HETEROCYCLES

Paper | Special issue | Vol. 79, No. 1, 2009, pp. 627-633
Received, 24th September, 2008, Accepted, 10th November, 2008, Published online, 13th November, 2008.
DOI: 10.3987/COM-08-S(D)28

■ Synthesis of 1,2,4-Triazin-5-ones through [4+2] Cycloaddition of 1,2,4-Triaza-1,3-dienes with Diphenylketene

Tatsuya Nakai, Kyoko Fukutomi, Hiroaki Yanagisawa, Tomomi Kawasaki, and Masanori Sakamoto*

Kyushu University of Health and Welfare, , Japan

Abstract

On heating 1,2,4-triaza-1,3-dienes 1 with diphenylketene, [4+2] cycloaddition took place smoothly to afford the corresponding 1,2,4-triazin-5-one derivatives 2 in good yield.

INTRODUCTION
Aza-Diels-Alder reaction provides one of the most useful methods for constructing a variety of six-membered heterocyclic systems containing one or more nitrogen atoms, which are important components of biologically active compounds.1 Particularly, a 1,2,4-triazin-5-one ring-system, including the selective phosphodiesterase type 5 inhibitor vardenafil for the treatment of male erectile dysfunction,2 is of interest in view of its biological activities.3 Although a [4+2] cycloaddition of 1,2,4-triaza-1,3-dienes with ketenes would directly produce 1,2,4-triazin-5-ones, to the best of our knowledge there are no reports on this type of reaction.4 Moreover, it is difficult to predict the formation of either 1,2,4-triazin-5-one or 1,2,4-triazin-6-one (Scheme 1). From our studies on hetero-Diels-Alder reactions,5 we have reported several types of cycloadditions of ketenes with 1-aza-,6 1,3-diaza-7 and 1,4-diaza-1,3-dienes8 (Scheme 2). This paper describes the first example of a [4+2] cycloaddition of 1,2,4-triaza-1,3-dienes with diphenylketene, resulting in the regioselective construction of a 1,2,4-triazin-5-one ring-system.

RESULTS AND DISCUSSION
The 1,2,4-triaza-1,3-dienes 1 were readily prepared by diazo coupling between ethoxybenzene and diazonium compounds derived from the corresponding amines, which were commercially available, according to the reported method.9 When 1,2,4-triaza-1,3-diene, (1,3,4-thiadiazo-2-lyl)azobenzene 1a was treated with diphenylketene in dry benzene under reflux conditions for 24 h, the [4+2] cycloaddition product 2a was obtained in 79% yield. The structure was assigned on the basis of analytical and spectral data. The infrared spectrum showed absorptions at 1716 cm-1 (C=O). The 13C NMR spectrum indicated signals of an amide carbonyl (δ 160.4 ppm) and quaternary carbon center (δ 75.2 ppm). The parent peak

ion in the mass spectrum appeared at m/e 442, showing a 1:1 adduct. Mass fragmentation analysis (Scheme 4 and Table 1) can rule out the regioisomer 2a’ to elucidate 2a. As well as the fragmentation pattern A as a retro-[4+2] cycloaddition, the peaks caused by fragmentation B were observed at m/z 301, 272 and 224. Ultimately the structure of 2a was determined by X-ray crystal-structure analysis (Figure 2).

Similar reactions of (1,3-thiazol-2-yl)- 1b and (1,3-benzothiazol-2-yl)-azobenzene 1c with diphenylketene proceeded with [4+2] cycloaddition to give the corresponding 1,2,4-triazin-5-ones 2b and 2c in 78% and 72% yields, respectively. These structures were confirmed by comparing with the mass fragmentation patterns of 1a, 1b and 1c (Table 1), all of which demonstrated the same fragmentation peaks causing fragmentation B.
In summary, we demonstrated the first example of the [4+2] cycloaddition of 1,2,4-triaza-1,3-dienes 1 with diphenylketene to provide 1,2,4-triazin-5-one derivatives 2 in good yields.

EXPERIMENTAL
All mps were measured on a Yanagimoto micromelting point apparatus, and are uncorrected. IR spectra were recorded with a Hitachi 270-30 spectrophotometer. NMR spectra were determined using a JEOL JNM-GX 270 spectrometer with tetramethylsilane as an internal standard. J-Values are given in Hz. Mass spectra were obtained using a JEOL JMS 700 instrument with a direct system. Column chromatography was carried out on silica gel (Merck, 400 mesh). 1,2,4-Triaza-1,3-dienes 1a-1c were prepared according to the reported procedures.9

2-(4-Ethoxyphenyl)-2,3-dihydro-7-methyl-3,3-diphenyl[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-one (2a)
A solution of 1a (248 mg, 1 mmol) and diphenylketene (320 mg, 1.65 mmol) was heated under reflux for 24 h in dry benzene (20 mL) under N2. The reaction mixture was condensed in vacuo to give a residue. The residue was purified by column chromatography on silica gel with n-hexane-AcOEt (10 : 1) to afford 2c (350 mg, 79%). Mp 168-170 ºC (ligroin); IR (KBr): 1716, 1622, 1582, 1508, 1478, 1450, 1322, 1248, 1216 cm-1; 1H NMR (CDCl3, 270 MHz) δ 1.30 (3H, t, J = 7.0 Hz), 2.35 (3H, s), 3.85 (2H, q, J = 7.0 Hz), 6.50 (2H, d, J = 8.9 Hz), 6.82 (2H, d, J = 8.9 Hz), 7.27-7.33 (6H, m), 7.38-7.42 (4H, m); 13C NMR (CDCl3, 67.8 MHz,) δ 160.4, 155.1, 154.2, 139.5, 139.2, 135.5 (2), 129.8 (4), 128.6 (2), 128.2 (4), 125.2 (2), 111.3 (2), 75.2, 63.4, 17.2, 14.8; Anal. Calcd for C25H22N4O2S: C, 67.85; H, 5.01; N, 12.66. Found: C, 67.93; H, 5.19; N, 12.70.
2-(4-Ethoxyphenyl)-2,3-dihydro-3,3-diphenylthiazolo[2,3-c][1,2,4]triazin-4-one (2b)
A solution of 1b (116.5 mg, 0.5 mmol) and diphenylketene (160 mg, 0.82 mmol) was heated at reflux for 9 h in dry benzene (20 mL) under N2. After concentrating the reaction mixture, the residue was purified column chromatography on silica gel with n-hexane-AcOEt (10 : 1) to afford 2b (166 mg, 78%). Mp 182-185 ºC (MeOH); IR (KBr): 1694, 1614, 1580, 1504, 1478, 1450, 1354, 1274, 1248 cm-1; 1H NMR (CDCl3, 270 MHz) δ 1.29 (3H, t, J = 6.9 Hz), 3.85 (2H, q, J = 6.9 Hz), 6.04 (1H, d, J = 4.6 Hz), 6.50 (2H, d, J = 9.0 Hz), 6.84 (2H, d, J = 9.0 Hz), 7.04 (1H, d, J = 4.6 Hz), 7.24-7.30 (6H, m), 7.37-7.41 (4H, m); 13C NMR (CDCl3, 67.8 MHz,) δ 162.3, 154.8, 139.7, 139.6, 135.7 (2), 129.7 (4), 128.5 (2), 128.2 (4), 124.9 (2), 120.2, 113.4 (2), 107.1, 73.9, 63.4, 14.8; Anal. Calcd for C25H21N3O2S: C, 70.24; H, 4.95; N, 9.83. Found: C, 70.20; H, 5.04; N, 9.97.

2-(4-Ethoxyphenyl)-2,3-dihydro-3,3-diphenylbenzothiazolo[2,3-c][1,2,4]triazin-4-one (2c)
A solution of 1c (283 mg, 1 mmol) and diphenylketene (320 mg, 1.65 mmol) was heated under reflux for 20 h in dry benzene (20 mL) under N2. The reaction mixture was condensed in vacuo to give a residue. The residue was purified by column chromatography on silica gel with n-hexane-AcOEt (10:1) to afford 2c (344 mg, 72%). Mp 161-163 ºC (EtOH); IR (KBr): 1707, 1630, 1582, 1506, 1339, 1281, 1244 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.30 (3H, t, J =7.0 Hz), 3.87 (2H, q, J = 7.0 Hz), 6.54 (2H, d, J = 9.2 Hz), 6.86 (2H, dt, J = 9.2 Hz), 7.16 (1H, td, J = 6.4, 1.5 Hz), 7.21 (1H, td, J = 6.4, 1.5 Hz), 7.25 (1H, dd, J = 7.9, 1.5 Hz), 7.28-7.31 (6H, m), 7.40-7.43 (4H, m), 8.30 (1H, dd, J = 7.9, 1.2 Hz); 13C NMR (CDCl3, 125.65 MHz) δ 163.6, 154.8, 139.5, 137.7, 136.0, 135.7 (2), 129.7 (4), 128.5 (2), 128.2 (4), 126.1, 126.0, 124.6 (2), 124.5, 121.8, 116.9, 113.5 (2), 75.0, 63.4, 14.8; Anal. Calcd for C29H23N3O2S: C, 72.94; H, 4.86; N, 8.80. Found: C, 73.09; H, 4.94; N, 8.86.

X-Ray structure analysis of compound 2a
Crystal data: C25H22N4O2S, M = 442.53, T = 298 K, Monoclinic, a = 23.432(8) Å, b = 12.908(6) Å, c = 16.132(3) Å, β = 110.23(2)°, V = 4578 (2) Å3 (from setting angles of 25 centered reflections with 33.74 < 2θ < 34.88; λ = 1.54178 Å), space group P21/c (#14), Z = 8, Dcal = 1.284 g cm-3, 0.70 x 0.50 x 0.30 mm, μ(Cu-Kα) = 14.91 cm-1.
Data collection and processing: Rigaku AFC7R four-circle diffractometer with fine-focused 8.3 kW rotating anode generator, ω/2θ scans with ω scan width (1.89 + 0.30 tan θ)°, graphite monochromated Cu-Kα radiation; 8956 reflections measured to 2θmax = 136.2, giving 8736 with I > 3σ(I), which were retained in all calculations. No decay correction was observed and no corrections were applied for absorption.
Structure solution and refinement: The structure was solved by direct methods using SIR92 and expanded using Fourier techniques DIRDIF94 and refined by the full matrix least-squares method with all non-H atoms anisotropic. All calculations were performed using the teXsan crystallographic software package of Molecular Structure Corporation. The weighting scheme w = 1/σ<συπ>2</συπ>(Fo) gave satisfactory agreement analyses. The final R-value was 0.062, Rw = 0.101. The maximum and minimum peaks on the final ΔF map corresponded to 0.36 and -0.27 e-/Å3, respectively.

ACKNOWLEDGEMENTS
We thank Dr. A. Katoh (Niigata University of Pharmacy and Applied Life Sciences) for his advice on mass fragmentation analysis. We are grateful to N. Eguchi, K. Satoh, and T. Koseki from the Analytical Center of our university for mass spectrometry measurements.

References

1. D. L. Boger and S. T.Weinreb, ‘Hetero Diels-Alder Methodology in Organic Synthesis’, Academic Press, San Diego, 1987, pp. 239-299; D. L. Boger, ‘Comprehensive Organic Synthesis’, ed. by B. M. Trost, Pergamon Press, Oxford, 1991, , vol. 5, pp. 451-512.
2. T. Reffelmann and R. A. Kloner, Expert Opin Pharmacother, 2007, 8, 965; CrossRef G. Ravipati, J. A. McClung, W. S. Aronow, S. J. Peterson, and W. H. Frishman, Cardiol Rev., 2007, 15, 76; CrossRef G. M. Keating and L. J. Scott, Drugs, 2003, 63, 2673. CrossRef
3. Recent examples: a) K. Sztanke, K. Pasternak, B. Rajtar, M. Sztanke, M. Majek, and M. Polz-Dacewicz, Bioorg. Med. Chem., 2007, 15, 5480; CrossRef b) K. Singh, M. S. Barwa, and P. Tyagi, Europ. J. Med. Chem., 2007, 42, 394; CrossRef c) K. Sztanke, K. Pasternak, J. Rzymowska, M. Sztanke, M. Kandefer-Szerszen, I. Dybala, and A. E. Koziol, Bioorg. Med. Chem., 2007, 15, 2837; CrossRef d) M. M. Ramla, M. A. Omar, A.-M. M. El-Khamry, and H. I. El-Diwani, Bioorg. Med. Chem., 2006, 14, 7324; CrossRef e) K. S. Kim, S. Lu, L. A. Cornelius, L. J. Lombardo, R. M. Borzilleri, G. M. Schroeder, C. Sheng, G. Rovnyak, D. Crews, R. J. Schmidt, D., K. Williams, R. S. Bhide, S. C. Traeger, P. A. McDonnell, L. Mueller, S. Sheriff, J. A. Newitt, A. T. Pudzianowski, Z. Yang, R. Wild, F. Y. Lee, R. Batorsky, J. S. Ryder, M. Ortega-Nanos, H. Shen, M. Gottardis, and D. L. Roussell, Bioorg. Med. Chem. Lett., 2006, 16, 3937; CrossRef f) S. C. Goodacre, D. J. Hallett, R. W. Carling, J. L. Castro, D. S. Reynolds, A. Pike, K. A. Wafford, R. Newman, J. R. Atack, and L. J. Street, Bioorg. Med. Chem. Lett., 2006, 16, 1582; CrossRef g) K. Sztanke, J. Rzymowska, M. Niemczyk, I. Dybala, A. E. Koziol, Europ. J. Med. Chem., 2006, 41, 1373; CrossRef h) C. D. Boyle, R. Xu, T. Asberom, S. Chackalamannil, J. W. Clader, W. J. Greenlee, H. Guzik, Y. Hu, Z. Hu, C. M. Lankin, D. A. Pissarnitski, A. W. Stamford, Y. Wang, J. Skell, S. Kurowski, S. Vemulapalli, J. Palamanda, M. Chintala, P. Wu, J. Myers, and P. Wang, Bioorg. Med. Chem. Lett., 2005, 15, 2365; CrossRef i) H. Haning, U. Niewoehner, T. Schenke, T. Lampe, A. Hillisch, and E. Bischoff, Bioorg. Med. Chem. Lett., 2005, 15, 3900; CrossRef F. Manetti, S. Schenone, F. Bondavalli, C. Brullo, O. Bruno, A. Ranise, L. Mosti, G. Menozzi, P. Fossa, M. L. Trincavelli, C. Martini, A. Martinelli, C. Tintori, and M. Botta, J. Med. Chem., 2005, 48, 7172. CrossRef
4. There are a few known cycloaddition of 1,2,4-triaza-1,3-dienes with alkenes and alkynes giving 1,2,4-triazines: L. Bruche, L. Garanti, and G. Zecchi, J. Chem. Soc., Perkin Trans. 1, 1982, 755; CrossRef G. Ege, K. Gilbert, and H. Franz, Synthesis, 1977, 556; CrossRef M. H. Elnagdi, M. R. H. Elmoghayar, E. M. Kandeel, and M. K. A. Ibrahim, J. Heterocycl. Chem., 1977, 14, 227; CrossRef V. M. Cherkasov, I. A. Nasyr, and V. T. Tsyba,, Kim. Geterotsikl. Soedin, 1970, 1704.
5. M. Sakamoto, T. Kawasaki, K. Ishii, and O. Tamura, Yakugaku Zasshi, 2003, 123, 717. CrossRef
6. M. Sakamoto, K. Miyazawa, K. Kuwabara, and Y. Tomimatsu, Heterocycles, 1979, 12, 231; CrossRef M. Sakamoto, T. Nakai, H. Yanagisawa, and T. Kawasaki, Heterocycles, 2009, 77, 409. CrossRef
7. a) M. Sakamoto, K. Miyazawa, and Y. Tomimatsu, Chem. Pharm. Bull., 1974, 22, 2201; b) M. Sakamoto, K. Miyazawa, and Y. Tomimatsu, Chem. Pharm. Bull., 1976, 24, 2532; c) M. Sakamoto, K. Satoh, M. Nagano, M. Nagano, and O. Tamura, J. Chem. Soc., Perkin Trans. 1, 1998, 3389. CrossRef
8. a) M. Sakamoto and Y. Tomimatsu, Yakugaku Zasshi, 1970, 90, 1386; b) M. Sakamoto, K. Miyazawa, Y. Ishihara, and Y. Tomimatsu, Chem. Pharm. Bull., 1974, 22, 1419.
9. J. Goerdeler, H. Haubrich, and J. Galinke, Chem. Ber., 1960, 93, 397. CrossRef