Synlett 2016; 27(06): 864-867
DOI: 10.1055/s-0035-1561332
letter
© Georg Thieme Verlag Stuttgart · New York

A Versatile One-Pot Procedure for the Synthesis of 5-Aryl-6H-1,3,4-thiadiazine-2-amines from Aromatic Ketones

Rafael Hartmann
a  OnTarget Chemistry AB, Virdings allé 18, Uppsala, SE-75450, Sweden   Email: fredrik.lehmann@ontargetchemistry.com
,
Jonas Malmström
a  OnTarget Chemistry AB, Virdings allé 18, Uppsala, SE-75450, Sweden   Email: fredrik.lehmann@ontargetchemistry.com
,
Graham Sibley
b  F2G Ltd, Lankro Way, Manchester, M30LX, UK   Email: gsibley@f2g.com
,
Fredrik Lehmann*
a  OnTarget Chemistry AB, Virdings allé 18, Uppsala, SE-75450, Sweden   Email: fredrik.lehmann@ontargetchemistry.com
› Author Affiliations
Further Information

Publication History

Received: 28 October 2015

Accepted after revisison: 30 December 2015

Publication Date:
20 January 2016 (online)


Abstract

6H-1,3,4-Thiadiazines are a promising class of non-aromatic heterocycles for the agricultural and pharmaceutical industry. Although known for a long time, they have not received widespread attention, in part due to their cumbersome synthesis. The novel route described herein for the direct transformation of aromatic alkyl ketones into 5-aryl-6H-1,3,4-thiadiazine-2-amines provides moderate to excellent yields while employing readily available reagents under mild reaction conditions.

 
  • References and Notes

    • 1a Bose PK. J. Indian Chem. Soc. 1924; 1: 51
    • 1b Bose PK. J. Indian Chem. Soc. 1925; 2: 95
    • 2a Vasil’eva TM, Makarov VA, Chupakhin ON, Sidorova LP, Perov NM, Rusinov VL. Eksp. Klin. Farmakol. 2009; 72: 27
    • 2b Logvinova IS, Makarov VA, Chupakhin ON, Sidorova LP, Perov NM, Rusinov VL. Eksp. Klin. Farmakol. 2013; 76: 13
    • 3a Sarapultsev AP, Chupakhin ON, Sarapultsev PA, Rantsev MD, Medvedeva SU, Sidorova LP, Abidov MT, Danilova IG. Curr. Pharm. Dec. 2013; 20: 1980
    • 3b Sarapultsev P, Chupakhin O, Sarapultsev A, Rantsev M, Sidorova L, Medvedeva S, Danilova I. Int. J. Exp. Pathol. 2012; 93: 18
    • 4a Johnston VK, Maley D, Gagnon RC, Grassmann CW, Behrens SE, Sarisky RT. Biochem. Biophys. Res. Commun. 2003; 311: 672
    • 4b Nguyen TT, Gates AT, Gutshall LL, Johnston VK, Gu B, Duffy KJ, Sarisky RT. Antimicrob. Agents Chemother. 2003; 47: 3525
    • 4c Gu B, Johnston VK, Gutshall LL, Nguyen TT, Gontarek RR, Darcy MG, Tedesco R, Dhanak D, Duffy KJ, Kao CC, Sarisky RT. J. Biol. Chem. 2003; 278: 16602
    • 5a Breuer E, Frant J, Reich R. Expert Opin. Ther. Pat. 2005; 15: 253
    • 5b Schröder J, Henke A, Wenzel A, Brandstetter H, Stammler HG, Stammler A, Pfeiffer WD, Tschesche H. J. Med. Chem. 2001; 44: 3231
  • 6 Medina-Franco JL, Martinez-Mayorga K, Meurice N. Expert Opin. Drug Discov. 2014; 9: 151
  • 7 Pitt WR, Parry DM, Perry BG, Groom CR. J. Med. Chem. 2009; 52: 2952
    • 8a Usol’tseva SV, Andronnikova GP, Mokrushin VS. Chem. Heterocycl. Compd. 1991; 27: 343
    • 8b Novikova AP, Perova NM, Chupakhin ON. Chem. Heterocycl. Compd. 1991; 27: 1159
  • 9 Novikova AP, Perova NM, Egorova LG. Chem. Heterocycl. Compd. 1991; 27: 666
  • 10 Usol’tseva SV, Andronnikova GP, Nikolaeva SL, Lebedev AT, Shevyrin VA. Chem. Heterocycl. Compd. 1991; 27: 442
    • 11a Shubakar K, Umesha KB, Srikantamurthy N, Chethan J. Bulg. Chem. Commun. 2013; 45: 274
    • 11b Thibault TD. US 4,436,549, 1984
  • 12 Kulikova B, Ezhova GI, Kravchenko NE, Dorofeeva OV, Kulikov AS, Zavozin AG. Russ. Chem. Bull., Int. Ed. 2007; 56: 1631
  • 13 Beyer H, Lässig W, Bulka E. Chem. Ber. 1954; 87: 1385
  • 14 Busby RE, Dominey TW. J. Chem. Soc., Perkin Tans. 2 1980; 890
  • 15 Lee CJ, Bae YH, Chang S.-K. Bull. Korean Chem. Soc. 2003; 24: 408
  • 16 General Procedure for the Preparation of 5-Aryl-6H-1,3,4-thiadiazine-2-amines – Exemplified for Table 1, Entry 5 To a solution of TsOH·H2O (5 mmol) and NBS (0.5 mmol) in MeCN (25 mL) was added 4-methoxyacetophenone (0.5 mmol), and the mixture was heated to reflux. After 2 h, the solution was cooled to 0 °C, 4 Å MS; 5 min later TSC (0.55 mmol) was added, and the resulting suspension was stirred for 1 h. KOH (4.5 mmol) was added, and the suspension was heated to reflux once again. After 30 min, the mixture was allowed to cool to room temperature. The reaction mixture was filtered, and the solid residue was washed with MeOH. The solvents were evaporated in vacuo, and the residue was purified by flash chromatography on silica (CH2Cl2–MeOH–NH3, 10:1:0.1% v/v) to yield 5-(4-methoxyphenyl)-6H-1,3,4-thiadiazine-2-amine as a brown, crystalline solid (0.069g, 72% yield). Flash chromatography should be carried out as quickly as possible to minimize product decomposition on silica. 5-(4-Methoxyphenyl)-6H-1,3,4-thiadiazine-2-amine (Table 1, Entry 5) Yield: 0.067 g (61%); brown, crystalline solid. 1H NMR (400 MHz, DMSO-d 6): δ = 7.86–7.82 [m, 2 H, (CH)2,arom], 7.02–6.97 [m, 2 H, (CH)2,arom], 6.92 (br s, 1 H, NH), 3.83 (s, 3H , OCH3), 3.64 (s, 2 H, CH2S). 13C NMR (100 MHz, DMSO-d 6): δ = 160.7 [C(=NNR)(CH2)Ph], 153.2 (COCH3), 147.6 [C(=NNR)(NH2)S], 128.1 (C2,arom-ortho), 127.4 (Carom-thiadiazidinyl), 114.1 (C2,arom-meta), 55.3 (CH2).
  • 17 When the synthesis of 5-phenyl-6H-1,3,4-thiadiazine-2-amine was repeated on a scale of 2.0 g (16.7 mmol), flash chromatography yielded a brown oil rather than a yellow solid. Although LC–MS showed a high degree of purity, the product was further purified as follows: The oil was taken up in a small amount of MeOH, the solution was warmed to reflux, and the same volume of Et2O was added slowly. Whilst continuing to heat, more Et2O was added dropwise until precipitation occurred. The yellow crystals were filtered off, the volume of the residual oil was reduced in vacuo, and the crystallization procedure was repeated twice more to yield 5-phenyl-6H-1,3,4-thiadiazine-2-amine as a yellow-brown, crystalline solid (1.56 g, 49% yield).