Catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides via selective C-F bond activation

A regioselective carbosilylation of alkenes has emerged as a powerful strategy to access molecules with functionalized silylated alkanes, by incorporating silyl and carbon groups across an alkene double bond. However, to the best of our knowledge, organic fluorides have never been used in this protocol. Here we disclose the catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides mediated by tBuOK. The main feature of this transformation is the selective activation of the C-F bond of an organic fluoride by the silyl boronate without undergoing potential side-reactions involving C-O, C-Cl, heteroaryl-CH, and even CF3 groups. Various silylated alkanes with tertiary or quaternary carbon centers that have aromatic, hetero-aromatic, and/or aliphatic groups at the β-position are synthesized in a single step from substituted or non-substituted aryl alkenes. An intramolecular variant of this carbosilylation is also achieved via the reaction of a fluoroarene with a ω-alkenyl side chain and a silyl boronate.

T he use of two independent reactants for the transitionmetal-catalyzed difunctionalization of alkenes has emerged as a powerful strategy to access molecules with multiple functional groups, by incorporating two new functional groups across an alkene double bond [1][2][3][4][5][6] . One of the two coupling partners commonly used in this context are activated halogenated arenes or alkanes, or an equivalent thereof (Ar-X or Alkyl-X; X = e.g., I, Br, Cl, OTf, or OMs). Reactions using these molecules generally proceed via oxidative addition and/or radical processes [7][8][9][10][11][12][13][14][15] . In contrast, fluorinated compounds such as aryl or alkyl fluorides have not yet been used as a counterpart for the difunctionalization of alkenes due to the high bond-dissociation energy of the carbon-fluorine (C-F) bond (Fig. 1a).
In recent years, a variety of organofluorine compounds has become ubiquitous due to the rapid establishment of technologies for their synthesis [16][17][18] . There are more than 340 registered fluoro-pharmaceuticals 19 with complex structures and more than 425 registered fluoro-agrochemicals 20 . It has been estimated that there are more than 8,800,000 commercially available fluoroarenes (SciFinder®). Thus, the functionalization of organic fluorides via the cleavage/activation of C-F bonds in organic fluorides is a dynamic and emerging area of research that will expand the utility of organofluorine molecules [21][22][23][24] . However, the chemical transformation of fluoro-organic compounds via C-F bond cleavage under very mild conditions is still rare. For example, aryl fluorides have rarely been functionalized due to the difficulty of oxidative addition of low-valent transition metals to C(sp 2 )-F bonds, whereas the field of C(sp 2 )-F cleavage using silyl cooperativity and/or transition-metal catalysis has also benefited from a wide breadth of research, especially in the last decade [24][25][26][27][28][29][30] . Activation of C(sp 3 )-F bonds in aliphatic fluorocarbons is mostly limited to reactive benzyl or allylic fluorides where p-block-based Lewis acids with high fluoride affinity are usually required [31][32][33] . Thus, the activation of inert C-F bonds in aromatic and aliphatic organic fluorides under mild conditions remains highly challenging.
To realize the difunctionalization of alkenes using organic fluorides as one of the coupling partners, we decided to investigate the carbosilylation of alkenes [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] . This reaction provides functionalized organosilicon compounds directly from simple alkenes, compounds that are much sought-after materials in organic synthesis 50,51 , electronics 52,53 , photonics 54 , and drug discovery 55 . Despite previous successes in the hydrosilylation of alkenes 56,57 , research on the carbosilylation of alkenes is still in its infancy [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] . One of the early milestones in this area is the work by Terao and colleagues 37 . They disclosed a titanocene-catalyzed carbosilylation of alkenes using alkyl bromides and chlorides with chlorosilanes mediated by the Grignard reagent. For recent examples, Engle and colleagues 42 reported a Pd-catalyzed arylsilylation of alkenes using dimethylphenyl silyl boronate PhMe 2 -SiBPin and aryl triflates. Zhang and Hu 49 demonstrated an arylsilylation of acrylates with tri(trimethylsilyl)silane and aryl bromides using a nickel/photoredox catalyst. Although several achievements have been reported in carbosilylation reactions of alkenes under metal-catalyzed and photo-induced conditions, the present methods are still limited by the substrate scope. Besides, the aryl and alkyl fluorides have never been used for the threecomponent carbosilylation of alkenes. Our group has been engaged in the development of efficient methods for the selective functionalization of C(sp 2 )-F and C(sp 3 )-F bonds under mild conditions both with 58 or without 58-61 the use of transition metals. In this context, our recent report on the defluorosilylation of organic fluorides using silyl boronates and with or without a Ni catalyst 58 inspired us to undertake a much more challenging research topic: the difunctionalization of alkenes with aryl or alkyl fluorides in the presence of silyl boronates via C-F bond cleavage (Fig. 1b).
Herein, we disclose a protocol consisting of the catalyst-free defluorinative carbosilylation of alkenes with silyl boronates and fluorinated compounds with an inert C(sp 3 )-F or C(sp 2 )-F bond. A wide variety of aryl fluorides and alkyl fluorides are smoothly incorporated into the alkenes via the cleavage of a C-F bond in the presence of silyl boronates to provide β-functionalized silyl alkanes in good to excellent yield, without any help of transitionmetal catalysis nor photoredox system. The alkene, aryl fluoride, and alkyl fluoride substrate scope tolerated by this reaction is extensive. Unsubstituted styrene derivatives as well as substituted and conjugated aryl alkenes react smoothly with a great variety of aryl or alkyl fluorides and silyl boronates. This allows access to a library of silyl compounds that regioselectively incorporate aryl, heteroaryl, and/or alkyl units at the β-carbon of the silyl alkanes. The reaction proceeds with high regio-and chemoselectivity. Aryl and conjugated alkenes are reactive, whereas non-aryl alkenes are entirely unreactive. The potentially cleavable C-O bond of ethers 62 , C-Cl bonds 63 , and the C(sp 2 )-H bond of heteroaromatic compounds 64,65 are well-tolerated. Most significantly, the C(sp 3 )-F bond of the trifluoromethyl (CF 3 ) group 66 remains intact. An intramolecular carbosilylation via the cleavage and coupling of a C-F bond was also achieved. Three-component coupling reactions involving drug derivatives that contain a fluoride moiety were also demonstrated to prove the utility of this transformation in the drug discovery process. The reaction should proceed through a cascade radical process initiated by singleelectron transfer, which was supported by the experimental studies.

Results and discussion
Optimization of the reaction conditions. We first investigated the reaction of 4-fluorobiphenyl (1a) with styrene (3a) in the presence of the silyl boronate Et 3 SiBpin and a variety of catalysts (Table 1, also see Supplementary Tables S1-S5 for more details).   Using the conditions described in our earlier report 58 on the defluorosilylation of aryl fluorides [Et 3 SiBpin (1.5 equiv), Ni (COD) 2 (10 mol%), and potassium tert-butoxide (KOtBu, 2.5 equiv) in cyclohexane/tetrahydrofuran (THF) at room temperature], the expected biphenyl-phenylethyl-triethylsilane 4aa was obtained regioselectively in 32% yield (entry 1, Table 1). Encouraged by this initial attempt, the optimum amount of base required was explored and 4.0 equiv of KOtBu was found to be the most suitable quantity (entries 1-3). We next varied the equivalents of Et 3 SiBpin used and found that 2.0 equiv was the optimum amount (entry 4). After slight modifications to the solvent ratios, including testing a single solvent, the binary solvent cyclohexane/THF (8/1, v/v) was found to be most suitable (entry 5). Notably, reducing the Ni(COD) 2 catalyst loading to 1 mol% afforded 4aa in 99% yield, which is similar to that obtained in entry 5, within 2.5 h without eroding the reaction efficiency (entry 6). Replacement of KOtBu with NaOtBu resulted in the formation of 4aa in merely 15% yield (entry 7). In the absence of a base or when using other bases (LiOtBu, KOMe, or KHMDS), the desired product was not obtained (entries 8 and 9). Moreover, a large excess of 3a had a negative effect on the reaction yield (entry 10). To ascertain the effect of Ni(COD) 2 , we finally examined the reaction without Ni catalyst. We were very supersized that the transformation occurred efficiently even in the absence of Ni(COD) 2 to generate 4aa in 94% yield (91% isolated yield, entry 11). The results are almost identical to the reaction with Ni catalysis (entry 6). We thus decided the further examination using the different substrates under the two type conditions, with or without Ni(COD) 2 .
Furthermore, we examined both the chemoselectivity and siteselectivity of the alkenyl moiety (Fig. 4). (E)-Buta-1,3-dien-1- ylbenzene (3n) was site-selectively converted into the 1,4-type arylsilylation product 4an in 41% yield with an E/Z ratio of 1.1/1 (determined by 1 H nuclear magnetic resonance (NMR) analysis), whereas no 1,2-adduct was observed (Fig. 4a). Conversely, phenoprene 3o preferably furnished 4ao (65%), a compound with a quaternary carbon center, under the standard reaction conditions via the 1,2-arylsilylation process and not the 1,4process (Fig. 4b). When we examined the reaction of 1-(but-3-en-1-yl)-2-fluorobenzene (6a) with 3a in the presence of Et 3 SiBpin, only the three-component condensation product 7aa was obtained in 51% yield, whereas the intramolecular product was not detected (Fig. 4c). For the reaction of 6-fluorohex-1-ene (2k) and 10-fluorodec-1-ene (2l) having a terminal olefin moiety with styrenes 3a and 3i, the three-component condensation products 5ka and 5li were obtained in 93% and 70% yields, respectively, whereas the intramolecular products were not detected (Fig. 4d, e). In contrast, an intramolecular carbosilylation was achieved via the reaction of styrene-substituted fluoroarene 6b-6d with Et 3 SiBpin under identical conditions to furnish 8b-8d, molecules with a quaternary carbon center, in 81-95% yield (Fig. 4f-h). The five-component condensation was observed for the reaction of difunctionalized 1,8-difluorooctane (2m) with styrene 3c and Et 3 SiBpin to provide 5mc in 88% yield (Fig. 4i). It should be noted that, under the applied conditions, bromo-, and iodosubstituted arenes 9, 10 afforded a mixture of two-component condensation products of silylated 11 and borylated 12 compounds, whereas the targeted three two-component product 4aa was not detected (Fig. 4j). We also attempted the reaction of alkyl chloride 13 instead of alkyl fluoride 3a under the same conditions. Although the three-component product 5aa was obtained by alkyl fluoride 3a, the two-component product, triethyl(phenethyl)silane (14), made from 3a and Et 3 SiBPin, was obtained in 22% yield without incorporation of alkyl chloride 13 (Fig. 4k). Alkyl bromide and iodide were also not converted into 5aa under identical conditions ( Supplementary Fig. 5). Encouraged by the results, we attempted the chemoselective activation of the alkyl C-F bond over the alkyl C-Cl bond by the competitive reaction between 2a and 13. Interestingly, the alkyl fluoride 2a was consumed to 5aa (95%), whereas the alkyl chloride 13 was recovered (90%, Fig. 4l, more details in Supplementary Figs. 6-8). These behaviors show the advantage of fluorine in our reaction system compared to commonly used halogens both in aromatic and aliphatic cases.
Mechanistic study. Based on this consideration and on the results obtained so far, a radical pathway seems to be a viable hypothesis. To gain an insight into the reaction mechanism, some experiments were undertaken. First the transformation of 1a with 3a to 4aa under the best conditions was significantly inhibited by the addition of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) (Fig. 5a). These results strongly suggested the reaction involves radical species. We also attempted the same reaction in the presence of Ni catalyst. The same results were obtained. We next examined the radical clock experiment with the substrate containing a cyclopropyl moiety at the α-position of the styrene derivative 3p (Fig. 5b). The silylated ring-opening product 15 was obtained as a major product in 55% yield and most of the aryl fluoride 1a was recovered. On the other hand, the expected threecomponent product was not clearly observed, the trace of the desired material was detected only by gas chromatography-mass spectrometry (GCMS). The results are also in good agreement with the radical-mediated reaction mechanism, as the potential cyclopropyl carbinyl radical is known to spontaneously rearrange to allylcarbinyl radical. Furthermore, the substrate 6e having both fluoroarene and styrene moieties was transformed into the silylcyclopropyl compound 16 in 76% yield (Fig. 5c), which also supports the radical pathway. The treatment of 2k with Et 3 SiBPin in the absence of styrenes 3 predominantly gave a silylalkene 17 in 73% yield via C-F bond activation, whereas the transformation was completely inhibited by the addition of TEMPO independent of the existence of Ni catalyst (Fig. 5d). Thus, the generation of radical species does not require the reaction with styrenes 3.
Based on both the experiments' results here and in previous reports 44,[67][68][69][70][71][72][73][74] , we propose a single-electron transfer/radicalmediated carbosilylation reaction mechanism triggered by the known ability of KOtBu to serve as a single-electron reductant 75,76 (Fig. 5e). First, Et 3 SiBpin reacts with a molecule of KOtBu to form an intermediate A. The formation of A has previously been confirmed by the Avasare group based on density functional theory calculations 77 . We also confirmed the intermediate A by the 11 B-NMR and 29 Si-NMR study   58 . Next, a single-electron transfer process would start by the additional amount of KOtBu as a trigger 75,76 . Namely, a single electron is transferred from t-butoxy anion ( − OtBu) to the silicon atom of intermediate A to furnish a triethylsilyl radical˙SiEt 3 via a cleavage of the Si-B bond. The t-butoxy radical˙OtBu is also generated, which would be captured by the borate anion B. The mechanisms for the cleavage of Si-B bonds are various; the radical-mediated Si-B bond cleavage 78-80 should be highly acceptable due to the experimental results using t BuOK 75,76 . The generated triethylsilyl radical˙SiEt 3 reacts with styrene 3a to give a radical adduct C. The radical cascade process should happen between the radical species C, aryl 1 or alkyl fluorides 2, t-butoxy radical˙OtBu, and borate anion B in the transition state TS-I, where the C-F bond of aryl 1 or alkyl fluorides 2 is activated by the approach of K + . The boron atom in B would also participate in activation of the C-F bond. Finally, the C-C bond formation is completed under concomitant generation of stable D [BPin(OtBu) 2 ]K ( Supplementary Fig. 14) 58 and KF to furnish the desired three-component adduct 4 or 5. The generation of benzyl radical species C was supported by the cyclopropyl experiments (Fig. 5b, c). It should be noted that through the experiments, we observed side products such as Et 3 Si-SiEt 3 and double styrene adducts 18. These formations can be explained by the dimerization of triethylsilyl radical˙SiEt 3 and the overreaction of benzyl radical C with styrene 3a.
In conclusion, we have developed a carbosilylation of alkenes that uses silyl boronates and organic fluorides, and that proceeds via the activation of an inert C-F bond without a catalyst. This reaction should be initiated by the radical cleavage of Si-B bond via a single-electron transfer from t BuOK. A variety of βfunctionalized silyl compounds can be synthesized efficiently and rapidly in good to excellent yield under very mild conditions at room temperature. The most significant feature of this protocol is its broad substrate scope. This highly efficient protocol accepts a variety of fluorides, including aryl and alkyl fluorides, and even transforms sterically demanding secondary alkyl fluorides. A broad range of aryl alkenes, such as styrene derivatives and αsubstituted aryl alkenes, are also tolerated by this method. Silyl boronates were identified as viable substrates. Moreover, the chemo-and site-selectivity displayed in this reaction are remarkable. Aryl alkenes selectively react in the presence of non-aryl alkenes and an intramolecular carbosilylation was achieved with substrates that possess both fluoroarene and aryl alkene moieties. The tolerance of the reaction toward different functional groups is also significant. Substrates with ether, CF 3 , and hetero-aromatic moieties react smoothly without the detection of C-O cleavage, C-F bond activation, or C-H activation; only the inert C-F bonds of the fluoroarenes and fluoroalkanes are activated. Notably, this method also allows for the synthesis of silyl compounds with a quaternary carbon center at the β-position. The 1,4-type addition carbosilylation of 1,3dienes was also achieved. Given the high number of fluorinated compounds that are commercially available, including structurally complex pharmaceuticals, agrochemicals, and functional materials, this protocol widens the potential utility of organosilicon compounds in organic synthesis, the structural design of lead drug compounds, and functional materials.
Finally, the limitations of the method should be mentioned. The conjugated diene is acceptable but electron-deficient acrylates and acrylamides are not suitable. Internal styrenes such as cisstilbene and trans-β-methylstyrene did not react (Supplementary Figs. 1 and 2). The chemoselective activation of aromatic C-F bonds over aromatic C-Br and C-I bonds is difficult, whereas the only aromatic fluoride was transformed into the desired threecomponent product (Supplementary Figs. 3 and 4).

Methods
General procedure for the defluorinative carbosilylation of alkenes 3 using R 3 SiBpin and aryl fluorides 1 or alkyl fluorides 2. In a N 2 -filled glovebox to a flame-dried screw-capped test tube were added organic fluorides 1 or 2 (0.20 mmol, 1.0 equiv), silyl boronates R 3 SiBpin (0.4 mmol, 2.0 equiv), alkenes 3 (0.40 mmol, 2.0 equiv), KOtBu (90 mg, 0.8 mmol, 4.0 equiv), and cyclohexane/THF (1.5 mL, 8/ 1, v/v) sequentially. The tube was then sealed and removed from the glovebox. The mixture was stirred at room temperature for 2.5 h. To the reaction tube was added hexane (5 mL) and then it was subjected to filter through a short silica pad, washed with Et 2 O, and concentrated under vacuum, followed by 3-fluoropyridine (8.6 μL, 0.1 mmol) as an internal standard for NMR analysis. The mixture was then concentrated again to give the residue, which was purified by column chromatography on silica gel to give the corresponding carbosilylation products 4 or 5.

Data availability
The data supporting the findings of this study are available within the paper and its Supplementary Information. All relevant data are also available from the authors.