Addition reactions of acetylenic esters with monosubstituted thioureas

摘要

1428 J.C.S. Perkin I Addition Reactions of Acetylenic Esters with Monosubstituted Thioureas By Libero ltalo Giannola and Salvatore Palazzo,' lstituto di Chimica Farmaceutica Applicata, Universith di Palermo, Via Archirafi 32,Palermo, Italy Pasquale Agozzino and Liliana Lamartina, lstituto di Chimica Organica, Facolts di Farmacia, Universita di Palerrno, Italy Leopoldo Ceraulo, lstituto di Chimica Farmaceutica e Tossicologica, Universith di Palermo, Via Archirafi 32, Palermo, Italy Monoalkyl-substituted thioureas react with dimethyl acetylenedicarboxylate to give, in a good yield, two different dihydrothiazinones, and not one compound only as has been claimed previously. The structures of the adducts were assigned on the basis of i.r. and 'H n.m.r. spectroscopy, and mass spectrometry.EARLIERpapers from these laboratories have described the use of substituted thioureas in the syntheses of 1,3-thiazines. A survey of the literature revealed that Lown and Ma,2 using n.m.r. and mass spectrometry, assigned the dihydrothiazinone ring structure to the products of the reaction between dimethyl acetylene- dicarboxylate (DAD) (1) and thioureas (2). The (a)S. Palazzo and G. Lombardo, Gazzelta, 1963, 93, 207; (b) S. Palazzo, L. I. Giannola, and S. Caronna, Alti Accad. Sci. Lett. Arti, Palerrno, 1974, 33 (N),421. reported data of such adducts and their perhydro-derivatives conclusively indicate a dihydrothiazinone ring, including the chemical' evidence of Winterfeldt et aL3 However, we were very surprised that in the addition reaction of DAD to N-methylthiourea, the presence of a methyl group could lead to a single product.J. W. Lown and J. C. N. Ma, Canad. J. Ckem., 1967, 45, 939. (a)E. Winterfeldt and J. M. Nelke, Chem. Ber., 1967, 100, 3671; (b) E. Winterfeldt, ibid., 1967, 100, 3679. 1978 Consequently, we have repeated the reaction under the same experimental conditions.2 ICI NH -R R-Ny.C02Me HNyFCa(lr + C=S __c HN 4-R-N1I 0 0COzMe NH2 SCHEME Reaction of DAD with monosubstituted thioureas 1 RESULTS AND DISCUSSION In our experiments, as we expected, two products in nearly equimolecular amounts were obtained when N-methylthiourea reacted with DAD (Scheme 1). The two products (3) and (4) were separable by t.1.c. with a large RF difference (0.18),using the same eluant as ref.2. Compounds (3) and (4) were also separable by fractional crystallization and had very different melting points : (3) m.p. 280-281 "C, (4) m.p. 170-172 "C. The analytical and molecular-weight data showed that (3) and (4)were isomers. The mass spectra of the two isomers were closely similar and both showed the main fragmentation process of the dihydrothiazinone ring structure (Scheme 2).2 Additional confirmation is pro- vided by the close similarity of the cleavage modes of (3) and (4) with all the characteristic features upon electron impact shown by the dihydrobenzothiazinones, for which an unequivocal assignment is de~cribed.~, Therefore (3) and (4) differ only in the position of the methyl group.The lH n.m.r. spectrum of (3) [(CD,),SO] (Table 1) shows a singlet at 6 3.70 (3 H, C0,Me) and a doublet at 6 3.10 (3 H) (J5 Hz) that collapses to a singlet after ex- change with D20; this is consistent with an NHMe group. Therefore, for (3) this result is good evidence for the structure [(3a) 3-) (3b)], with 90% present as the tautomeric form (3b) [10% of the tautomer (3a) based on the singlet at 6 3.081. Confirmation of structure (3) is given by methyl- ation. When (3) is allowed to react with methyl iodide, it gives a dimethyl derivative (5) (Table l), which is different from the adduct (6) obtained by reacting NN'- dimethylthiourea with DAD. A peak at m/e 170 (4%) was found in the high-resolution mass spectrum of (5) 'H.Boshagen, W. Geiger, H. Hulpke, and C. Wunsche, Chew. Ber., 1971, 104, 3757. 1429 corresponding to loss of NMe, from the molecular ion. This spectrum is also consistent with the fragmentation patterns shown in Scheme 2. Compound (4) must be a positional isomer of (3) and it is assigned the structure shown; its lH n.m.r. spectrum (CDC1,) exhibits a singlet at 6 3.80 (3 H) for the C0,Me group and a singlet at 6 3.30 (3 H) assigned to the methyl of the endocyclic nitrogen. Compound (4)is identical to that which Winterfeldt et aZ,3aobtained by methyl- ation of the thiourea-DAD adduct (7). 1.r. spectra (Table 1) are diagnostic in assigning the two structures. The i.r. spectrum of (3) shows the absorption of a strongly polar CN double bond at 1545 cm-l.This band, characteristic of an NCNCO group, is absent in the spectrum of (4), in accord with the assigned structures. Lown and Ma assigned the structure of their sole product using lH n.m.r. spectroscopy. While their data in CDC1, are consistent with those of our compound (a), they assigned to the product structure (3a), based on a hypothetical splitting (J 5 Hz), due to the proton- ation in trifluoroacetic acid of the basic exocyclic nitrogen. They also described a similar splitting of the exocyclic NMe signal in the n.m.r. spectrum (in trifluoro- acetic acid) of the NN'-dimethylthiourea-DAD adduct (6). We recorded lH n.m.r. spectra of pure samples of (3), (4), and (6) in trifluoroacetic acid and never observed splitting, but only sharp singlets for each methyl group.The only acceptable explanation for these discrepancies is that Lown and Ma worked on an equimolar mixture of the two isomers. Their 'compound' has m.p. 253-254 "C. We checked that the crude product of the reaction melted at 253-254 "C when recrystallized twice from methanol, a solvent unsuitable for separation of the two isomers. While (3) is almost insoluble in chloroform, (4)is very soluble; and both are soluble in trifluoroacetic acid. This means that when recording lH n.m.r. spectra, they used a chloroform solution containing only (4)and a trifluoroacetic acid solution containing both compounds. Thus the lH n.m.r. spectrum of our reaction mixture in trifluoroacetic acid showed two singlets for the two NMe groups separated by 5 Hz, of similar intensity because the mixture was nearly equimolar: this is the 'doublet ' of Lown and Ma.While the signals of the ester methyls over- lapped perfectly, and thus appear as one signal, they surprisingly failed to record that the signals of the two vinyl protons were also separated by 5 Hz. We have also studied the reaction between other asymmetric thioureas and DAD and found that when N-ethylthiourea is reacted with DAD, two isomers (8) (m.p. 188-190 "C) and (9) (m.p. 161-162 "C) are obtained (ratio ca. 2.5: 1). These two isomers are correlated, both by RF values and i.r. and U.V. spectra, with (3) and (4) respectively. The lH n.m.r.spectrum of (8)shows a multiplet centred at 6 3.55 (2 H, NHCH,CH,) 6 L. Ceraulo, P. Agozzino, M. Ferrugia, and L. I. Giannola, 4th National Congress of Mass Spectrometry, Catania, 12-14 September 1977, Italy. 1430 J.C.S. Perkin I which becomes a quartet when exchanged with D,O. These data are consistent with the structure (Sa). The lH n.m.r. spectrum of (9) is consistent with the structure shown. m/e 141 , mle ZOO(W*) 0 m/e 159 (3) R1= Me R2 = H (4) R1= H R2 = Me EXPERIMENTAL ~.p.swere determined on a Buchi-Tottoli capillary apparatus. 1.r. spectra were recorded on a Perkin-Elmer 157 i.r. spectrophotometer as Nujol mulls, and U.V. spectra [CO*Me] L m/e 144 m/e 116 / m/e 85 n/e 58 SCHEME Mass-spectral fragmentation of adducts (all transitions shown are metastable-supported) 2 Mass spectrometry is also useful in distinguishing the two kinds of structures (3a) and (8a) and (4) and (9).Mass spectra of (8) and (9) showed a fragment corres- ponding to [M -Me]+ which is much more abundant for (8) (80%)than (9) (4%). This is in agreement with the comparatively higher stability of the ion (10) HI 0 0 (10) (11 1 compared with (11). A careful survey of the mass spectra of (3) and (4) showed a similar behaviour for the [M -HI+ ion of (3) (1.5%) compared with (4) ((0.2 Yo). In conclusion, when DAD reacts with monoalkyl- thioureas (at least for small alkyl substituents), the two expected dihydrothiazinone isomers are formed in comparable amounts.for ethanolic solutions with a Perkin-Elmer model 200 spectrophotometer. lH N.m.r. spectra were recorded on Varian A-60 (probe temperature 40 "C) and JEOL C-60H (probe temperature 25 "C) instruments with tetramethyl- silane as internal standard. Low and high resolution mass spectra were run on a JEOL-JMS-OlSG-2 double- focusing mass spectrometer operating with an electron-beam energy of 75 eV and 10 kV accelerating voltage. Exact mass measurements, performed at 15 000 resolving power, were carried out to an accuracy of fl0 p.p.m. of the theoretical values. The detailed mass-spectra are deposited as Supplementary Publication No. SUP 22316 (2 pp.) .* Thin-layer chromatography for confirming com- pound purity utilized 0.25-mm silica gel plates (Merck) with fluorescent indicator, and ethyl acetate-benzene (7 : 3) or methanol-ethyl acetate (2.5 : 97.5) solvent systems. M.p.s, crystallization solvents, yields, and analytical data are given in Table 2.Preparation of Methyl 2-Alkylimino-4-oxo-3,4-dihydro-2H-and 2-Alkylamino-4-oxo-4H-1,3-thiazine-6-carboxylates (3) and (8)and Methyl 3-Alkyl-2-imino-Coxo-3,4-dihydro-2H-1,3-thiazZne-6-carboxylates(4)and (9) .-A solution of DAD (0.12 mol) in warm methanol (50 ml) was added to a stirred * For details see Notice to Authors No. 7, J.C.S. Perkin I, 1977,Index issue. 1978 1431 methanolic solution of the appropriate thiourea (0.1 mol). in boiling absolute methanol (100 ml) was added dropwise In a few minutes crystals separated, and the reaction set with stirring a methanolic solution (20 ml) of sodium aside overnight.The resulting crude mass was extracted methoxide (0.02 g-atom of sodium). The mixture was with benzene (3 x 40 ml), the benzene-soluble residue was cooled to 0 "C and filtered to yield the sodium salt of (3) washed with warm chloroform (2 x 10 ml), and recrystal- (0.007 mol). A solution of the sodium salt of (3) (0.005 lized from methanol. Two recrystallizations were sufficient mol) in absolute methanol (20ml) and methyl iodide (0.05 TABLE1 Spectroscopic data for thiourea-DAD adducts 0 0 1.r. (cm-l) 1H N.m.r. (6) r-li r A v Com-ester amide U.V. Vinyl C0,Me pound R1 Ra R1 Ra NH CO CO NC=NCO (nm) (lH,s) (3H,s) NR' NRa Solvent (3) Me H 3 150 1710 1685 1545 288 6.60 3.70 3.10 (3 H, d, 9.80 (1 H, (CD,),SOJ 5 Hz) broad)7.30 4.05 3.55 (3 H, S) CF3COaH (4) H Me 3 250 1720 1680 308 6.80 3.80 7.60 (1H, 3.30 (3 H, s) CDC1, broad)6.62 3.78 10.28 (1 H, 3.18 (3 H, S) (CD,),SOsharp) I, 7.38 4.05 3.63 (3 H, S) CF3COaH (5) Me Me 1700 1678 1560 298 6.98 3.90 3.25 (3 H, s) 3.50 (3 H, s) CDCl, Me Me 1710 1650 310 7.42 4.05 3.52 (3 H, s) 3.58 (3 H, s) CF,CO,H (6) H H 3 240 1710 1680 1560 278 6.60 3.76 9.50 (2 H, broad) (CD3),S0 Et H 3 150 1705 1685 1545 292 6.60 3.80 3.55(2H,m, 9.70(1 H, (CD,),SOCH,CH3) broad)1.20 (3H, t, J 7 Hz, CHaCH3)(9) H Et 3250 1705 1675 310 6.60 3.75 9.95 (1H, 3.77 (2 H, 9, (CD,),SO sharp) I, J 7 Hz, CHaCH3)1.15 (3 H, t, J 7 Hz, CH2CH3) With D,O collapses to a singlet.Exchangeable with deuterium oxide. e For these protons Lown and Ma reported a signal at 6 6.69 (2 H) in the same solvent. With D,O becomes quartet (J7 Hz). TABLE2 Physical data for thiourea-DAD adducts Molecular Analysis (%) weight (by Found RequiredCrystallization M.p. Yield mass spectro- 7 7 solvent ("C) (%) metry) CHNS EHNS Methanol 280-281 43 200 42.15 3.9 14.1 16.25 42.00 4.03 14.00 15.99 Methanol 170-1 7 2 38 200 42.2 3.9 14.15 16.2 42,.00 4.03 14.00 15.99 Methanol-water 135-1 36 25 214 44.95 4.6 13.15 15.1 44.86 4.71 13.08 14.94 (1: 1)Methanol 160-1 61 82 214 45.0 4.5 13.15 15.1 44.86 4.71 13.08 14.94 Acetic acid 275 70 186 38.9 3.2 15.1 17.35 38.72 3.25 15.05 17.19 (decomp.)Methanol 188-190 54 214 44.95 4.6 13.1 15.15 44.86 4.71 13.08 14.04 Cyclohexane 161-162 22 214 45.0 4.55 13.25 15.15 44.86 4.71 13.08 14.04 to produce an analytically pure sample of (3) or (8). The mol) were refluxed for 5 h, the mixture poured into water benzene extracts were combined and evaporated off and and the resulting oil separated by decantation. The oil was after cooling a white product separated. Two recrystalliz- dissolved in methanol and the alcoholic solution poured ations from methanol were sufficient to produce an ana- into water giving crude (5) (0.001 5 mol). Two crystal- lytically pure sample of (4) or (9). lizations from methanol-water (1 : 1) gave white crystals of Preparation of Methyl 2-(NN-Dimethylamino)-4-oxo-1,3-(5),m.p. 135-136 "C. thiazzne-6-carboxylate (5).-To a solution of (3) (0.01 mol) [7/1912 Received, 1st November, 19771