Trifluoromethyl 1,2,3-triazoles synthesis

Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-677-imidazo[l,2-fc]-l,2,4-triazol-6-ones 162 was obtained by an iminophosphorane-mediated annulation <06EJ04170>. 8-Trifluoromethyl-l,2,4-triazolo[4,3- >]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one... 

Dandia, A., Singh, R., Sachdeva, H. and Arya, K., Microwave-assisted one pot synthesis of a series of trifluoromethyl substituted spiro [indole triazoles], /. Fluorine Chem., 2001, 111,61-67. 

The synthesis of fluotrimazole starts from m-xylene. Peroxide catalyzed perchlorination converts this to m-trichloromethyl-benzo-trichloride. m-Trichloromethyl-benzotrifluoride is then obtained by selective chlorine/fluorine exchange. This key product is also readily accessible on a technical scale by conproportionation of the two corresponding m-trihalomethyl-benzotrihalogenides. Friedel-Crafts reaction with benzene leads to trifluoromethyl-tritylchloride, which reacts smoothly with 1,2,4-triazole in polar solvents to give fluotrimazole. 

Click chemistry also found applications in peptides and peptidomimetics. Alkyne-azide cycloaddition between two peptide strands provided an efficient convergent synthesis of triazole ring-based P-tum mimics <07CC3069>. The synthesis of a-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected a-propynyl proline in the presence of Cu(I) sulfate <07SL2882>. The synthesis of new trifluoromethyl peptidomimetics with a triazole moiety has been reported <07TL8360>. 

Polyfluorinated target molecules are obtained when both building blocks are fluorinated and/or perfluoroalkylated. A typical example for this type of condensation is the synthesis of a tris(trifluoromethyl)-substituted 1,3,4-triazole from 3,5-bis(trifluoromethyl)benzhydrazide and trifluoroaceta-midine (78BRP1510647). 

Eswaran et al. [16] reported the successful synthesis of new 5-(4-amino substi-tuted-8-(trifluoromethyl)quinolin-3-yl)-4-(un)substituted phenyl-4//-1,2,4-triazole-3-thiols (iv) carrying biologically active groups. 

The preparation of a wide variety of 4-alkyl-1,2,3-triazoles (13-1) has been accomplished by the direct addition of hydrazoic acid or trimethyl-silylazide to various terminal alkynes (Eq. 27). In general, the yields are good, but the lower homologs are better made either through the silyl derivative or by decarboxylation (Eq. 28). A novel approach has been applied by Haszeldine and his collaborators to the synthesis of the 4-(trifluoromethyl) (1.3-2) substituent (Eq. 29). The yield, based on unrecovered starting material, is near quantitative, and this method clearly deserves further development. 

Funabike, K. Noma, N. Kuzuya, G. Matusi, M. Shibata, K. A direct and general synthesis of 5-substituted 3-trifluoromethyl-l,2,4-triazoles via the three component condensation reaction of ethyl trifluoroacetate, hydrazine and amidines. J. Chem. Res. Synop. 1999, 300-301, 1999, 1301-1308. 

Triazole Derivatives. Triazole derivatives are known to possess tumor necrosis factor-a (TNF-a) production inhibitor activity. The synthesis of triazole derivatives can be achieved from alkynes or diynes by a tandem cascade reaction involving 1,3-dipolar cycloaddition, anionic cyclization and sigmatropic rearrangement on reaction with sodium azide. Some of the benzoyl triazole derivatives were considered to be potent local anaesthetics and are comparable with Lidocaine. The triazoles can also be prepared from benzoyl acetylenes,triazoloquina-zoline derivatives, 2-trifluoromethyl chromones, aliphatic alkynes, 2-nitroazobenzenes, ring opening of [ 1,2,4]triazolo [5,1-c] [2,4]benzothiazepin-10 (5//)-one, alkenyl esters and dendrimers. A number of these reactions are outlined in eqs 44 8. 

Kobayashi et al. elaborated an unusual pathway for the synthesis of 2,3-bis(trifluoromethyl)indoles [32], Photolysis of the l-phenyl-4,5-bis(tri-fluoromethyl)-lH-l,2,3-triazole in hexane proceeded very slowly to afford the indole 68 in 44 % yield. It was proposed, that after homolytic nitrogen extrusion, the carbene 67 was formed. Intramolecular cyclization led to the indole 68. 

Some approaches to the synthesis of trifluoromethyl-l,2,3-triazoles by the azidation of compounds containing not a triple but a double C=C bond were described. In this case apparently a functional group elimination occurs in situ to provide the formation of an additional carbon-carbon bond. For instance, Miethchen et al. described a synthesis of 4-trifluoromethyl-1,2,3-triazole 53 linked to the C -atom of D-galactose and D-altrose. 1,3-Dipolar cycloaddition using the monosaccharide azides and the perfluoroalkyl- substituted phenylvi-nylsulfones was performed [55, 56],... 

According to Shreeve et al 4-trifluoromethyl-l,2,3-triazole 58 may be synthesized as a result of 1,3-dipolar cycloaddition of TMSNj to trifluoropro-pyne in the presence of Cu(I) [62], The synthesis of perfluoroalkyl-l,2,3-tri-azoles was also described in the earlier cited paper of Taylor et al. [35], In this study the reaction was investigated between perflnoropropadiene with phenyl azide resulting in regioisomeric 1,2,3-triazole containing at the endocyclic carbon atoms both the fluorine atom and the CFj-gronp. 

Periluoroalkyl-1,2,4-triazoles are often formed by rearrangement of other heterocycles or by cyclization of carboxylic acid hydrazides or their analogues. In 1962 Brown and Cheng described for the first time the synthesis of 3,5-bis(perfluoroaIkyl)-l,2,4-triazoles 70 by treatment of bis(perfluoroaIkyl)-1,3,4-oxadiazoles with methylamine [71], The method for the synthesis of NH-unsubstituted 3,4-bis(perfluoropropyl)-l,2,4-triazole by the action of P2O5 on the corresponding hydrazine was also reported in this paper. Thirty years later Threadgill et al. [72] prepared 3,5-bis(trifluoromethyl)-4-(3-benzyloxypropyl)-4H-1,2,4-triazole by the reaction of 2,5-bis(trifluoromethyl)-l,3,4-oxadiazole with 3-benzyloxypropylamine in methanol (reflux, 9 days). 

It should be noted that in 1998 El-Sayed and Khodairy recognized that thiones 72 are versatile snbstrates for the synthesis of fused and spiroheterocycUc systems [75], Recently Chen et al. synthesized 4-amino-5-(trifluoromethyl)-4H-l,2,4-triazole-3-thiol 73 from thiocarbohydrazide [76]. The latter compound in its turn served as a reagent for the preparation of new functional triazole derivatives 74 and 75 [76],... 

The synthesis of potentially biologically active substances whose structure contained a fragment of 5-trifluoromethyl-l,2,4-triazole linked to pyrazolo- or imidazolopyridine core 81 were presented in the article of Roberts et al. [80]. One of the typical schemes of the synthesis of such compounds includes a hydra-zinolysis of the cyano group. Subsequent acylation with trifluoroacetic anhydride (TFAA) followed by the closure of the triazole ring afforded 81 (yields unknown). 

XiongZ, QiuX-L, Huang Y, Qing F-L (2011) Regioselectivity synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues via TBS-directed 1,3-dipolar cycloaddition reaction. J Fluorine Chem 132 166-174... 

Rozin YA, Leban J, Dehaen W, Nenaidenko VG, Muzalevskiy VM, Eltsov OS, Bakulev VA (2012) Regioselective synthesis of 5-trifluoromethyl-l,2,3-triazoles via CF3- directed cycUzation of 1-trifluoromethyl-1,3-dicarbonyl compounds with azides. Tetrahedron 68 614-618... 

El-Sayed AM, Khodairy A (1998) Synthesis of new fused and spiroheterocycles derived from 4-amino-5-mercapto-3-trifluoromethyl-l,2,4-triazole. Phosphoras Sulfur Silicon 132 41—52... 

Sosnovskikh VY, Usachev BI (2002) A convenient synthesis of 4(5)-(2-hydroxyaroyl)-5(4)-trifluoromethyl-l,2,3-triazoles from 2-tiifluoromethylchromones and chromen-4-imines. Mendeleev Commun 12 75-76... 

Messerle and coworkers reported that a cationic iridium(lll) complex with a methyl-bridged bipyrazoyl or pyrazoyl-l,2,3-triazole (N-N) ligand [lr(N-N)Cp Cl] B Ar 4 (B Ar ".j = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) had catalytic activity for the synthesis of tricyclic indoles [161]. The process... 

Scheme 4.13 Regioselective synthesis of 5-trifluoromethyl-l,2,3-triazoles via CFj-directed...

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