1.2.4- Triazoles, 5-trifluoromethyl

Three skeleton atoms of a hetero-l,3-diene are incorporated into a five-membered ring system on reaction with 1,2 [n,n] compounds (e.g., hydrazines, reaction type 4, equation 10). On further heating in the presence of azobisiso-butyronitrile (AIBN), the bis(trifluoromethyl)-substituted 1,2,4-triazolines are transformed into 5-tnfluoromethyl-l,2,4-triazoles in high yield [t02 (equation 22). 

Ligands with S donors in addition to N and or O donors bound to Co11 are reasonably large in number. For example, the 4-amino-3-alkyl-l,2,4-triazole-5-thione can bind Co11 as a chelate employing the primary amine and thione substituents on the five-membered ring,510 whereas the trifluoromethyl ligand (afmt) forms [Co(afmt)2(H20)2](N03)2, defined as the A -irons isomer... 

Because of its great reactivity PTAD has found wide use in the interception of reactive, unstable dienes. For example, unstable isoindenes,226 3a//-indenes,146 1,3-divinylallenes,227 and benzene oxides228 have all been successfully trapped with PTAD. 4-(4-Bromophenyl)-l,2,4-triazole-3,5-dione (5, R = 4-Br—C6H4) is often used if the derivatives ai e required for X-ray structure determination.229 Azodicarboxylic esters have been used to trap tetra(trifluoromethyl)cyclobutadiene,230 and spiro[4.4]nonatetraene.231... 

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... 

Ethoxyvinyl trifluoromethyl ketone 243 reacts slowly at elevated temperature with aryl and benzyl azides to provide triazoles 245 in good yield (51-88%). The reactions, carried out neat, are completed usually in 2-3d(days). However, a longer reaction time (6 d) is required for 2-methylphenyl azide due to its steric hindrance. 5-Ethoxytriazolines 244, the expected intermediates in this process, readily eliminate ethanol under the reaction conditions and cannot be isolated (Scheme 34) <2002JFC(116)81 >. 

A potentially profitable discovery was that dibromide 74 will undergo an Ullman-type coupling to give the corresponding bis(l,2,4-triazole) 76 in 51% the reaction conditions employed were chosen in order that a trifluoromethyl substituent could be introduced but this reaction did not occur, the biaryl bond formation being preferred (Equation 27) <2006T3301 >. 

Chen and coworkers have developed two new phosphorescent blue emitters, which have two identical 2-(2,4-difluorophenyl)pyridine ligands and are derivatives of the Firpic compound, iridium(III) bis(4,6-difluorophenylpyridinato)-3-(trifluoromethyl)-5-(pyridin-2-yl)-1, 2,4-triazolate (Firtaz) and iridium(III) bis(4,6-difluorophenylpyridinato)-5-(pyridin-2-yl)-l//-tetrazolate (FirN4) (Scheme 3.90) [314]. Both these two blue emitters show a 10-nm blue-shift of the emission compared with Firpic. Unfortunately, the efficiency of such blue emitters is inferior to those of Firpic and Fir6. There is no lifetime data reported for such devices. 

The thermodynamic properties of 3,5-bis(trifluoromethyl)-l,2,4-triazole have been measured and discussed in the light of the conclusions provided by ab initio calculations (MP2/6-31G //6-31G level of accuracy) applied to trifluoromethyl-substituted triazoles, the parent triazole and pyrazole. It is worth noticing that 21 is more stable than 21a by... 

The gas phase basicity of 3,5-bis(trifluoromethyl)triazole (22) has been determined by Fourier transform ion cyclotron resonance mass spectrometry as —50.2 + 0.8 kJ mol <94JOC1039). The proton affinity related to ammonia was calculated as — 60.5 kJ mol . 

The only reported 19F study is that of Middleton and Metzger339 on 2,4,6-tris(trifluoromethyl)imidazo[l,5-6]-s-triazole and derivatives, and results are assembled in Scheme 25 (solvent acetone reference CCljF). 

Substitution of a trifluoromethyl group in the 3-position of the benzene ring and alkylation of the 4-amino group, as in norflurazon (16) (69FRP1575643), turns the pyridazin-3-ones into inhibitors of carotenoid biosynthesis. A similar substitution pattern occurs in fluridone (17) (74GEP2537753). The long-established l,2,4-triazol-3-ylamine, known as amitrole, and... 

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 diphosphabenzvalene-phenyl azide adduct (Scheme 22) undergoes a similar retro addition when treated with silica gel to yield l-phenyl-4,5-bis(trifluoromethyl)-1,2,3-triazole the fate of the diphosphabicyclobutane part, however, is not clear.165... 

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. 

Second, intramolecular cyclization involving the azido group and the double bond could yield 1,2,3-triazoline derivatives these may be thermally unstable and may undergo nitrogen elimination to afford azirine derivatives. The reaction of perfluoro-2-methylpent-2-ene with NaN3 in a 1 2 acetonitrile-ethanol mixture at — 10°C (2 h) yielded stable 5-ethoxy-5-pentafhioroethyl-4,4-bis(trifluoromethyl)-4,5-dihydro-1H-1,2,3-triazole 9, whose structure was confirmed by X-ray analysis, Fig. 1 (01 JFC(110)21, 97ZOR772). 

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>. 

The cycloadducts obtained often undergo elimination reactions with heteroaromatization under the reaction conditions or on heating as demonstrated by the transformation of bis(trifluoromethyl)-substituted 1,2,4-triazolines into 5-trifluoromethyl-l, 2,4-triazoles in the presence of azobisi-sobutyronitrile (AIBN) (88CZ109) (Scheme 22). 

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). 

A/ -Methyl-A -trifluoroacetylaminoguanidine prepared from A -methyl-A -aminoguanidine and trifluoroacetic anhydride undergoes a 1,5-cyclocondensation reaction to give a pharmaceutically active trifluoromethylated 1,2,4-triazole (80FRP2477150) (Scheme 49). 

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