Synlett 2017; 28(04): 456-460
DOI: 10.1055/s-0036-1588099
letter
© Georg Thieme Verlag Stuttgart · New York

Thieme Chemistry Journals Awardees – Where Are They Now?
A Cascade Synthesis of 1,2,4-Triazin-3(2H)-ones Using Nitrogen-Substituted Isocyanates

Mohammed A. Dahab
a  Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
,
Joshua S. Derasp
b  Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie, Ottawa, ON, K1N 6N5, Canada   Email: andre.beauchemin@uottawa.ca
,
André M. Beauchemin*
b  Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie, Ottawa, ON, K1N 6N5, Canada   Email: andre.beauchemin@uottawa.ca
› Author Affiliations
Further Information

Publication History

Received: 25 October 2016

Accepted after revision: 26 October 2016

Publication Date:
10 November 2016 (eFirst)

These authors contributed equally

Abstract

A cascade synthesis of 1,2,4-triazin-3(2H)-ones is reported from readily accessible α-amino ketones and phenyl carbazate as a masked N-isocyanate precursor. The mild protocol provides a simple route to products with substitution patterns which are difficult to form directly. This also presents the first N-isocyanate cascade requiring the use of acidic conditions, which accelerates formation of the hydrazone intermediate and the cyclization step. This cascade further highlights that high control can be achieved in reactions forming highly reactive N-isocyanate intermediates.

Supporting Information

 
  • References and Notes

    • 1a Trost BM. Science 1983; 219: 245
    • 1b Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257

      For selected publications on 1,2,4-triazinone bioactivity, see:
    • 2a Abdel-Halim AM, el-Gendy Z, Abdel-Rahman RM. Pharmazie 1995; 50: 726
    • 2b Bhatia PA, Brooks CD. W, Basha A, Ratajczyk JD, Gunn BP, Bouska JB, Lanni C, Young PR, Bell RL, Carter GW. J. Med. Chem. 1996; 39: 3938
    • 2c Schmitz WD, Brenner AB, Bronson JJ, Ditta JL, Griffin CR, Li Y.-W, Lodge NJ, Molski TF, Olson RE, Zhuo X, Macor JE. Bioorg. Med. Chem. Lett. 2010; 20: 3579
    • 2d Sztanke K, Tuzimski T, Sztanke M, Rzymowska J, Pasternak K. Bioorg. Med. Chem. 2011; 19: 5103
    • 2e Saad HA, Moustafa AH. Molecules 2011; 16: 5682

      For selected publications on 1,2,4-triazin-3(2H)-one bioactivity, see:
    • 3a Kristinsson H. US 4931439, 1990
    • 3b Martin M, Nadler G, Zimmermann R. US 4933336, 1990
    • 3c Coates WJ. US 4906628, 1990
    • 3d Betebenner DA, Chen X, Condon SL, Cooper AJ, Dickman DA, Hannick SM, Herrin TR, Kempf DJ, Kolaczkowski L, Kumar GN, Liu J.-H, Norbeck DW, Oliver PA, Patel KM, Plata DJ, Sham HL, Stengel PJ, Stoner EJ, Tien J.-HJ. EP1 170289A2, 2002
    • 3e Nagato S, Kawano K, Ito K, Norimine Y, Ueno K, Hanada T, Amino H, Ogo M, Hatakeyama S, Ueno M, Groom AJ, Rivers L, Smith T. US 2003225081, 2003
    • 3f Grauert M, Bakker R, Breitfelder S, Buettner F, Eickelmann P, Fox T, Grundl M, Lehmann-Lintz T, Rist W. WO 2011138427, 2011
    • 3g Oi N, Tokunaga M, Suzuki M, Nagai Y, Nakatani Y, Yamamoto N, Maeda J, Minamimoto T, Zhang M.-R, Suhara T, Higuchi M. J. Med. Chem. 2015; 58: 8444
    • 3h Yang Y, Liu Y, Song H, Li Y, Wang Q. Bioorg. Med. Chem. 2016; 24: 391
    • 3i Liang C, Pan S, Yang S, Wang J. WO 2016023877, 2016
  • 4 European Food Safety Authority EFSA Journal 2014; 12: 3817

    • For selected publications on 1,2,4-triazin-3(2H)-one syntheses, see:
    • 5a Biltz VH. Justus Liebigs Ann. Chem. 1905; 339: 243
    • 5b Busch M, Kuspert K. J. Prakt. Chem. 1936; 144: 273
    • 5c Polonovski M, Pesson M, Rajzman P. C. R. Hebd. Seances Acad. Sci. 1954; 238: 695
    • 5d Mustafa A, Asker W, Mansour AK, Zaher HA. A, Eloui AR. J. Org. Chem. 1963; 28: 3519
    • 5e Holland DG, Amstutz ED. Recl. Trav. Chim. Pays-Bas 1964; 83: 1047
    • 5f M’Packo JP, Vinot N. C. R. Seances Acad. Sci., Ser. C 1970; 1201
    • 5g Paudler WW, Lee J. J. Org. Chem. 1971; 36: 3921
    • 5h Vinot N, M’Packo JP. Bull. Soc. Chim. Fr. 1972; 4637
    • 5i Daunis J, Pigiere C. Bull. Soc. Chim. Fr. 1973; 2818
    • 5j Daunis J, Djouai-Hifdi L, Lopez H. J. Heterocycl. Chem. 1979; 16: 427
    • 5k Nakayama Y, Sanemitsu Y, Mizutani M, Yoshioka H. J. Heterocycl. Chem. 1981; 18: 631
    • 5l Teraji T, Shiokawa Y, Okumura K, Sato Y. US 4616014, 1986
    • 5m Lozanova K, Simov D, Kalcheva V. Chem. Heterocycl. Compd. 1987; 23: 1024
    • 5n Milcent R, Yver B, Barbier G. J. Heterocycl. Chem. 1992; 29: 959
    • 5o Miki H, Iwanaga K, Matsuno T, Aoki I. US 5994355, 1999
    • 5p Nagato S, Kawano K, Ito K, Norimine Y, Ueno K, Hanada T, Amino H, Ogo M, Hatakeyama S, Ueno M, Groom AJ, Rivers L, Smith T. WO 200222587, 2001
    • 5q Kelly MJ, Jacobson RM. US 2004019209, 2004
    • 5r Verardo G, Geatti P, Merli M, Strazzolini P. Eur. J. Org. Chem. 2006; 2638
    • 5s Darwish ES, Abdelhamid IA, Nasra MA, Abdel-Gallil FM, Fleita DH. Helv. Chim. Acta 2010; 93: 1204
    • 5t Egorov IN, Tseitler TA, Zyryanov GV, Rusinov VL, Chupakhin ON. ARKIVOC 2011; (x): 312
    • 5u Wang B, Ke S, Kishore B, Xu X, Zou Z, Li Z. Synth. Commun. 2012; 42: 2327
    • 5v Egorov IN. Z. Naturforsch., B: J. Chem. Sci. 2014; 69: 899
  • 6 Shao J, Liu X, Shu K, Tang P, Luo J, Chen W, Yu Y. Org. Lett. 2015; 17: 4502
    • 7a Clavette C, Gan W, Bongers A, Markiewicz T, Toderian A, Gorelsky SI, Beauchemin AM. J. Am. Chem. Soc. 2012; 134: 16111
    • 7b Gan W, Moon P, Clavette C, DasNeves N, Markiewicz T, Toderian A, Beauchemin AM. Org. Lett. 2013; 15: 1890
    • 7c Garland K, Gan W, Depatie-Sicard C, Beauchemin AM. Org. Lett. 2013; 15: 4074
    • 7d Clavette C, Vincent Rocan J.-F, Beauchemin AM. Angew. Chem., Int. Ed. 2013; 52: 12705
    • 7e Lavergne K, Bongers A, Betit L, Beauchemin AM. Org. Lett. 2015; 17: 3612
    • 7f Vincent-Rocan J.-F, Clavette C, Leckett K, Beauchemin AM. Chem. Eur. J. 2015; 21: 3886
    • 7g Vincent-Rocan J.-F, Derasp JS, Beauchemin AM. Chem. Commun. 2015; 51: 16405
    • 7h Ivanovich RA, Vincent-Rocan J.-F, Elkaeed EB, Beauchemin AM. Org. Lett. 2015; 17: 4898
    • 7i Vincent-Rocan J.-F, Ivanovich RA, Clavette C, Leckett K, Bejjani J, Beauchemin AM. Chem. Sci. 2016; 7: 315
    • 7j Derasp JS, Vincent-Rocan J.-F, Beauchemin AM. Org. Lett. 2016; 18: 658
    • 7k Ivanovich RA, Clavette C, Vincent-Rocan J.-F, Roveda J.-G, Gorelsky SI, Beauchemin AM. Chem. Eur. J. 2016; 22: 7906
    • 7l An J, Alper H, Beauchemin AM. Org. Lett. 2016; 18: 3482
    • 7m Bongers A, Ranasinghe I, Lemire P, Perozzo A, Vincent-Rocan J.-F, Beauchemin AM. Org. Lett. 2016; 18: 3778
    • 7n For a review of N-isocyanate chemistry, see: Vincent-Rocan J.-F, Beauchemin AM. Synthesis 2016; 48: 3625
    • 8a Dirksen A, Dawson PE. Bioconjugate Chem. 2008; 19: 2543
    • 8b Kool ET, Park D.-H, Crisalli P. J. Am. Chem. Soc. 2013; 135: 17663
    • 8c Crisalli P, Kool ET. Org. Lett. 2013; 15: 1646
  • 9 Wentrup C, Finnerty JJ, Koch R. Curr. Org. Chem. 2011; 15: 1745

    • For an entry into stable α-amino carbonyl compounds, see:
    • 10a Hili R, Yudin AK. J. Am. Chem. Soc. 2006; 128: 14772
    • 10b He Z, Zajdlik A, Yudin AK. Acc. Chem. Res. 2014; 47: 1029

      For examples of citric acid-catalyzed condensations, see:
    • 11a Blanksma J. Recl. Trav. Chim. Pays-Bas 1939; 58: 497
    • 11b Gergely J, Morgan JB, Overman LE. J. Org. Chem. 2006; 71: 9144
    • 11c Dinore JM, Yelwande AA, Palve MP, Sapkal AV. Int. J. Pharm. Pharm. Res. 2016; 6: 349
  • 12 Recrystallization resulted in a 60% yield of the desired compound while the remaining 28% was obtained through column purification. See Supporting Information for details.
  • 13 General Procedure for the Cascade Reaction In a dry microwave vial equipped with a stir bar, the α-amino ketone (1.05 equiv) was added to phenyl carbazate (1.0 equiv) and citric acid (1.0 equiv). The vial was then sealed and purged with argon followed by the addition of purified THF (1.0 M). The resulting solution was left stirring at r.t. for 12–16 h. The reaction mixture was concentrated under reduced pressure, diluted with a sat. NaHCO3 solution (20 mL), and extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over NaSO4, filtered, and concentrated under reduced pressure. The crude products were purified by column chromatography or through recrystallization in MeOH.
  • 14 4,6-Diphenyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (3a) Synthesized according to the general procedure using α-amino ketone 1a (0.133 g, 0.630 mmol), phenyl carbazate (0.0912 g, 0.600 mmol), and citric acid (0.115 g, 0.600 mmol), then purified THF (0.6 mL, 1.0 M) was added under argon. The resulting solution was left stirring at r.t. for 12 h. The title compound was purified by column chromatography (5% EtOAc–CH2Cl2) to yield a white solid (0.186 g, 74%). TLC: Rf  = 0.23 in 5% EtOAc–CH2Cl2. 1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.68 (ddd, J = 4.4, 2.5, 1.4 Hz, 2 H), 7.44 (t, J = 2.7 Hz, 2 H), 7.42 (dd, J = 2.7, 1.6 Hz, 4 H), 7.40 (d, J = 3.1 Hz, 1 H), 7.31–7.26 (m, 1 H), 4.74 (s, 2 H). 13C NMR (101 MHz, CDCl3): δ = 151.5, 143.3, 140.4, 133.4, 130.0, 129.2, 128.8, 126.6, 125.3, 124.5, 47.7. IR (ATR diamond): 3216, 3097, 1662, 1625, 1593, 1195, 772 cm–1. HRMS (EI): m/z calcd for C15H13N3O [M]+: 251.1053; found: 251.1056.
  • 15 Procedure for the Primary α-Amino Ketone: 6-Phenyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (3m) In a dry microwave vial equipped with a stir bar, 2-aminoacetophenone hydrochloride (0.103 g, 0.600 mmol) was added to a solution of phenyl carbazate (0.273 g, 1.80 mmol) in EtOH (1.20 mL, 0.50 M) and refluxed under argon for 24 h. The reaction mixture was concentrated under reduced pressure, and dry loaded onto silica gel. The title compound was purified by column chromatography (100% EtOAc to 5% MeOH–CH2Cl2) to yield a white solid (0.0813 g, 77%). TLC: Rf  = 0.27 in 5% EtOAc–CH2Cl2. 1H NMR (400 MHz, DMSO-d 6): δ = 9.90 (d, J = 1.8 Hz, 1 H), 7.63–7.61 (m, 2 H), 7.40–7.34 (m, 3 H), 7.22 (s, 1 H), 4.60 (d, J = 1.8 Hz, 2 H). 13C NMR (101 MHz, DMSO-d 6): δ = 152.4, 141.9, 134.6, 129.7, 129.0, 125.5, 40.5.