Fusedv-triazolo-heterocycles. Synthesis of 4h-v-triazolo1,5-d1,3,4oxadiatines

摘要

J. CHEM. SOC. PERKIN TRANS. I 1985 Fused v-Triazolo-heterocycles. Synthesis of 4H-v-Triazolol,5-d I,3,4oxa-diazines l Nestor A. Rodios * Laboratory of Organic Chemistry, University of Thessaloniki, Thessaloniki, Greece The synthesis of some 4H-v-triazolol,5-4 1,3,4oxadiazine derivatives, which constitute a novel heterocyclic ring system, is described. They are prepared by heating of the corresponding 5-bromomethyl- 1 -(N,N-diaroylamino) -v-triazoles. The spectroscopic data of these new compounds are also reported. Following our previous studies on u-triazole derivatives 2-4 we have now prepared several 4-aryl-5-bromomethyl- l-(N,N- diaroy1amino)-u-triaoles (2) from the corresponding 5-methyl- derivatives (l),in order to use them as starting materials in the synthesis of fused u-triazolo-heterocycles.(11 (2) a; Ar2 = Ar' = Ph b Ar2 = Ph, Ar' = p-MeOC,H, c; Ar2 = Ph, Ar' = p-CIC,H,d; ArZ = Ph, Ar' = o-ClC,H, e; Ar2 = Ph,Ar' = o-O,NC,H, t Ar2 = p-MeOC,H,, Ar' = Ph g; Ar2 = p-ClC,H,, Ar' = Ph Compounds (2) were prepared in good yield by reaction of (1) with N-bromosuccinimide (NBS) in carbon tetrachloride in the presence of dibenzoyl peroxide (DBP). They are stable crystalline compounds. Their i.r. spectra show peaks for v-at 1720-1 750 cm-'. In the 'H n.m.r. spectra, the CH2Br protons appeared at 6 4.6-4.8and in their mass spectrum they showed the molecular ion peak (M"), as well as peaks corre- sponding to the ions M -28+, Ar'CO', Ar2-C=C-CH2Br+', and Ar2-CS-CH2+.Their analytical and spectral data are given in the Table. We have found that heating of the compounds (2) at temperatures above their melting points (170-200 "C) leads to the formation of the 4H-3,6-diaryl-u-triazolo1,5-d1,3,4-oxadiazines(3)and the corresponding aroyl bromides (4). In the (3a-g) case of the compounds (2) with melting points higher than 200 "C, as well as for the derivatives with an ortho-substituent in the aroyl moiety (2d, e), the yields of the u-triazolo-oxadiazines (3)were very poor, because of decomposition of the reaction products. Better results were obtained when the reaction was carried out in a tetralin solution in the presence of potassium or sodium carbonate and at lower temperatures, i.e. between 150 and 170 "C. The above method is analogous to that of van Al~hen,~who first synthesized the 4,5-dihydro-6H-1,3,4-oxadiazine ring system by heating A"-chloroacetylhydrazides and related compounds with sodium carbonate in acetone in a sealed tube.Other reported preparations of this heterocyclic ring are based on the cyclization of the appropriate derivatives of a~ylhydrazides.~-~ Reaction of (2a) with sodium hydroxide in dimethyl-formamide (DMF), by a method analogous to that reported by Gaozza and Laudan,' failed to give the expected (3a), but gave instead the 1-benzamido-5-hydroxymethyl-u-triazole (5). Treatment of (2a) with sodium hydroxide in a methanolic solution gave the 5-methoxymethyl-derivative (6).Treatment of (2a) with potassium phthalimide (PhthN-K+) in DMF gave compound (3a) and N-benzoylphthalimide (7).DMF PhthN'K' (6) 70 OC The structures of compounds (3) have been established by examining their analytical and spectral data. Thus, in the i.r. spectrum they showed a weak peak at 1620 cm-', which is attributed to the C=N bond stretching vibration. In the 'H n.m.r. spectrum, taken in CDC1, the methylenic protons of the oxadiazine ring resonated at 6 5.8-5.9, whereas the aromatic protons gave the expected pattern for the two aryl rings. The CH20 carbon appeared in the 13C n.m.r. spectrum at ca. 63 p.p.m., whereas a peak at CQ. 154 p.p.m. was in accord with the presence of the C=N carbon lo of the oxadiazine ring. In the mass spectrum, besides the molecular ion peak (M"), they gave also peaks corresponding to the M -28+' ion (which is characteristic for the triazole ring)'' and also peaks corresponding to the Ar'CO+ and Ar'CN'' ions as well as to the Ar2-C=C-CH20+ and Ar2-C=C-CH2 fragments.+ Heating of compound (3a) with concentrated hydrochloric acid gave the 1-amino-4-phenyl-u-triazole(8), which is in agreement with structure (3).Experimental M.p.s were determined on a Kofler hot-stage apparatus and are uncorrected. 1.r. spectra were recorded as Nujol mulls on M.p. Yield Table. Physical, spectral, and analytical data for compounds (2) 'H nmr. (6, CDCI,) A I bsol; Aroyl groups 4-Aryl group Found v,ax.lcm-' (Ar'CO) (Ar2) (Required )-No. ("C) () (nujol) Solvent* (Cd) CH2Br (-*,o-"-,P-(-*-, 0-m-,p-Mass spectrummlz (r.i.) Formula C H N (2a) 142-144 70 Benzene-1735 ca.7.5 462, 460 (M') C23H17BrN402 60.15 3.8 12.15 LP 1710 (1 1 H, m) 434,432 (M' -28) (59.88) (3.71) (12.14) 196, 194, 115, 105 (100) (2b) 132-134 85 Benzene-1715 7.46 494,492 (M' -28) C2sH2,BrN404 57.4 4.0 10.55 LP 1700 (3 H, m) 196,194, (57.59) (4.06) (10.75) 135 (loo), 115 (2c) 205-207 85 Benzene-1740 7.43 530, 528 (M') C23H1 5BrC12N402 52.35 2.7 10.5 LP 1 720 (7 H, m) 502, 500 (M' -28) (52.11) (2.85) (10.57) 196, 194, 139 (loo), 115 (2d) 206-209 90 CH2Cl2-1740 7.49 530, 528 (M') C23Hl SBrC12N402 52.25 2.75 10.7 Et20 1 730 (3 H, m) 502, 500 (M' -28) (52.1 1) (2.85) 10.57) 1712 196, 194. 139 (loo), I15 (h) 207-210 90 CH2C12-1 750 4.80 ca.7.7 8.27 ca. 7.7 7.46 C23H1SBrNS06 50.05 2.75 14.95 Et,O 1740 (2 H,s) (8 H,m) (2 H,m) (8 H, m) (3 H,m) (50.11) (2.74) 15.24) (2f) 146-148 80 Benzene-1735 4.59 7.93 7.4 1 7.75 7.02 492,490 (M') C24H 1gBrN403 58.45 3.85 11.25 LP 1 710 (2 H, s) (4 H,m) (6 H, m) (2 H, d) (2 H,d) 464,462 (M+ -28) (58.67) (3.90) 1 1.40) + 145. 105 (100) (2g) 173-176 75 CH2C1,-1 745 4.58 7.92 7.45 7.75 7.45 496; 494 iM+j C23Hl,BrCIN402 55.75 3.25 11.45 c1E Et,O 1 715 (2 H, s) (4 H,m) (8 H, m) (2 H, d) (8 H, m) 468,466 (M+-28) (55.72) (3.25) (1 1.30) 5 149,105 (100) * LP = Light petroleum. 50 J. CHEM. SOC. PERKIN TRANS. I 1985 a Perkin-Elmer 257 spectrometer. 'H N.m.r. and 13C n.m.r. spectra were obtained on a Varian CFT-20 spectrometer in CDCl, with tetramethylsilane (TMS) as internal standard.The mass spectra were obtained on a Hitachi-Perkin-Elmer RMU 6L spectrometer and elemental microanalyses were per- formed with a Perkin-Elmer 240 analyser. Column chromato- graphy was performed over Merck Kieselgel 60, particle size 0.063--0.200mm. Light petroleum refers to that fraction of b.p. 60-80 "C. Ether refers to diethyl ether. Compounds (l).-These were prepared by thermal isomeriz- ation from the corresponding triazolyl-isoimides as previously de~cribed,'~.'~and their analytical and spectral data were in agreement with their ~tructure.~,' 4-Aryl- 5-bromomethyl- 1-(N,N-diaroy1arnino)-v-triazoles(2).General Procedure.-To a refluxing solution of (1) (5 mmol) in carbon tetrachloride (50 ml) were added recrystallized N-bromosuccinimide (1.0 g, 5.5 mmol) and dibenzoyl peroxide (0.3 g). The mixture was refluxed for a further 4-6 h and the succinimide formed was filtered off.The filtrate was washed with water (4 x 20 ml), dried and evaporated. The 5-bromo- methyl derivative (2) crystallized on treatment with ether, and was isolated by filtration. This product was pure enough for further reaction. For elemental analysis it was recrystallized from CH,Cl,-ether or C6H6-light petroleum. Analytical and spectral data of compounds (2) are given in the Table. 4H-3,6-Diaryl-v-triazolo1,5-d 1,3,40xadiazines (3):General Procedure.-Method A. Compound (2)(0.1-1 .O mmol) was heated in an oil-bath at 180-190deg;C for 30 min.For compounds (2) which have higher m.p.s, the temperature was raised to their m.p.s; the solids, on melting, turned dark brown. After cooling, the solidified brown mass was washed on a glass filter with ether in order to remove aroyl bromide. The u-triazolo-oxadiazine (3) was isolated and recrystallized from dichloromethane-ether. Better purification was achieved by sublimation of the crude product at 180-190deg;C at 0.2-0.5 mmHg, or by column chromatography over SO, using ethyl acetate-light petroleum (2:8) as eluant. The aroyl bromide (4) was then either isolated from the ether washings and identified by its i.r. spectrum, or it was hydrolysed and isolated as the corresponding substituted benzoic acid. Method B. A mixture of (2) (0.5-1.0 mmol) and anhydrous potassium carbonate (0.2 g, 1.5 mmol), (or the equivalent amount of anhydrous sodium carbonate), in tetralin (4 ml) dried over 4 A molecular sieves, was heated at 160-170 "C for 40 min.After cooling, CH,Cl, (30 ml) was added and the mixture was washed with water (2 x 20 ml). The solution was then dried and the CH,Cl, removed. With time, crystals of the u-triazolo- oxadiazine (3)precipitated from the tetralin solution and these were filtered off, washed with ether, and recrystallized from the appropriate solvents. 4H-3,6-Dipheny1-v-tr iazoIo 1,5-d 1,3,4oxadiazine (3a).-Method A. Compound (2a) (0.7 g, 1.5 mmol) was heated at 190 "C for 30 rnin to give the u-triazolo-oxadiazine (3a)(0.22 g, 5373, m.p.237 "C (subl.) (Found: C, 70.0 H, 4.4; N, 20.25. C16H12N,0 requires C,69.55; H, 4.38; N, 20.28); v,,,. 1 620 (C=N) cm-'; 6,5.80 (2 H, s, CH,O), 7.53 (8 H, m), and 8.12 (2 H, m); 6, (20 MHz, CDCl,) 63.4 (CH,O), and 154.4 (C=N); m/z 276 (M+,1.573248(M+ -28,1.3), 115 (4973, and 105 (Ar'CO', 100). 4H-6-p-Methoxyphenyl-3-phenyl-v-triazolo 1,5-d1,3,43-oxadiazine (3b).-Method A. Compound (2b)(0.52 g, 1 mmol) was heated at 180 "C for 30 rnin to give the v-triazolo- oxadiazine (3b)(0.2 g, 6673, m.p. 230-232 "C (from CH,Cl,- ether) (Found: C, 67.0; H, 4.55; N, 17.95. C1,Hl,N,O, requires C, 66.66; H, 4.61; N, 18.29); vmaX.1 610 (C=N) cm-'; 6, 5.82 (2 H, s, CH20), 3.86 (3 H, s, MeO), 6.93 (2 H, d), 7.40 (3 H, m), 7.58 (2 H, m), and 8.18 (2 H, d); 6, (20 MHz, CDCl,) 63.2 (CH,O), 153.8 (C=N); m/z 306 (M', 1.6), 278 (M' -28, 2.5), 135 (Ar'CO+, loo), and 115 (24).4H-6-p-Chlorophenyl-3-phenyl-v-triazolo1,5-d 1,3,4-oxa-diazine (amp;).---Method B. A mixture of (2c) (0.22 g,0.41 mmol) and K2C03 (0.1 g, 0.7 mmol) in tetralin (3 ml) was heated at 180 "C for 50 rnin to give the v-triazolo-oxadiazine (3c)(0.03 g, 24), m.p. 260-262 "C (Found: C, 62.05; H, 3.25; N, 18.1. C16H1 ,ClN,O requires C, 61.85; H, 3.57; N, 18.03); v,,,. 1 610 (C=N) cm-'; 6, 5.90 (2 H, s, CH,O), 7.45 (5 H, m), 7.61 (2 H, m), and 8.05 (2 H, d); m/z 310(M+, l.l),282 (M' -28,2.2), 139 (Ar'CO+, loo), and 115 (76). Method A. Compound (2c)(0.2 g, 0.38 mmol) was heated at 205 "C for 40 min to give a crude product, m.p.200-250 "C. This was chromatographed on SiO, (using CHCl, as eluant) to give the u-triazolo-oxadiazine (amp;) (0.013 g, llx),m.p. 252- 256 "C, which was identical with that isolated by method B. 4H-6-o-Chlorophenyl-3-phenyl-v-triazolo1,5-d 1,3,4-oxa- diazine (3d).-Method B. A mixture of (2d)(0.8 g, 1.5 mmol) and Na,CO, (0.2,2 mmol) in tetralin (4 ml) was heated at 170 "C for 40 min to give a crude product (0.17 g) which was chromato- graphed on SiO, using ethyl acetate-light petroleum (2:8) as eluant to give the u-triazolo-oxadiazine (3d)(0.093 g, 20), m.p. 172-174 "C (from CH,Cl,-ether-light petroleum) (Found: C, 61.75; H, 3.55; N, 17.95. C16Hl ,ClN,O requires C, 61.85; H, 3.57; N, 18.03); v,,,. 1 620 (C=N) cm-'; 6, 5.90 (2 H, S, CH,O), 7.44 (5 H, m), 7.62 (2 H, m), ca.7.8 (1 H, m); m/z 310 (M', l), 282 (M+ -28,1), 139 (Ar'CO', loo), and 115 (80). 4H-6-o-Nitrophenyl-3-phenyl-v-triazolol,S-d 1,3,4-oxa-diazine (3e).-Method B. A mixture of (2e) (0.276 g, 0.5 mmol) and K,CO, (0.15 g, 1 mmol) in tetralin (4 ml) was heated at 170 "C for 50 rnin to give the v-triazolo-oxadiazine (3e)(0.03 g, 19), m.p. 228-230 "C (from CH,Cl,-ether) (Found: C, 59.7; H, 3.35; N, 21.65. C16HllN503 requires C, 59.81; H, 3.45; N, 21.8);v,,,. 1 620 (GN) cm-'; 6, 5.82 (2 H, S, CH,O), 7.45 (3 H, m), ca. 7.7 (4 H, m), and 8.05 (2 H, m); m/z 321 (M', 0.3), 293 (M' -28,0.6), 150 (Ar'CO+, 18), and 115 (100). 4H-3-p-Methoxyphenyl-6-phenyl-v-triazolo1,5-d 1,3,4-oxadiazine (3f).--Method A.Compound (2f)(0.66 g, 1.3 mmol) was heated at 170deg;C for 30 min to give the u-triazolo-oxadiazine (3f)(0.16 g, 3973, m.p. 223-225 "C (subl.) (Found: C, 66.35; H, 4.55; N, 18.4. C,,Hl,N402 requires C, 66.66; H, 4.61; N, 18.29); v,,,. 1 615 (C=N) cm-'; 6, 3.82 (3 H, S, MeO), 5.82 (2 H, s, CH,O), 6.94 (2 H, d), 7.50 (5 H, m), and 8.06 (2 H, m); 6, (20 MHz, CDCl,) 63.3 (CH,O), and 154.4 (C=N); m/z 306 (M', 2.8), 278 (M+ -28,1), 145 (loo), and 105 (Ar'CO', 74). 4H-3-p-Chlorophenyl-6-phenyl-v-triazolo1,5-d 1,3,4-oxa-diazine (3g).-Method B. A mixture of (2g) (0.496 g, 1 mmol) and K,CO, (0.2 g, 1.5 mmol) in tetralin (4 ml) was heated at 170 "C for 50 rnin to give the u-triazolo-oxadiazine (3g)(0.1 g, 3373, m.p.289-291 "C (from CHCl,) (Found: C, 61.5; H, 3.5; N,17.95. C16H1 ,ClN40 requires C, 61.85; H, 3.57; N, 18.03); v,,,, 1 620 (GN)cm-'; 6, 5.86 (2 H, S, CH20), 7.40 (2 H, d), ca. 7.5 (5 H, m), and 8.07 (2 H, m); m/z 310 (M', 1.5), 282 (M+ -28, 0.3), 149 (2079, 105 (Ar'CO+, 100). Reaction of (2a) with Potassium Phthalimide in DMF.-A mixture of (2a)(0.23 g, 0.5 mmol) and potassium phthalimide (0.13 g, 0.7 mmol) in DMF (5 ml) was stirred at 25 "C for 40 min and then heated at 70 "C for 20 min. The mixture was cooled, diluted with water (70 ml) and extracted with CHCl, (30 ml). The chloroform solution was washed with 0.2wNaOH (20 ml) and water (20ml), and upon evaporation gave an oily mass; this, on treatment with ethyl ether, gave white crystals (0.027 g, 2073, m.p.235-237 "C, of the u-triazolo-oxadiazine (3a) identical with an authentic specimen by i.r., 'H n.m.r., and mass spec- troscopy. From the ether solution a crystalline product (0.025 g) was precipitated, which was identified as the N-benzoyl-phthalimide (7), m.p. 158-163 "C (lit.,I4 169 "C); vrnax.1 790, 1 760,1740, and 1 700cm-'; m/z 251 (M', 88), 223 (M+ -28, 28), and 105.(PhCO+, 100). Acid Hydrolysis of(3a).-A solution of v-triazolo-oxadiazine (3a) (0.14 g, 0.5 mmol) in concentrated hydrochloric acid (7 ml) was refluxed for 2 h, after which it was made alkaline (Na,CO,, pH 8) and extracted with CH,Cl, (60 ml). Evaporation of the solvent from the extract gave the 5-hydroxymethyl-4-phenyl-l-amino-v-triazole (8) (0.034 g, 3773, m.p.161-163 "C (from MeOH-Et,O) (Found: C, 56.75; H, 5.3; N, 29.3. C,H,,N,O requires C, 56.83; H, 5.30; N, 29.45); v,,,. 3 370,3 340,3 200br, and 1 610cm-'; 6, (CDCl, + (CD3)2SO} 4.77 (2 H, S, CH,O), 6.20(1 H, s, exchangeable with D20, OH), 7.40(3 H, m), and 7.80 (2 H, m); m/z 191 (M' + 1,279,190 (M+,1.6), 189 (M+ -1, 2.3), 175(M+ -15,1.4), 173(M+ -17,1.4), 162(M+ -28, 11), 149 (64), 131 (PhCamp;CH,OH+, loo), and 115 (93). Reaction uf(2a) with NaOH in Me0H.-To a mixture of NaOH (1.0 g) in MeOH (10 ml) a solution of (2a) (0.115 g, 0.25 mmol) in MeOH (5 ml) was added and the mixture was heated at 60deg;C for 3 h; it was then diluted with water (70 ml) and extracted with CHCl, (30 ml). The alkaline solution was acidified (pH 2) and extracted with CHCl, (50 ml).The extract was evaporated to give an oily mass which, on treatment with ether-light petroleum, gave the 1-benzamido-5-methoxymethyl-4-phenyl-v-triazole (6) (0.055 g, 71), m.p. 128-131 "C (from ether-light petroleum) (Found: C, 66.1; H, 5.2; N, 18.45. C17H16N,0, requires C, 66.22; H, 5.22; N, 18.17); v,,,. 3 200 (NH), and 1 705 (C4) cm-'; 13~3.26 (3 H, s, MeO), 4.49 (2 H, s, CH,O), 7.40 (6 H, m), 7.66 (2 H, m), 7.93 (2 H, m), and 11.0 (1 H, s, NH); m/z 308 (M', 0.4), 280 (M+ -28, 673, 146 (PhCXCH,OMe+, 879,115 (46), and 105 (100). J. CHEM. SOC. PERKIN TRANS. I 1985 Reaction of(2a) with NaOH in DMF.-A mixture of (2a) (0.3 g, 0.65 mmol) and NaOH (0.2 g, 5 mmol) in DMF (5 ml) was heated at 100 "C for 2 h.The DMF was then removed on an evaporator and the residue washed repeatedly with CH,C12 and ether, after which the remaining solid was dissolved in water (20 ml) and acidified (pH 2), to precipitate 1-benzamido-5-hydroxy- methyl-4-phenyl-u-triazole (5); this was filtered off (0.125 g, 65), m.p. 214-216 "C (from MeOH) (Found: C, 65.1; H, 4.75; N, 19.35. C16H,,N402 requires C, 65.30; H, 4.79; N, 19.04); vmax.3 210br, 1715, and 1710 (M)cm-'; 6, {CDCl, + (CD,), SO} 4.20 (1 H, br, exchangeable withpD2-O:73m, 4.65 (2 H, s, CH,O), 7.50 (6 H, m), 7.98 (4 H, m), and 12.2 (1 H, s, exchangeable with D,O, NH); m/z 294 (M+,0.3), 266 (M+ -28, 3.773, 132 (PhCSCH,OH+, 19), 131 (PhC=CCH,O+, 2273,115 (25), 105 (98), and 103 (100).References 1 N. A. Rodios, 'Proceedings of the 2nd Balkan Chemistry Days,' Varna, Bulgaria, 1983, p. 1.81. 2 N. E. Alexandrou and E. D. Mikromastoras,J. Org. Chem., 1972,37, 2345. 3 N. A. Rodios and N. E. Alexandrou, J. Heterocycl. Chem., 1978, 15, 1255. 4 N. A. Rodios and A. G. Coutsolelos, J. Heterocycl. Chem., 1983,20, 1469. 5 J. van Alphen, Rec. Trav. Chim., 1928,47,673; 1929,48,163; 1929,48, 41 7. 6 D. L. Trepanier, V. Spracmanis, D. S. Tharpe, and D. E. Krieger, J. Heterocycl. Chem., 1965,2,403. 7 C. H. Gaozza and S. Laundan,J. Heterocycl. Chem., 1970,7,928. 8 A. J. Elliot and M. S. Gibson, J. Org. Chem., 1980,45,3677. 9 C. Farina, G. Pifferi, F. Nasi, and M. Pinza, J. Heterocycl. Chem., 1983,20,979, and references cited therein. 10 N. A. Rodios, J. Heterocycl. Chem., 1984, 21, 1169. 11 N. E. Alexandrou and E. D. Micromastoras, Tetrahedron Lett., 1968, 237. 12 N. E. Alexandrou and C. P. Hadjiantoniou, J. Heterocycl. Chem., 1977,14,269. 13 N. A. Rodios, Org. Magn. Reson., in the press. 14 A. Fono, Chem. Ind., 1958,414. Received 28th September 1984; Paper 411668