8664
Acknowledgements
We thank Derek Kennedy for NMR experiments, Paul Byway for mass spectral analysis, and
Gary Hope and Andrew Gibson for GC analyses.
References
1. Regoli, D.; Boudon, A.; Fauchere, J.-L. Pharmacol. Rev. 1994, 46, 551.
2. Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz,
M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M. J.; Williams, A. R.; Rycroft, W.;
Hargreaves, R.; MacIntyre, D. E. J. Med. Chem. 1998, 41, 4607.
3. Apart from compound 5 which was used crude in the subsequent step, all new compounds gave spectroscopic data
in agreement with the assigned structures.
4. Shvaika, O. P.; Baranov, S. N.; Artemov, V. N. Dokl. Akad. Nauk SSSR 1969, 186, 1102; Chem. Abstr. 1969, 71,
70540r.
5. 2-Chloro-1,1,1-trimethoxyethane (8) is available from Aldrich Chemical Company (cat. number 43 794-8). Two
literature syntheses of this compound have been reported: Moos, W. H.; Gless, R. D.; Rapoport, H. J. Org. Chem.
1981, 46, 5064; McElvain, S. M.; Nelson, J. W. J. Am. Chem. Soc. 1942, 64, 1825. The most recent involved the
radical chlorination of trimethyl orthoacetate, while the earlier used the methanolysis of imidate salt i, itself formed
by Pinner reaction of chloroacetonitrile. We examined the latter route and found that chloroacetamide was the
primary by-product from the methanolysis reaction, however, it was not observed in the crude material as it
partitioned to the aqueous phase. This side reaction is related to the acid-catalysed decomposition of orthoester
8 in the triazolinone synthesis where chloromethane is also co-produced.
Interestingly, condensation of semicarbazide·HCl with imidate i only led to triazolinone 4 when the reaction was
conducted in methanol. Orthoester 8 is assumed to be an intermediate in this condensation and it was observed
1
when following the reaction by H NMR spectroscopy.
6. A mixture of semicarbazide·HCl (100 g, 0.90 mol), orthoester 8 (305 g, 2.0 mol) and MeOH (1.0 L) was stirred
at 20°C for 3 days. The solvent was then removed under reduced pressure and toluene (1.0 L) was added and the
slurry concentrated further to remove residual MeOH. The mixture was then cooled to 0°C and filtered to afford
3-chloromethyl-1,2,4,-triazolin-5-one (4) (117 g, 98%) as a white solid (mp 197–199°C), 1H NMR (250 MHz,
DMSO-d6) 4.43 (2H, s, CH2
6
), 11.48 (1H, s, NH
6 ) and 11.64 (1H, s, NH6
); 13C NMR (62.9 MHz, DMSO-d6) 36.9
(ClCH2), 144.6 (CH2C
6
6
ꢀN) and 156.9 (NHCONH); Anal. calcd for C3H4ClN3O: C, 26.98; H, 3.02; Cl, 26.55; N,
6
31.47. Found: C, 27.01; H, 2.92; Cl, 26.34; N, 31.21.
7. For example, the use of 8 in the synthesis of benzothiazoles/benzoxazoles and oxazoles: Mylari, B. L.; Scott, P.
J.; Zembrowski, W. J. Synth. Commun. 1989, 19, 2921; Kamata, K.; Sato, H.; Takagi, E.; Agata, I.; Meyers, A.
I. Heterocycles 1999, 51, 373.
8. For other syntheses of 3-substituted-1,2,4-triazolin-5-ones, see: (a) Rigo, B.; Valligny, D.; Taisne, S. Synth. Commun.
1988, 18, 167; (b) Milcent, R.; Nguyen, T.-H. J. Heterocycl. Chem. 1986, 23, 881; (c) Adembri, G.; Camparini,
A.; Ponticelli, F.; Tedeschi, P. J. Chem. Soc., Perkin Trans. 1 1981, 1703; (d) Scott, F. L.; Lambe, T. M.; Butler,
8
R. N. J. Chem. Soc., Perkin Trans. 1 1972, 1918; (e) Un, R.; Ikizler, A. Chim. Acta Turc. 1975, 3, 113.
9. A mixture of chlorotriazolinone 4 (8.30 g, 62.2 mmol) in DMF (80 mL) was added dropwise to a cooled (0°C),
stirred mixture of amine·p-TSA 3 (36.8 g, 60.4 mmol) and powdered K2CO3 (9.18 g, 66.4 mmol) in DMF/water
(122 mL, 60:1). After 2 hours, water (400 mL) was added and isolation of the resulting precipitate afforded compound
1 (31.8 g, 99%), which was identical (1H NMR, 13C NMR, mp, HPLC retention time) to that previously reported.2
10. The condensation of semicarbazide·HCl with trimethyl orthoformate (rt, MeOH, 1 h) afforded the parent triazolinone
in quantitative yield.