Multi-substituted trifluoromethyl alkene construction via gold-catalyzed fluoroarylation of gem-difluoroallenes

An unprecedented fluoroarylation of 1,1-difluoroallenes with a cost-effective nucleophilic fluoride reagent and aryldiazonium salts is reported. This visible light promoted gold-catalyzed reaction allows a stereo- and regioselective incorporation of both the fluorine atom and aryl group, enabling a straightforward construction of multi-substituted trifluoromethyl alkenes. Under the mild reaction conditions, a nice tolerance of diverse functional groups is achieved. The high regioselectivity for fluorine-incorporation is rationalized by considering the thermodynamic driving force of trifluoromethyl group formation, whereas the counterintuitive stereoselectivity that aryl is installed on the side of the bulkier γ-substituent is interpreted by alleviating the increasing 1,3-allylic interaction in the gold-coordinated allene intermediate en route to the product.


Introduction
Fluorine-decorated molecules, compared with their non-uorinated analogues, oen exhibit fundamentally differing physicochemical and biological properties because of the unique character of the uorine element. 1,24][5][6] To this end, diverse bespoke reagents and synthetic strategies have been successfully developed in recent decades. 7,8Among these protocols, the uoroarylation of p systems, which permits the concomitant incorporation of a uorine atom and an aryl group, proves to be a versatile platform for the rapid buildup of molecular complexity.Continuing endeavors from the synthetic community have thus been rewarded by a prominent advance in this area. 9,102][13][14] Consequently, the pursuit of more enabling protocols that employ readily available, cost-effective nucleophilic uorination reagents is still in high demand.Recent advances from the groups of Loh and Feng, 15 Ogoshi and Ohashi, 16 Malcolmson 17 and Zhang 18,19 have demonstrated the feasibility of transition metal-catalyzed uoroarylation of specic alkene derivatives, such as gem-diuoroalkenes and tetrauoroethylene, though somewhat expensive silver uoride is frequently required.By contrast, further extrapolation of this chemistry to accommodate allene counterparts is far less explored, probably due to the more complicated reactivity prole and potential selectivity issues.It is of note that Doyle and co-workers disclosed an elegant protocol leading to an expedient uoroarylation of mono-substituted allene substrates, although the regioselectivity of uorineincorporation was not that encouraging (Scheme 1a). 20Very recently, by making use of readily available Et 3 N$3HF as the uoride, our group had reported the rst example of goldcatalyzed uoroarylation of allenoates (Scheme 1b). 21,22otwithstanding the advance in this vein, devising more efficient synthetic protocols for structurally diversied uorinated frameworks is still of particular importance.
8][29] In the context, the Witting-type olenation [30][31][32] and transition-metalcatalyzed cross-coupling reactions 26,27,[33][34][35] evolve to be the state of the art, despite the remaining issues such as strongly basic reaction conditions, volatile and expensive tri-uoromethyl reagents, and poor stereoselectivities.With our continuing interest in the uoroarylation of p systems, 15,21,36,37 we would like to report herein our latest advancement in this territory (Scheme 1d).Notable features include: (i) the coordination of the allene motif by the in situ generated trivalent gold complex not only prompts the nucleophilic uorination via substrate activation, but more importantly induces a cascade which eventually affords the triuoromethyl alkene with high stereoselectivity; (ii) the uoroarylation is subjected to a chargecontrolled scenario, by which the nucleophilic attack of uoride selectively targets the a-carbon atom, while the formation of the triuoromethyl in turn permits a thermodynamic driving force for such a step.

Results and discussion
We began our initial studies by using 1,1-diuoroallene 1a and aryldiazonium salt 2a as the model substrates.To our delight, when [Au(PPh 3 )]Cl and Et 3 N$3HF were used as the catalyst and uoride source, reaction carried out in MeCN under 5 W blue LEDs afforded the desired product 3aa in 62% NMR yield (Table 1, entry 1). 38Further screening showed that the nucleophilic uorides such as CsF, n Bu 4 NF and pyridine$xHF were not effective (Table 1, entries 2-4).Low yields and stereoselectivity were obtained when DCE or DMF was employed as the solvent (Table 1, entries 5 and 6).Gold catalyst analysis indicated that [Au(PPh 3 )]NTf 2 was also suitable, affording 3aa in 56% yield and better stereoselectivity (Table 1, entries 1, 7 and 8).Considering that the merger of gold and photoredox catalysis is the prevailing strategy to improve reaction turnover, [39][40][41] the inuence of photocatalysts in this reaction is further interrogated.Among a panel of photocatalysts, xanthone turned out to be optimal, resulting in a sharp increase of reaction efficiency and stereo-selectivity (Table 1, entries 9-12).Further control experiments veried the indispensability of the gold catalyst (Table 1, entry 13), whereas the photocatalyst and light irradiation were benecial (Table 1, entries 8, 12 and 14). 42ith the optimal reaction conditions in hand, the substrate scope with respect to both 1,1-diuoroallene 1 and aryldiazonium salt 2 was subsequently examined, and the results are summarized in Table 2.A variety of functionalized monoalkyl substituted gem-diuoroallenes (1a-1r) were well accommodated, leading to the corresponding triuoromethyl alkenes in moderate to high yields and good E/Z-selectivities.Functionalities such as phenyl (1a and 1b), halogen (1c and 1d), and ester (1e) on the tethered carbon chain proved to be well tolerated.Furthermore, 1,1-diuoroallenes substituted with electron-decient arene (1f) or electron-rich furan (1g) also engaged in this reaction smoothly to afford the desired 3fa and 3ga in 54% and 56% yields, respectively.To our delight, hydroxycitronellalderived allene 1h was also well tolerated, delivering 3ha in good yield and stereo-selectivity.To evaluate the inuence of steric hindrance on the E/Z selectivity of this protocol, a series of gem-  a Unless otherwise noted, all the experiments were conducted with 1a (0.1 mmol), 2a (2.0 equiv.),Et 3 N$3HF (10 equiv.),catalyst (10 mol%), and PC (5 mol%) in MeCN (1 mL) under 5 W blue LEDs for 12 h in a Schlenk tube under N 2 ; yield was determined by crude 19 F NMR with 1-iodo-4-(triuoromethyl)benzene as the internal standard and the E/Z ratio was also determined by crude 19 F NMR; isolated yield was indicated in the parentheses.diuoroallenes containing secondary alkyl substitutes at the g position were assessed.In general, the desired products 3ia-3na were readily obtained with high E/Z ratios (>15/1).Notably, substrates bearing an additional alkene motif did not show any interference with the desired uoroarylation as demonstrated by the examples of 3la and 3na.Alicyclic 1,1-diuoroallenes also participated in this reaction without any issue (1m and 1n).Furthermore, sterically more hindered tertiary alkyl-substituted allenes were also proved to be applicable in this protocol (3oa-3ra).The generality with regard to aryldiazonium salt was also investigated, and substrates bearing a wide range of electronwithdrawing or electron-donating groups were compatible.Functional groups such as ketone (3ab-3ad), nitro (3ae), CF 3 (3af), Ms (3ag), ester (3ah) and OMe (3ak) were well tolerated.When naphthyl diazonium salt 2j was employed, product 3aj was isolated in 57% yield with excellent stereo-selectivity.Furthermore, aryldiazonium salts with halogen substitutes underwent this uoroarylation uneventfully, providing the potential handle for further synthetic elaboration through the well-developed cross-coupling reactions.In addition, aryldiazonium salts derived from (+)-menthol (2p) and coumarin 120 (2q) were amenable to this reaction, showcasing the synthetic potential of this protocol.g,g-Disubstituted gem-diuoroallenes were also competent to deliver the desired tetra-substituted triuoromethyl alkenes in moderate to good yields (3sa-3afa).
Consistent with the outcomes of monoalkyl-substituted gem-diuoroallenes, these reactions inclined to deliver the Eisomers by introducing the aryl group from the side of the bulkier substituent.It is a rational corollary that the stereoselectivity would deteriorate to a certain extent with a decrease of steric discrepancy between the two substituents, however, the reversion of E/Z-selectivity in the case of 3ta is still somewhat surprising.Allene substrates bearing a wide range of functionalities, such as aryl uoride (1u), aryl chloride (1v), alkyl (1w), alkenyl (1y), alkyl chloride (1z), cycloalkyl (1aa, 1ab and 1ae), Boc-protected amine (1ac), and thioether (1ad), all uneventfully participated in this transformation with good yields and stereoselectivities.Of note, substrates derived from more complex molecules, such as those based on piperonyl acetone (1x) and DL-a-tocopherol (1af), were also well amenable to this reaction.][45][46] To shed more light on the reaction mechanism, a series of control experiments were conducted (Scheme 2).At the outset, we tried to gure out whether Au I or Au III activated gem-diuoroallene toward nucleophilic uorination.Control experiments between allene 1a and Et 3 N$3HF indicated that no reaction occurred in the absence of the gold catalyst (Scheme 2a, entry (1)).The addition of either Au I or Au III salt to this reaction led to the formation of hydrouorination product 3a, showing that both Au I and Au III catalysts could activate the allene substrate, and Au III was superior probably because of its stronger Lewis acidity (Scheme 2a, entries 2 and 3).It was found that the addition of AgBF 4 and PPh 3 was benecial, which demonstrated that cationic Au III could serve as a more powerful p acidic catalyst (Scheme 2a, entries 4 and 5).To further distinguish the activation mode, Ar-Au III species II 0 was prepared and employed in the reaction of 1a and 2e.While no reaction occurred in the absence of the silver additive, uoroarylation product 3ae was obtained in 73% yield with the addition of AgBF 4 (Scheme 2b).A stoichiometric experiment between Ar-Au III species II 0 and 1a could also afford 3ae in modest yield and AgBF 4 was proved to be necessary for productivity (Scheme 2c).These results further attested the amenability of the cationic high-valent gold species in catalyzing this transformation.Subsequently, a contrasting experiment between 1,1-dibromoallene 1ag and 2a under standard reaction conditions turned out to be unsuccessful, which underlines the key role of the gem-diuoro substituents in this reaction (Scheme 2d). 47,48n the basis of these results, a plausible mechanism was proposed (Scheme 3).The reaction started with oxidative addition of aryldiazonium salt 2 to the Au I catalyst I by the assistance of photoredox catalysis, delivering the actively cationic Ar-Au III species II. 49,50Then, the coordination of gem-diuoroallene 1 to the Au III center affords intermediate III. 21,51,52The electronwithdrawing ability of the two uorine atoms renders the acarbon of intermediate III electron-decient, thus making it susceptible to the ensuing nucleophilic attack by uoride.Upon regioselective nucleophilic uorination, triuoromethyl vinyl gold complex IV is formed.Subsequent reductive elimination provided the desired product 3 accompanied by regeneration of the Au I catalyst.The E-selectivity of this transformation might be ascribed to the alleviation of 1,3-allylic interaction in the transition state or intermediate IV.

Conclusions
In summary, a novel synthetic protocol for the expedient assembly of multi-substituted triuoromethyl alkenes through the uoroarylation of gem-diuoroallene has been successfully developed.By visible-light-promoted gold catalysis, this reaction features high stereo-and regioselectivities, wide functional group tolerance and broad substrate scope.Furthermore, the uorine substituent is demonstrated to be of vital importance for the success of this reaction, guaranteeing a chargecontrolled nucleophilic uorination on one hand, and providing extra thermodynamic driving force by the generation of the triuoromethyl group on the other.

Scheme 1
Scheme 1 Intermolecular fluoroarylation of allenes and representative bioactive molecules containing the trifluoromethyl alkene skeleton.

Table 1
Reaction condition optimization a

Table 2
Substrate scope a a See the ESI for reaction details.