(Fluoro)alkylation of alkenes promoted by photolysis of alkylzirconocenes

Difluoroalkylated compounds have important applications in pharmaceutical, agrochemical, and materials science. However, efficient methods to construct the alkylCF2–alkyl bond are very limited, and the site-selective introduction of a difluoromethylene (CF2) group into an aliphatic chain at the desired position remains challenging. Here, we report an unprecedented example of alkylzirconocene promoted difluoroalkylation of alkyl- and silyl-alkenes with a variety of unactivated difluoroalkyl iodides and bromides under the irradiation of visible light without a catalyst. The resulting difluoroalkylated compounds can serve as versatile synthons in organic synthesis. The reaction can also be applied to activated difluoroalkyl, trifluoromethyl, perfluoroalkyl, monofluoroalkyl, and nonfluorinated alkyl halides, providing a general method to controllably access fluorinated compounds. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway induced by a Zr(iii) species is involved in the reaction, in which the Zr(iii) species is generated by the photolysis of alkylzirconocene with blue light.


Introduction
The site-selective introduction of uorine atom(s) into organic molecules has important applications in medicinal chemistry, chemical biology, and materials science. 1 For instance, biologically active molecules containing a diuoromethylene (CF 2 ) moiety at the specic position exhibit improved bioactivities compared with their nonuorinated counterparts, because the CF 2 can change the metabolic stability, conformation, acidity and polarity of the molecules. 2 Some important pharmaceuticals containing the CF 2 moiety have been discovered for the treatment of tumors and other deceases, such as gemcitabine, 3 vinunine, 4 and lubiprostone 5 (Fig. 1A). To this end, efforts toward the development of efficient methods to access CF 2containing molecules have been witnessed over the past decade. 6 However, most of these developed synthesis methods mainly focus on the preparation of diuoroalkylated arenes (ArCF 2 R) with CF 2 at the benzylic position. 6a,7 To date, efficient methods to site-selectively introduce CF 2 into an aliphatic chain remain limited. The traditional method to prepare diuoroalkylated compounds relies on the deoxyuorination of the carbonyl group with dialkylaminosulfur triuorides, such as diethylaminosulfur tri-uoride (DAST). 8 But the modest functional group tolerance of this method restricts its synthetic applications. Another common method to synthesize such a valuable uorinated structure is based on the nucleophilic addition of diuoroalkylating reagents to aldehydes, ketones, and imines ( Fig. 1B(a)). 6c,9 However, owing to the instability of nucleophilic diuoroalkylating reagents, usually a p-system adjacent to the CF 2 moiety, is needed to stabilize the diuoroalkyl anion, 10 making the method difficult in constructing the alkylCF 2 -alkyl bond. Although nucleophilic substitution of aliphatic electrophiles with carbon nucleophiles is well known, the adoption of a similar strategy to react diuoroalkyl halides with aliphatic nucleophiles remains challenging and has not been reported yet. 11 In this context, transition-metal 12 or photo-redox 13 catalyzed diuoroalkylation reactions to construct the alkylCF 2 -alkyl bond have been developed ( Fig. 1B(b) and B(c)). These methods either need activated coupling partners, such as allylic substrates 12a and p system functionalized diuoroalkyl halides 12b (XCF 2 -FG, FG ¼ p system, transition-metal catalyzed process), or are difficult to be used in the reaction of aliphatic alkenes with XCF 2 -alkyl (e.g. for the photoredox catalyzed process), 13c thus restricting their widespread synthetic applications.
To overcome these limitations and meet the increasing demands of life and materials sciences, new methods that can extend the diversity of the diuoroalkylated structure with siteselective introduction of CF 2 into the aliphatic chain at the desired position are highly desired. Herein, we report an unprecedented example of catalyst free diuoroalkylation of silyl-and alkyl-alkenes with unactivated diuoroalkyl halides promoted by photolysis of alkylzirconocenes (Fig. 1C). The reaction can also be applied to p-functionalized diuoroalkyl, triuoromethyl, peruoroalkyl, monouoroalkyl, and non-uoroalkyl halides, providing a general method to access uoroalkylated alkanes. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway induced by a Zr(III) species is involved in the reaction, in which the Zr(III) species is generated by the photolysis of alkylzirconocenes with visible light. This protocol paves a new way to construct the alkyl-uoroalkyl bond by using readily available uoroalkyl halides and aliphatic alkenes.

Results and discussion
Inspired by our nickel-catalyzed diuoroalkylation cross-coupling, 12b,c,14 we chose unactivated diuoroalkyl iodide 1a 15 and alkylzirconocene 2a as the model substrates (Table 1), in which alkylzirconocene can be readily prepared from the corresponding alkene 5 and Schwartz reagent (HZrCp 2 Cl, 6). 16 Directly adopting the nickel-catalyzed cross coupling failed to provide desired diuoroalkylated alkane 3a (entry 1). In contrast, the irradiation of the nickel catalyzed reaction with a blue LED (12 W) generated product 3a in 51% yield along with 27% yield of hydrodeiodinated by-product 4a (entry 2). 17 The absence of the nickel catalyst could also provide a comparable yield (entry 3), and no reaction occurred without the blue LED (entry 4), demonstrating that blue light is essential in promoting the reaction. These mild conditions are quite different from the challenge S N 1 or S N 2 substitution of diuoroalkyl halides, because of the difficulty in forming a diuoroalkyl carbocation (S N 1) or the repulsion of the lone pairs of uorine atoms to the carbon nucleophile (S N 2). 18 This difference implies a novel mechanism, which is discussed below. Encouraged by these results, we tested a series of reaction parameters (for details, see the ESI †), and found that the use of 3.0 equiv. of 2a with NMP as the solvent could provide 3a in 81% yield (62% isolated yield) (entry 5).
Because 2a was derived from the reaction of 6 with excessive silylalkene 5a (Table 1), this posed a question whether 5a, instead of 2a, is involved in the formation of 3a. To identify the role of 2a, we prepared 2a by reaction of alkylmagnesium bromide 7 with ZrCp 2 Cl 2 (Scheme 1a). 19 However, no 3a was observed by reaction of 2a with 1a (Scheme 1a). In contrast, the addition of 5a to the reaction could provide the desired product in 48% yield (Scheme 1b). These ndings suggest that excessive silylalkene 5a in the reaction is the substrate responsible for generating 3a with 1a. This deduction was further supported by the addition of another silylalkene 5b to the reaction mixture of 1a, 2a, and 5a under the irradiation of blue light, in which both diuoroalkylated products 3a and 3a 0 were formed (Scheme 1c). Since [Zr]-migration from alkylzirconocene to alkene cannot occur (Scheme 1d), 20 these results clearly demonstrate that the alkene is the substrate to react with diuoroalkyl halide. In addition, the reaction of alkene 5a with 1a in the absence of 2a under the irradiation of a blue LED did not lead to 3a (Scheme 1e), demonstrating that the alkylzirconocene is essential in promoting the reaction.
Based on the above results, we reoptimized the reaction conditions, and found that the use of 2.5 equiv. of 5a, 1.2 equiv.
of 6, and 1.0 equiv. of 1a could provide 3a in a comparable yield (80% determined by 19 F NMR and 62% isolated yield) (for details, see the ESI †). With the viable reaction conditions in hand, we examined the substrate scope of this process (Scheme 2A). Generally, the reaction of silylalkene 5a with a series of unactivated diuoroalkyl iodides (ICF 2 -alkyl) 1 furnished the corresponding products 3 efficiently. The chain length of 1 did not affect the reaction efficiency. Substrates 1 bearing a linear aliphatic chain from one to ve carbons underwent the coupling smoothly (3a-3k). The reaction exhibited good functional group tolerance. A variety of important functional groups, such as ester, silyl ether, arylchloride, and nitrile, were compatible with the reaction conditions (3a-3g, 3i, 3j, and 3l). Even alkylchloride-and sulphonatecontaining substrates (3h and 3k) were competent coupling partners, providing good opportunities for downstream derivatization. The reaction was not restricted to diuoroalkyl iodides, as unactivated diuoroalkyl bromides were also suitable substrates (3i-3l), with 3.5 equiv. of alkene and 1.8 equiv. of 6 needed. Replacing silylalkene 5a with siylalkene 5b led to comparable yields (3d, 3g, and 3j), suggesting that 5a and 5b possess similar reactivity. Notably, the steric diuoroalkyl iodide substituted with a cyclohexyl group was also applicable to the reaction (3m). In addition to XCF 2 -alkyl (X ¼ I, Br), the reaction of 5a with functionalized diuoroalkyl bromides proceeded smoothly (3n-3r). Bromodiuoroacetate and bromodi-uoroacetamide showed higher reactivity than those of XCF 2alkyl, while gem-diuoroproparyl bromides and heteroaryl substituted diuoromethyl bromide provided comparable yields. The reaction is readily scalable, as demonstrated by the gram-scale synthesis of 3d and 3g without the erosion of the reaction efficiency. Chlorodiuoroacetate was also examined, but poor yield (19%) was obtained by reaction with 5a and 2a.
We next examined the substrate scope of alkenes 5. The reaction of XCF 2 -alkyl (X ¼ I, Br) 1 with compounds 5 bearing a different chain length furnished the corresponding products smoothly (8a-8k). However, styrene was not applicable to the reaction. The successful production of 8i and 8j with alkyl bromide intact demonstrates that the alkyl bromides are less reactive than the diuoroalkyl iodides and bromides, due to the strong electron-withdrawing effect of the CF 2 group that enables the diuoroalkyl iodides and bromides to relatively more easily accept an electron than their nonuorinated counterparts via a SET pathway. Most importantly, a boronate-containing substrate was also applicable to the reaction (8k and 8m). Since boronate is a useful synthetic handle in organic synthesis, the resulting boronate-containing products should serve as a versatile building block for organic synthesis. Notably, the cyclic alkene did not affect the reaction efficiency, and norbornene provided compound 8l in 76% yield. In addition, the reaction of diuoroacetate bromide with alkenes, including linear and cyclic alkenes, proceeded smoothly, and afforded the corresponding products 8m-8q with high efficiency. The reaction can also be extended to triuoromethyl, peruoroalkyl, and monouoroacetyl iodides and bromides, with moderate to good yields obtained (9a-9c). Remarkably, nonuorinated alkyl halides were also applicable to the reaction. Tertiary alkyl bromide bearing an ester group (9d) and 2-bromomalonate (9e) underwent the coupling efficiently; even Boc-protected 4-iodopiperidine afforded 9f in good yield, thus demonstrating the generality and advantage of this catalyst free, visible light induced process.
Given that the alkylzirconocene is essential in promoting the reaction, but is not the substrate for generating the desired product, we envisioned that alkylzirconocene may functionalize an initiator in the reaction. In this way, we can use a simple alkylzirconocene in combination with different alkenes and uoroalkyl halides to construct alkylCF 2 -alkyl bonds. Compared with the above synthetic procedure, this alternative process does not need the preparation of different alkylzirconocenes and enables uoroalkylation of a variety of alkenes bearing different functional groups that are sensitive to HZrCp 2 Cl, thus expanding the substrate scope of the current protocol. Accordingly, we prepared alkylzirconocene 2c by reaction of allylbenzene with HZrCp 2 Cl. As shown in Scheme 2B, the treatment of 2c with bromodiuoroacetate and the cyclobutene derivative under the irradiation of blue light afforded product 10a in 50% yield. Since a four-membered ring and diuoroacetyl are important structural motifs in medicinal chemistry, 21 compound 10a would have applications in the synthesis of biologically active molecules. The terminal alkene bearing an amide proton was also applicable to the reaction, providing 10b in good yield. In addition to bromodi-uoroacetate, unactivated diuoroalkyl bromides and iodides were also competent coupling partners to react with a variety of complex molecule derived alkenes (10c-10h). Estone-and sulbactam-containing alkenes underwent the diuoroalkylation reaction smoothly (10d and 10e). Peptide and carbohydrate derivatives were also suitable substrates (10f and 10g); even febuxostat bearing a heteroarene was also amenable to the reaction (10h). Thus, the current protocol represents a facile route for applications in medicinal chemistry.
To demonstrate the synthetic utility of this method, transformations of the resulting diuoroalkylated compounds were conducted (Scheme 3). The silyl group on compounds 3 can be readily converted into a hydroxyl. As shown in Scheme 3A, the treatment of compounds 3e, 3i, and 3m with TBAF, followed by KF Scheme 2 (A) lkylzirconocene promoted fluoroalkylation of alkenes with (fluoro)alkyl halides under the irradiation of blue light. (B) Alkylzirconocene 2c promoted fluoroalkylation of alkenes with difluoroalkyl halides under irradiation of blue light. a Reaction conditions: 1 (0.3 mmol, 1.0 equiv.), 5 (2.5 equiv.), 6 (1.2 equiv.), and NMP (3 mL). b 5 (3.5 equiv.) and 6 (1.8 equiv.) were used. c 2c (1.5 equiv.), 5 (1.5 equiv.), and 6 (2.0 equiv.), and NMP (3 mL) were used. d Gram scale synthesis. and H 2 O 2 , afforded alcohols 11d, 11h, and 11l with high efficiency. 22 Given the important applications of alcohols in organic synthesis and the unique properties of the CF 2 moiety, these CF 2containing alcohols offer good opportunities in the synthesis of bioactive molecules. The resulting diuoroalkylated products can also serve as a useful building block for organic synthesis. As shown in Scheme 3B, the gram-scale synthesis of compound 3p under standard reaction conditions proceeded smoothly. The selective deprotection of 3p provided terminal alkyne 12 in 85% yield. The transformation of its carbon-carbon triple bond afforded a,b-unsaturated ketone 13 efficiently. 23 The reaction of 13 with N-Me indole in the presence of BF 3 $Et 2 O afforded 14 in 70% yield, which was subsequently converted into alcohol 15 in 56% yield.
To gain mechanistic insight into the reaction, we conducted several radical clock experiments with a-cyclopropylstyrene 16 as a probe ( Fig. 2A). 24 When compound 16 was added to the reaction mixture of diuoroalkyl bromide 1g and alkylzirconocene 2b, two ring expanded products 17 (8% yield) and 18 (13% yield) were obtained under standard reaction conditions ( Fig. 2A(a)). The treatment of 2b with 16 under the irradiation of blue light also provided 17 in 15% yield, but no 17 was observed in the absence of blue light ( Fig. 2A(b)). In addition, no 18 was provided when 1a was treated with 16 under the irradiation of blue light ( Fig. 2A(c)). These results suggest that visible light can induce alkylzirconocene 2b to generate an alkyl radical; in the meanwhile, 2b can also induce diuoroalkyl bromide to generate a diuoroalkyl radical under the irradiation of blue light. Because an alkyl radical (I) can be generated by photolysis of alkylzirconocene under the irradiation of blue light, we proposed that a Zr(III) species [ZrCp 2 Cl] was formed simultaneously during this process, as illustrated in Fig. 2B. 25 The Zr(III) subsequently reacted with uoroalkyl halide to produce a uoroalkyl radical via a SET pathway. We also conducted light-dark experiments under standard reaction conditions (see the ESI †), and found that no reaction occurred in the dark, suggesting the essential role of blue light in promoting the reaction. This result demonstrates that a radical chain mechanism is unlikely involved in the reaction. Aer the uoroalkyl radical was generated, we proposed that it directly reacted with the alkene to generate a new alkyl radical (II), which subsequently abstracted a proton from the solvent to produce the nal product (Fig. 2B). 26 As for the radical (I) generated from alkylzirconocene, it can also be quenched by the solvent or undergo a homo-coupling reaction. This deduction was supported by the GC-MS analysis of the reaction, in which homo-coupling product III and a large amount of alkane IV were observed (for details, see

Conclusions
In conclusion, we have developed a general and catalyst-free method for the uoroalkylation of alkenes promoted by photolysis of alkylzirconocenes. The reaction exhibits high functional group tolerance and broad substrate scope. A wide range of silyl-and alkyl-alkenes as well as uoroalkyl halides, including diuoroalkyl, triuoromethyl, peruoroalkyl, and monouoroalkyl bromides and iodides, were suitable substrates. In particular, the adaptability of the readily available unactivated diuoroalkyl halides and aliphatic alkenes to the reaction paves a new way for the construction of alkylCF 2 -alkyl bonds. The reaction can also be applied to nonuorinated alkyl halides, thus demonstrating the generality of this protocol further. Furthermore, the use of simple alkylzirconocene, instead of generating different alkylzirconocenes between HZrCp 2 Cl and a series of alkenes, signicantly expands the substrate scope, including a variety of complex molecules that are sensitive to HZrCp 2 Cl. The synthetic utility of this protocol has also been demonstrated by the transformations of  diuoroalkylated compounds, providing good opportunities in medicinal chemistry. Preliminary mechanistic studies reveal that a SET pathway induced by a Zr(III) species is involved in the reaction, in which the Zr(III) species is generated by the photolysis of alkylzirconocenes with blue light. This intriguing pathway may prompt great interest in using the photolysis of organozirconium for organic synthesis.

Data availability
The authors declare that all the data supporting the ndings of this study are available within the paper and its ESI. For characterization data and all NMR spectra for all new compounds see ESI. † Author contributions X. Z. and X. R. conceived and designed the experiments. X. Z. directed the project. X. R. performed the experiments and mechanistic studies. X. G. and Q.-Q. M. prepared some starting materials and performed some reactions for the preparation of compounds 3 and 8-9. X. Z. wrote the paper. S. Z. revised the paper. All authors discussed the results and commented on the manuscript.

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