Fluoro-l,2,4-triazoles

Advantage was taken of the greater reactivity of the 5-position compared to the 3-position of l-aIkyl-3,5-dibromo-l,2,4-triazoles (e.g., 139) toward nucleophilic substitution to prepare l-alkyl-3-fluoro-l,2,4 triazoles 140 by halogen exchange. The initial fluorination product was deprotected to give the bromo—fluoro derivative 141 and this was used for subsequent synthetic manipulations. Included was the preparation of a 3,5-difluoro derivative 142 (Fig. 3.84). 

The nucleophilic exchange of one bromine atom in l-benzyl-3,5-dibromo-l,2,4-triazole 21 with fluorine under the action of CsF followed by the photoinitiated elimination of the benzyl protective group led to the formation of 3-bromo-5-fluoro-lH-1,2,4-triazole 22 in 59 % overall yield. The alkylation of this substrate gave l-alkyl-3-fluoro-l,2,4-triazoles for the first time. Both bromine atoms were substituted to provide the corresponding difluoro derivative 24 under the same reaction conditions, but using l-(3,5-dimethoxybenzyl)-3,5-dibromo-l,2,4-triazole 23 as substrate for fluorination [32]. 

Naik SR, Witkowski JT, Robins RK (1973) A novel route to 3(5)-fluoro-l,2,4-triazoles and 8-fluoropurines by displacement of the nitro group. J Org Chem 38 4353 354... 

As may be expected, the bromine substituent in 3-bromo-5-fluoro-17/-l,2,4-triazoles 57a-c can be displaced using a variety of nucleophiles. In particular, treatment of compound 57c with cesium fluoride gave the corresponding difluoro derivative 58 (Equation 18) <1998S1357>. 

Chemical Name 4-Pyrimidineethanol, a-(2,4-difluorophenyl)-5-fluoro-p-methyl-a-(lH-l,2,4-triazol-l-ylmethyl)-, (R-(R, S ))-... 

Analogously, ethyl 4-fluoro-3-methylcrotonate is brominated with NBS in the presence of AIBN and then reacted with triethyl phosphite to produce good yields (72-78%) of a-fluorophosphonate, a key intermediate in the synthesis of fluorinated vitamin A esters (Scheme 3.3)7 Following a similar procedure (radical bromination and Michaelis-Arbuzov rearrangement), ( )-l-fluoro-3-(l-trityl-l,2,4-triazol-3-yl)-2-propenylphosphonate, a good inhibitor of imidazoleglycerol phosphate dehydratase, has been prepared in 25% overall yield. ... 

A search of the literature revealed no reports of unsubstituted 4(5)-fluoro-l,2,3-triazole. 4(5)-Trifluoromethyl-1,2,3-triazole (153) was prepared by the reaction of TMSCHNg with trifluoroacetonitrile (Fig. 3.88). The formation of the A-silylated intermediate was ascribed to TMS-migration. °... 

A-Substituted 4- or 5-fluoro-l,2,3-triazoles have been prepared by 1,3-cycloaddition reactions with azides. For example, reaction of perfluoropropadiene with phenylazide produces a mixture of regioisomeric 1,2,3-triazoles substituted with the phenyl, fluoro, and trifluoromethyl groups (Fig. 3.90). The major isomer was... 

Zumbrunn, A. The first versatile synthesis of l-alkyl-3-fluoro l/7-[l,2,4]-triazoles. Synthesis 1998, 1357-1361. 

A synthetic route to 1-alkyl-1,2,4-triazoHimi 4-nitroimides was developed based on alkylation of the metal salts of 4-nitramino-1,2,4-triazole with halo- and dihaloalkanes (Scheme 9) [44]. These salts are 1-methyl-1,2,4-triazolum 4-nitroimide (31a), 1-ethyl-1,2,4-triazolum 4-nitroimide (31b), l-(2-oxapropyl)-1,2,4-triazolium 4-nitroimide (32a), 1-ethoxycarbonylme-thyl-1,2,4-triazolium 4-nitroimide (32b), 1-methoxymethyl-1,2,4-triazolium 4-nitroimide (33a), l-(4-fluoro-4,4-dinitro-2-oxabutyl)-l,2,4-triazohum 4-nitroimide (33b), l-(2,3-dihydroxypropyl)-l,2,4-triazoHimi 4-nitroimide (34), bis(nitroimido-l,2,4-triazolium-l-yl)ethane (35), l,3-bis(4-nitroimido-l,2,4-triazolium-l-yl)-2-oxapropane (36), and l,3-bis(4-nitroimido-l,2,4-triazol-ium-l-yl)-3-oxapentane (37). 

An example of synthesis of N-fluoro-1,2,4-triazole was described in the patent of Strazdina and Grinstein [6, 17]. Here l-flnoro-3,5-dibromo-l,2,4-triazole 8 was obtained by treating the heterocyclic substrate with the hypohalous acid or its derivatives at -40 to -h50 C in water or an organic solvent in the presence of bases. Langlet and Oslmark in a patent [18] have described the application of isomeric fluoro-triazolones 9,10 as components of explosive compositions, but the data on the synthesis of these substances have been not reported. 

A widely used method of the preparation of versatile 1,2,3-triazoles and tetrazoles consists in the reaction of azides with fluorine-containing compounds with multiple bonds. For example, this approach afforded N-substituted 4(5)-fluoro-l,2,3-triazoles 27,28 by the 1,3-dipolar cycloaddition of perfluoropropadiene to phenyl azide [35], In the course of the reaction a mixture of regioisomeric 1,2,3-triazoles was formed l-phenyl-4-fluoro-5-trifluoromethyl-l,2,3-triazole 27 was considerably prevailed. On the contrary, the reaction of phenyl azide with the perfluoropropyne resulted in predominantly the isomer that was minor in the previous scheme. 

Reck et al. demonstrated that phenylsulfinic acid was eliminated in course of 1,3-dipolar cycloaddition involving l-fluoro-l-(phenylsulfonyl)ethylene and (5R)-3-[4-(l,l-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one. As a result a mixture of regioisomeric 4- and 5-fluoro-l,2,3-triazoles 29, 30 in 7 1 ratio was formed in 28 % overall yield. Compounds 29,30 may be regarded as effective antimicrobial agents [36]. 

Hale JJ, Mills SG, MacCoss M, Finke PE, Cascieri MA, Sadowski S, Ber E, Chicchi GG, Kurtz M, Metzger J, Eiermann G, Tsou NN, Tattersall FD, Rupniak NMJ, Williruns AR, Rycroft W, Hargreaves R, MacIntyre DE (1998) Structural optimization affording 2-(R)-(l-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-l,2,4-triazol-... 

The reaction of a solution 2-hydrazinobenzothiazoles in DMF with formic acid, benzoyl chloride, or acetyl chloride, in the presence of potassium carbonate, gave the 8-fluoro-9-substituted-[l,3]-benzothiazolo[5,l-3]3-substi-tuted-1,2,4-triazoles in good yield, as shown for 6-fluoro-7-(2 -nitrophenylamino)-2-hydrazinobenzothiazole 395 yielding compound 396 (Equation 75) <2004IJH89>. 

Place 300 milliliters of dimethylformamide (DMF) into a flask, and then add and dissolve 4.4 grams of 3-nitro-1,2,4-triazole (obtained in step 2) while stirring the DMF. Stir the DMF mixture for 1 hour at room temperature (while stirring, keep the flask sealed from the air). After 1 hour, place the mixture into a cold water bath, and then add 10 grams of l-fluoro-3,5-diamino-... 

Due to the low solubility of cobalt(II) fluoride in most solvents, formation of cobalt fluoro N-donor complexes (which are the only low-valent cobalt fluorides which are reliably reported) features a variety of starting materials. A common theme that runs throughout this work has been the use of [Co(BF4)2] as the fluoride source, and the subsequent controlled decomposition to obtain a metal-bound fluoride. This has been done, for example, with tris- (3,5-dimethyl-pyrazol-l-yl)methyl amine (amtd) to give [M2(amtd)2F(BF4)3(EtOH)Y(H20)] (M = Co, Cu, Zn x = 0-1.5, y = 1-2). The cobalt complex has been structurally characterised by X-ray diffraction [Fig. 3] [57]. Similarly, the combination of [M(BF4)2] (M = Mn, Co, Ni), [M(N03)2], NH4(NCS) and 3,5-diethyl-1,2,4-triazole (detrH) produces... 

Regueiro-Ren A, Xue QM, Ueda Y et al (2009) HIV-1 attachment inhibitors structure-activity relationships leading to the identification of l-(4-henzoylpiperazin-l-yl)-2-(4-fluoro-7-(l//-l,2,3-triazol-l-yl)-l//-pyrrolo[2,3-c]pyridin-3-yl)ethane-l,2-dione. Abstract MEDI-450. 238th ACS national meeting, Washington, DC... 

In general the information on the synthesis and properties of the N-fluorinated derivatives of 1,2,3- and 1,2,4-triazoles is very scanty [6]. The data about N-fluorotetrazoles are totally absent today. We discuss below the results of the few publications considering the synthesis of N-fluoro-1,2,3- and l,2,4-fliazoles. This desultory information is difficult to classify since the most of these papers lack any experimental details on the synthesis of the compounds of this type and the proofs confirming the structure. 

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