Highly stereoselective nickel-catalyzed difluoroalkylation of aryl ketones to tetrasubstituted monofluoroalkenes and quaternary alkyl difluorides† †Electronic supplementary information (ESI) available. CCDC 1565189 and 1880997. For ESI and crystallographic data in CIF or other electronic format see 

A nickel-catalyzed difluoroalkylation of aryl ketones to furnish highly stereo-defined tetrasubstituted monofluoroalkenes or quaternary alkyl difluorides has been established.


Introduction
Organouorine compounds have been widely used in pharmaceuticals, agrochemicals, and special materials, due to their unique chemical and physical properties brought by the selective incorporation of uorine atom(s) or uorinated moieties into organic molecules. 1 For example, as an ideal peptide bond isostere in medicinal chemistry, monouoroalkene exists widely in a great number of biologically active molecules with different pharmacological activities (Scheme 1). 2 Moreover, monouorinated olens have recently drawn ever-increasing attention considering their potential application in materials science, 3 and their capability as synthons for facile synthesis of uorinated compounds in organic synthesis. 4 Accordingly, various classical olen-construction strategies, including Wittig, 5 Julia, 6 Horner-Wadsworth-Emmons 7 and Peterson 8 reactions, have been applied to synthesize monouoroalkenes, 9 but complete stereoselective control remains a big challenge, especially for the construction of tetrasubstituted mono-uorinated olens. Meanwhile, the multistep preparation of starting materials will inevitably affect the atom-and step-economy of the transformation, thus hampering their application in further organic derivations. Therefore, the development of a facile method for general and selective synthesis of tetrasubstituted monouoroalkenes is still highly desirable.
Transition-metal-catalyzed uoroalkylation has long been realized as an expedient and efficient strategy to incorporate uorine into organic molecules. 10 Due to the ready availability, low cost, low or no toxicity, and unique catalytic characteristics, the rst-row transition metals, including Ni, Co, Fe, etc., have recently been widely used in uoroalkylation of various organic compounds. 11 In particular, as an economic alternative to palladium and copper catalysts, nickel is more nucleophilic and the oxidation of low-valent nickel species (Ni(0) or Ni(I)) prefers a single electron transfer process, thus offering an ideal solution to uoroalkylation when relatively "harder" uoroalkyl Scheme 1 Biologically active molecules containing stereodefined monofluoroalkenes.
halides are used as the coupling partners. 12 While various synthesis methods for uoroalkylated arenes, alkenes and alkynes have been well established, nickel-catalyzed uoroalkylation for selective construction of C(sp 3 )-CF 2 R bonds on the alkyl chain still remains a major problem, 13 and the only example was limited to the manipulation of the primary alkylzinc species by the Zhang group (Scheme 2). 14 Moreover, as the known methods to synthesize tetrasubstituted mono-uoroalkenes were still hampered by the requirement of prefunctionalized substrates and/or poor stereocontrol, 15 the stereoselective synthesis of tetrasubstituted monouoroalkenes from readily available reagents still remains a key issue to be resolved.
Herein, we reported a nickel-catalyzed diuoroalkylation of secondary and tertiary C-H bonds in aryl ketones with uoroalkyl halides, which furnished tetrasubstituted mono-uoroalkenes and quaternary alkyl diuorides, respectively. This reaction has demonstrated high reactivity, broad scopes and mild conditions, thus enabling the late-stage uorinecontaining modication of bioactive molecules. This method offers a solution for expedient construction of mono-uoroalkenes from readily available materials, and provides an efficient approach for the synthesis of bioactive uorinated compounds for the discovery of lead compounds in medicinal chemistry.

Results and discussion
Our study commenced with 1,2-diphenylethan-1-one (1a) as the pilot substrate in the presence of a catalytic amount of [NiCl 2 -$(PPh 3 ) 2 ] (10 mol%) and XantPhos (10 mol%) in THF at À10 C. When 2-bromo-2,2-diuoroacetate (2a) was used as the uoroalkylating reagent, to our delight, the monouoroalkene (3a) was obtained smoothly in 85% yield, albeit with a relatively lower E/Z selectivity (4/1). Considering that the size of the R group in uoroalkylating reagents has an obvious effect on the E/Z ratio of produced alkene, to improve the E/Z selectivity, diuoroacetamides (2b-2c) were next tested in our catalytic system. As expected, N,N 0 -diethyl-2,2-diuoroacetamide (2b) gave monouoroalkene 3b in a higher E/Z ratio (7/1), and more bigger N,N 0 -diphenyl-2,2-diuoroacetamide (2c) afforded the desired 3c with an excellent E/Z selectivity in high yield (91% yield, > 99/1 E/Z). The structure of E-isomer 3c was conrmed by X-ray single crystal diffraction. 19 In full compliance with the experimental data of base screening, the replacement of LDA with other inorganic bases indicated that t BuOK quenched the reaction completely and LiHMDS and KHMDS could also promote the reaction albeit in lower yields (59% and 44%, entries 4-6), which clearly demonstrated that LDA plays an important role in the catalytic cycle. Next, a scrupulous catalyst screening, including different kinds of nickel sources, indicated that [NiCl 2 $(PPh 3 ) 2 ] was still the optimal catalyst (Table 1, entries 7-10, for more details, see Table S3 in the ESI †). While the addition of exogenous phosphines provided higher yields of the product, a broad ligand screening, including a great variety of phosphine, nitrogen and carbene ligands, has also been carried out (Table 1, entries 11-16, see also Table S4 †). Of note is that XantPhos was still the best choice of ligand, furnishing the desired product 3c with excellent yield and E : Z ratio (Table 1, entry 3). To our interest, this diuoroalkylation of secondary aryl ketones proceeded at a low temperature (À10 C). The examination of reaction temperature showed that an even lower temperature of À30 C still afforded the products with high yield, but higher temperature (0 C) resulted in a remarkable reduction (Table 1, entries [17][18]. Finally, the control experiment in the absence of [NiCl 2 $(PPh 3 ) 2 ] afforded none of the monouoroalkene 3c (Table 1,
With the optimized conditions in hand, we next started to investigate the substrate scope of this nickel-catalyzed sequential uoroalkylation/deuorination reaction. As shown in Table  2, a great number of secondary C-H bonds on different kinds of aryl ketones were uoroalkenylated successfully with high stereoselectivity and uorinated tetrasubstituted olens were obtained. The substituent effects of the both aryl rings were rst examined. A variety of secondary aryl ketones 1 with para-, meta-, as well as ortho-substituents on both aryl rings were smoothly uoroalkenylated to afford the corresponding mono-uoroalkenes with high E-selectivity (>99/1). Both electrondonating groups, including Me (3d, 3q) and OMe (3e-3g, 3l-3n, 3o), and electron-withdrawing groups such as F (3x, 3z), Cl (3s, 3w), Br (3t, 3v) and CF 3 (3y), on the phenyl rings were well compatible with the standard conditions. Of note is that the bromo substituent, as well as relatively inactive halides including chloro and uoro atoms on the aryl rings were tolerant, offering the foreseeable potential for further synthetic elaboration of monouoroalkenes. To our satisfaction, not just acyclic ketones, cyclic ketones (3aa-3ad) could also undergo the process smoothly under this catalytic system, albeit in a slightly lower yield.
To demonstrate the synthetic potential of this catalytic method, further transformations of monouorinated alkene 3s via nucleophile-promoted deuorination, which enabled the facile synthesis of tetrasubstituted alkenes, were studied. To our delight, as shown in Scheme 3, the treatment of 3s with 1.2 equiv. of EtMgBr proceeded smoothly, affording the ethylated alkene 6 in 51% yield. The X-ray crystal structure of olen 6 (ref. 19) unambiguously established the geometry of this all-carbon double bond, which was formed through deuorination of enol 3s 0 to deliver the thermodynamically stabilized alkene. By using such a deuorination protocol, monouoroalkene 3s could also be transformed into arylated and alkynylated olens (7, 8), and heteroatomsubstituted olens (9, 10) in good yields, respectively. As a vital structural motif existing in various functionalized molecules, stereodened tetrasubstituted olens have been widely explored for their potential application in molecular devices and liquid crystals, and used as key synthons in total synthesis of natural products and complexity-generating synthesis. 3,4 Considering the good functional group tolerance and mild conditions revealed in these nickel-catalyzed reactions, the application prospects of both transformations were further demonstrated via late-stage uoroalkylation of secondary and tertiary C-H bonds in biologically active complex molecules. As shown in Scheme 4, estrone derivative 11 was smoothly mono-uoroalkenylated in 51% yield, and the uorinated multifunctional compound 12 enabled the facile synthesis of more complex (non-)uorinated derivatives via diverse transformations. Meanwhile, donepezil, 17 known as an acetylcholinesterase inhibitor for Alzheimer's disease, could also be diuoroalkylated successfully with good yields, in which ester (14a) and benzo[d]oxazole (14b) on the uoroalkylating reagents were well tolerated. All these latestage modications of complex molecules consistently proved that this newly developed catalytic system offered an efficient method for expedient synthesis of tetrasubstituted mono-uoroalkenes and quaternary alkyl diuorides.
As an extra advantage of this catalytic transformation, our control experiments further conrmed a clear uorine effect. 5g As shown in Scheme 5, the subjection of non-halogenated primary bromide 15a to the standard conditions with or without the addition of the nickel catalyst could result in product 16 as expected, albeit with a relatively lower yield for the latter case. Compared with the control experiment using uorinated reagent 2c (entry 19, Table 1), in which none of the desired product 3c was obtained, such results clearly demonstrated that the diuoroalkylating reagents exhibited totally different reactivity from their non-uorinated analogues. Indeed, a similar analogue 15b, in which only a uorine atom was replaced by bromine, affords none of the desired mono-uoroalkene 3c, even if the bromine group could serve as a better leaving group. These interesting results revealed that the selective introduction of uorine atom(s) into the substrates may inuence the intrinsic reactivity of the substrates, and helped design new reaction patterns following the strategy by using uorine-containing compounds.
To gain some insights into the mechanism of this transformation, a series of control experiments were next carried out (Scheme 6). Firstly, the subjection of b-piene to the standard conditions could afford the cycle-opening product 18 in 18% yield along with 20% yield of the desired diuoroalkylated product 5a. When the radical scavenger TEMPO was used as the additive, the model reactions were completely inhibited, and the TEMPO-CF 2 COOEt was determined by 19 F NMR analysis (eqn (2)). These results indicated that a diuoroalkyl radical was in situ generated and involved in the catalytic cycle. Moreover, the pre-synthesized Ni(I)Cl(PPh 3 ) 3 could give almost the same result as Ni(II) species used in the reaction system. All these results implied that the diuoroalkyl radical was generated by single-electron-oxidation of Ni(I) with diuoroalkyl bromide 2, and Ni(I) served as an active catalytic species. Finally, the sequential addition of the enol 1a 0 , which is in situ generated from the mixture of 1a (1 equiv.)/LDA (1.05 equiv.), and then uoroalkylating reagent 2c (3 equiv.) into the prepared stoichiometric Ni(I) species furnished the uoroalkenylated product 3c in a comparable yield in eqn (5), but the reverse order of sequential addition gave only 11% yield of 3c. These results demonstrated that the nickel-catalyzed single-electronreduction of uoroalkyl halides took place aer the transmetallation step of Ni(I) species with the enol anion.
Based on the above mentioned results and the previous reports, 18 a base-promoted C-H uoroalkylation via a Ni(I)/Ni(III) catalytic cycle involving a uoroalkyl radical was proposed. As shown in Scheme 7 (for the generation of Ni(I) species, see ESI Fig. S6 †), the transmetallation between Ni(I) catalyst A and in situ generated enol anion B gave the Ni(I) complex C and D, which furnished the Ni(II) species E and the diuoroalkyl radical via a single-electron oxidation by uoroalkyl bromide 2. The following radical oxidation of Ni(II) species E afforded Ni(III) intermediated F, followed by reductive elimination resulting in alkyl diuoride 5 when tertiary aryl ketone was used as the substrate (R ¼ aryl or alkyl). Instead, starting from a secondary ketone (R ¼ H), deuorination took place through an E2 elimination process and furnished a tetrauoroalkylated mono-uoroalkene 3 as the nal product.

Conclusions
In summary, we have developed a nickel-catalyzed diuoroalkylation of a-C-H bonds of aryl ketones, which furnished highly stereo-dened tetrasubstituted monouoroalkenes or quaternary alkyl diuorides from secondary or tertiary ketones. Mechanistic investigations indicated that these C-H uoroalkylation reactions proceed via a Ni(I)/Ni(III) catalytic cycle involving an in situ generated uoroalkyl radical. An obvious uorine effect was observed in the reaction, and this novel method has demonstrated high stereoselectivity, mild conditions, broad scope, and synthetic potential for further transformation and late-stage uoroalkenylation (or uoroalkylation) of complex molecules. Further exploration of the scope and other useful derivations are still underway in our laboratory.

Conflicts of interest
There are no conicts to declare.