J. CHEM. SOC. PERKIN TRANS. I 1988 Spectrometric and Chemical Studies of 5-Acyl- and 5-Nitroso-2-(N,N- d isu bst ituted Ami no)t h iazoles Timothy N. Birkinshaw, G. Denis Meakins," and Simon J. Plackett Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX I 30Y The conformational preferences of 2-(N,N-disubstituted amino)thiazoles having a 4-substituent (R1) and a 5-acyl group (R2CO) have been established by i.r. spectrometry and a crystallographic examination. In solution the compounds with R2 = aryl and R1 = Me or aryl exist predominantly or entirely in the carbonyl 0,s-anti arrangement; for those with R' = aryl and R2= Me the syn rotamer is the main form but a small amount (ca. 15) of the anti rotamer is present. Nitrosation of 4-aryl-2-dimethylaminothiazoles gives 5-nitroso derivatives, and these are probably the first authentic nitrosothiazoles.The barrier to rotation of the dimethylamino group is unexpectedly high (AGL8 = 69 kJ mol-'), exceeding even that of the 5-trifluoroacetyl analogues. The first part of this work is concerned with stereochemical Table 1. Crystallographic results (standard deviations in parentheses)features arising from rotation of the acyl group in 5-acyl-2-(N,N- for compound (lc)disubstituted amin0)thiazole.s; the second part deals with the preparation of 5-nitroso analogues and the barrier to rotation of their 2-dimethylamino groups. The conformational preferences of 5-acetyl-2-(N,N-disubsti-tuted amino)thiazoles, unsubstituted or with methyl, t-butyl or phenyl groups at the position 4, were examined in an earlier study ' using i.r.and X-ray methods. While the 4-H and 4-Ph compounds, in solution, exist predominantly as the carbonyl 0,s-synrotamers (structure as in Table 2) the 4-But compounds adopt the 0,s-anti arrangement, and with the 4-Me derivatives both forms, of approximately equal stability, are present. These results established a useful general relationship for the rota- tional isomers of 5-acetyl compounds, namely, that the anti forms have i.r. CO stretching bands at higher wavenumbers than those of the syn rotamers. The investigation has now been extended to the 5-MeCO compounds with substituted phenyl groups at position 4, and the 5-ArCO compoundsZa with methyl or aromatic groups at position 4 (see Table 2).Interest was mainly in the comparison between isomeric pairs in which the R' and R2groups are interchanged. It transpired that the i.r. results, in isolation, could not be interpreted unambiguously and, therefore, to provide a firm basis one of the 5-ArCO compounds (lc) was examined crys- tallographically. The structure (Table 1) adopted represents a compromise between the tendencies to maximise mesomeric interaction and to avoid steric interference. Of the groups attached to the carbonyl function the 2-aminothiazole system is the more electron-releasing; the CO group is thus rotated less from the plane of the thiazole nucleus (1 1") than from that of the phenyl ring (34"), and the bond from the carbonyl group to the thiazole nucleus (1.460 A) is shorter than that to the phenyl ring (1.491 A).The N-phenyl group is directed towards the sulphur atom, as in other 2-(N-methylanilin0)thiazoles;'~~that one orientation is markedly the more stable is confirmed by the lack of splitting of the N-Me 'H n.m.r. signals of compounds (la+) at temperatures down to -90 "C. In contrast the a-protons of the hexahydroazepine ring in compounds (2a-c) become non- equivalent at ca. -20 "C (source frequency 90 MHz). For the present purpose the salient feature is that compound (lc) exists in the anti arrangement with the carbonyl group and the thiazole ring almost coplanar. To assess the possible advantage of using F.T. i.r. spectro- metry in the present work two compounds (la) and (lb) from the earlier study were re-examined.There is good agreement between the results, but the improved data-processing facilities reveal the presence of a minor CO band, not detected pre- Q f 4cr7, AC'5' Planes and atoms contained 1 Thiazole 1.729(2) cs(it~(l-~(1-~(2-~(3)1 1.3 13(2) 2 Carbonyl 1.3 70( 2) CC~~tC(6)-c(7FO(1)1 1.374(3) 3 C-Phenyl 1.750(2) aromatic ring containing C(7) 1.357(2)4 Ex0 N 1.454(3) CC( 1 )-C(4)-c(5FWl 1.433(2) 5 N-Phenyl 1.497(2) aromatic ring containing C(5) 1.460(2)1.226(2) Dihedral angles (") between planes 1.49l(3) Planes 1-2 168.86(2)Planes 1-3 135.99(3) Perpendicular distances (A)Planes 1-4 8.43(3)Planes 1-5 108.36(2) C(8Fplane 1 -0.0099(2) Planes 2-3 34.09(2) N(2Fplane 4 -0.006(3) Planes 4-5 114.34(3) viously, in the 4-phenyl compound (lb).The capabilities of high-resolution i.r. spectrometry, even with solution spectra, are illustrated by the results with the isotopic mixture (11)2b (last entry in Table 2): the absorptions of the CH,CO and CD,CO groups can be detected separately in the bands arising from both stereochemical forms. Replacement of the 2-(N-methylanilino) group in compounds Table 2. Infrared CO bands of 5-acyl-2-(N,N-disubstitutedamino)-thiazoles The positions of bands (cm-' at 303 K) are followed, in parentheses, by their percentage areas R' 0 (1) @ = N(Me)Ph anti SYn Compd. R' R2 Solvent Form Anti SYn (la)"yb Me Me {CCl, 1659(63) 1635(37) MeCN 1653(41) 1625(59) (2a)" Me Me {CCl, 1 653(56) 1 628(44) MeCN 1646(36) 1618(54) (lb)b Ph Me -CCI, 1667iioj i637i9oj (2b) Ph Me CCl, 1662(8) 1 634(92) (lc) Me Ph CCI, 1 630(100)(2c) Me Ph 1662(15) 1635(85)(la) C6H,0Me-p Me MeCN 1 659(17) 1 627(83) (le) Me C6H40Me-p eel, 1 628( lo()) {CCl, 1 667(20) 1 638(80)(If) C,H,Cl-p Me MeCN 1662(18) 1631(82) (1g) Me C6H4Cl-p cc14 1 631(100) (lh) C6H4OMe-p Ph CCI, 1608(100)(li) Ph C6H40Me-p eel, 1618(100) (1j) C6H4Cl-p Ph CCl, 1 622(100)(lk) Ph C6H4OCl-p ccl4 1619(100) " Overtone region (CCl,): compound (la) 3 298(68), 3 250 (32); compound (2a) 3 287(59), 3 234(41). Ref.1. 'Ref. 26. (1) by the more electron-releasing hexahydroazepin- 1-yl group compounds (2) causes a small decrease in wavenumber.Within each of the three sets of ketones (R' = Me, R2 = Ar; R' = Ar, R2 = Me; R' = Ar, R2 = Ar) there is a consistent conformational preference. The main form of the 5-acetyl compounds (R' = Ar, R2 = Me) is the syn rotamer' and a small amount (ca. 15) of the anti rotamer is present. Single CO bands for the isomeric 4-methyl compounds (R' = Me, R2 = Ar) establish that they exist predominantly or entirely in one form which, from the crystallographic work, is identified as the anti rotamer. The third set (R' and R2 both aromatic) also have single bands, at positions which show that they too adopt the anti arrangement. Heterocyclic compounds in which both syn and anti arrange-ments of an x-formyl or x-acetyl group coplanar with the nucleus are free from strain have an intrinsic preference for the syn rotamer 'v4 (probably because this has the carbonyl group and the formal 4,5-double bond in a transoid orientation). To attain the planar (acetyl group-thiazole ring) syn conformation the 4-Ar-5-MeCO compounds must undergo an out-of-plane twist of the aromatic ring the dihedral angle is 45" in the 4-phenyl ketone (lb)', and the difference in stability between the alternative forms is only ca.4.3 kJ mol-'. Although it was expected that the isomeric 4-Me-5-Arc0 compounds would similarly accommodate the syn arrangement an over-riding tendency for avoiding proximity of the methyl and aromatic groups appears to prevail, and the anti arrangement is adopted.When both the R',R2 groups are aromatic prohibitive J. CHEM. SOC. PERKIN TRANS. I 1988 Scheme 1. Nitrosation of 2-(N-monosubstituted and N,N-disubstituted amino)thiazoles AcOH-NaNOZ Me Singlets :icjNH*N:CMe2-1'Nd 162-049 (3) I HONMxiN R bsol; C.JNMe2S NYMeMe 2.0682.084 (6) (5) Ac OH-NaN02bsol; (7) 0-(8) R' R2 repulsion is unavoidable in the syn form, and the -9 carbonyl group can approach coplanarity with the thiazole ring in only the anti rotamer. There are few reports of compounds formulated as nitroso- thiazoles. The status of the earliest representative (2-methyl- imino-3-nitroso-2,3-dihydrothiazole)is doubtful in view of later work.6 A yellow (sic) product formed by nitrosating 4-phenyl-2-p-tolylaminothiazolewas represented ' as the 5-nitroso derivative; reduction gave, in low yield, an unstable amine.Nitrosation of 2-amino- and 2-methylamino-4-phenyl- thiazole under acid conditions gave salts (presumed to be 5-nitroso compounds) from which small amounts of 5-benzyl- ideneaminothiazoles were obtained by reduction and condens- ation with benzaldehyde.' More recently the 'H n.m.r. spectra of the yellow products formed by nitrosating four 2-hydrazino- 4-methylthiazoles were interpreted as showing that they are tautomeric mixtures of 5-nitrosothiazoles and 5-oximino-2,5- dihydrothiaz~les.~One of these nitrosations, that of 2-iso- propylidenehydrazino-4-methylthiazole(3), was repeated here (Scheme 1). Examination of the starting material and product (obtained after purification in 70 yield) at 300 MHz showed an appreciable difference in their isopropylidene signals.This is understandable on the basis of the 5-oximino structure (5) (possibly with the assignments indicated), but if the reaction involves only the introduction of a remote 5-nitroso group structure (4) hardly any effect would be expected. Conversion of the initial products into the more stable 5-oximino com- pounds probably occurred in all the reported preparation^,^-^ and it is unlikely that an authentic nitrosothiazole had been isolated. The nitroso-oximino isomerisation would be prevented by disubstitution of the 2-amino group. Nitrosation of several J. CHEM. SOC. PERKIN TRANS. I 1988 Table 3.Crystallographic data for compound (lc) Formula c,8H f,N,OSRel. mol. mass 308.4 Cr stal class Monoclinic1 10.8 50(2) ;;A 13.682(2) CIA 11.617(3) a/" 90 PI" 111.21(2)Weights 766,855,15,81 rl" 90 uiA3 1608 Space group flC Z 4 DJMg m-3 1.274 F(ow 648 Crystal 0.25 x 0.5 x 0.75 size/mmRadiation CU-K, CI (cm-') 17.6 (sin w")nlax. 0.636 Total I" 4 619 Unique zb 2 825 nc 3 R 0.0426 Rw 0.062 1 Amax./e A-3d 0.3 Total number of reflections measured. Number of reflections with intensity significantly above the background intensity. 'Criterion for recognising observed reflections I no(Z). Maximum height in final difference electron density synthesis. 4-alkyl-2-dimethylaminothiazoles,e.g. (6; R = Bu'), gave green solutions, but after work-up mixtures of colourless products were obtained.However, from the 4-p-substituted phenyl analogues (6a-c) the deep-green nitroso compounds (7a-c) were obtained as crystalline products. These are stable as solids, and as solutions in non-polar solvents below ca. 60deg;C; they are unusual in showing two NMe 'H n.m.r. signals at room temperature. Rotational barriers in the literature (e.g., Me,NNO*' 95.3 kJ mol-'. Me,NCHO " 87.8, Me,NC,H,NO-p l2 50.6, Me,NC,H,CHO-p ' 45.1) suggested that 5-nitrosothiazoles should have values somewhat, but not greatly, higher than those of the corresponding 5-carbaldehydes in which AG;,, for rotation about the C(2)-N bond is cu. 53 kJ mol-'. The values found for the 5-nitroso compounds (near 69 kJ mol-', Scheme) are much higher, and exceed even those of the related 5-trifluoro- acetyl- and 5-nitro-thiazoles (56 and 57.5 kJ mol-', respec-tively).This outcome is surprising, but there is little quanti- tative information about the nitroso group's electronic effects (for example, a o-value is not available), and it may be that in certain structural environments the nitroso group exerts an extremely strong -M effect. The present results establish that the dipolar canonical, presumably the 0,s-syn form (8), makes an unusually large contribution to the structure of 2-amino-5- nitrosothiazoles; that this canonical is the counterpart of the 5-oximino structure as in (5) favoured by nitroso compounds which are free to isomerise may be significant.Experimental Crystallographic Work.-The determination was carried out as described in ref. 3; a complete account is given elsewhere,15 and the customary crystallographic material is available from the Cambridge Crystallographic Data Centre.* The results, in standard form, are shown in Tables 3 and 4. 221 1 Table 4. Atomic co-ordinates for compound (lc) xla Ylb zic 0.455 2(5) 0.289 l(2) 0.375 l(2) 0.491 O(2) 0.056 3(2) 0.231 5(2) 0.289 2(2) 0.106 4(4) 0.104 4( 1) 0.137 O(1) 0.134 5(1) 0.059 7(2) 0.102 O(2) -0.029 2(2) -0.200 l(4) -0.221 3(2) -0.022 l(2) -0.044 5(2) -0.352 l(2) -0.436 O(2) -0.435 l(2) 0.323 8(3) 0.299 6(3) 0.242 8(4) 0.207 l(3) 0.625 O(2) -0.056 5(2) 0.005 8(2) 0.094 2(2) 0.144 6(2) 0.122 O(2) -0.534 3(3) -0.633 2(2) -0.632 8(2) -0.535 8(2) 0.045 7(2) 0.739 5(2) 0.736 2(2) 0.847 9(2) 0.150 6( 1) 0.203 8(2) 0.200 O(2) 0.003 9(2) -0.101 3(2) -0.133 3(2) 0.962 4(2) 0.967 O(2) 0.158 O(2) 0.1 14 O(2) -0.060 2(3) 0.046 l(3) 0.857 4(2) 0.107 9(2) 0.079 5(2) 0.362 4(2) 0.261 5(2) 0.194 9(2) 0.644 8(2) 0.152 O(2) 0.088 3(1) 0.147 8(2) 0.122 l(1) 0.100 8(2) -0.122 2(1) -0.334 l(2) 0.156 5(1) Spectrometric Work.-1.r.spectra of solutions in dry solvents were recorded at 303 K on a Perkin-Elmer 1750 Fourier Transform spectrometer (at a spectral slit-width of 0.5 cm-') operating with a 3700 Professional Computer. 'H N.m.r. spectra, apart from those in Scheme 1, were recorded at 90 MHz. Chemical shifts refer to solutions in CDC1, at 305 K.Rotational barriers (statistical errors amp; 3 kJ mol-') were obtained by examining solutions in CD,C1, over the range 180-310 K and processing the results as described in ref. 3. Preparative Work.-A solution of NaNO, (0.45 g) in water (20 ml) was added during 20 min to a solution of 2-iso- propylidenehydrazino-4-methylthiazole' (3) (1.02 g) in OM HCl (0.65 m1)-water (20 ml) which was stirred at 2deg;C. The cooling bath was removed, and the mixture was stirred for 2 h. The insoluble material was collected and dried to give a yellow solid (1.05 g) which, after two crystallisations from EtOH, afforded 5-hydroxyimino-2-isopropylidenehydrazono-2,3-di-hydrothiazole (5) (0.78 g), m.p. 204-210 "C (decomp.) lit.,' 21amp;213 "C (decomp.); v,,,,(Nujol) 1 635 cm-' (C=N); mjz (chemical ionization) 199 (M + l)', 10073 and 198 (21).4-Aryl-2-dimethyluminothiuzoles (6).-Treatment of p-bromo-, p-chloro-, and p-methyl-phenacyl bromide with N,N-dimethylthiourea in Me,CO (boiling under reflux for 2 h) by the general procedure l4 gave the 4-p-bromophenylthiazole (6a) (82), 6 3.04 (s, 6 H, NMe,), 4-p-chlorophenyl-2-dimethyl-uminothiuzole (6b) (7979, m.p. 59-60 "C (from MeOH) (Found: C, 55.2; H, 4.6; N, 11.8. C, ,HI ,ClN,S requires C, 55.3; H, 4.6; N, 11.7); 6 6.61 (1 H, s, 5-H) and 3.06 (s, 6 H, NMe,); and 2-dimethylamino-4-p-tolylthiazole(6c)(83), m.p. 67-68 "C (from MeOH) (Found: C, 66.1; H, 6.3; N, 12.6. C,,H,,N,S requires C, 66.0; H, 6.5; N, 12.8);6 6.59 (1 H, s, 5-H) and 3.03 (s, 6 H, NMe,).4-Aryl-5-nitrosothiuzoles (7).-A solution of NaNO, (0.81 g) in water (10 ml) was added during 15 min to a solution of the 4-p-bromophenylthiazole (6a) (1.72 g) in AcOH (20 ml) which * See Instructions for Authors, J. Chem. SOC.,Perkin Trans. I, 1988, Issue 1. was stirred at 2 "C. After a further 5 min, the mixture was diluted with ice-water (25 ml), basified (Na,CO,), and extracted with CHCl,. Removal of solvent at 20deg;C/15 mmHg gave a green solid (1.65 g) which was stirred with dry CHCl, (25 ml) at 40 "C for 10 min. Filtration, and storage of the filtrate at 2deg;C for 2 days gave large green crystals. Recrystallisation afforded 4-p-bromophenyl-2-dimethylamino-5-nitrosothiazole (74(1.21 g), m.p.146-147deg;C (Found: C, 42.4; H, 3.3; N, 13.3. C, ,H,,BrN,OS requires C, 42.3; H, 3.2; N, 13.5); 6CDCl,-(CD,),SO 3.20 and 3.49 (two s, each 3 H, NMe,); m/z 313 and 311 (M+,38) and 44 (100); h,,,.(EtOH) 428 nm (E 1930). Similarly, the thiazoles (6b) and (6c)gave 4-p-chlorophenyl-2-dimethylamino-5-nitrosothiazole(7b) (61), m.p. 139-141 "C (Found: C, 49.1; H, 3.9; N, 15.5. CllH,,CIN,OS requires C, 49.3; H, 3.8; N, 15.7);6CDC1,-(CD3),S0 3.25 and 3.54 (NMe,); h,,,,(EtOH) 428 nm (E 3 200); and 2-dimethylamino-5-nitroso-4-p-tolylthiazole (7c) (69), m.p. 155-1 56 "C from CHC1,-light petroleum (b.p. 6amp;80 "C) (Found: C, 58.1; H, 5.2; N, 16.9. C,,H,,N30S requires C, 58.3; H, 5.3; N, 17.0);6 2.42 (3 H, s, CH,Ar) and 3.19 and 3.47 (NMe,); m/z 247 (M+, 8) and 59 (100).Acknowledgements We thank Dr. C. K. Prout for the crystallographic examination, and Keble College, Oxford, for the award of a Senior Scholarship (to S. J. P.) J. CHEM. SOC. PERKIN TRANS. I 1988 References 1 J. M. Caldwell, G. D. Meakins, R. H. Jones, T. R. Kidd, and K. Prout, J. Chem. Soc., Perkin Trans. 1, 1987, 2305. 2 (a)J. C. Brindley, J. M. Caldwell, G. D. Meakins, S. J. Plackett, and S. J. Price, J. Chem. Soc., Perkin Trans. 1, 1987, 1153; R. A. Funnell, G. D. Meakins, J. M. Peach, and S. J. Price, ibid., 1987; (6) S. J. Plackett, Part I1 Thesis, Oxford, 1986. 3 D. W. Gillon, I. J. Forrest, G. D. Meakins, M. D. Tirel, and J. D. Wallis, J. Chem. SOC., Perkin Trans. 1, 1983, 241. 4 Leading references cited by P. T. Kaye, R. Macrae, G. D. Meakins, and C. H. Patterson, J. Chem. Soc., Perkin Trans. 2, 1980, 1631. 5 E. Naf, Justus Liebigs Ann. Chem., 1891, 265, 108. 6 Y. Tamura, H. Hayashi, E. Saeki, J-H. Kim, and M. Ikeda, J. Heterocycl. Chem., 1974, 11, 459. 7 R. Walther and H. Roch, J. Prakt. Chem., 1913,87, 27. 8 H. Beyer and H. Drews, Chem. Ber., 1954,87, 1500. 9 E. Campaigne and T. P. Selby, J. Heterocycl. Chem., 1980, 17, 1249. 10 K. H. Abramson, P. T. Inglefield, E. Krakower, and L. W. Reeves, Can.J. Chem., 1966,44,1685; C. E. Looney, W. D. Phillips, and E. L. Reilly, J. Am. Chem. SOC., 1957, 79, 6136. 11 M. Rabinovitz and A. Pines, J. Am. Chem. SOC., 1969, 91, 1585. 12 D. D. McNicol, R. Wallace, and J. C. D. Brand, Trans. Faraday Soc., 1965, 61, 1. 13 F. A. L. Anet and M. Ahmed, J. Am. Chem. Soc., 1964, 86, 119. 14 T. N. Birkinshaw, D. W. Gillon, S. A. Harkin, G. D. Meakins, and M. D. Tirel, J. Chem. Soc., Perkin Trans. 1, 1984, 147. 15 T. R. Kidd, Part I1 Thesis, Oxford, 1984. Received 18th September 1987; Paper 7/1670
展开▼
