Efficient Synthesis of 5-Fluoroalkylated 1H-1,2,3-Triazoles and Application of the Bromodifluoromethylated Triazole to Prepare New gem-Difluorinated Triazole Compounds

Abstract

A series of 5-fluoroalkylated 1H-1,2,3-triazoles was prepared in good yield by the regiospecific 1,3-dipolar cycloaddition reaction of the (Z) ethyl 3-fluoroalkyl-3-pyrrolidino-acrylates with aryl or benzyl azides. In the cases of benzyl azides, addition of Na₂CO₃ was crucial for a high yield of the triazoles. The tetrakis(dimethylamino)ethylene (TDAE) promoted reaction of the bromo-difluoromethylated 1H-1,2,3-triazole with aldehyde afforded a new class of novel gem-difluorinated triazole compounds.

Key words

acrylates - 1,3-dipolar cycloaddition - fluoroalkylated 1H-1,2,3-triazole - tetrakis(dimethylamino)ethylene - gem-difluorinated compound

References

• 1 Wamhoff H. In Comprehensive of Heterocyclic Chemistry   Vol. 5:  Katritzky AR. Rees CW. Elesevier; New York: 1996.  p.705 
• For review see:
• 2a Finley KA. Triazoles: 1,2,3, In Heterocyclic Compounds   Vol. 29:  Montgomery JA. John Wiley and Sons Inc.; New York: 1980. 
• 2b Gilchrist TL. Gymer GE. In Advance in Heterocyclic Chemistry   Vol. 16:  Katritzky AR. Boulton AJ. Academic Press; New York: 1974.  p.33 
• 2c Gilchrist TL. Heterocyclic Chemistry   3rd ed.:  Addiso Wesley Longman; Beijing: 1997.  p.304 ; and ref. 1
• 3 Abu-Orabi ST. Al-Hamdany R. Shahateet S. Abu-Shandi K. Heterocycl. Commun.  2000,  6:  443 
• 4a Bertelli L. Biagi G. Calderone V. Giorgi I. Livi O. Scartoni V. Barili PL. J. Heterocycl. Chem.  2000,  37:  1169 
• 4b Lonning PE. Eur. J. Cancer  2000,  36 (Suppl. 4):  S81 
• 5 Kirk-Othmer Encycopedia of Chemical Technology   2nd ed.:  Wiley-Interscience; New York: 1964.  p.737 
• 6 Itoh Y. Ma FH. Hoshi H. Oka M. Noda K. Ukai Y. Kojima H. Nagano T. Toda N. Anal. Biochem.  2000,  287:  203 
• 7 Mori Y, Osawa M, Hori M, and Nagashima T. inventors; Eur. Pat. Appl. EP  1081250.  ; Chem. Abstr. 2001, 134, 210398
• 8 Philips D. Photochemistry  1971,  2:  795 
• 9a Yanase Y, Yoshikawa Y, Kawashima H, Takashi A, and Akase T. inventors; Jpn. Kokai Tokkyo Koho JP  2001072507.  ; Chem. Abstr. 2001, 134, 233062
• 9b Yanase Y, Yoshikawa Y, and Takashi A. inventors; Jpn. Kokai Tokkyo Koho JP  2001072512.  ; Chem. Abstr. 2001, 134, 233064
• For example see:
• 10a Allessandro DI. Patrizia S. Anonella C. Laura B. Allessandro M. Gianna R. Tetrahedron Lett.  1995,  36:  9031 
• 10b Kobayashi Y. Yamashita T. Takahashi K. Kuroda H. Kumadaki I. Chem. Pharm. Bull.  1984,  32:  4402 
• 11 For example see: Kadaba PK. Stanovnik B. Tisler M. Advances in Heterocyclic Chemistry   Academic Press; New York, London: 1980.  p.219 ; see also ref.^2b
• 12a Filler R. Kobayashi Y. Yagupolskii LM. Organofluorine Compounds in Medical Chemistry and Biochemical Applications   Elesevier; Amsterdam: 1993. 
• 12b Smart BE. , J. Fluorine Chem.  2001,  109:  3 
• 13a Carpenter W. Haymaker A. Moore DW. J. Org. Chem.  1966,  31:  789 
• 13b Saunier YM. Danion-Bougot R. Danoin D. Carrie R. Tetrahetron  1976,  32:  1995 
• 13c Kobayashi Y. Fujino S. Hamana H. Hanzawa Y. Morita S. Kumadaki I. J. Org. Chem.  1980,  45:  4683 
• 14 Peng WM. Zhu SZ. Jin GF. Tetrahedron  2001,  57:  5781 
• 15a Tozer MJ. Herpin T. Tetrahedron  1996,  52:  8619 
• 15b Burkholder CR. Dolbier WR. Medebielle M. J. Fluorine Chem.  2001,  109:  39 
• 16a Burkholder CR. Dolbier WR. Medebielle M. J. Org. Chem.  1998,  63:  5385 
• 16b Burkholder CR. Dolbier WR. Medebielle M. Ndedi A. Tetrahetron Lett.  1998,  39:  8853 
• 17 Metzger JO. Angew. Chem. Int. Ed.  1998,  37:  2975 
• 18 Balicki R. Pol. J. Chem.  1984,  58:  85 
• 19 Chen QY. Jiang XK. Chen BQ. Scientia Sinica  1966,  4:  498 
• 22 Norman SB. Plunkett AO. J. Chem. Soc., Chem. Commum.  1973,  188 
• 23a Goldsmith D. Soria JJ. Tetrahetron Lett.  1991,  32:  2457 
• 23b Funicello M. Spagnolo D. Sanirato P. J. Chem. Soc., Perkin Trans. 1  1990,  2971 
• 24a Burkholder C. Dolbier WR. Medebielle M. Aitmoliand S. Tetrahedron Lett.  2001,  42:  3077 
• 24b Burkholder C. Dolbier WR. Medebielle M. Tetrahedron Lett.  1997,  38:  821 

20

The analytical and spectroscopic data for triazole 3aa was demonstrated as an example. 5-Chlorodifluoromethyl-1-phenyl-1 H -1,2,3-triazole-4-carboxylic Acid, Ethyl Ester(3aa): Mp: 69.5-70.5 °C. [Found: C, 47.80; H, 3.35; N, 14.24. C₁₂H₁₀ClF₂N₃O₂ requires C, 47.78; H, 3.34; N, 13.93%]. IR(film): 2982, 1723, 1593, 1560, 1497, 1375, 1296, 1254, 1238, 1153, 1094, 1058, 1008, 906, 771 cm^-1. ¹H NMR (60 MHz, CDCl₃): δ = 1.47 (3 H, t, J = 7.0 Hz), 4.52 (2 H, q, J = 7.0 Hz), 7.34-7.74 (5 H, m). ¹⁹F NMR (56.4 MHz, CDCl₃): δ = -44.5; EI-MS: m/z (%) = 302/304 (10/3) [M⁺ + 1], 256/258 (12/4), 245/247 (10/3), 189 (42), 170 (33), 144 (19), 77 (100) [Ph⁺].

21

Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Center as supplementary publication numbers CCDC 196350. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [Fax:[phone] or e-mail: [e-mail]. ac.uk].

25

5-(1,1-Difluoro-2-hydroxy-2-phenyl-ethyl)-1-pheny-l-1 H -1,2,3-triazole-4-carboxylic Acid, Ethyl Ester(7a): Mp: 146.0-148.0 °C. Found: C, 61.41; H, 4.78; N, 10.97. C₁₉H₁₇F₂N₃O₃ requires C, 61.12; H, 4.59; N, 11.25. IR(film): 3445, 3065, 2984, 1778, 1717, 1595, 1546, 1497, 1249, 1231, 1170, 1077, 1014, 766, 738, 693 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.51 (3 H, t, J = 7.2 Hz), 4.01 (1 H, d, J = 3.9 Hz), 4.55 (2 H, q, J = 7.2 Hz), 5.63 (1 H, ddd, J = 12.7, 8.7, 3.9 Hz), 6.89-7.49 (10 H, m). ¹⁹F NMR (282 MHz, CDCl₃): δ = -100.3 (AB-d, J = 273.0, 12.7, 8.7 Hz); EI-MS: m/z (%) = 373 (8) [M⁺], 353 (15), 328 (1), 300 (3), 281 (1), 104 (25), 77 (100) [Ph⁺], 51 (20).