution and extracted with CHC13. The CHC13 layer was dried over MgSO4 and concentrated under reduced pressure. The precipitate formed was collected by filtration and purified by recrystallization from petroleum ether to give 10 (0.8 g, 80%) as yellow prisms, mp Ž. Thermal Transformation of 3d, e, g to 7d, e, g and 8d, e, g. General Procedure A solution of 3d, e, g (5 mmol) in benzene (50 ml) was refluxed for the time shown in Table II. After removal of the solvent, the residue was purified by silica gel column chromatography using hexane-ether (1 : 4) as the eluent to give the corresponding 7d, e, g and 8d,

11 1870 Vol. 35 (1987) e, g. The results are shown in Table II. The IRspectra of 7d and 8d were identical with those of corresponding authentic samples prepared in the reported manner.3' 5) The structural assignments of 7e, g and 8e, g were achieved on the basis of comparison of their IR and NMR spectra with those of authentic 7d and 8d. Acknowledgment The authors are grateful to Dr. S. Suzuki of this college for mass spectral measurements. References and Notes 1) Part XII: Y. Yamamoto and Y. Morita, Chem. Pharm. Bull., 34, 1980 (1986). 2) a) Y. Oikawa, K. Sugano, and O. Yonemitsu, J. Org. Chem., 43, 2087 (1978); b) K. Mohri, Y. Oikawa, K. Hirao, and O. Yonemitsu, Heterocycles, 19, 515 (1982); c) Idem, ibid., 19, 521 (1982); d) Idem, Chem. Pharm. Bull., 30, 3097 (1982); e) Y. Yamamoto, S. Ohnishi, and Y. Azuma, ibid., 30, 3505 (1982); f) I. Iwataki, S. Makizawa, and K. Saito, Japan. Patent, [Chem. Abstr., 92, 58755r (1980)]; g) Idem, ibid., [Chem. Abstr., 92, 41966n (1980); h) T. A. Hasse and K. Salonen, Synth. Commun., 10, 221 (1980). 3) a) M. Sato, H. Ogasawara, E. Yoshizumi, and T. Kato, Chem. Pharm. Bull., 31, 1902 (1983); b) Idem, Heterocycles, 17, 297 (1982). 4) M. Sato, H. Ogasawara, and T. Kato, Chem. Pharm. Bull., 32, 2602 (1984). 5) T. Kato and Y. Yamamoto, Chem. Pharm. Bull., 13, 959 (1965). 6) A. Maujean and J. Chuch, Tetrahedron Lett., 1976, ) IR spectra of the known compounds were identical with those of corresponding authentic samples prepared by the reported methods. 8) The reasons for the differences of thermal stability of 3 and the alternative decompositions of 3 to 4 or 7 are not clear. 9) Chemoselective synthesis of the 1,3-oxazine-5-carboxylic acids 5 and the fl-lactams 8 from acyl Meldrum's acids 1 and Schiff bases 2 will be described in the accompanying paper: Y. Yamamoto and Y. Watanabe, Chem. Pharm. Bull., 35, 1871 (1987).