Recent progress in the trifluoromethylation of alkenes with Togni’s reagents

Recent progress in the trifluoromethylation of alkenes with Togni’s reagents is reviewed. Seven approaches to the trifluoromethylation of alkenes are summarized: (i) oxytrifluoromethylation, (ii) aminotrifluoromethylation, (iii) allylic trifluoromethylation, (iv) cyanotriﬂuoromethylation, (v) trifluoromethylazidation, (vi)

In 2011, the groups of Buchwald 23 and Wang 24 showed that Togni's reagents can be used as a clean source of the CF3 radical for the trifluoromethylation of alkenes.These trifluoromethylations rely on Cu(I) catalysis, and experimental evidence for the involvement of free CF3 radicals was provided (Scheme 2).Based on these results, Li and Studer 25 used the readily available sodium aminoalkoxide 1 as a single-electron-transfer (SET) reagent for the reduction of Togni's reagents to generate the CF3 radical along with the corresponding persistent TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) radical.A proposed mechanism for this trifluoromethylation reaction is depicted in Scheme 3. Reaction of Togni's reagents with a copper catalyst generates a CF3 radical (Scheme 2), 23,24 followed by radical addition and single-electron oxidation to give intermediate C. 26 Subsequent trapping of the carbocation C with a nucleophile leads to the desired product D. It is assumed that trifluoromethylation of olefin substrate E might be achieved using a copper-based strategy involving the generation of an allylic radical and a subsequent CF3 transfer (Scheme 3, Path A). [27][28][29] Alternatively, if Togni's reagent 1 could be used as an electrophilic CF3•equivalent, the final product F may be generated through an atom transfer radical addition type pathway (Scheme 3, Path B). 30 Finally, an electrophilic trifluoromethylation proceeding via a cationic intermediate may also be viable (Scheme 3, Path C).

Scheme 3
CAUTION! Togni's reagents were reported to be explosive, and should only be handled with the appropriate knowledge and safety measures. 31Togni's reagent 1, which showed a decomposition energy of 502 J/g in the DSC-measurement, is dangerously explosive and may only be transported by approval of the national competent authority.Another critical property of Togni's reagent 1 is the fast combustion when ignited.The substance vaporizes quickly without flame when ignited with a match corresponding to a combustion factor BZ6 which is the same classification as that of black powder. 31Togni's reagent 2 produces a melting signal with an onset at 77 °C followed by a decomposition with a strong exotherm of 790 J/g with an onset at 135 °C and a maximum heat flow of 6 W/g in an aluminum pan with pierced lid. 31

Oxytrifluoromethylation
Recently, an easy-to-conduct, transition-metal-free trifluoromethylaminoxylation of alkenes using the commercially available Togni's reagent 1 was developed by Li and Studer (Scheme 4). 25 Styrene and styrene derivatives were readily oxytrifluoromethylated and the corresponding products 2 were isolated in good yields.A side product in these radical trifluoromethylations was TEMPOCF3 resulting from the direct trapping of the CF3 radical with TEMPO.

Scheme 4
In 2012 and 2013, Buchwald and co-workers 26,32 reported a simple and mild method for the oxytrifluoromethylation of unactivated alkenes bearing a hydroxy or carboxylic group in the presence of Togni's reagent 1 and a catalytic amount of [(MeCN)4Cu]PF6 (Scheme 5).A series of unsaturated aliphatic and aromatic carboxylic acids or alcohols were found to undergo the desired transformation to give the corresponding trifluoromethylated lactones or cyclic ethers in good yields and useful enantiomeric excesses.

Scheme 5
A mild and convenient method for the efficient oxytrifluoromethylation of unactivated alkenes based on a copper-catalyzed oxidative difunctionalization strategy was developed by the research groups of Szabó and Sodeoka in 2012 (Scheme 6). 33,34Szabó et al. showed that alkenes undergo smooth addition reactions with Togni's reagent 1 using CuI as catalyst. 32The reaction proceeds with higher yield, high regioselectivity and more cleanly for electron-rich styrenes.
Vinyl sulfide substrates reacted similarly to styrenes to give the expected trifluoromethyl benzoate products.Sodeoka and co-workers 34 showed that oxytrifluoromethylation reaction of styrene derivatives was achieved with high efficiency in the presence of [(MeCN)4Cu]PF6 catalyst and Togni's reagent 1. Oxytrifluoromethylation of styrene derivatives bearing an oxygen atom or no heteroatom on a phenyl ring and N-protected aniline derivatives proceeded smoothly to give the corresponding products in high yields.

Scheme 8
Copper-catalyzed aminotrifluoromethylation of alkenyl amine derivatives for the generation of various pyrrolidine or aziridine derivatives was developed by Sodeoka and co-workers in 2013 (Scheme 9). 35In the aminotrifluoromethylation, reactions of substrates bearing an electrondonating group on the aniline ring were faster than those of substrates with an electronwithdrawing group.Without a substituent on the aromatic ring the yield was somewhat lower (70 %), although the reaction still proceeded smoothly.Encouraged by these results, the aminotrifluoromethylation of the 4-methoxy-N-pentenylaniline derivative 17 was also attempted, and the pyrrolidine derivative 18 was obtained in 76 % yield.

Allylic trifluoromethylation
In 2011 a CuCl-catalyzed allylic trifluoromethylation reaction, which provides a general and straightforward way to synthesize allylic trifluoromethylated compounds under mild conditions, was developed by Wang and co-workers (Scheme 10). 24The simple alkenes, aliphatic aldehyde group, and tert-butyldimethylsilyl (TBDMS) ether protecting group were tolerated in the reaction, with the desired product being obtained in excellent yield.Other linear allylic trifluoromethylated compounds were obtained in 48-93% yield, when terminal olefins bearing ester, amide, benzoate, benzenesulfonate, phthalimide functional groups and an aromatic moiety were employed as substrates.Cyclohexene, cycloheptene and a substrate featuring an exocyclic double bond at the cyclohexyl ring were also tested with Togni's reagent 1, affording the corresponding trifluoromethylated cycloalkene and CF3-containing cyclohexane derivative in acceptable yields (44-55%).

Scheme 10
In addition, Loh's group 37,38 developed olefinic trifluoromethylation of enamides and C-H trifluoromethylation of electron-deficient alkenes by taking advantage of neighboring directing groups with Togni's reagent 1 in the presence of [(MeCN)4Cu]PF6 or CuCl as catalyst (Scheme 11).The reactions tolerated a wide variety of substrates with both electron-donating and electron-withdrawing substituents to produce the desired trifluoromethylation products in moderate to excellent yields.
On the basis of experimental results and related precedent, the reaction mechanism proposed is as depicted in Scheme 12.The reactive intermediate A, arising from the reaction between Togni's reagent 1 and Cu(I), reacts with enamide to produce the iodo(III) cyclopropane B, 39,40 which is expected to be in equilibrium with the corresponding α-iodo(III) imine.Subsequent reductive elimination from B generates the α-trifluoromethyl imine intermediate C, which can react via two divergent routes depending on the solvent and catalyst used.Using the CuCl-methanol system, the imine intermediate is sequestered by the methanol solvent to form the N-acyl-β-trifluoromethyl enamines 22, while with the Cu(MeCN)4PF6-THF system, intermediate C goes on to form complex D, with the nitrogen bound to the Lewis acidic Cu(I) catalyst, which in turn induces α-proton elimination or transfer to deliver the final olefinic trifluoromethylation product.

Cyanotrifluoromethylation
Szabó and co-workers 41 reported that under appropriate reaction conditions CuCN in combination with Togni's reagent 1 is suitable for selective introduction of the CF3 and CN groups to styrenes, thus creating two C−C bonds in a single addition reaction (Scheme 13).
Styrenes with an electron withdrawing group proved to be particularly useful substrates for cyanotrifluoromethylation.However, the reaction of styrenes 25a under the standard reaction conditions afforded oxytrifluoromethylated product 27 in 87% yield.

Scheme 14
On the other hand, Liang et al. reported the Cu(OTf)2-catalyzed intermolecular cyanotrifluoromethylation of alkenes based on the difunctionalization strategy. 42In most cases, alkenes 25 proceeded smoothly to transform into the cyanotrifluoromethylation products 26 in moderate to good yields, and the substrates bearing electron-donating groups gave higher yields than those containing electron-withdrawing groups on the aromatic rings.A possible mechanism for cyanotrifluoromethylation of alkenes with Togni's reagent 1 is shown in Scheme 14. 42

Trifluoromethylazidation
Liu and co-workers reported that a novel copper-catalyzed intermolecular trifluoromethylazidation of alkenes delivered vicinal CF3-substituted alkyl azides in one step, when the less reactive Togni's reagent 2 is employed as a CF3 source (Scheme 15). 43Substrates 28, having various substituents (R) on the aromatic ring, including electron-donating and electronwithdrawing groups, were tolerated under the reaction conditions to give the desired products 29 in good yields.A range of 1,1-dialkyl-substituted alkenes 30 or cyclic substrates from five-to eight-membered rings 32 were suitable for this trifluoromethylazidation reaction and gave the tertiary alkyl azides 31 or the trifluoromethylated cyclic organoazides 33 in good yields.(5 mol%)

Scheme 18
A possible mechanism for carbotrifluoromethylation of alkenes with Togni's reagent 1 is shown in Scheme 19.First, a single-electron transfer (SET) takes place from Cu(I) catalyst to togni reagent 1 to generate a Cu(II) complex and a trifluoromethyl radical species, which reacts with the alkene of substrate 38 to form a radical intermediate A, followed by a cyclization with the sulfonylbenzene ring to give another radical intermediate B. After aromatization, the trifluoromethylated cyclization product 39 is formed.

Trifluoromethylation-rearrangement
In 2013, Wu's group 47 reported a novel trifluoromethylation-rearrangement reaction of allylic alcohols employing Togni's reagent 1 with CuI as catalyst.Similar reactions have later been reported by Tu and co-workers. 48These methods enable the construction of both Csp3-CF3 bonds and a quaternary carbon center.A wide variety of β-trifluoromethyl α-aryl ketones with different substituents can be easily prepared under mild conditions (Scheme 20).
To gain further understanding about the migration step, Wu's group conducted computational studies using 40a as a model compound (Scheme 21).The calculation indicated that the para-trifluoromethylphenyl group migrates preferentially over the phenyl group when radical intermediate B is involved.Moreover, the preferential migratory aptitudes of non-orthosubstituted aryl groups over ortho-substituted ones were also reproduced, with the migration occurring via radical intermediate B. Therefore, a simplified catalytic cycle for the rearrangement is proposed (Scheme 21  electron-deficient aryl group via spiro [2,5]octadienyl radical C produces intermediate D. Singleelectron transfer (SET) between Cu II and D delivers the desired product 41a with concomitant loss of a proton, and regenerates the active copper(I) species.When ortho substituent(s) are present on one of two aryl groups in 40a, the migration of the non-ortho-substituted aryl group might be more favorable, generating a sterically less congested radical C.

Conclusions
In summary, due to the great importance of the CF3-containing compounds in pharmaceutical and agrochemical industries, much attention has been focused on the trifluoromethylation of alkenes with Togni's reagents for the construction of C-CF3 bond in recent years.In this review, we classified trifluoromethylation reactions under seven headings: oxytrifluoromethylation, aminotrifluoromethylation, allylic trifluoromethylation, cyanotrifluoromethylation, trifluoromethylazidation, carbotrifluoromethylation and trifluoromethylation-rearrangement.Most of the newly developed methods facilitate convenient trifluoromethylation of alkenes under mild conditions with high regioselectivity and in good to excellent yield.With the rapid development of new chemistry in recent years, new and effective approaches to the trifluoromethylation of alkenes with Togni's reagents can be expected.

Acknowledgement
We are grateful to the Chongqing Vocational Institute of Safety and Technology for financial support.

Table of Contents
Scheme 8).This method provides access to the synthesis of trifluoromethylated pyrrolidines or indolines in good to excellent yields.