J. CHEM. SOC. PERKIN TRANS. I 1989 Synthesis, Structure, and Acylating Properties of 1 -Aroyl oxy-4,5-d i met hyl-1,2,3-t riazoles A. B. Theocharis, A. J. Maroulis, C. P. Hadjiantoniou-Maroulis, and N. E. Alexandrou * Laboratory of Organic Chemistry, Aristotelian University of Jhessaloniki,540 06 Jhessaloniki, Greece Lead tetra-acetate oxidation of M-hydroxyimino aroylhydrazones of biacetyl (1) gives 1 -aroyloxy-4,5- dimethyl-I ,2,3-triazoles (2),the structures of which were confirmed by X-ray analysis. A mechanism for this reaction is discussed. The products (2) are effective aroylating agents for the amino function under mild conditions. The lead tetra-acetate (LTA) oxidation of nitrogen hetero- allylic systems of a-dicarbonyl compounds is a well established synthetic route to nitrogen heterocycles.' Until now these LTA oxidations were exclusively restricted to derivatives with the same heteroallylic group (i.e.bishydrazones and dioximes etc.).As an extension to our ~tudies,~.~ we describe the oxidation of z-hydroxyimino aroylhydrazones of biacetyl (1) with LTA, to give triazoles as the main products. The oxidation of such compounds is to our knowledge unprecedented. The analogous a-hydroxyimino arylhydrazones of a-diketones give, upon ~xidation,~2-aryl- 1,2,3-triazole 1-oxides and upon dehydra- tion 2-aryl- 1,2,3-triazoles, whereas the a-hydroxyimino aroylhydrazones of 1,2-naphthoquinone yield upon cyclization naphtho- 1,2,4-triazine l-oxides.6 Furthermore, the a-hydroxy- imino semicarbazones react with thionyl chloride to give 2-carbamoyl- 1,2,3-triazoles. The starting materials, a-hydroxyimino aroylhydrazones of biacetyl (la+), were prepared in high yields (75-90%) by the addition of equimolar amounts of the corresponding aroyl- hydrazines to methanolic solutions of biacetyl mono-oxime at room Oxidation of (1) in dry dichloromethane suspension with 1 equiv.of LTA at 0 "C gave l-aroyloxy-4,5-dimethyl-1,2,3-triazoles (2) and 0-aroyl a-hydroxyimino aroylhydrazones of biacetyl (3) (20% each) and also 0-aroylbiacetyl mono-oxime (4) and the corresponding benzoic acids in lower yields (10%) (Scheme 1). However, when a solution of (1) in acetic acid- MeYNoH Me ANNHCOAr Me Me m +k N4COAr 'N' Me ANNHCOAr (3) MeYNocoArAr CO,H Me A\O (41 a; Ar = Ph b; Ar = p-MeC,H, c; Ar = p-CIC& d; Ar = p-O2NC6H, e; Ar = pMeOC6H4 Scheme 1.dichloromethane (1:2) was gradually added to a solution containing an excess of LTA in dichloromethane only product (2) was isolated in considerably higher yields (Table 1). It is suggested that the reaction products, the l-aroyloxy- 4,5-dimethyl-l,2,3-triazoles(2) (Scheme 2), are formed by the oxidative cyclization of (l),via the 2-aroyl-1,2,3-triazole oxides (5) in agreement with previous reports [equation (l)]. Although intramolecular [1,3]aroyl migration may account for the conversion of (5) into (2) an intermolecular aroyl transfer is also possible. Formation of (3) may result from aroylation of the starting material by the aroyloxytriazole (2) produced during the course of the reaction. The latter is supported by the fact that treatment of the starting material (1) with (2) in dichloromethane at 0°C gave the product (3) in almost quantitative yield [equation (2)].Further oxidation of (3) with LTA gives the 0-aroylbiacetyl mono-oxime (4). MeYNoH Me Me m 11.31 N+ ,NOCOAr (1)-Arc0 N Scheme 2. 1-Aroyloxy- 1,2,3-triazoles may, in principle, exist as any one of the three isomeric forms (2), (5), and (6)(Scheme 3). The isomerism between N-and 0-acylated benzotriazol- 1-01s has been extensively studied since the latter are considered impor- tant catalysts in stereoselective peptide ~ynthesis.'~-' In a recent study the N-versus 0-substitution of alkoxycarbonyl-, acyl-, and sulphonate derivatives of benzotriazol- 1-01 was also examined.' The aroyl group position in the oxidation product of a-hydroxyimino aroylhydrazones of biacetyl, was established t The preparation of (la) has been reported by H.von Pechmann and W. Bauer, Ber., 1909, 42, 673. However, no details were given. J. CHEM. SOC. PERKIN TRANS. I 1989 Table 1. Physical, spectral, and analytical data for l-aroyloxy-4,5-dimethyl-l,2,3-triazoles(2) and O-aroyl-a-hydroxyiminoaroylhydrazones of biacetyl a Elemental analysis (%) Found (required) Yield * M.p. vmax.(Nujol)/cm-' P (%I ("C) (C=O) G,(CDCI3)' Formula C H N 9 (46) Oil 1 7Ud 2.18 (3 H, s), 2.34 (3 H, s), 7.5k7.88 cl lHllN3O2 e,f (3 H, m), 8.17-8.30 (2 H, dd) 8 (35) Oil 1 780d 2.18(3 H, s), 2.33 (3 H, s), 2.50 (3 H, s),7.48(2H,d, J 15 Hz), 8.22(2 H,d, J 15 Hz)15 (38) 120-122 1785 2.15 (3 H, s), 2.34(3 H, s), 7.54 (2 H, d, c,1H10N302C1 52.41 3.98 16.56 J 16 Hz), 8.04 (2 H, d, J 16 Hz) (251.55) (52.47) (4.01) (16.70) 9 (40) 164-166 1795 2.25(3 H, s), 2.37(3 H, s), 8.45 (4 H, s) C11H10N404 50.28 3.81 20.99 (262.10) (50.36) (3.85) (21.38) 23 (48) 129-1 30 1775 2.20 (3 H, s), 2.35 (3 H, s), 4.05(3 H, s), cl 2H13N30J 58.08 5.31 17.18 7.02(2H, s, J 15 Hz), 8.12 (2 H, s, J 15 Hz) (247.12) (58.27) (5.30) (1 7.00) 29 198-1 99 1 750,1 660 2.35 (3 H, s), 2.40 (3 H, s), 7.5-8.3 cl gH1 7N303 66.84 5.18 13.07 (10H, m) (323.15) (66.84) (5.30) (13.00) 30 207-209 1 750, 1680 2.32(3 H, s), 2.40(3 H, s), 2.43 (6 H, s), C20H21N303 68.45 6.03 12.09 7.2-8.1 (8 H, m) (351.18) (68.34) (6.03) (1 1.96)17 190-192 1 750, 1695 2.35 (6 H, s), 7.4-8.2 (8 H, m) C12Hl5N3O2CIZ 57.60 4.10 11.28 (376.04) (57.44) (4.02) (11.17) 15 1 89-1 90 1 780,1 680 2.38 (3 H, s), 2.42 (3 H, s), 8.4-8.6 C18H15N507 52.16 3.62 17.02 (8 H, m) (413.15) (52.28) (3.66) (16.95) 10 204-206 1 750, 1650 2.40(3 H, s), 2.58(3 H, s), 3.90 (6 H, s),7.0-8.4 (8 H, m) Correct molecular ion peaks were observed in the mass spectra.Values in parentheses represent the yields of the oxidation with excess LTA. N.m.r. spectra of compounds (3) were recorded in CDC13&F3C02H solution. Neat. m/z217 (M+,5%). Oil not analysed. m/z231 (M', 6%). Table 2. Reaction of 1-aroyloxytriazoles (2) with amines Yield Reaction R R' PA)" time H CH2C02Et (87) 1 min H CH,CO,Et 95 1 min H CH ,CO Et (57) 10min H CH2C02Et (65) 4h H CH,CO,Et 97 10min H Ph 92 24 h Figure 1.X-Ray crystal structure of compound (2)H p-ClC,H, 81 4h Me Ph 66 48 h a Values in parentheses represent the yields of the one-pot procedure N-acyl benzotriazoles of 163.0 and 169.3 p.p.m. and were based on the amount of the corresponding a-hydroxyimino The X-ray analysis confirmed l8 that the compounds (2) existaroylhydrazone (1). solely in the O-acylated form (Figure 1). The high reactivity of the aroyloxytriazoles (2) towards the unchanged starting material (1) prompted us to investigate Me Me Me Me Me Me their use as amino-protection agents. The recent reports concerning the acylating properties of the analogous l-aroyl- m -+ N* ,N-OCOAr N -ArCO-N, +N-o-oxybenzotriazoles are of special significance in this field.Using N 'N' N l-aroyloxytriazoles (2) in dioxane solutions at room tempera- I(2 1 ArCO (61 ture, in the presence of a small amount of triethylamine, we converted a variety of amines and an or-amino acid ester into (5 1 the corresponding anilides and amides (7)(Scheme 4, Table 2). Use of the new acyl transfer agents offers the advantage ofScheme 3. the very mild reaction conditions required as well as that of a simplified product isolation procedure resulting from the high water solubility of the by-product 4,5-dimethyl- 1,2,3-triazol- by an X-ray crystallographic analysis of compound (2c), the 1-01(8).N-and O-acylated forms not being readily distinguished by Finally, although several fused benzotriazol- 1-01s have been spectral methods.For instance, carbonyl absorption in the i.r. spectra of N-acylated benzotriazol-1-01s 'o~'1~'3occurs at Me Me1 73@-1 750 cm-' and at 1795-1 840 cm-' for O-acylated mforms.''-I4 The corresponding absorption for compounds (2) (2) + R-NH + N+ ,N-OH-R-NCOAr was inconclusive, being observed at 1 775-1 795 cm-' in both I I N Nujol mull and dioxane solution. The I3C n.m.r. spectrum of (2e) was similarly inconclusive with respect to the site of the acyl group since it showed a 13Ccarbonyl shift at 165.4 p.p.m. This value lies between the reported carbonyl shifts for 0-and Scheme 4.J. CHEM. SOC. PERKIN TRANS. I 1989 reported, non-fused 1,2,3-triazol-l -oh, namely 1,2,3-triazol- 1-01 ** and the 4-pivaloyl-1,2,3-triazol-l-ol,21were only recently reported. The 4,5-dimethyl-l,2,3-triazol-l-ol(8) was isolated from the hydrolysis mixture of 1-aroyloxytriazole (2) after tedious attempts and identified by its spectral properties and elemental analysis. Experimental M.p.s were determined using a Kofler hot-stage apparatus and are uncorrected. 1.r. spectra were recorded for Nujol mulls or liquid films on a Perkin-Elmer 297 spectrometer. 'H N.m.r. spectra were recorded on a Varian A-60A or Bruker AW 80 instrument; unless otherwise stated, samples were dissolved in deuteriochloroform with tetramethylsilane as internal stand- ard.I3C N.m.r. spectra were recorded on a Varian CFT-20 spectrometer. The mass spectra were obtained using a Hitachi- Perkin-Elmer RMU-6L spectrometer and elemental micro- analyses were performed with a Perkin-Elmer 240 B analyser. Column chromatography on silica gel was performed using Merck Kieselgel GF,,,. Preparative thin layer chromatography (p.t.1.c.) was performed on plates coated with the same material. Light petroleum refers to the fraction b.p. 4&60 "C. Oxidation of CI-Hydroxyimino Aroylhydrazones of Biacetylwith 1 Equiv. of L TA: General Procedure.-A stirred suspension of compound (1) (6 mmol) in dry dichloromethane (30 ml) was cooled at 0 "C and a solution of LTA (6.6 mmol) in the same solvent was added dropwise. The additional mixture was stirred at 0°C for an additional 15-30 min until the reaction was essentially complete (t.1.c.).The excess of LTA was then reduced by aqueous sodium thiosulphate (10%). The organic layer was washed with brine, dried (Na,SO,), and evaporated under reduced pressure at room temperature. The residual light yellow oil crystallized with time or upon addition of diethyl ether and was recrystallized from a chloroform-light petroleum to give compound (3). The mother liquor was concentrated and the resulting oily matter was column chromatographed with benzene-acetone (9 :1)as eluant. The following compounds were obtained. O-Aroylbiacetyl mono-oxime (4) (identified by com- parison of its i.r. spectrum with that of an authentic sample prepared by a standard method), 1 -aroyloxy-4,5-dimethyltri- azole (2) (yields are given in Table l), and arenoic acid.Oxidation of a-hydroxyimino Aroylhydrazones of Biacetyl with Excess of LTA: General Procedure.-A solution of (1) (1 mmol) in acetic acid-dichloromethane (1 :5, 30 ml) was added over 20 min to a stirred solution of LTA (4 mmol) in dry dichloromethane (30 ml). The solution was stirred at 0 "C for 30 min and then aqueous sodium thiosulphate (10%) was added. The organic layer was separated, washed with brine, dried, and evaporated. The resulting residue was either chromatographed, (2a) and (2b),or recrystallized from the appropriate solvent (2c-e) (Table 1). Aminolysisof 1-Aroyloxy-4,5-dimethyl- 1,2,3-triazoles: General Procedure.-The aroylations were effected by treatment of the corresponding amine with an equimolar amount (1-2 mmol) of 1-aroyloxy-4,5-dimethyl- 1,2,3-triazole (2) in the presence of triethylamine (1-2 drops) in either dioxane or THF (5-10 ml) at room temperature.The reaction mixture was stirred for the appropriate time (see Table 2) and then diethyl ether (60 ml) was added. The ethereal layer was washed with hydrochloric 621 acid (2~), aqueous sodium hydrogen carbonate (573,and water, dried, and evaporated under reduced pressure. The amides thus obtained were chromatographically pure and identified by com- parison of their m.p.s and i.r. spectra with those of authentic samples prepared by known procedures. The best way we found to shorten the experimental procedure and to increase the overall yield of amide was to perform the oxidation, and the protection of the amino group without isolation of the intermediate aroyloxytriazole (2).4,5-Dimethyl- 1,2,3-triazol- 1-01 (8).-1 -Aroyloxy-4,5-di-methyl-1,2,3-triazole (2a), (2c), or (2e) (1 mmol) was dissolved in 5% aqueous sodium hydroxide (5 ml) and after 10 min the mixture was acidified with hydrochloric acid (2~). The water was azeotropically removed with benzene under reduced pressure and the dry residue extracted with chloroform. The organic layer was dried and concentrated and the residue was chromatographed (p.t.1.c.; eluant ethyl acetate). Compound (8) was recovered from the silica gel by multiple extraction with acetonitrile (total yield 4573, m.p.11&112 "C (CHC1,-light petroleum). v,,,,(NuJol or KBr), 3 300br, 2 400br, 1 900br, and 1 620s cm-l; G,(CDCl,) 2.20 (3 H, s, Me), 2.31 (3 H, s, Me), and 16.87(1 H, s, OH); m/z 113 (M', 5%),97,85,69, and 68 (Found: C, 42.05; H, 6.1; N, 37.05. Calc. for C, 42.45; H, 6.24; N, 37.16%). References 1 R. N. Butler, in 'Synthetic Reagents,' ed. J. P. Pizey, Wiley, New York, 1977, vol. 3, ch. 4; R. N. Butler, Chem. Rev., 1984, 84, 249. 2 S. Lekopoulou, J. Stephanidou-Stephanatou,C. Tsoleridis, and N. Alexandrou, Helv. Chim. Acta, 1985, 68, 1748; E. Malamidou- Xenikaki and N. Alexandrou, Tetrahedron Lett., 1982, 23, 3957. 3 A. J. Maroulis and C. P. Hadjiantoniou-Maroulis, J. Heterocycl. Chem., 1986, 21, 1653.4 M. Begtrup and J. Holm, J. Chem. SOC.,Perkin Trans. I, 1981, 503; K. Kiouplidis, Ph.D. Thesis, University of Zurich, 1980. 5 R. F. Coles and C. S. Hamilton, J. Am. Chem. 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A. Kavounis, A. P. Bozopoulos, C. J. Cheer, P. J. Rentzeperis, and A. B. Theocharis, Acta Crystallogr., Sect. C, 1988, 44, 1063. 19 S. Kim and H. Chang, J. Chem. Sac., Chem. Commun., 1983, 1357; J. Takeda, K. Tsuboyama, M. Hoshino, M. Kishino, and H. Ogura, Synthesis, 1987, 557. 20 C. Guimon, S. Khayar, G. Pfister-Guillouzo, and M. Begtrup, Spectrosc. Lett., 1987, 20, 105. 21 G. L'abbC, F. Godts, and S. Toppet, Tetrahedron Lett., 1983,24,3149. Received 28th June 1988; Paper 8/02569J
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