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 alkenes with two different functional groups are useful for preparing organic compounds, but the construction of two new C–C bonds is challenging. Here, the authors report cobalt-catalyzed regioselective difluoroalkylarylation of alkenes with solid arylzinc pivalates and difluoroalkyl bromides, through a cascade Csp3 ‒Csp3/Csp3 ‒Csp2 bond formation.

Transition-metal-catalyzed regioselective difunctionalizations of olefins 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 -[M] intermediate [49][50][51][52] , it still remained challenging to construct two C-C bonds through transition-metal catalyzed multicomponent dicarbofunctionalization of alkenes (Fig. 1a) [53][54][55] . Importantly, highly regioselective Nicatalyzed alkylarylation of vinylarenes with alkyl halides and arylzinc iodides has been recently developed by Giri and coworkers 56 , they further extended the substrate scope to α-halocarbonyl derivatives (Fig. 1a) 57 . Besides, the installation of fluorine 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 fluoroalkylation have been achieved in recent years [64][65][66][67][68] . It is worth noting that the elegant Ni-catalyzed tandem difluoroalkylation-(alkyl)arylation of enamides to the synthesis of difluoroalkylated amides was 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 fluorinated compounds were 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 .
Recently, our laboratory reported the fluorine installation through cobalt-74 and copper-catalyzed 75 alkyne and alkene difunctionalization strategies. In this work, we report a versatile cobalt-catalyzed regioselective difluoroalkylarylation of (un)activated alkenes and 1,3-dienes with polyfunctionalized arylzinc pivalates and difluoroalkyl bromides (Fig. 1b), which provides an expedient method to install fluorine into complex compounds. Of special interest in this cobalt catalysis is that the arylzinc pivalates seem very crucial for promoting the overall catalytic efficacy.
Lei [76][77][78] demonstrated 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 trans-metalation 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 (Note: PhZnOPiv was prepared from PhMgCl and Zn(OPiv)2 with 1:1.2 ratio; Ph2Zn‧ 2Mg(OPiv)Cl was prepared from PhMgCl and Zn(OPiv)2 with 2:1 ratio; PhZnX was prepared from PhMgX and ZnX2 with 1:1.2 ratio; Ph2Zn‧2MgCl2 was prepared from PhMgCl and ZnCl2 with 2:1 ratio), were also performed under the ligand-free cobalt catalysis (Fig. 2b). Interestingly, all of these reactions were almost finished within remarkably short reaction times of only 15 min. It is worth noting that significantly 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 organozinc pivalates stand out among salt-supported organometallics, thus displaying the distinct advantage of reacting well in our regioselective cobaltcatalyzed difluoroalkylarylation of olefins.
Subsequently, the versatility of this optimized cobalt(II) catalyst was examined in a range of difluoroalkylarylation reactions with various polyfunctionalized arylzinc pivalates 3 (Fig. 3a). All arylzinc pivalates were prepared from the corresponding aryl halides by Mg insertion in the presence of LiCl 80 . 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 para-and/or metal-substituted arylzinc pivalates were identified as viable nucleophiles for difluoroalkylarylation with bromodifluoroacetate (1a) and 4methoxystyrene (2a) to afford the desired products 4-16 in moderate yields. More sterically hindered 4-chloro-2-  methylphenylzinc pivalate was successfully employed, leading to the desired difluoroalkylarylated 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. Thus far, electron-withdrawing groups substituted arylzinc pivalates proven to be unsuitable nucleophiles.
Transformations of unactivated alkenes are acknowledged widely as a challenge in transition-metal-catalyzed difunctionalization of alkenes [49][50][51][52][53][54][55][56][69][70][71] . The reaction conditions previously optimized for the alkenylarenes led to an unsatisfactorily low yield of 57, because significant amounts of a Heck-type coupling product were formed as well. However, we were delighted to find that the transformation of the unactivated alkene difluoroalkylarylation process was significantly improved when using dppbz (L9, 10 mol%) as the ligand, leading to 57 in 54% yield. A number of unactivated alkenes were readily converted into the desired difluoroalkylarylated products 58-63 in moderate yields (See more details from the Supporting Information). Moreover, various synthetically valuable functional groups, including chloro, ether, and ester, remained intact by the cobalt catalyst (Fig. 4a). Beyond that, the possibility of cobalt-catalyzed difluoroalkylation to form an allyl radical, which subsequently underwent 1,3-shift and Csp 3 -Csp 2 cross-couplings with arylzinc pivalates, was also investigated (Fig. 4b). Indeed, difluoroalkyl bromide 1k and a quite range of functionalized (hetero)aryl-zinc reagents were realized: 1,4-difunctionalization of 1,3-dienes with good regioselectivity and diastereoselectivity, thus furnishing 64-74 in 43-98% yields, albeit products 73 and 74 were obtained with 1:1 E:Z selectivity and 4:1 regioselectivity, respectively. To our delight, 1,3-octadiene was proven to be a suitable substrate as well, giving the product 75 with high diastereoselectivity.
To further illustrate the potential applications of this cobaltcatalyzed regioselective difluoroalkylarylation in late-stage functionalizations of pharmaceutically active molecules, alkenylarenes derivatized from (pre-)drug molecules, such as febuxostat, canagliflozin, as well as indomethacin, were well difluoroalkylarylated with arylzinc pivalates and α-bromodifluorocarbonyl compounds or bromodifluoromethylphosphonate, leading to the corresponding products 76-82 in 30-96% yields. These results show the potential utility of this protocol for the discovery of bioactive drugs. Importantly, citronellol derivative was readily incorporated into the product 83 with remarkably high regioselectivity and chemoselectivity. Moreover, an unactivated alkene bearing a 4hydroxycoumarin proved to be a viable substrate as well, albeit delivering the phosphonate 84 in a rather modest yield. Finally, we showed that isopropenylzinc pivalate is well suited for the cobalt-catalyzed difluoroalkylalkenylation, although the reaction proceeded with lower yield (Fig. 4c).
Intrigued by the high regioselectivity and efficacy of our cobaltcatalyzed difluoroalkylarylation, a series of intermolecular competition experiments were performed (Fig. 5). A competition experiment between bromodifluoroacetate (1a) and 2-bromo-2methylpropanoate showed that BrCF 2 CO 2 Et reacted much faster than these α-bromocarbonyl compounds. These findings can be rationalized in terms of a prioritized direct halogen atom abstraction from difluoroalkyl bromides via single-electron transfer from a cobalt catalyst (Fig. 5a) 81 . Intermolecular competition experiments with different alkenylarenes and arylzinc pivalates revealed electron-rich styrenes and electron-deficient arylzinc pivalates to be slightly reactive substrates (Fig. 5b, c). These results suggested that vinylarenes and arylzinc reagents might not be involved in the rate-determined step 56 .
Beyond that, the radical-clock experiment with substrate 88 bearing a radical clock cyclopropane moiety, the ring-opened difluoroalkylarylated product 89, was generated in 11% yield. Similarly, both three-and two-component coupling products were observed when using N,N-diallyl-2-bromo-2,2-difluoroacetamide (90) as a radical probe under the standard reaction conditions, the cyclized products 91 (dr = 2:1) and 92 were generated in 17% and 34% yields, respectively. Moreover, a difluoroalkylated benzylic radical homocoupling dimer 93 was detected by GC as well. With these findings, we propose that this cobalt-catalyzed difluoroalkylarylation involves a single-electrontransfer (SET) process (Fig. 6a).
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 52,72,73,82,83 . On the other hand, a mechanism involving Co (I)/(III) couple was also proposed for many cobalt-catalyzed crosscouplings [37][38][39]81 . 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 homoproducts of 94a and 94b in near-0.5 equiv ratio to that of CoBr 2 , respectively. These findings support the formation of a Co(I) species based on the stoichiometry shown in Fig. 6b. In this context, the well-defined Co(I) complex, such as CoCl(PPh 3 ) 3 was proved to be active for the desired difluoroalkylarylated process, yielding product 4 in 66%, while Co 2 (CO) 8 gave a poor yield (Fig. 6c). Further experiments to examine the catalytic activity of the in situgenerated 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 bromodifluoroacetate 1a (0.3 mmol) and another 0.5 mmol of phenylzinc pivalate. The difluoroalkylarylated 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 (Fig. 6d). These findings are consistent with the in situ-generated low-valent cobalt(I) species that might be the active catalyst for the current three-component cross-coupling reaction. A series of EPR spin-trapping experiments show the existence of Ccentered 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 84 . These results strongly supported that the single-electron-transfer process for the activation of BrCF 2 R was only promoted by the in situ-formed Co(I) species (Fig. 6e). Based on the above experimental findings, along with previous mechanistic insights [37][38][39]74,81 , a mechanism for this regioselective cobalt-catalyzed difluoroalkylarylation of alkenes has been proposed as shown in Fig. 6f. The reduction of the precatalyst CoBr 2 with arylzinc pivalates forms the catalytically active Co(I) species (A), which reduces difluoroalkyl bromides (1) by SET and generates difluoroalkyl radical B, then followed by a facile radical addition of B into olefins (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 trans-metalation with ArZnOPiv (3) to lead to the organocobalt(III) species D. Subsequent reductive elimination finally delivers the difluoroalkylarylated product and regenerates the active cobalt(I) catalyst (path a). In addition, another possible pathway is that transmetallation of arylzinc pivalates could also occur 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 find that this cobalt-catalyzed difluoroalkylarylation can be easily scaled up to gram level. Under the optimized reaction conditions, the difluoroalkylarylated product 95 was afforded with high efficacy (65% yield, Fig. 7a). Finally, we further demonstrated the synthetic potential of this cobalt-catalyzed difluoroalkylarylation strategy through the late-stage modification of the obtained difluoroalkylarylated products. For example, the resulting N-morpholino amide 95 can be readily converted into various ketones by treating with Grignard reagents, thus furnishing the products 97a-b in moderate yields. Moreover, the reduction of the ester group of substrate 4 by using NaBH 4 provides the corresponding alcohol 98, which readily undergoes various derivatizations (Fig. 7b).

Discussion
In conclusion, we have reported the practical cobalt catalysis for regioselective difluoroalkylarylation of alkenes or 1,3-dienes with functionalized arylzinc pivalates and difluoroalkyl 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 difluoroalkylarylated products with predictable regioselectivity and high diastereoselectivity. The reaction proceeds under remarkable mild conditions with high efficacy, 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 show the potential applications of this protocol for the discovery of bioactive drugs. Beyond that, among a series of kinetic experiments with six types of phenylzinc reagents, these solid arylzinc pivalates displayed the distinct advantage of reactivity for the current reaction. Detailed mechanistic studies demonstrated that the reaction undergoes a direct halogen atom abstraction via single-electron transfer from the in situ-formed cobalt(I) species to difluoroalkyl bromides.

Methods
Cobalt-catalyzed difluoroalkylarylation of alkenes. A suspension of CoBr 2 (10 mol%), olefin (0.25 mmol, 1.0 equiv), difluoroalkyl 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 under reduced pressure and the remaining residue was purified by column chromatography on silica gel to yield the desired products.

Data availability
The authors declare that all other data supporting the findings of this study, including experimental procedures and compound characterization, are available within the article and its Supplementary Information files.