Organozinc pivalates for cobalt-catalyzed difluoroalkylarylation of alkenes

Installation of fluorine into pharmaceutically relevant molecules plays a vital role in their properties of biology or medicinal chemistry. Direct difunctionalization of alkenes and 1,3-dienes to achieve fluorinated compounds through transition-metal catalysis is challenging, due to the facile β-H elimination from the Csp3‒[M] intermediate. Here we report a cobalt-catalyzed regioselective difluoroalkylarylation of both activated and unactivated alkenes with solid arylzinc pivalates and difluoroalkyl bromides through a cascade Csp3‒Csp3/Csp3‒Csp2 bond formation under mild reaction conditions. Indeed, a wide range of functional groups on difluoroalkyl bromides, olefins, 1,3-dienes as well as (hetero)arylzinc pivalates are well tolerated by the cobalt-catalyst, thus furnishing three-component coupling products in good yields and with high regio- and diastereoselectivity. Kinetic experiments comparing arylzinc pivalates and conventional arylzinc halides highlight the unique reactivity of these organozinc pivalates. Mechanistic studies strongly support that the reaction involves direct halogen atom abstraction via single electron transfer to difluoroalkyl bromides from the in situ formed cobalt(I) species, thus realizing a Co(I)/Co(II)/Co(III) catalytic cycle.

Transition metal-catalyzed regioselective difunctionalizations of ole ns with two different functional groups have been recognized as an increasingly viable tool for preparing complex organic compounds from readily available starting materials. [46][47][48] However, due to the facile β-H elimination from the Csp 3 - [49][50][51][52] it still remained challenging to construct two new C-C bonds through transitionmetal catalyzed multicomponent dicarbofunctionalization of alkenes (Scheme 1a). [53][54][55] Importantly, highly regioselective Ni-catalyzed alkylarylation of vinylarenes with alkyl halides and arylzinc iodides has recently developed by Giri and coworkers, [56] they further extended the substrate scope to α-halocarbonyl derivatives (Scheme 1a). [57] Besides, the installation of uorine into bioactive molecules uniquely plays a vital role in their properties of relevance to biology or medicinal chemistry. [58][59][60][61][62][63] although major advances in transition-metal-catalyzed uoroalkylation have been achieved in recent years. [64][65][66][67][68] It is worth noting that the elegant Ni-catalyzed tandem di uoroalkylation-(alkyl)arylation of enamides to the synthesis of di uoroalkylated amides were illustrated by Zhang and coworkers. [69][70][71] To the best of our knowledge, organozinc reagents for transition-metal-catalyzed difunctionalization of alkenes and 1,3dienes to achieve uorinated compounds was rather rare and limited to the use of nickel catalysis with activated alkenes. [71] In particular, the much less toxic and industrial friendly cobalt catalysts, have unfortunately thus far proven elusive for the aforementioned three component cascade coupling reactions. [72][73] As a part of our continuous program in uorine installation via alkene difunctionalization strategy, [74][75] we herein report a versatile cobalt-catalyzed regioselective di uoroalkylarylation of (un)activated alkenes and 1,3-dienes with polyfunctionalized bench-stable arylzinc pivalates and di uoroalkyl bromides (Scheme 1b), which provides an expedient method to install uorine into complex compounds. Of special interest in this cobalt-catalysis is that the arylzinc pivalates seem very crucial for promoting the overall catalytic e cacy.
Lei [76][77][78] demonstrated rst that arylzinc reagents prepared by different methods possess very different kinetics in palladium-and nickel-catalyzed oxidative couplings, and further X-ray absorption spectroscopy studies show that changing the halide anion from Cl to Br or I will result in an increase of the Zn-C bond distance and thereby improve the transmetallation rate. [79] In order to preliminarily reveal the different kinetics between this solid zinc reagent and conventional zinc reagents, a series of control experiments with six different phenylzinc reagents, which prepared by transmetallation of the corresponding phenylmagnesium halides and zinc halides, [80] were also performed under the ligand-free cobalt catalysis (Scheme 2). Interestingly, all of these reactions were almost nished within remarkably short reaction times of only 15 min. It is worth noting that signi cantly reduced conversions of 4 were observed when using PhZnX (X = Cl, Br or I), Ph 2 Zn 2MgCl 2 or Ph 2 Zn 2Mg(OPiv)Cl instead of PhZnOPiv. Moreover, the results of comparison experiments between Ph 2 Zn 2Mg(OPiv)Cl and Ph 2 Zn 2MgCl 2 show the superiority of the former as well. Hence, these observations highlighted that the presence of M(OPiv) 2 (M = Mg or Zn) has made these new organozinc pivalates stand out amongst salt-supported organometallics, thus displaying the distinct advantage of reacting well in our regioselective cobalt-catalyzed di uoroalkylarylation of ole ns.
Subsequently, the versatility of this optimized cobalt(II) catalyst was examined in a range of di uoroalkylarylation reactions with various polyfunctionalized arylzinc pivalates 3 (Scheme 3). All arylzinc pivalates were prepared from the corresponding aryl halides by Mg insertion in the presence of LiCl. [81] Although the neocuproine (L5) gave the optimal results in the model reaction, in our efforts to extend the substrate scope of this domino reaction, ligand-free CoBr 2 proved to be superior (see the results of products 7,9,11). A variety of paraand/or metalsubstituted arylzinc pivalates were identi ed as viable nucleophiles for di uoroalkylarylation with bromodi uoroacetate (1a) and 4-methoxystyrene (2a) to afford the desired products 4-16 in moderate yields. More sterically hindered 4-chloro-2methylphenylzinc pivalate was successfully employed, leading to the desired di uoroalkylarylated product 17 in 62% yield. Notably, ferrocenylzinc pivalate, as well as 3-thienylzinc pivalate also smoothly underwent the cobalt-catalyzed cascade cross-coupling, albeit yielding the products 18-19 in relatively lower yields.
Besides, the unactivated alkene furnished the desired di uoromethylarylated phosphonate 46 as well, albeit in a modest yield (Scheme 5b). Additionally, using as substrate of α-bromodifluoromethyl substituted benzoxazole proved to be viable with versatile cobalt catalyst and, thereby, provided 47-48 as the products in 51-55% yields (Scheme 5c). Remarkably, this cobalt-catalyzed regioselective di uoroalkylarylation reaction was further extended to the decorated di uoroalkyl bromides (Scheme 5d).
Functional groups, such as arylsulfonate, ester, were well tolerated under the standard reaction conditions, thus delivering the desired products 49-52 in good yields and with high diastereoselctivity of 51 (dr > 20:1).
To further illustrate the potential applications of this cobalt-catalyzed regioselective di uoroalkylarylation in late-stage functionalizations of pharmaceutically active molecules, alkenylarenes derivatized from (pre-)drug molecules, such as febuxostat, canagli ozin, as well as indomethacin, were well di uoroalkylarylated with arylzinc pivalates and α-bromodi uorocarbonyl compounds or bromodi uoromethylphosphonate, leading to the corresponding products 72-77 in 30-96% yields. These results show the potential utility of this protocol for the discovery of novel bioactive drugs. Importantly, citronellol derivative was readily incorporated into the product 78 with remarkably high regioselectivity and chemoselectivity. Moreover, an unactivated alkene bearing a 4-hydroxycoumarin proved to be viable substrate as well, albeit delivering the phosphonate 79 in a rather modest yield. Finally, we showed that isopropenylzinc pivalate is well suited for the cobalt-catalyzed di uoroalkylalkenylation, although the reaction proceeded with lower yield (Scheme 7).
Intrigued by the high regioselectivity and e cacy of our cobalt-catalyzed di uoroalkylarylation, a series of intermolecular competition experiments were performed (Scheme 8). A competition experiment between bromodi uoroacetate (1a) and 2-bromo-2-methylpropanoate showed that BrCF 2 CO 2 Et reacted much faster than these α-bromocarbonyl compounds. These ndings can be rationalized in terms of a prioritized direct halogen atom abstraction from di uoroalkyl bromides via single electron transfer from a cobalt catalyst (Scheme 8a). [83] Intermolecular competition experiments with different alkenylarenes, and arylzinc pivalates revealed electron-rich styrenes and electron-de cient arylzinc pivalates to be slightly reactive substrates (Scheme 8b and 8c). These results suggested that vinylarenes and arylzinc reagents might not be involved in the rate-determine step. [56] Beyond that, radical-clock experiment with substrate 83 bearing a radical clock cyclopropane moiety, the ring-opened di uoroalkylarylated product 84 was generated in 11% yield. Similarly, both three-and two-component coupling products were observed when using N,N-diallyl-2-bromo-2,2-di uoroacetamide (85) as a radical probe under the standard reaction conditions, the cyclized products 86 (dr = 2:1) and 87 were generated in 17% and 34% yields, respectively. Moreover, a di uoroalkylated benzylic radical homocoupling dimer 88 was detected by GC as well. With these ndings, we propose this cobaltcatalyzed di uoroalkylarylation involves a single-electron-transfer (SET) process (Scheme 9a).
According to the earlier mechanistic studies for cobalt-catalyzed cross-coupling reactions with using organomagnesium reagents, an in situ low-valent Co(0) was proposed as the catalytically active species. [52,[72][73][84][85] On the other hand, a mechanism involving Co(I)/(III) couple was also proposed for many cobalt-catalyzed cross-couplings. [37][38][39]83] Therefore, we performed experiments of CoBr 2 (1.0 equiv) with excess of ArZnOPiv under typical reaction conditions for 30 min. These reactions furnished the corresponding homo-products of 89a and 89b in near 0.5 equiv ratio to that of CoBr 2 , respectively. These ndings support the formation of a Co(I)-species based on the stoichiometry shown in scheme 9b. In this context, the well-de ned Co(I)-complex, such as CoCl(PPh 3 ) 3 was proved to be active for the desired di uoroalkylarylated process, yielding product 4 in 66%, while Co 2 (CO) 8 gave a poor yield (Scheme 9c).
Further experiments to examine the catalytic activity of the in situ generated low-valent cobalt(I) species were performed. A mixture of vinylarene 2a (0.25 mmol) and CoBr 2 (0.025 mmol) was treated with 2.0 equiv of 3,4-(methylenedioxy)phenylzinc pivalate (0.05 mmol) at 23 °C for 30 min to generate the proposed Co(I)-species, followed by addition of bromodi uoroacetate 1a (0.3 mmol) and another 0.5 mmol of phenylzinc pivalate. The di uoroalkylarylated product 4 was isolated in 57% yield as the sole product, while the product 11 was obtained in 79% yield when exchanging the order of the two arylzinc reagents (Scheme 9d). These ndings are consistent with the in situ generated low-valent cobalt(I)species might be the active catalyst for the current three-component cross-coupling reaction. A series of EPR spin-trapping experiments show the existence of C-centered radicals trapped by DMPO (g=2.0066, A N = 13.9 G, A H = 19.3 G), which was considered to be •CF 2 R. [86] These results strongly supported the single electron transfer progress for the activation of BrCF 2 R was only promoted by the in situ formed Co(I)species (Scheme 9e).
Based on the above experimental ndings, along with previous mechanistic insights, [37-39, 74, 83] a mechanism for this regioselective cobalt-catalyzed di uoroalkylarylation of alkenes has been proposed as shown in Scheme 10. The reduction of the precatalyst CoBr 2 with arylzinc pivalates forms the catalytically active Co(I)-species (A), which reduces di uoroalkyl bromides (1) by SET and generates di uoroalkyl radical B, then followed by a facile radical addition of B into ole ns (2) to afford a secondary alkyl radical species, along with subsequent rapid trapping with L n Co(II)XBr (X = Br) into intermediate C, which undergoes transmetalation with ArZnOPiv (3) to lead to the organocobalt(III) species D. Subsequent reductive elimination nally delivers the di uoroalkylarylated product and regenerate the active cobalt(I)-catalyst (path a). In addition, another possible pathway is that transmetallation of arylzinc pivalates could also occurred after the initial reduction step, thus in situ forming the L n Co(I)X (X = Ar) species as the catalyst to promote the SET process. Radical addition and reductive elimination give rise to the desired products and regenerate the active Co(I)-species (path b).
We were also pleased to nd that this cobalt-catalyzed di uoroalkylarylation can be easily scaled up to gram level. Under the optimized reaction conditions, the di uoroalkylarylated product 90 was afforded with high e cacy (65% yield, Scheme 10a). Finally, we further demonstrated the synthetic potential of this cobalt-catalyzed di uoroalkyarylation strategy through the late-stage modi cation of the obtained di uoroalkylarylated products. For example, the resulting N-morpholino amide 90 can be readily converted into various ketones by treating with Grignard reagents, thus furnishing the products 92a-b in moderate yields. Moreover, the reduction of the ester group of substrate 4 by using NaBH 4 provides the corresponding alcohol 93, which readily undergoes various derivatization (Scheme 11b).

Conclusion
In conclusion, we have reported the rst practical cobalt-catalysis for regioselective di uoroalkylarylation of alkenes or 1,3-dienes with functionalized arylzinc pivalates and di uoroalkyl bromides. This simple cobalt-catalyst enables three-component cross-couplings through cascade Csp 3 -Csp 3 /Csp 3 -Csp 2 bond formation in one-pot fashion, thus generating di uoroalkylarylated products with predictable regioselectivity and high diastereoselectivity. The reaction proceeds under remarkable mild conditions with high e cacy, excellent functional group tolerance, as well as a broad substrate scope. Notable features of this approach are the use of less toxic and low-cost cobalt catalyst, as well as user-friendly solid zinc reagents. Straightforward late-stage functionalizations of pharmaceutically active molecules shown the potential applications of this protocol for the discovery of novel bioactive drugs. Beyond that, among a series of kinetic experiments with six type of phenylzinc reagents, these bench-stable solid arylzinc pivalates displayed the distinct advantage of reactivity for the current reaction. Detailed mechanistic studies demonstrated the reaction undergoes a direct halogen atom abstraction via single electron transfer from the in situ formed cobalt(I) species to di uoroalkyl bromides.

Methods
General procedure for the cobalt-catalyzed di uoroalkylarylation: A suspension of CoBr 2 (10 mol %), ole n (0.25 mmol, 1.0 equiv), di uoroalkyl bromide (0.5 mmol, 2.0 equiv) and aryl zinc pivalates (0.5 mmol, 2.0 equiv) in degas MeCN (1.0 mL) was stirred at 23 °C for 3 h under an atmosphere of Ar. At ambient temperature, the solvent was evaporated in vacuo and the remaining residue was puri ed by column chromatography on silica gel (n-hexane/EtOAc) to yield the desired products.

Additional Information
Supplementary information and chemical compound information are available in the online version of the paper. Reprints and permissions information is available online at www.nature.com/reprints. Correspondence and requests for materials should be addressed to J.L., and A.L..