An ANRORC approach to the synthesis of perfluoroalkylated 1,2,4-triazole-carboxamides

A series of perfluoroalkyl-1,2,4-triazole-carboxamides has been obtained through an ANRORC-like rearrangement ( A ddition of N ucleophile, R ing-O pening and R ing-C losure) of 5-perfluoroalkyl-1,2,4-oxadiazole-3-carboxamides with methylhydrazine or hydrazine. The initial addition of the bidentate nucleophile to the electrophilic C(5) of the 1,2,4-oxadiazole ring, followed by ring opening and ring closure, leads to the formation of triazoles in good yield under mild experimental conditions. In some cases, a competitive ANRORC-enlargement reaction to form 1,2,4-triazin-6-ones was also observed. Obtained carboxamidotriazoles have also been explored as precursors for the synthesis of 3(5)-perfluoroalkyl-1,2,4-triazoles


Introduction
Synthesis of fluorinated heterocycles represents an interesting research field due to their unique properties.In particular, in the last years, fluorinated 1,2,4-triazoles have attracted much attention because of useful applications in many areas.In the field of material science they have been employed as room temperature ionic liquid, 1 liquid crystals 2 as well as ligands in blue emitting Iridium complex for OLED devices. 3As pharmaceuticals they have been proposed as COX inhibitors, 4 as potent non-nucleoside inhibitors of the HIV-1 reverse transcriptase, 5 and Sitagliptin (MK0431), a trifluoromethylated 1,2,4-triazole derivative, is employed in the treatment of type II diabetes. 6Moreover, fluorinated 1,2,4-triazole salts have been employed as catalysts in the Stetter reaction. 7On the other hand, 1,2,4-triazole-carboxamides have emerged as an important class of antiviral compounds.For instance, Ribavirin, a triazole-carboxamide nucleoside, was the first synthetic nucleoside showing antiviral activity against several viruses. 8o date, it is still the only low molecular-weight drug available for treating viral infections caused by hepatitis C virus (HCV), 9 although some other triazole-carboxamide derivatives have been proposed for the treatment of HCV, 10 and showed activity against the tobacco mosaic virus. 11Finally, 1,2,4-triazole-carboxamide have been recently exploited as structural motifs in the field of pseudo-peptide engineering. 12In the frame of our research on fluorinated heterocycles, we have recently used the ANRORC approach as a valuable method for the obtainment of several fluorinated heterocyclic targets. 13ANRORC processes (consisting of an initial Attack of Nucleophile followed by Ring-Opening and Ring-Closure) have been extensively studied by Van der Plas and his coworkers 14 and represent an useful tool, in the hand of the synthetic heterocyclic chemist, to achieve the ring transformation of heterocyclic systems.In this context, we have recently investigated the reactivity of 5-perfluoroalkyl-1,2,4-oxadiazoles 1 with bidentate nucleophiles such as hydrazine, methylhydrazine or hydroxylamine, and reported their ANRORC-like rearrangements into triazoles 3, 13a,b,f 1,2,4-oxadiazole regioisomers 4, 13e and 1,2,4-triazines 5,6.13a,d From a mechanistic point of view, 1,2,4-oxadiazole 1 reacted as a 1,3-dielectrophilic reagent; in fact, the presence of a strongly electronwithdrawing perfluorinated chain makes the C(5) (of the azole ring) a good electrophilic site, and allows the initial nucleophilic attack and ring-opening steps.In the subsequent steps, the cyclization can lead to different rings, depending on the nature of electrophilic sites present on the open-chain intermediate 2 (Scheme 1).Moreover, considering the regiochemical issue related to the use of asymmetric dinucleophiles, attack of the -NH 2 moiety to the C(5) of the oxadiazole was preferentially observed in all the studied cases.

Scheme 2
The obtained 1,2,4-oxadiazoles 8 were reacted in DMF at room temperature with the chosen hydrazine reagent.Unfortunately, the reaction with phenylhydrazine produced a complex mixture of products and was not considered of synthetic utility.On the other hand, when methylhydrazine was employed as nucleophile, 1-methyl-3-perfluoroalkyl-1,2,4-triazole-5carboxamide 9a-c were obtained in good yield (Scheme 3, Table 1).On the other hand, by using hydrazine as nucleophile, besides the expected fluorinated 1,2,4-triazoles 10a-c, formation of 1,2,4-triazinones 11 13a was observed in some cases (Scheme 3, Table 1).The structures of fluorinated triazoles 9 and 10 were confirmed by analytical and spectroscopic data  The regiochemistry of methyl-1,2,4-triazoles 9 was assigned by means of HMBC experiments.Representatively, the 1 H- 13 C HMBC spectrum of 9c revealed the presence of a long-range coupling between the methyl signal at 4.16 ppm and the quaternary carbon at 149.0 ppm.On the other hand, the long-range coupling has not been observed between the methyl hydrogens and the quaternary C(3) carbon at 151.1 ppm, easily recognizable as a triplet because of geminal C-F coupling ( 2 J C-F = 28.6 Hz) with the CF 2 moiety.Finally, long-range coupling between the two methyl signal of dimethylamino moiety (3.14 and 3.32 ppm) and remaining quaternary carbon at 157.9 ppm, allows the identification of the latter as the carboxamido carbon.
Interestingly, with methylhydrazine, formation of fluorinated methyl-triazinones 12 was not observed (see Scheme 3).The absence of these compounds from reaction mixtures was determined by using authentic samples of 12 as reference.13a From a mechanistic point of view, formation of the obtained compounds could be explained on the basis of two competitive ANRORC-like rearrangements (Scheme 4).In our opinion, when the reaction is performed with methylhydrazine, path b results suppressed probably due to steric hindrance between the -NHMe and dimethylamino groups, which inhibits the cyclization step.On the other hand, in the reaction with hydrazine, the two paths became competitive and the 10:11 product ratio is affected by the length of the perfluoroalkyl chain.In fact, triazole yield increase with carbon number of the R F chain, while, at the same time, a decrease in triazine yield is observed.These data suggest that the fluoroalkyl moiety size has a role in determining the regioselectivity during the cyclization step of intermediate 13.

Conclusions
In conclusion, an ANRORC approach for the synthesis of various fluorinated 1,2,4-triazolecarboxamides has been developed.In its turn, obtained triazole-carboxamide has been used as precursors for the synthesis of mono-substituted perfluoroalkyl-1,2,4-triazoles.

Experimental Section
General Procedures.Melting points were determined on a Reichart-Thermovar hot-stage apparatus and are uncorrected.IR spectra (Nujol) were determined with a Shimadzu FTIR-8300 instrument; 1 H and 13 C NMR spectra were recorded on a BRUKER 300 Avance spectrometer with TMS as an internal standard.GC-MS determinations were carried out on a VARIAN STAR 3400 CX/SATURN 2000 system.Flash chromatography was performed by using silica gel (Merck, 0.040-0.063mm) and mixtures of ethyl acetate and petroleum ether (fraction boiling in the range of 40-60 °C) in various ratios.Compounds 7a-c 13a were obtained as previously reported.

Hydrazinolysis reactions of 1,2,4-oxadiazoles 8 in DMF. General procedure
To a mixture of oxadiazole 7 (1 mmol) in DMF (3 mL), an excess of methylhydrazine or hydrazine (3 eq.) was added.After stirring for 3h at rt the mixture was diluted with 1 M HCl (50 mL) and extracted with EtOAc.The organic layer was dried over Na 2 SO 4 and evaporated.The residue was then chromatographed.

ISSN
( 1 H NMR, IR and GC-MS), while triazinones 11a,b were identified by comparison with authentic sample obtained from ANRORC rearrangement of the corresponding esters 7a,b with hydrazine.13a F =CF 3 b: R F = C 3 F 7 c: R F = C 7 F 15

Scheme 3 Table 1 .
Products distribution for hydrazinolysis reactions of oxadiazoles 8