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 (online)

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‡ 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.

Key words

N-isocyanates - cascade reaction - 1,2,4-triazin-3(2H)-one - α-amine ketone

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1588099.
  • Supporting Information
 

  • References and Notes


      • 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
      CrossrefPubMedSearch in Google Scholar
    • 3h Yang Y, Liu Y, Song H, Li Y, Wang Q. Bioorg. Med. Chem. 2016; 24: 391
      CrossrefPubMedSearch in Google Scholar
    • 3i Liang C, Pan S, Yang S, Wang J. WO 2016023877, 2016
  • 4 European Food Safety Authority EFSA Journal 2014; 12: 3817
  • 6 Shao J, Liu X, Shu K, Tang P, Luo J, Chen W, Yu Y. Org. Lett. 2015; 17: 4502
    CrossrefPubMedSearch in Google Scholar
  • 9 Wentrup C, Finnerty JJ, Koch R. Curr. Org. Chem. 2011; 15: 1745
    CrossrefSearch in Google Scholar
  • 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.