A rhodium-catalyzed transannulation of N -(per)fluoroalkyl-1,2,3-triazoles under microwave conditions – a general route to N -(per)fluoroalkyl-substituted five-membered heterocycles †

A rhodium-catalyzed transannulation via ring-opening of N -(per)- fluoroalkyl-substituted 1,2,3-triazoles followed by cycloaddition with diﬀerent nitriles, enol ethers, isocyanates and silyl ketene acetals under microwave heating provided a highly eﬃcient route to previously unreported N -(per)fluoroalkyl-substituted imidazoles, pyrroles, imidazolones and pyrrolones, respectively. These reactions were found to be applicable to the synthesis of a variety of 5-membered heterocyclesbearing diﬀerent(per)fluoroalkyl substituents aswell asboth electron-donating and electron-withdrawing groups attached to the heterocyclic core.

We initiated our studies using the reaction between 4-methoxyphenyl-substituted 1-trifluoromethyl-1,2,3-triazole 1c and benzonitrile with a rhodium(II) acetate dimer as a catalyst.While conventional heating of the mixture in 1,2-dichloroethane (DCE) gave poor conversion to product 3c (Table 1, entry 1), full conversion of 1c and moderate isolated yield of 3c were achieved by microwave heating (entry 2).Use of a two-fold excess of benzonitrile led to an increase in the yield to 51% (entry 3).Reaction temperature and time optimization revealed that 140 1C and 20 min were optimal.Finally, switching to Rh 2 (Oct) 4 and using chloroform as the solvent afforded the optimized 72% isolated yield of 3c (entry 7).Importantly, the reaction did not take place without the rhodium catalyst or with CuTC (entry 8).
Subsequently, the scope of the reaction was studied under the optimized conditions (Table 2).We tested the transannulation reaction with nitriles on variously substituted aromatic N-perfluoroalkyl-triazoles (Scheme 3).Electron-rich substrates such as 4-methoxy-and 4-methyl-substituted triazoles (1b, 1c) were found to be more reactive and produced higher yields than electron-poor substrates (such as 1f).It is worth noting that this reaction is applicable for the synthesis of the ethoxycarbonyl-substituted aliphatic triazole 3m as well, presumably due to the ability of the CO 2 Et group to stabilize the forming rhodium carbenoid intermediate similarly to the aryl group despite the reported lower stability of electron-poor carbenoids. 19e found the reaction to be rather insensitive to the electronic nature of the nitrile.The yields were excellent in the case of electron-rich, neutral and mildly electron-poor aromatic nitriles and aliphatic nitriles.Only highly electronpoor 4-nitrobenzonitrile reacted much slower under the conditions, thus providing the product in moderate yield.
Longer carbon chain N-perfluoroalkyl triazoles participated in the transannulation reaction with equal efficiency to their CF 3 analogues and high yields of pentafluoroethyl-and perfluoropropyl-substituted imidazoles (3n and 3o, respectively) were obtained.Moreover, tetrafluoroethylene-containing substrates with phenoxy or pyrazolyl functional groups were tolerated, providing a route to multifunctionalized N-fluoroalkylated imidazoles 3p and 3q.
N-(Per)fluoroalkyl pyrroles are previously unreported and attractive targets, which might be accessible by the transannulation of triazoles 1 with vinyl ethers.First, the reaction with ethyl vinyl ether was tested in order to form 4,5-unsubstituted N-(per)fluoroalkyl pyrroles.Indeed, the transannulation in the presence of the Rh 2 (Oct) 4 catalyst took place with concomitant ethanol elimination under the reaction conditions to afford pyrroles 4 in high yields (Table 3).In the case of 4e, a mixture of 4e and 4e 0 (1 : 1.2) formed; in the case of 4g, only compound 4g 0 was observed.In both cases, the treatment of the crude reaction mixture with TsOH resulted in the formation of the desired pyrroles 4e and 4g, respectively.2,4-Disubstituted pyrrole 4h was successfully prepared by the reaction with 2-methoxypropene.The only limitation of the methodology was observed in the preparation of 3,4-disubstituted pyrrole in the reaction with 1-ethoxypropene, where 4i was isolated in low yield.
A comparison of the reactivity of 1a with ethyl vinyl ether and vinyl acetate revealed that while in the case of ethyl vinyl ether ethanol elimination from intermediate 4a 0 proceeded smoothly under the reaction conditions, whereas in the case of vinyl acetate intermediate 4a 00 preferentially undergoes hydrolysis and a mixture of the desired 4a and 5a was obtained (Scheme 2).After having developed an efficient strategy for the preparation of unknown N-(per)fluoroalkylated imidazoles and pyrroles, we set to investigate the application of the methodology for the preparation of other unreported classes of compounds -N-perfluoroalkyl imidazolones and pyrrolones.Gratifyingly, N-trifluoromethylsubstituted imidazolone 6 was prepared by transannulation of 1b with phenylisocyanate (Scheme 3).For the preparation of N-trifluoromethyl pyrrolone 7, one-pot two-step synthesis with silyl ketene acetal, followed by the treatment with TBAF, was used (Scheme 4).
In order to compare the reactivities of previously described N-tosyl and our N-perfluoroalkyl triazoles in the Rh-catalyzed transannulation reaction, a competitive experiment was performed between equimolar amounts of 1d and N-tosyl triazole 8. From the composition of the reaction mixture analyzed by 19 F NMR, it is clear that 1d reacted somewhat slower than 8, however, the reactivity difference is small (Scheme 5).
A plausible mechanism for the transannulation process mirrors the one proposed for N-Ts triazoles.Triazole 1 upon treatment with the Rh II catalyst at elevated temperature is transformed into the key rhodium iminocarbene intermediate A (Scheme 6).Formal [3+2] cycloadditions with 2p components provide zwitterionic species B-E (the actual mechanism might be more complex and can involve the formation of ylides and metallacyclobutenes or in the cases of pyrroles and pyrrolones the formation of cyclopropanes followed by the Cloke rearrangement). 20,22,24The subsequent elimination of the rhodium catalyst (and optional group deprotection or elimination) affords the final products.
The stability of N-perfluoroalkyl imidazoles and pyrroles under acidic or basic conditions at ambient temperature (18 h reaction time) was also investigated.Imidazole 3g was treated with 0.5 M NaOH in CD 3 OD.Proton-deuterium exchange (H/D 81 : 19) of the aromatic hydrogen was observed, suggesting its considerable C-H acidity.When the solution of 3g was treated with 1.2 M sulfuric acid in CD 3 OD, a shift of the aromatic hydrogen signal in 1 H NMR spectrum from 7.90 ppm to 8.45 ppm was observed.Treatment of 4b with 0.5 M NaOH or 1.2 M sulfuric acid in CD 3 OD led to no significant change in the NMR spectra.In all the cases, no decomposition or hydrolysis of 3g or 4b was observed by NMR, showing good stability of these N-trifluoromethylated nitrogen heterocycles in acidic and basic media.
In conclusion, we have developed a highly efficient method for the synthesis of a broad range of previously unreported  N-fluoroalkyl-substituted five-membered heterocycles based on a microwave heating-assisted rhodium-catalyzed transannulation of N-fluoroalkyl-substituted triazoles.This way, a variety of structurally diverse N-fluoroalkyl pyrroles, pyrrolones, imidazoles and imidazolones have been prepared in a straightforward manner.These novel classes of fluorinated compounds should be attractive for discovery programs.It was found that transannulations are not only limited to N-tosyl triazoles but also work with N-CF 3 triazoles and proceed with benzonitrile with a comparable reactivity.N-Trifluoromethyl imidazoles and pyrroles are hydrolytically stable in both acidic and basic media.
This work was financially supported by the Czech Academy of Sciences (Research Plan RVO: 61388963).

aScheme 4 Scheme 5 Scheme 6
Scheme 2 A comparison of the reactivity of 1a with ethyl vinyl ether and vinyl acetate.

Table 2
Synthesis of N-(per)fluoroalkyl imidazoles by transannulation a a Isolated yields.

Table 3
Synthesis of pyrroles by transannulation with vinyl ethers a