Heterocyclic transformations part 4: a facile transformation of 3-alkyl-6-methyl-1,3-oxazine-2,4(3H)-diones to 6-substituted 5-acetyluracils and 6-thioxo-1,3,5-triazine-2,4(1H,3H,5H)-diones

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1992 Heterocyclic Transformations Part 4: la A Facile Transformation of 3-Alkyl-6-methyl-I ,3-oxazine-2,4(3H)-diones to 6-Substituted 5-acetyluracils and 6-Thioxo-I ,3,5-triazine-2,4(1 H,3H,5H )-diones Harjit Singh," Pawan Aggarwal and Subodh Kumar Department of Chemistry, Guru Nanak Dev University, Amritsar- 143 005, India 3-Benzyl-6-methyl-I ,3-oxatine-2,4(3H) -dione 1 (R = CH,Ph) reacts under phase-transfer catalytic conditions with amides and thioamides to give 6-substituted 5-acetyluracils and with malonamide to give a bicyclic pyridopyrimidine system. Similar reactions of 1 with thioureas provide 6-thioxo- I83,5-triazine-2,4( 1 H,3H,5H) -diones, but with ureas, the substituents influence the mode of the reaction and the nature of the products.The synthetic scope and utility of these reactions has been examined. 6-Methyl-1,3-oxazine-2,4(3H)-dione1,a versatile intermediate, reacts chemoselectively with a variety of nucleophiles in synthetically useful reactions. Alkylamines react at C-2 of 1 to form intermediates 2 which cyclodehydrate (path a) to provide a regiospecific synthesis of 1-substituted 6-methyluracils 3.'* We predicted that if the amine nitrogen carried a substituent with appropriately placed functionality, the intermediate 4, could undergo alternative cyclizations, regiospecifically directed, to provide new synthetic strategies. Here we report that 6-methyl- 1,3-oxazine-2,4(3H)-diones 1 react with amides, thioamides, diamides, ureas and t hioureas under phase transfer catalytic conditions to give a facile and selective synthesis of a variety of heterocycles.Results and Discussion 3-Benzyl-6-methyl-l,3-oxazine-2,4(3H)-dione1 (R = CH,Ph) with formamide under phase transfer catalytic conditions (DMF-K2C03-tetrabutylammonium hydrogen su1fate)t at 40-50 "C, gave a compound (m.p. 135 "C, M + 244, mol. formula C13H12N203) the properties of which were consonant with either of the isomeric structures, 5-acetyl-3-benzyluracil5aand 3-benzyl-1-formyl-6-methyluracil6 (R' = H). In its 'H NMR spectrum, the appearance of one downfield 3 H singlet at 6 2.55 (COCH,) as compared with a 6-CH3 signal at 6 2.30 in 6- methyluracil'and the absence of a signal for 5-H (6 5.7)' of the latter favoured assignment of structure 5a for this compound.Its 13C NMR (APT)' showed six negative signals (five quaternary- Arc, C-5, 3 x C==Oand one methylene) and five positive signals (CH3, 3 x ArCH, C-6) which further corrobor- ated the structure 5a. Similarly, 1 (R = CH,Ph) reacted with acetamide, butanamide, benzamide, o-, m-,p-chlorobenzamide and urethane $ to give the respective 5-acetyluracils 5bh. It was observed that aliphatic amides formed 5 in better yields than aromatic amides. In case of o-chlorobenzamide, the ortho substituent adversely affected the yield of product. In a reaction of 1 (R = CH2Ph) with a heteroaromatic amide-nicotinamide; 3-benzyl-6-methyluracil3 (R = CH2Ph, R' = H) was formed along with 5-acetyl-3-benzyl-6-(3-pyridyl)uracil 5i.6-Carba-t 1 (R = CH,Ph) failed to react with formamide when heated (150-160 "C) or in DMF under reflux; with formamide in DMF containing NaH at ambient temperature it mainly decomposed and in MeCN in the presence of Et,N, it was unchanged; under PTC conditions (MeCN- K,CO,-tetrabutylammonium hydrogen sulfate), product 5 was formed in poor yields. 1Dehydration has been preferred over the elimination ofethanol from 5 (R = OEt). la 0 R-N MeOAN R' 3 6 Scheme 1 a, R' = H; b, R' ClC,H,; f, R' = m-ClC,H,; C5H4N 4 0 (S)O=C--R''I 00 " 8rs, 7 /lb H 5 = Me; c, R' = Pr; d, R' = Ph; e, R' = o-g, R' = p-CIC,H,; h; R' = OEt; i, R' = 3- moyl-1,3-dimethyluracil with 1 (R = CH,Ph) gave only 3 (R = CH,Ph, R' = H) (76).Compound 1 (R = H) due to ease in generation of the anion at N-3 under these PTC con- ditions, failed to react with amides. Compound 1 (R = CH,Ph) failed to react with an unsaturated amide (acrylamide), an N-alkylamide (N-methylacetamide) and stearamide. The thioamides, thioacetamide, thiobenzamide and o-chloro- thiobenzamide with 1 (R = CH,Ph) under the above PTC conditions gave 5b,5d and 5e respectively only in marginally better yields. The reactions of 1 (R = CH,Ph) with thioamides in NaH/DMF formed 5 in lower yields (< 10) and 1 (R = CH,Ph) decomposed. With malonamide under above PTC conditions 1 (R = CH,Ph) gave a compound (90) (m.p. 280 "C, M+ 283, mol. formula C,,H13N30,) the 'H NMR spectrum ofwhich showed the presence of Me, CH2Ph and olefinic-H (6 6.45) and lacked any additional CH, signal for CH2CONH2 of analogues of structures 5 and 3.Its 13C NMR (APT), showed five positive signals (Me, SH and 3 x ArCH) and eight negative signals (NCH,, Arc, C-4a, C-5, C-8a, 3 x C=O).From these data, it was asssigned the structure, 3-benzyl-5-methylpyrido4,3-dJ-pyrimidine-2,4,7( 1 H,3H,6H)-trione 8.Compound 1 (R = CH2-Ph) with succindiamide gave 3 (R = CH,Ph, R' = H) (60) and succinimide (25), m.p. 122-124 "C (lit.: 123-125 "C), but it did not react with glutaramide. The formation of 5,could involve initial attack of amide/ thioamide nitrogen* at C-2 of 1 (R = CH,Ph) to give the intermediate 7, which followed path b for cyclization (Scheme 1) and gave 6-substituted 5-acetyluracil derivatives 5.Formation of 3-benzyl-6-methyluracil3 (R = CH,Ph, R' = H) (m.p. 193- 195 "C; lit.,6 m.p. 194198 "C) in the reaction of nicotinamide could be ascribed to the competitive formation of 3-benzyl-6-methyl- 1 -(3-pyridylcarbonyl)uracil 6 (R = 3-py) through path a (Scheme 1) and ease of its subsequent hydrolysis to nicotinic acid (m.p. 235-237 "C; lit.,7 m.p. 236239 "C), which was isolated. In the reaction of 1 (R = CH,Ph) with malonamide, initially formed intermediate 9followed path b to give 10which further cyclodehydrated to 8. In the reaction of succindiamide, formation of five-membered ring (path c) 9dominated over six- membered ring formation (path b) and succinimide was eliminated to give 11, which cyclodehydrated to 3 (Scheme 2).This mode was further supported by failure of succindiamide to form succinimide under the same PTC conditions. 00 00 9 10 I c,n =2 0 8 O / --.+ -3 R=CH*Ph, R'= H H e + ph2,aH NO Me HZ 11 Scheme 2 * Under PTC conditions anion could be generated.5 J. CHEM. SOC. PERKIN TRANS. I 1992 Urea and 1 (R = CH2Ph) under solid-liquid PTC conditions (DMF-K,CO,-tetrabutylammonium hydrogen sulfate) at 40-50°C gave 3-benzyl-6-methyluracil 3 (R = CH,Ph, R' = H) in 44 yield. 1-Methylurea and 1 (R = CH,Ph) gave 3 (R = CH,Ph, R' = CH,) (25) along with another compound (< 1) (m.p. 101-102 "C, M+ 257), which from its 'H NMR spectrum was assigned the structure, 3-acetyl-l-benzyl-2- hydroxy-4-methyl-6( 1H)-pyridone 12.1,3-Dimethylurea with 1 (R = CH,Ph) under PTC conditions gave a multitude of products (TLC) from which one product (473, m.p.137-139 "C (M+ 247, mol. formula C12H13N303 from elemental analysis) could be isolated. From its spectral data, this compound could be assigned the structure, 3-benzyl- 13- dimethyl- 1,3,5-triazine-2,4,6( 1 H,3H,SH)-trione 13. 1 -Phenyl-urea did not react with 1 (R = CH,Ph) probably because of steric constraints. Thiourea with 1 (R = CH,Ph) gave a compound (55) (m.p. 224-226 "C, M+ 235, mol. formula C,,H,N,O,S) the 'H NMR spectrum of which exhibited two singlets at 6 4.95 (2 H) and 7.10 (5 H) due to NCH2Ph group and a 2 H exchangeable broad signal at 6 12.50. These data suggested either of the isomeric structures, 3-benzyl-6-thioxo-l,3,5-tri-azine-2,4(1H,3H,5H)-dione 14a (R = CH,Ph, R' = H) and 3-benzyl-6-imino-1,3,5-thiadiazine-2,4-dione15 (R = CH,Ph, R = H) for this compound. Its I3C NMR spectrum showed the presence of only three sp2 quaternary carbons S 134.69 (s, Arc), 146.23 (s, C=O)and 175.34 (s, GS) and corroborated the symmetrical structure 14ain which the two carbonyl carbon signals could overlap.Similarly, 1 (R = CH,Ph) with 1-methyl-2-thiourea and 1-ethylthiourea gave 3-benzyl-5-methyl- 6-thioxo-l,3,5-triazine-2,4(lH,3H,5H)-dione 14b (52, M + 249, m.p. 191-192 "C) and 3-benzyl-5-ethyl-6-thioxo-1,3,5-tri-+azine-2,4( 1 H,3H,SH)-dione 14c (50, M 263, m.p. 190-192 "C), respectively. Because of the presence of different substituents at N-1, N-3 and N-5 positions, compounds 14b and 14c became unsymmetrical and in their 13C NMR spectra exhibited four quaternary sp2 hybridised carbons 14b 6 134.55 Ihe OsC-NHR' 13 12 0 NR' -CH2COMe 7 0 0 OANAS-OANANRH H 14 15 Scheme 3 a, R = CH,Ph, R' = H; b, R = CH,Ph, R' = Me; c, R = CH,Ph, R' = Et; d, R = Me, R' = H; e, R = R' = Me; f, R = (CH,),CN, R' = H; g, R = (CH,),CN, R' = Me; h, R = (CH,),-CO,Et, R' = H; i, R = (CH,),CO,Et, R' = Me J.CHEM. SOC. PERKIN TRANS. I 1992 Table 1 Physical and spectral data of compounds 5a-i and 8 ~~~ ~ Reaction M.p. ("C) Yield temp. (I/"C) Compd. solvent () time r/h 6 He 5a 5b 5c 135 EtOH 150-152 CCHClJ 73 48 40-50 3 50-60 lo (TFA) 2.55 (3 H, s, COCH,), 5.0 (2 H, s,NCH,),7.10(5 H,s,ArH), 8.20(1 H, S, 6-H).(CDCI,) 2.20 (3 H, S, 6-CH3), 2.40 (3 H, s,COCH,),4.90(2 H,s,NCH,),6.80- 7.10(5 H,m,ArH), lO.lO(1 H, br,NH, exchanges with D,O) 1.90(2 H,m,CH,CH,),2.40-2.80(5 H, m, COCH,, 6-CH,), 5.0 (2 H, s, NCH,), 6.90-7.35 (5 H, m, ArH), 10.50 (1 H, br, NH, exchanges with (CDCIJ 1.0 (3 H, t, J 6, CH3), 1.33- 244 (1) 258 (97) 286 (53) 1675,1610 1705,1650 1700,1680, 1640 306.1 (5.76), 249.7 (4.1), 227.7 (4.3), 205.1 (6.3) 276.5 (1 1.4), 230.3 (1 1.2), 208.1 (13.1) 276.1 (12.1), 231.3 (11.9), 207.9 (14.2) sd 5e 210-212 MeOH 170-172 MeOH 38 (45)' 22 (26)' 50-60 lo 50-60 6.5 (CDCI, + TFA) 2.15 (3 H, s, COCH,), 5.05 (2 H, s, NCH,), 7.0- 7.25 (10 H, m, ArH) (CDCI,) 2.40(3 H, s,COCH,), 5.0 (2 H, s, NCH,), 7.10-7.40 (9 H, m, ArH), 10.0 (1 H, br, NH, exchanges with D,O) 320 (98) 354 (70) 1685,1620 1690,1660, 1640 282.9 (9.6), 234.1 (15.2), 209.5 (17.3) 287.1 (1 3.6), 253.3 (10.4), 214.1 (21.3) 51 sg 5h 5i * 8 195-197 MeOH 220-222 MeOH 280 MeOH 31 35 90 50-60 4.5 50-60 4.5 W50 3.5 D2O)(CDCI, + TFA) 2.35 (3 H, s, COCH,), 5.10 (2 H, s, NCH,), 7.10- 7.55 (9 H, m, ArH) (CDCI, + TFA), 2.35 (3 H, s, COCH,), 5.15 (2 H, s, NCH,), 7.10- 7.50 (9 H, m, ArH) (CDCI,) 1.30(3H,t, J7,CH3,2.25(3 H, S, COCHJ,4.20(2 H,q,J 7, OCHZ- CH,), 4.90 (2 H, S, NCH,), 6.85-7.20 (5 H, m, ArH), 10.45 (1 H, br, NH, exchanges with D,O) COCH,),5.0(2 H,s,NCH,),7.0-7.55 (9 H, m, ArH), 8.50 (1 H, br, NH, exchanges with D,O) (CDCI, + TFA) 2.95 (3 H, s, CH,), 5.10 (2 H, s, NCH,), 6.45 (1 H, s, (CDCI, 'H,-DMSO), 2.45 (3 H, S, 354 (100) 354 (100) 288 (75) 321 (100) 283 (100) 1690,1630 1690,1630 1705,1600 1695,1660 1680 284.7 (ll.l), 230.0 (18.0), 216.1 (23.9) 285.1 (1 2.4), 236.9 (20.8), 21 1.3 (20.7) 267.7 (10.6), 210.7 (14.9) 267.7 (10.6), 222.7 (16.2), 210.7 (19.4) 269.3, 244.1,209.5 8-H), 7.0-7.30 (5 H, m, ArH) a Elemental analyses: 5a (Found: C, 64.7; H, 4.75; N, 11.2.C,,H,,N,O, requires C, 64.93; H, 4.91; N, 11.47); 5b (Found: C, 64.8; H, 5.35; N, 10.6. Cl,H,4Nz03 requires C, 65.11; H, 5.42; N, 10.85); 5c (Found: C, 66.85; H, 6.25; N, 9.5. C,,H,,N,O, requires C, 67.13; H, 6.29; N, 9.79); 5d (Found: C, 70.86; H,4.92; N, 8.52. C,,H,,N,O, requires C, 71.25; H, 5.00, N, 8.75); 5e (Found C, 64.3; H, 4.25; N, 7.9.C,,H,,C1N2O3 requires C, 64.31; H, 4.21; N, 7.89); 5f (Found C, 64.75; H, 4.25; N, 7.4. C,,H,,CIN,O, requires C, 64.31; H, 4.21; N, 7.89); 5e (Found: C, 64.4; H, 4.3; N, 7.8. C,9H,,CIN,03 requires C, 64.31; H, 4.21; N. 7.89); Si (Found: C, 67.25; H, 5.0; N, 13.35. C1,H,,N,O, requires C, 67.28; H, 4.67; N, 13.08); 5h (Found: C, 62.3; H, 5.45; N, 9.5. C,,Hl,N20, requires C, 62.50; H, 5.55; N, 9.72); 8 (Found: C, 63.8; H, 4.4; N, 14.5. C,,H,,N,O, requires C, 63.60, H, 4.59; N, 14.84). 'Solvent of the crystallization. 'Yields in the reactions of thioamides. dAnother product isolated- 3-benzyl-6-methyluracil3 (14), m.p. 193-195 "C (CHC1,); m/z 216 (100); G,(CDCI, + 'H,-DMSO), 2.0 (3 H, s, CH,), 4.85 (2 H, s, NCH,), 5.35 (1 H, s, 5-H), 6.75-7.20 (5 H, m, ArH), 10.20 (1 H, br, NH, exchanges with D,O); vrnax/cm-l 1740 (M)and 1630 (GO); k,,(MeOH)/nm 260.5 (9.9 x lo3) of 209.7 (14.1 x lo3). "5a: 6,(CDCI, + C2Hb-DMS0)(APT) 29.98 (+ve, CH,), 42.35 (-ve, CH,), 107.22 (-ve, Arc), 126.20 (+ve, ArCH), 127.43 (+ve, ArCH), 127.82 (+ve, ArCH), 139.37 (-ve, C-5), 160.03 (-ve, C=O), 162.25 (+ve, 6-H), 163.92 (-ve, M),193.78 (-ve, C=O);5i GL~CDCI,+ DMSO) 31.15 (4,CH,), 42.96 (t, CH,), 112.76 (s, Arc), 122.31 (d, PyC,), 126.88 (d, ArCH), 127.65 (d, ArCH), 128.07 (d, ArCH), 135.31 (d, PyC,), 135.45 (s, C=C), 147.52 (d, PyC,), 150.22 (s, PyC,), 150.48 (d, PyC,), 152.12 (s, GO), 154.72 (s, C=C), 160.79 (s, Ca), 196.74 (s, C=O); 5h: Gc(CDCI,): 14.19 (9, OCH,CH,), 18.11 (9, COCH,), 43.97 (t, NCH,), 61.54 (t, OCH,), 106.43 (s, Arc), 127.78 (d, ArCH), 128.39 (s, ArCH), 128.92 (d, ArCH), 136.17 (s, C-5), 152.10, 153.70 (s, C=O, C-6), 160.08 (s, M),164.31 (s, C=O); ,(INEPT): 14.20 (+ve, CH,), 18.14 (+ve, COCH,), 43.97 (-ve, OCH,), 61.57 (-ve, NCH,), 127.78 (+ve, ArCH), 128.39 (+ve, ArCH) and 128.92 (+ve, ArCH).(Arc), 145.32 (C=O), 147.35 (C=O), 176.32 (CS); 14c: 6 134.55 Thus, contrary to the effect of substituents in thioureas in their 146.57 (C=O),(Arc), 145.12 (M), 175.32(C=S)with two very reactions with 1, the N-3 substituents in 1 had no adverse effect closely placed carbonyl signals. Compound 1 (R = CH2Ph) in these reactions. with 1,3-dimethyl-2-thiourea gave a multitude of products Initially, in the reactions of ureas and thioureas with N-alkyl- (TLC) from which only compound 12 could be isolated in < 1 6-methyl-1,3-0xazine-2,4(3H)-diones 1, the NH , group of yield.1-Phenylthiourea failed to react with 1 (R = CH2Ph) ureas/thioureas attacks 1 at C-2 to give the intermediate probably because of steric constraints. 16 which could follow three pathways b, c, d for cyclization To investigate the effect of substituents of 1, in their reactions (Scheme 3). In reactions of urea and 1-methylurea, 16 mainlywith t hioureas, 3-su bstituted- 1,3-oxazine-2,4( 3H)-diones 1 cyclized through path b to give 17 (R = CH2Ph) which then R = Me, (CH2),CN, (CH2),C02Et were obtained from lost isocyanate to form 3-benzyl-6-methyluracil 3. The iso- 6-methyl-1,3-0xazine-2,4(3H)-dione and appropriate halides.cyanates were trapped in ammonia solution and their respective Compound 1 R = Me, (CH,),CN, (CH,),CO,Et with ureas were isolated. In the reaction of 1,3-dimethylurea where thiourea and 1-methylthiourea gave corresponding 6-thioxo- cyclization route b in 16 was hindered, it followed path c to 1,3,5-triazine-2,4(1H,3H,SH)-dione 14d-i in 42-57 yields. form 3-benzyl-1,3,5-triazine-2,4,6(1H,3H,SH)-trione 13.In the 1142 J. CHEM.SOC. PERKIN TRANS. i 1992 Table 2 Physical and spectral data of compounds 13 and 14a-i Reaction Compd. M.p. ("C) solvent Yield () temp. (I/"C) time r/h 6 H' 13 14a 14b 14C 14d 14e 14f 14g 14h 137-139 CCHCl3I 224-226 MeOH 191-192 MeOH 190-192 MeOH 252 MeOH 209-210 MeOH 209 MeOH 169 MeOH 89-90 MeOH 4 55 52 52 57 55 49 48 42 40-50 IS 40-50 C2.51 5-c51 50-60 51 70-80 5 70-80 6 70-80 8 70-80 8 70-80 8 (CDCI,) 3.15 (6 H, s, 2 x NCH,), 4.80 (2 H, s, NCH,), 6.85-7.15 (5 H, m, ArH) s, NCH,), 7.10(5H, s, ArH), 12.50(2H, br, 2 x NH, exchanges with D,O) s, NCH,), 4.85 (2 H, s, NCH,), 7.0-7.35(5H,m,ArH),12.65(1H,br,NH, exchanges with D,O) (CDCl, + TFA) 1.34 (3 H, t, CH,), 4.40 (2 H, q, CH,), 5.12 (2 H, s, NCH,), 7.37-7.41 (5 H, m, ArH) (CDCI, + TFA) 3.40 (3 H, s, NCH,) (CDCI, + C2H6-DMSO) 4.95 (2 H, (CDCI, + 2H,j-DMSO) 3.50 (3 H, (CDCI, + TFA) 3.35 (3 H, s, NCH,), 3.70 (3 H, s, NCH,) 2 x CH,), 4.25 (2 H, t, J 7, NCH,) (CDCI, + TFA) 2.0-2.80 (4 H, m, (2 H, t, J7, NCH,) (CDCI, + TFA), 1.35 (3 H, t, J 7, OCH,CH,), 1.90-2.70 (4 H, m, (CDCl, + TFA), 2.10-2.70 (4 H, 2 x CH,), 3.80 (3 H, S, NCH,), 4.25 247 (100) 235 (79) 249 (92) 263 (95) 159 (34) 173 (100) 212 (25) 226 (86) 259 (56) 1700,1675 1740, 1655 1740, 1660 1760, 1900 1750, 1675 1740, 1685 2250, 1745, 2240, 1735, 1700 1680 1715, 1680 208.7 (10.3) 269.9 (27.3), 207 (12.6) 267.9 (25.8), 208.3 (12.5) 270.7 (20.4), 207.7 (9.7) 268.9 (21.4), 204.9 (5.7) 267.3 (17.1), 206.1 (5.2) 270.3 (20.3), 206.9 (6.95) 167.5 (22.2), 228.5 (3.4) 270.1 (12.6) 2 x CH,), 3.9W.50 (4 H, m, NCH, and OCH,) 14i 89-90 42 70-80 7 (CDCl,) 1.30 (3 H, t, J 7, OCH,CH,), 273 (63) 1730, 1670 267.5 (20.8), 228.9 (3.0) CCHC13I 1.80-2.50 (4 H, m, 2 x CH,), 3.60 (3 H, s, NCH,), 3.80-4.30 (4 H, m, NCH, and OCH,), 10.0 (1 H, br, NH, exchanges with D,O) ~~~~~ Elemental analyses: 13 (Found: C, 58.1; H, 5.3.C,,H,,N,O, requires C, 58.29; H, 5.26); 14a (Found: C, 51.2; H, 4.0 N, 17.45. C,,H,N,O,S requires C, 51.06; H, 3.82; N, 17.87);14b (Found: C, 53.2; H, 4.35; N, 16.4.C, 1HllN302S requires C, 53.01; H,4.41; N, 16.86); 14d (Found: C, 30.1; H, 3.05; N, 26.1. C4H,N,02S requires C, 30.18; H, 3.14; N, 26.41); 14e (Found: C, 34.1; H, 3.9. C5H,N,02S requires C, 34.68; H, 4.04); 14f (Found: C, 39.4; H, 3.45; N, 26.15. C,H8N4O,S requires C, 39.62; H, 3.77; N, 26.41); 14g (Found: C, 42.2; H, 4.45. C8H1,,N.,O,S requires C, 42.47; H, 4.42); 14i (Found: C, 43.6; H, 5.3; N, 15.1. C,,H,,N,O,S requires C, 43.95; H, 5.49; N, 15.38); Solvent of crystallization.' 14a: Gc(CDC1, + DMF) 42.17 (t,NCH,) 125.71, 126.23, 126.57(d,ArCH), 134.69(s,ArCH), 146.23(s,-), 17~134(C=!3);Gc(INEPT)(CDC1,+ DMF)42.17(-ve,CH2) 125.71, 126.23,126.57(+ve, ArCH); 14b:G,(CDCl, + DMF) 33.18 (q, CH,), 44.0 (t, CH,), 126.50, 127.09, 127.32 (d, ArCH), 134.63 (s, Arc), 145.32(s, C=O), 147.35 (s, C=O), 176.05 (s, CS); G,(INEPT)(CDCl, + DMF) 33.18 (+ve.CH,), 44.0 (-ve, CH,), 126.50, 127.09, 127.32 (+ve, ArCH); 14c Gc(CDC1, + DMF) 9.86 (9, CH,), 41.0 (t, CH,), 43.35 (t, CH,), 125.85, 126.49, 126.62 (d, ArCH), 134.55 (s, ArC), 145.12 (s, C=O), 146.57 (s, GO), 175.32 (s, C=S), F,(INEPT)(CDCI, + DMF) 9.83 (+ve, CH,), 40.99 (-ve, CH,), 43.37 (-ve, CH,), 125.84, 126.40, 126.62 (+ve, ArCH); 14g: G,(dioxane + CDCI,) 17.40 (CH,), 24.06 (CH,), 34.78 (CH,), 41.35 (CH,), 119.31 (C=N), 146.80 (GO), 148.32 (C=O), 176.31 (GO), S,(INEPT)(dioxane + CDCI,): 14.70 (-ve, CH,), 24.06 (-ve, CH,), 34.78 (-ve, CH,) and 41.35 (-ve, CH,).reactions of thioureas with 1 (R = alkyl), the intermediate 16 could straightaway cyclize by route c to form the triazine derivatives 14. But the absence of this mode in the reactions of 1 with biprotic ureas pointed to the alternative mode involving the participation of sulfur in 16 (Scheme 3; path d) followed by elimination of the CH,COCH3 group* to give the thiadiazine 1415, which in the presence of added base (K2C03)could undergo 5 Dimroth rearrangement' to 14. The observation that S-Scheme 4 methylthiourea failed to react with 1 further supported the mode d of reaction. ExperimentalThe mass spectra of 6-substituted 5-acetyl-3-benzyluraciis M.p.s were determined in capillaries and are uncorrected.'H 5, in general constitute loss of (i) PhCH, (path x), (ii) and I3CNMR spectra were recorded on JEOL-JNM (60 MHz)PhCH=N=C--O+ ion (path y) attended by an additional and Brucker AC 200 instruments for solutions in CDCI,/*H,- H-shift and (iii) CH, (path z) (Scheme 4). With 6-thioxo- DMSO or TFA using TMS as internal standard. IR spectra 1,3,5-triazine-2,4(1H,3H,SH)-diones 14, the major mass were recorded for KBr pellets on a Pye-Unicam SP3-300spectral fragmentation modes constitute, (i) the loss of SH to spectrophotometer and UV spectra on a Shimadzu-UV-240generate M+ -33 ions, (ii) the formation of RNCO+ ions instrument. Mass spectra were run on JEOL JMS-D-300 and +(path x) and (iii) the loss of HNCS to give a peak at M -59 VG micromass 7070F machines operating at 70 eV at CDRI, (path y) (Scheme 4).However in compounds 14b, 14e, 14g and Lucknow and RSIC, Chandigarh. Thin layer chromatography 14i, the loss of CH,N=C=S is not observed (path z). was performed on precoated TLC plates of silica gel G or silica gel 60 HFZs4. Column chromatography was carried out using silica gel (60- 120). * In the reaction of 1 (R = CH,Ph) with thiourea, the effluent gases were passed through aqueous 2,4-dinitrophenylhydrazine to give acetone 2,4-dinitrophenylhydrazone,m.p. 127 "C m.p. 128 "C). Reactions of 6-Methyl-1,3-0xazine-2,4-(3H)-diones1 with J. CHEM. SOC. PERKIN TRANS. I 1992 Am ides and Th ioamides: General Procedures.-3 -Benzyl-6-methyl-1,3-0xazine-2,4(3H)-dione (2.2 g, 0.01 mol), alkane/ arene amideslthioamides (0.012 mol), anhydrous K2C03 (3.3 g, 0.024 mol) and tetrabutylammonium hydrogen sulfate ( -20 mg) were taken up in DMF (20 cm3) and the mixtures stirred at 40-80 "C.The progress of the reactions was monitored by TLC. After completion of the reaction (3-10 h), the reaction mixture was neutralised with dilute HCl and the suspended solid was filtered off and washed with ethyl acetate. Combined filtrate and washings were evaporated under reduced pressure. The residue was column chromatographed over silica gel with benzene and benzene-ethyl acetate as eluents to give, 5-acetyluracil deriva- tives (Table 1).Synthesis of 3-Substituted 6-Methyl-1,3-oxazine-2,4(3H)-dione Derivatives 1 R = (CH,)3CN, (CH,),CO,Et.-Method A. 6-Methyl-1,3-oxazine-2,4(3H)-dione(1.27 g, 0.01 mol), was stirred in acetonitrile (50 cm3) containing anhydrous potassium carbonate (4.1 g, 0.03 mol) and triethylbenzylammonium chloride (-20 mg) for 1 h at ambient temperature. 4-Chloro bu tyronitrile/ethy1 4-chloro bu t yra te (0.012 mol) was then added and the reaction mixture was stirred. After com- pletion of the reaction (TLC, 18-25 h), the solid was filtered off and washed with acetonitrile. The filtrate and washings were combined and the solvent was distilled off to leave a residue. This was column chromatographed over silica gel using benzene and benzene-ethyl acetate as eluents to give compounds 1R = (CH2)3CN, (CH,)3CO,Et.Method B. 4-Chlorobutanonitrile/ethyl 4-chlorobutyrate (0.012 mol) was refluxed in acetone (dry) with sodium iodide (0.013 mol) for 1 h. 6-Methyl-1,3-oxazine-2,4(3H)-dione(0.01 mol) was then added along with anhydrous potassium carbonate (0.03 mol) and the reaction mixture was refluxed. After completion of the reaction (TLC, 8 h), the mixture was worked up as above. 3-(3-Cyanopropyl)-6-methyl-1,3-oxazine-2,4( 3H)-dione 1 R = (CH,),CN: (A) 18 h (50 "C), (45); (B) 8 h (55), m-p. liquid; m/z 194 (M', 6);G,(CDC13) 1.80-2.65 (7 H, m, CH3 and 2 x CH,), 4.0 (2 H, t, J 7, NCH,) and 5.85 (1 H, s, CH); 1143 3.80-4.40 (4 H, m, NCH, and OCH,) and 5.75 (1 H, s, H); v,,,(CHC13)/cm-' 1780 (M),1750 (C=O) and 1720 (0); h,,,(MeOH)/nm 227.5.Reactions of 3-alkyl-6-methyl-1,3-0xazine-2,4(3H)-diones1 with ureas and thioureas. These were performed as those with amides and the data for the products formed are recorded in Table 2. Acknowledgements We thank UGC (India) for financial assistance, CDRI (Lucknow), RSIC (Chandigarh) and TIET (Patiala) for mass spectral and elemental analyses. Financial assistance from UGC under COSIST and SAP programmes is gratefully acknowledged. References 1 (a) Part 3. S. Kumar, S. S. Chimni and H.Singh, J. Chem. SOC., Perkin Trans. 1, 1991, 1391 and references therein; (b) S. Ahmed, R. Lofthouse and G. Shaw, J. Chem. SOC., Perkin Trans. 1, 1976, 1969; (c) T. Kato and N. Katagiri, Heterocycles, 1980, 14, 1333; (4 M.Sainsbury in Comprehensive Heterocyclic Chemistry, Synthesis and uses of Heterocyclic Compoun ed. A. R. Katritzky and C. W. Rees, 1984, vol. 3, 995; (e) T. Kinoshita, K. Takeuchi, M. Kondoh and S. Furukawa, Chem. Pharm. Bull., 1989, 37, 2026; cf) H. Singh, P. Aggarwal and S. Kumar, Indian J. Chem., Sect. B, 1989, 28, 950; (g) H. Singh, P. Aggarwal and S. Kumar, J. Chem. Res., 1991, (S)362. 2 J. P. Kokko, L. Mandell and J. H. Goldstein, J. Am. Chem. SOC., 1962,84,1042. 3 J. K. M. Sanders and B. K. Hunter, Modern NMR Spectroscopy, Oxford University Press, Oxford, 1987, p. 74. 4 H. T. Clarke and L. D. Behr, Org. Syntheses, Coll. Vol. 2, 1943,562. 5 P. Singh, K. Deep and H. Singh, J. Chem. Res., 1984, (S)71; (M) 0636. 6 The Chemistry of Heterocyclic Compounds; The Pyrimidines, Part 1, ed. D. J. Brown and S. F. Mason, Interscience, 1962,534. 7 M. Goese, J.Am. Chem. SOC., 1941,63,2283. 8 K. Hirota, K. A. Watanabe and J. J. Fox, J. Org. Chem., 1978, 43, 1193 and references therein. 9 A Text-Book of Practical Organic Chemistry by A. I. Vogel, ELBS and v,,,(CHC13)/cm-' 2250 (C=N), 1750 (C=O) and 1700 (0);Longman, 1975,346. h,,,(MeOH)/nm 227.9. 3-(Ethoxycarbonylpropyl)-6-methyG1,3-oxazine-2,4(3H)-dione 1 R = (CH,),CO,Et: (A) 25 h (50 "C) (35); (B) 8 h (55); m.p. 52 "C (CHC13); m/z 241 (M+,45); G,(CDC13) 1.25 (3 H, t, J 7, OCH,CH3), 1.80-2.50 (7 H, m, 2 x CH,, CH3), Paper 1/06487H Received 30th December 199 1 Accepted 10th February 1992