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Synlett 2009(5): 735-738  
DOI: 10.1055/s-0028-1087928
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Domino Reaction for the Construction of New 2-Oxo[1,2,4]triazolo[5,1-c][1,4]thiazines

Orazio A. Attanasia, Samuele Lillinia, Fabio Mantellini*a, Jesús M. de  los Santosb, Roberto Ignaciob, Francisco Palacios*b
a Istituto di Chimica Organica, Università degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti 24, 61029 Urbino (PU), Italy
b Departamento de Química Orgánica I, Facultad de Farmacia, Universidad del País Vasco, Apartado 450, 01080 Vitoria, Spain
Fax: +39(0722)303441; e-Mail: fabio.mantellini@uniurb.it;
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Publication History

Received 17 November 2008
Publication Date:
24 February 2009 (online)

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Abstract

The synthesis of highly functionalized α-thiohydrazones by Michael addition of 3-mercapto-2-ketones to 1,2-diazabuta-1,3-dienes is described. The phosphorylated α-thiohydrazones were hydrolyzed into β-ketophosphine oxides or phosphonates containing a mercapto ketone in the α position, while the α-thiohydrazones with a carboxylate group were subsequently transformed into 2-oxo-2,3,8,8a-tetrahydro-1H-[1,2,4]triazolo[5,1-c][1,4]thiazines by means of a domino reaction.

Key words

1,2-diazabuta-1,3-dienes - [1,4]thiazines - [1,2,4]triazol-2-ones - Michael addition - domino reaction.

    References and Notes

  • 1 Iwahara S. Iwasaki T. Hasegawa Y. Psychopharmacologia  1968,  13:  341 
    CrossrefGoogle Scholar
  • 2 Oelssner W. Peinhardt G. Buge A. Pharmazie  1985,  40:  320 
    Google Scholar
  • 3 Parish FA. Med. Times  1959,  87:  1488 
    Google Scholar
  • 4 Moriyama H. Tsukida T. Inoue Y. Yokota K. Yoshino K. Kondo H. Miura N. Nishimura S. J. Med. Chem.  2004,  47:  1930 
    CrossrefGoogle Scholar
  • 5 Arranz ME. Diaz JA. Ingate ST. Witvrouw M. Pannecouque C. Balzarini J. De Clercq E. Vega S. Bioorg. Med. Chem.  1999,  45:  3475 
    Google Scholar
  • 6 Srivastava SK. Yadav R. Srivastava SD. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2004,  43:  399 
    Google Scholar
  • 7 Budriesi R. Cosimelli B. Ioan P. Lanza CZ. Spinelli D. Chiarini A. J. Med. Chem.  2002,  45:  3475 
    CrossrefGoogle Scholar
  • 8 Galanski ME. Erker T. Handler N. Lemmens-Gruber R. Kamyar M. Studenik CR. Bioorg. Med. Chem.  2006,  14:  826 
    CrossrefGoogle Scholar
  • 9 Heers J. Backx JJ. Cutsem JV. J. Med. Chem.  1984,  27:  894 
    CrossrefGoogle Scholar
  • 10 Mullican MD. Wilson MW. Connor DT. Kostlan CR. Schrier DJ. Dyer DD. J. Med. Chem.  1993,  36:  1090 
    CrossrefPubMedGoogle Scholar
  • 11 Neslihan D. Reyhan U. Ahmet D. Bioorg. Med. Chem.  2002,  10:  3717 
    CrossrefGoogle Scholar
  • 12 Xu Y. Mayhugh D. Saeed A. Wang X. Thompson RC. Dominianni SJ. Kauffman RF. Sing J. Bean JS. Bensch WR. Barr RJ. Osborne J. Montrose-Rafizadeh C. Zink RW. Yumibe NP. Huang N. Luffer-Atllas D. Rungta D. Maise DE. Mantlo NB.
    J. Med. Chem.  2003,  46:  5121 
    CrossrefGoogle Scholar
  • 13 Cowden CJ. Wison RD. Bishop BC. Cottrel IF. Davies AJ. Dollong U. Tetrahedron Lett.  2000,  41:  8661 
    CrossrefGoogle Scholar
  • 14 SciFinder Scholar, CAS   American Chemical Society; Columbus OH: 2006. 
    Google Scholar
  • 15 Aitken RA. In Comprehensive Heterocyclic Chemistry III   Vol. 8:  Katritzky AR. Elsevier; Oxford: 2008. 
    Google Scholar
  • For some recent applications, see:
  • 16a Dixon S. Wang X. Lam KS. Kurth MJ. Tetrahedron Lett.  2005,  46:  7443 
    Google Scholar
  • 16b Freed JD. Hart DJ. Magomedov NA. J. Org. Chem.  2001,  66:  839 
    Google Scholar
  • 17 Landor SR. Landor PD. Seliki-Muruumu J. Fomum ZT. Mbafor JT. J. Chem. Soc., Perkin Trans. 1  1998,  1759 
    Google Scholar
  • 18 Attanasi OA. Filippone P. Lillini S. Mantellini F. Nicolini S. de los Santos JM. Ignacio R. Aparicio D. Palacios F. Tetrahedron  2008,  64:  9264 
    CrossrefGoogle Scholar
  • 21a Palacios F. Alonso C. de los Santos JM. Chem. Rev.  2005,  105:  899 
    Google Scholar
  • 21b Moonen K. Laureyn I. Stevens CV. Chem. Rev.  2004,  104:  6177 
    Google Scholar
  • 22 Palacios F. Aparicio D. López Y. de los Santos JM. Tetrahedron  2005,  61:  2815 
    CrossrefGoogle Scholar
  • 24 Watanabe Y. Usui H. Kobayashi S. Yoshiwara H. Shibano T. Tanaka T. Morishima Y. Yasuoka M. Kanao M. J. Med. Chem.  1992,  35:  189 
    CrossrefGoogle Scholar
  • For some recent developments, see:
  • 25a Attanasi OA. De Crescentini L. Favi G. Filippone P. Mantellini F. Santeusanio S. J. Org. Chem.  2002,  67:  8178 
    Google Scholar
  • 25b Attanasi OA. De Crescentini L. Filippone P. Mantellini F. Santeusanio S. ARKIVOC  2002,  (xi):  274 
    Google Scholar
  • 25c Attanasi OA. De Crescentini L. Favi G. Filippone P. Mantellini F. Santeusanio S. J. Org. Chem.  2004,  69:  2686 
    Google Scholar
  • 25d Attanasi OA. Favi G. Filippone P. Golobič A. Stanovnik B. Svete J. J. Org. Chem.  2005,  70:  4307 
    Google Scholar
  • 25e Attanasi OA. Baccolini G. Boga C. De Crescentini L. Filippone P. Mantellini F. J. Org. Chem.  2005,  70:  4033 
    Google Scholar
  • 25f Attanasi OA. De Crescentini L. Favi G. Filippone P. Lillini S. Mantellini F. Santeusanio S. Org. Lett.  2005,  7:  2469 
    Google Scholar
  • 25g Attanasi OA. De Crescentini L. Favi G. Filippone P. Golobič A. Lillini S. Mantellini F. Synlett  2006,  2735 
    Google Scholar
  • 25h Attanasi OA. Giorgi G. Favi G. Filippone P. Lillini S. Perrulli FR. Santeusanio S. Synlett  2007,  1691 
    Google Scholar
  • 25i Attanasi OA. Favi G. Filippone P. Lillini S. Mantellini F. Spinelli D. Stenta M. Adv. Synth. Catal.  2007,  349:  207 
    Google Scholar
  • 25j Attanasi OA. Favi G. Filippone P. Giorgi G. Mantellini F. Moscatelli G. Spinelli D. Org. Lett.  2008,  10:  1983 
    Google Scholar
  • 25k Karapetyan V. Mkrtchyan S. Schmidt A. Attanasi OA. Favi G. Mantellini F. Villinger A. Fischer C. Langer P. Adv. Synth. Catal.  2008,  350:  1331 
    Google Scholar
  • 26a Attanasi OA. Filippone P. Mei A. Santeusanio S. Synthesis  1984,  671 
    Google Scholar
  • 26b Attanasi OA. Filippone P. Mei A. Santeusanio S. Synthesis  1984,  873 
    Google Scholar
19

General Procedure for the Synthesis of α-Thiohydrazone 1,4-Adducts 3a-m: To an ice-cooled solution of 1,2-diazabuta-1,3-diene 1a,b,i as a mixture of E/Z isomers (1.0 mmol) in CH2Cl2 (5 mL), the 3-mercaptobutan-2-one 2a (1.1 mmol) or 3-mercaptopentan-2-one 2b (1.1 mmol) was added. The reaction was allowed to stir at r.t. for 4 h. The solvent was removed by rotary evaporation and the crude products were purified by crystallization for compound 3m or by flash column chromatography (silica gel, EtOAc) for compounds 3a,b,k,l to afford α-thiohydrazone 1,4-adducts derived from phosphine oxide and phosphonate-substituted 1,2-diazabuta-1,3-dienes. To obtain 3c-j, a stoichiometric amount of 1,2-diazabuta-1,3-dienes 1c-h (1.0 mmol) as a mixture of E/Z isomers [²6] was added to a solution of 3-mercaptobutan-2-one 2a (1.1 mmol) or 3-mercaptopentan-2-one 2b (1.1 mmol) in MeCN (20 mL) with magnetic stirring at r.t. The reactions were allowed to stand under these conditions for 2 h until the complete disappearance of the starting materials (monitored by TLC). The reaction solvent was then evaporated under reduced pressure and products 3c-j were purified by flash column chromatography (silica gel, EtOAc).
Ethyl 2-(Diphenylphosphoryl)-1-methyl-2-[(1-methyl-2-oxopropyl)sulfanyl]ethylidene-1-hydrazinecarboxylate (3a): yield: 433 mg (97%); obtained as a colorless solid as described in the general procedure; mp 143-145 ˚C. IR (KBr): 3457, 3195, 2978, 1733, 1533, 1436, 1236, 1042 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.19-1.23 (m, 6 H), 1.82 (s, 3 H), 1.90 (d, 3 H, 4 J PH = 1.1 Hz, major), 1.91 (d, 3 H, 4 J PH = 1.1 Hz, minor), 3.34 (q, 1 H, ³ J HH = 7.2 Hz, major), 3.40 (q, 1 H, ³ J HH = 6.8 Hz, minor), 4.19-4.22 (m, 2 H), 4.39 (d, 1 H, ² J PH = 10.0 Hz), 4.42 (d, 1 H, ² J PH = 9.6 Hz), 7.41-7.88 (m, 10 H). ¹³C NMR (75 MHz, CDCl3): δ = 13.4, 13.6, 14.4, 14.4, 16.1, 16.2, 25.1, 26.7, 48.7 (d, ³ J PC = 6.5 Hz), 49.4 (d, ³ J PC = 6.0 Hz), 52.1 (d, ¹ J PC = 65.5 Hz), 52.6 (d, ¹ J PC = 66.1 Hz), 61.7, 128.1, 128.2, 128.2, 128.3, 128.4, 128.6, 129.4, 130.0, 130.4, 130.6, 130.7, 130.7, 130.9, 131.0, 131.1, 131.1, 131.2, 131.2, 131.3, 131.4, 131.9, 131.9, 147.6, 148.4, 153.6, 204.4, 204.7. ³¹P NMR (120 MHz, CDCl3): δ = 28.1 (major), 28.4 (minor). HRMS: m/z [M+] calcd for C22H27N2O4PS: 446.1429; found: 446.1434.

20

General Procedure for the Synthesis of Mercapto Diketones 4a-e: To a solution of the α-thiohydrazone 3a,b,k,l,m (1.0 mmol) in MeCN (5 mL), Amberlyst 15H ion-exchange resin (50 mg) was added. The reaction was stirred at r.t. for 2 h. The solid was then filtered through a sintered glass vacuum filtration funnel. The filtrate was concentrated to dryness in vacuum. The crude products were purified by flash column chromatography (silica gel, EtOAc) to afford the corresponding mercapto diketones 4a-e.
3-[1-(Diphenylphosphoryl)-2-oxopropyl]sulfanylbutan-2-one (4a): isomeric mixture of the keto and enol tautomers; yield: 306 mg (85%); obtained as a colorless oil as described in the general procedure. IR (film): 3435, 3046, 2921, 1705, 1431, 1362, 1197, 1117 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 0.94 (d, 3 H, ³ J HH = 7.2 Hz), 1.24 (d, 3 H, ³ J HH = 7.2 Hz), 1.82 (s, 3 H), 1.91 (s, 3 H), 1.96 (s, 3 H), 2.37 (s, 3 H), 2.39 (s, 3 H), 3.31 (q, 1 H, ³ J HH = 7.2 Hz), 4.12 (d, 1 H, ² J PH = 12.0 Hz), 4.15 (d, 1 H, ² J PH = 11.1 Hz), 7.55-7.92 (m, 10 H). ¹³C NMR (75 MHz, CDCl3): δ = 15.1, 15.3, 21.1 (d, ³ J PC = 6.1 Hz), 24.6, 26.2, 26.7, 29.4, 48.6 (d, ³ J PC = 5.5 Hz), 48.7 (d, ³ J PC = 5.5 Hz), 52.5, 54.0 (d, ¹ J PC = 45.1 Hz), 54.7 (d, ¹ J PC = 45.5 Hz), 82.1 (d, ¹ J PC = 108.7 Hz), 128.2, 128.3, 128.5, 128.5, 128.6, 128.7, 131.1, 131.2, 131.2, 131.3, 131.4, 131.4, 131.5, 132.0, 132.2, 132.3, 132.3, 132.4, 132.5, 132.5, 132.6, 186.5 (d, ² J PC = 12.7 Hz), 200.8, 202.2, 203.6, 204.3, 205.9. ³¹P NMR (120 MHz, CDCl3):
δ = 26.8, 27.7, 41.4. HRMS: m/z [M+] calcd for C19H21O3PS: 360.0949; found: 360.0952.

23

General Procedure for the Synthesis of [1,2,4]Triazolo[5,1- c ][1,4]thiazines 7a-h: To obtain [1,2,4]triazolo[5,1-c][1,4]thiazines 7b-h, the α-thiohydra-zones 3d-j (1 mmol) were refluxed in MeCN for 26-48 h. To prepare compounds 7b-h directly, a stoichiometric amount of 1,2-diazabuta-1,3-dienes 1d-h (1 mmol) was added to a solution of 3-mercaptobutan-2-one 2a (1.1 mmol) or 3-mercaptopentan-2-one 2a (1.1 mmol) in MeCN (20 mL) with magnetic stirring at r.t. until the disappearance of the reagent, as evidenced by disappearance of typical red color of the 1,2-diazabuta-1,3-dienes 1. The crude was then refluxed for 26-48 h. In the case of 7a the hydrazone 3c (1 mmol) was refluxed for 28 h in the presence of a stoichiometric amount of Amberlyst 15H ion-exchange resin (1 mmol). After disappearance of the starting materials (monitored by TLC), the reaction solvent was evaporated under reduced pressure and products 7a-h were purified by flash column chromatography (silica gel; EtOAc-cyclo-hexane, 50:50).
Methyl 5,8,8a-Trimethyl-2-oxo-2,3,8,8a-tetrahydro-1 H -[1,2,4]triazolo[5,1- c ][1,4]thiazine-6-carboxylate (7a): yield: 72 mg (31%); obtained as a blue oil as described in the general procedure. IR (nujol): 3243, 1753, 1712, 1643 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 1.22 (d, 3 H, ³ J = 6.4 Hz), 1.39 (s, 3 H), 2.37 (s, 3 H), 2.58 (q, 1 H, ³ J = 6.4 Hz), 3.56 (s, 3 H), 8.38 (s, 1 H), 9.15 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 13.5 (q), 17.1 (q), 22.2 (q), 40.8 (d), 51.0 (q), 83.1 (s), 87.6 (s), 149.0 (s), 159.4 (s), 165.0 (s). MS: m/z (%) = 257 (96)[M+], 225 (100), 197 (67), 166 (57), 139 (81), 108 (16). Anal. Calcd for C10H15N3O3S: C, 46.68; H, 5.88; N, 16.33. Found: C, 46.82; H, 5.92; N, 16.19.