One-Pot (3 + 2) Cycloaddition–Isomerization–Oxidation of 2,2,2-Trifluorodiazoethane and Styryl Derivatives

A facile access to 5-aryl-3-trifluoromethylpyrazoles has been developed by a one-pot (3 + 2) cycloaddition–isomerization–oxidation sequence employing 2,2,2-trifluorodiazoethane and styryl derivatives. A broad variety of functional groups and good yields are achieved under mild conditions. Additionally, the functionalization of 3-trifluoromethylpyrazoles was studied. DFT calculations of the cycloaddition transition state energies are consistent with the experimentally observed reactivity.

P yrazole is a common heterocycle in bioactive compounds. 1 Among them, fluorinated pyrazoles 2 are interesting scaffolds due to the adjustments of physicochemical properties produced by the presence of C−F bonds. In the past decade, the number of reports related to trifluoromethyl derivatives has increased significantly, 2 with applications in pharmaceuticals, agrochemicals, or ligands for transition metals. Particularly, 5-aryl-3-trifluoromethylpyrazoles have successfully led to marketed drugs such as Mavacoxib 3a (veterinary) or Celecoxib 3b (anti-inflammatory) and related structures have been investigated. 3c,d This scaffold also exhibited herbicide activity, 2 and it has been recently applied in coordination chemistry 4 ( Figure 1).
Accordingly, various methodologies have reported the preparation of 5-aryl-3-trifluoromethylpyrazoles. The main strategies involved the condensation of 1,3-dicarbonyl compounds (or equivalents) with hydrazine, 5 and (3 + 2) cycloaddition reactions, also known as 1,3-dipolar cyclo-additions. 6−10 In the latter strategy, 2,2,2-trifluorodiazoethane 7 (CF 3 CHN 2 ) is certainly a suitable reagent to prepare trifluoromethylpyrazoles by cycloaddition. The reactivity toward alkynes has been deeply studied over the past few years, employing silver oxide as an activator, 8a DBU, 8b or flow chemistry conditions 8c,d (Scheme 1a). Recently, a Ntriftosylhydrazone derivative 8e has been reported to form the diazo compound in situ. Noteworthy, equimolecular amounts of metal or relatively high temperatures (80−100°C) were needed to proceed with the cycloaddition.
Another possibility is the (3 + 2) cycloaddition of trifluorodiazoethane with alkenes to give pyrazolines, which can then be transformed into the corresponding pyrazoles with an additional step. The pioneering work on this reaction by Atherton and Fields revealed a limitation in the scope of the reaction: only electron-deficient alkenes smoothly react with pure 2,2,2-trifluorodiazoethane. 9a−c Later, the cycloadditions of in situ generated CF 3 CHN 2 with electron-deficient alkenes were studied by Mykhailiuk. 9d More recently, Ma's group has also addressed the silver-catalyzed cycloaddition of trifluorodiazoethane with activated alkenes to yield aryl trifluoromethyl pyrazoles after in situ elimination of an electronwithdrawing group (−NO 2 or −CN) 10 (Scheme 1b).
Despite the interest in 5-aryl-3-trifluoromethylpyrazoles, there are no examples of cycloaddition reactions of trifluorodiazoethane with simple styrene derivatives without an additional electron-withdrawing group in the alkene. The reactivity described between these two reagents is limited to metal-or enzyme-catalyzed cyclopropanation reactions 11 and one example of a photocatalyzed hydroalkylation reaction. 12 In this context, we have focused our attention on the development of the cycloaddition of trifluorodiazoethane with styrene derivatives and in situ transformation to 5-aryl-3-trifluoromethylpyrazoles (Scheme 1c).
Our studies commenced by mixing 2,2,2-trifluorodiazoethane (1) in DCE solution with styrene (2a) as a benchmark reaction. The use of 2 equiv of styrene led to a cis−trans mixture (ca. 1:1) of 1-pyrazoline (3a) in low yield (Table 1, entry 1). Initial experiments showed that the higher the amount of styrene equivalents, the better the yields that were obtained (entries 1−3). We tested different solvent mixtures, such as toluene, decane, acetonitrile, THF, or DCM, and DCE was identified as the optimal solvent for this reaction. 13 Furthermore, the increase of the temperature from 25 to 40°C allowed the reduction of styrene equivalents with similar good yields (entries 3−4). Next, we investigated the effect of the reaction concentration, observing an improvement in yield with a higher concentration (entry 5). The use of an excess of trifluorodiazoethane produced unidentifiable byproducts resulting in lower yields of the pyrazoline 3a (entry 6).
Noteworthy, we noticed pyrazoline 3a partially isomerized to 2-pyrazoline 4a in the NMR tube in CDCl 3 . After screening several acidic and basic additives, 13 we observed the selective formation of compound 4a by treatment with NEt 3 . This cycloaddition−isomerization sequence could be performed in one-pot in good yield (Table 1, entry 7). We then focused on the direct synthesis of pyrazole 5a, promoted by oxidants such as MnO 2 , DDQ, or halogen-based oxidations (I 2 , Br 2 , NBS, and NIS), but gave incomplete conversion. Gratifyingly, PhI(OAc) 2 smoothly led to pyrazole 5a, and the employment of NEt 3 and PhI(OAc) 2 as additives allowed the one-pot formation of pyrazole 5a in 63% isolated yield after three chemical steps (entry 8). The addition only of the oxidant led to a low yield of 2-pyrazoline 4a (entry 9). Reaction with phenylacetylene instead of styrene was also tested under similar conditions (entry 10), giving a low conversion to pyrazole 5a.
With these optimized reaction conditions for the synthesis of pyrazoles, we moved on to explore the reaction substrate scope (Scheme 2). A wide range of substituted styrenes (alkyl, halogens, nitro, trifluoromethyl, ether, thioether, ciano, ester, and boronate substituents) were compatible with the reaction and afforded the 5-aryl-3-trifluoromethylpyrazoles products in moderate to good yields (50−75%). Furthermore, one ortho substituent did not display a negative effect on the product yield (5b, 5c, 5t), although a mesityl ring suppressed the reactivity (5u). For the highly deactivated substrates (5f, 5v), a mixture of 2-pyrazoline and pyrazole was obtained under standard conditions, and it was necessary to increase the PhI(OAc) 2 equivalents and temperature to achieve complete conversion to pyrazole. The reaction also exhibits tolerance to heterocycles such as pyridine (5x) or thiophene (5y), the latter obtaining the product in low yield. We have also examined tertbutyl acrylate, as a withdrawing group substituent in the olefin under our standard conditions, affording the pyrazole in 47% isolated yield (5z). No reaction was observed in the presence of aliphatic alkenes (1-hexene) or disubstituted olefins (stilbene or α-methylstyrene). In addition, a scale-up experiment (10 mmol) was performed under optimized conditions The Journal of Organic Chemistry pubs.acs.org/joc Note for styrene, and a 59% isolated yield was obtained. Notably, the in situ formation of the diazo compound from CF 3 CH 2 NH 2 · HCl 9d and NaNO 2 also provides a practical result, and these conditions could be extended to the pentafluoroethyl group 14 (5aa). Upon investigation of the scope of this reaction, we were interested in exploring the derivatization of these compounds. The N-arylation of 5-aryl-3-trifluoromethylpyrazole gives access to the synthesis of different drugs and pharmaceutical candidates ( Figure 1) and has been previously reported. 8 Therefore, we focused our attention on other functionalizations in the pyrazole. Bromination at the 4-position could be achieved with NBS as reagent in good yield (6, Scheme 3). Some 5-aryl-4-bromo-3-trifluoromethylpyrazole derivatives have recently showed considerable postemergent activity on weeds. 15 In addition, N-alkylation with ethyl 2-bromoacetate in basic medium was carried out to obtain 7 in moderate yield, a substructure present in Rovazolac (Figure 1).
To gain insight into the undescribed cycloaddition of trifluorodiazoethane with styrene derivatives, we performed DFT calculations to compare the transition state energies of the 1,3-dipolar cycloadditions between unsaturated systems and diazo compounds (2,2,2,-trifluorodiazoethane and ethyl diazoacetate). These results are in agreement with the experimental findings, with an increasing trend from the reaction of trifluorodiazoethane with ethyl acrylate, styrene, or hexene (Figure 2a−c). Moreover, the different energy values allowed us to justify the complete regioselectivity found in these reactions, as well as the lack of stereoselectivity. 13 The transition state energy for the reaction of trifluorodiazoethane with phenylacetylene shows a difference of ∼3 kcal/mol compared with styrene, which explains the low reactivity under these reaction conditions (Figure 2d). Finally, a similar comparison was performed using ethyl diazoacetate. A significant energy difference can be found between the reactions with ethyl acrylate or styrene (Figure 2e−f).
In summary, a one-pot three-step (3 + 2) cycloaddition− isomerization−oxidation sequence has been developed for the coupling of 2,2,2-trifluorodiazoethane and styrene derivatives to access 5-aryl-3-trifluoromethylpyrazoles. This protocol is metal-free, operationally simple, and scalable; features mild conditions; and has a broad substrate scope. Subsequent functionalization of 3-trifluoromethylpyrazoles, including bromination at position 4 or N-alkylation has been explored. Computational data of the transition state energies of the (3 + 2) cycloaddition justify the accessibility to the pyrazolines in the first step of our one-pot procedure.

■ ASSOCIATED CONTENT Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.