J. CHEM. SOC. PERKIN TRANS. I 1985 Ketone Enamines as Dipolarophiles towards C-Azidohydrazones Luca Bruch6, Luisa Garanti, and Gaetano Zecchi Dipartimento di Chimica Organica e lndustriale dell'Universita, Centro del C.N.R. per la Sintesi e Stereochimica di Speciali Sistemi Organici, 20 733 Milano, Italy The reaction of methyl azido(pheny1hydrazono)acetate (1) with the enamines (4)-(7) leads to different kinds of ring-closed products, namely lr2,4-triazines (8)-(lo), 1,2,3-triazoles (12)-(15), and 1,2,4- triazoles (16)-(19). An open-chain azo compound (20) is also formed. In one case, an intermediate 4,5-dihydro-1 H-l,2,3-triazole (1 1 ) has been isolated. A mechanistic picture is proposed involving preliminary cycloaddition of the azido group to the enamine and subsequent reaction of the 45-dihydro-1 H-lr2,3-triazoIes according to various concurrent pathways.Along a line of research dealing with the synthetic potential of C-azidohydrazones, we have reported that the reaction of com- pound (1) with aldehyde enamines gives 1,4,5,6-tetrahydro- 1,2,4-triazines and 1,2,4-triazoles, the formation of which has been tentatively ascribed to different modes of evolution of 4,Sdihydro- lH-1,2,3-triazole intermediates. * On studying the reaction of the same azidohydrazone (1) with ketone enamines, new results have been obtained which support the above mechanistic hypothesis and bring to light an intriguing variety of behaviour patterns by the primary cycloaddition products. Results and Discussion Compound (1) was treated with an excess of the enamines (4)-(7) in benzene solution under reflux as well as at room temperature.Apart from some uncharacterised material and trivial side-products such as the corresponding ketones and the hydrazones (2)and (3),*particularly in the case of (7) at 80 "C, the reaction led to the products listed in Table 1. Analytical and spectral data of the new compounds are presented in Table 2. For the 1,2,4-triazines (8)and (9),clear cut diagonistic evidence is given by the coupling (J 3.7 Hz) between the methine hydrogen and the NH group, which excludes regioisomeric structures having the carbocyclic double bond at position 5.The same is true for the exocyclic double bond in (10). In the case of the stereoisomeric pairs of the 1,2,3-triazoles (12j(15), the distinction between Z and E structures was based on the frequency of the carbonyl i.r.absorption, which is lower in (12) and (14) since the E configuration permits an intramolecular hydrogen bond between the NH and CO groups. The structure (20), suggested by analytical and spectral properties, was confirmed by an X-ray diffraction study.3 A control experiment showed that compound (11) is unstable, decomposing upon heat treatment to give the triazine (8)in fair yield. The most striking aspect of the above results is the apparent variety of products, the relative proportion of which is strongly dependent on the substituents at the ethylenic bond. However, the experimental findings can be reconciled within the frame of the mechanistic picture given in the Scheme, which involves the 1,3-dipolar cycloadducts (21) as the common first-formed products.The intermediacy of 4,5-dihydro- 1 H-1,2,3-triazoles previously proposed for the reaction of (1) with aldehyde enamines,' is now demonstrated by the isolation of (11) and its conversion into (8). In most cases, however, the initial COzMe I PhNH-N=C-X Me02C NHNGHz)n N, Ph (8)n= 1 (9)n=2 R', 0R2 c =c PhNH-N=C-N Y (11 1 Y = morpholino participation of the hydrazone moiety, both (23)and (25) are further transformed, thus giving rise to the final ring-closed products (8)--(10) and (16)-(17), respectively (see Scheme). It is noteworthy that tetrahydro-l,2,4-triazinesof type (24 R2 = H) have been found among the products of the reaction of (1) with aldehyde enamines; Me02 C fiNH7'Me Ph that (8)--(10) were obtained in the (12) R1 =Me.R2 =Et;(euro;)-isomer (13) R' =Me.R2=Et;(Z)-isomer (14) R' = H.R2= Ph ;(euro;1-isomer (15) R' = H .R2 =Ph ;(Z)-isomer (16) R=Et (15)constitutes a minor pathway, the main mode of evolution of (17) R=Ph(21) implies fission of the endocyclic N-N bond and loss either of nitrogen to give aziridines (23)or of a diazoalkane to give (18) R=Me amidines (25).Owing to the intramolecular, nucleophilic (19) R=H Y = morpholino cycloadducts(21) behave as transient intermediates in line with the known thermal lability of 4,5-dihydro-l H-1,2,3-triazole~.~ 2)-(1While morpholine elimination providing 1,2,3-triazoles 1904 J.CHEM. SOC. PERKIN TRANS. I 1985 Me02C N=NI (81-(10) R~CHN~i (21) COz Me I PhNH-NzC-N; )Nz (ii)I PhNH-N=C-N= CHRrsquo; C-CH RZ Y (28) 1 Me02 C C02MeIrY I (iv) PhNH -N=C-N=C-Y -c (16).(17) -YH R2 (29) (25)J. C02Me COzMe I (7) I -(3) _C(18). (19) PhNH-NZC-NH PhNH-N=C-NH -(20)bsol; bsol;C-CNz C-CHN=N-CH=CPh Yrsquo;l I I R2 Rrsquo; Y (26) (27) Y = morpholino Scheme. present case indicates that amine elimination from (24) occurs easily provided that an exocyclic double bond can be formed. The formation of the 1,2,4-triazoles (18) and (19) from (6) and (7) is rather surprising and cannot be accounted for by pathway (iii). A suggested hypothesis is that these products may be due to a side-reaction between the starting azidohydrazone and the diazoalkane formed along pathway (iii).This view was proved to be correct by the independent synthesis of (18) and (19) upon treatment of (1) with diazoethane and diazo- methane, respectively, in ethereal solution at room temperature. Although the intimate mechanism of this novel reaction is still to be elucidated, the intermediacy of the aldehyde imine-like intermediate (28)represents a plausible mechanism. In fact, it is known that compounds of type (28), arising from the condens- ation of C-aminohydrazones with aldehydes, cyclise to 4,5-dihydro- 1,2,4-triazoles which are easily converted into the corresponding 1,2,4-triazoles by exposure in air.5 Finally, as a tentative explanation of the isolation of (20), the following sequence is conceivable: (a)prototropic isomerisation of the dipolar intermediate (22) to the diazo compound (26), (6) electrophilic attack of the latter on the electron-rich carbon of the enamine (7), and (c)elimination of a molecule of (3)from the resulting azo derivative (27).This pathway would seem accept- able bearing in mind that 4,5-dihydro- 1 H-1,2,3-triazoles are known to equilibrate with amino substituted diazoalkanes and enamines have been shown to react with diazoalkanes to give open-chain azo derivatives.6 Table 1. Reaction of the azidohydrazone (1) with the enamines (4)--(7) Enamine Temp. (ldquo;C) Time (h) Yield () (4) 80 3 16 19 25 96 7 58 3 69 140 60 10 13 4 10 7 6 25 240 18 10 26 9 7 (7) 80 3 6 3 3 25 96 10 11 39 3 4 J.CHEM. SOC. PERKIN TRANS. I 1985 Table 2. Physical, spectral, and analytical data of new compoundsa Elemental analysis () M.P.~ (ldquo;C) vmax.(Nujo1) cm-rsquo; 6r.d I C Found (required) N , 129 132 121 130 (decomp.) 151 146 139 161 194 3 350 1700 3 350 1700 3 410 1700 3 340 1710 3 210 1 695 3 190 1710 3 200 1 690 3 180 1 705 2.2-2.7 (4 H, m), 3.90 (3 H, s), 4.24.5 (1 H, m), 5.17 (1 H, m), 5.6 (1 H, br s), 7.0-7.6 (5 H, m) 1.3-2.3 (6 H, m), 3.84.1 (4 H, overlapping signals), 5.20 (1 H, t, J4), 5.4 (1 H, br s), 7.0-7.6 (5 H, m) 1.30,1.35(6H,twod),3.85(3H,s),4.15(1H,dq,J6.5and3.7),rsquo; 5.10(1 H,q),6.4(1 H,brs),6.7-7.0(1 H,m),7.2-7.4(4H,m) 1.5-2.3 (6 H, m), 2.5-2.8 (4 H, m), 3.84.0 (7 H, overlapping signals),4.93(1 H,dd,J7and4),6.9-7.5(5H,m), 11.8(1 H,brs) 1.14 (3 H, t), 2.40 (3 H, s), 2.68 (2 H, q), 3.85 (3 H, s), 7.0-7.5 (5 H, m), 12.4 (1 H, br s) 1.13 (3 H, t), 2.30 (3 H, s), 2.61 (2 H, q), 3.93 (3 H, s), 7.0-7.5 (5 H, m), 9.8 (1 H, br s) 3.68 (3 H, s), 6.9-7.7 (10 H, m),7.85 (1 H, s), 12.3 (1 H, br s) 3.63 (3 H, s), 6.9-7.6 (10 H, m), 7.80 (1 H, s), 9.8 (1 H, br s) 3.02 (8 H, t), 3.75 (8 H, t), 6.84 (2 H, s), 7.2-7.6 (10 H, m) 65.5 (65.3) 66.4 (66.4) 64.9 (64.8) 57.9 (58.0) 58.8 (58.5) 58.6 (58.5) 63.3 (63.5) 63.6 (63.5) 71.6 16.2 (1 6.3) 15.6 (1 5.5) 16.2 (16.2) 22.4 (22.6) 24.2 (24.4) 24.3 (24.4) 21.8 (2 1.8) 21.6 (21.8) 14.0 (71.3) (1 3.8) a Correct molecular peaks were observed in the mass spectra.From di-isopropyl ether-benzene. Solvent: CD,COCD, for (lo),CDCI, for the other compounds. J in Hz. Quartet (J 6.5 Hz) after decoupling from the NH proton. 13CN.m.r. (CDCI,): 6 23.2 (t) 31.2 (t), 32.3 (t), 46.2 (t), 52.7 (q), 66.5 (t), 78.6 (d), 88.9 (s), 113.8 (d), 121.7 (d), 123.1 (s), 129.4 (d), 144.0 (s), and 162.9 (s). Experimental Reaction of the Azidohydrazone (1)with Diazomethane and ethereal solution of diazomethane (10ml)M.p.s were determined with a Buchi apparatus and are Diazoethane.-A 0.4~ uncorrected. 1.r. spectra were taken with a Perkin-Elmer 377 was added slowly to a solution of (1) (3.2 mmol) in anhydrous spectrophotometer. N.m.r. spectra were recorded with Varian ether (60 ml).The mixture was left at room temperature for 6 h. EM-390 (lsquo;H) and Bruker WPSOSY (I) instruments; chemical The solvent was evaporated and the residue chromatographed shifts are given in p.p.m. from internal SiMe,. on a silica gel column with dichloromethane as eluant to give Compounds (l),I (6),rsquo; and (7) were prepared as described (19)in 37 yield. in the literature. Compounds (4) and (5) are commercially Treatment of (1) with diazoethane according to the same available products. procedure gave (18)in 41 yield. Reaction of the Azidohydrazone (1) with the Enamines (4)-References(7).-Solutions of (1) (10 mmol) and the enamine (22 mmol) in 1 L. BruchC, L. Garanti, and G. Zecchi, J. Chem. SOC., Perkin Trans. I,dry benzene (150 ml) were subjected to the temperatures and 1984,1427.reaction times given in Table 1.The solvent was evaporated 2 R. Fusco and R. Romani, Gazz. Chim. Iral., 1946,76,419. under reduced pressure and the remaining mixture was left in 3 T. Pilati, to be published. VLICUO to remove volatile side-products. The residue was 4 J. Bourgois, M.Bourgois, and F. Texier, Bull. SOC.Chim. Fr., 1978, chromatographed on a silica gel column with benzene-ethyl 485 and references cited therein. acetate (1 :1) as eluant. Products (in order of elution) and yields 5 C. Temple, Jr., lsquo;Triazoles- 1,2,4,rsquo; ed. J. A. Montgomery, Interscience, are reported in Table 1. New York, 1981, pp. 64and 503. Melting points, spectral data, and elemental analyses of the 6 J. F. McGarrity, in lsquo;The Chemistry of Diazonium and Diazo new compounds are presented in Table 2. Compounds (16),rsquo; Groups,rsquo; ed. S. Patai, Interscience, New York, 1978, p. 215. 7 R. Stradi and D. Pocar, Chim. Id., 1971,53,265.(17),9 (l8),rsquo;*and (19) are known in the literature. 8 S. Bradamante, S. Maiorana, and G. Pagani, J. Chem. SOC.,Perkin Trans. 1,1972,282. 9 G.W. Sawdey, J. Am. Chem. SOC.,1957,79,1955.Thermolysis of the Dihydrotriazole (1l).-A solution of (1 1) 10 H. Stetter, R.Engl, and H. Rauhut, Chem. Ber., 1959,92, 1184. (0.15 g) in dry benzene (20 ml) was refluxed for 24 h. After 11 K. Matsumoto, M. Suzuki, M. Tomie, N. Yoneda, and M. Miyoshi, removal of the solvent, the residue was chromatographed on a Synthesis, 1975,609. silica gel column with benzene-ethyl acetate (1 :1) as eluant to afford compound (8)in 67 yield. Received 2nd January 1985; Paper 5/014
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