Integrated redox-active reagents for photoinduced regio- and stereoselective fluorocarboborylation

Vinylboronates and alkylboronates are key components in variegated transformations in all facets of chemical science. The synthesis of vinylboronates and alkylboronates suffers from step-tedious and poor stereoselective procedures. We have developed a regulated radical difunctionalization strategy for the construction of fluorine-containing vinylboronates and alkylboronates with an integrated redox-active reagent IMDN-SO2RF. This bench-stable imidazolium sulfonate cationic salt offers a scalable and operational protocol for the fluoroalkylation-borylation of unsaturated hydrocarbons in a high regio- and stereoselective manner. The products can be further transformed into valuable fluorinated building blocks.

D ifunctionalization of alkenes and alkynes has been widely explored for rapid diversification of double/triple bonds [1][2][3][4][5][6] . Traditional transition metal-catalyzed difunctionalization methods have been well-developed to control the regioselectivity and stereoselectivity 7,8 . Along these lines, cascade radical addition of unsaturated hydrocarbons in the absence of metallo-intermediate has been realized through careful manipulation of the radical reactivities [9][10][11] . A single process to achieve radical difunctionalization with extensive functionality tolerance, especially fluorine-containing moieties, is of great value in altering the physical and biological properties of the unsaturated hydrocarbons 4,[12][13][14][15][16][17][18] . Studer and co-workers 19 have reported a radical 1,2-trifluoromethylboration of unactivated alkenes using gaseous CF 3 I. Meanwhile, the direct 1,2-fluoroalkylboration of alkynes has also been explored [20][21][22] . The consequential vicinial vinylboronates, which can be readily transformed to a myriad of fluorine-containing building blocks, have been seldom realized. The only two existing approaches of trifluoromethylated vinylboronates were derived from fluorinated alkynes 23 and oxiranes 24 . The inaccessibility of those pre-functionalized precursors and operationally tedious procedures prohibited the stepwise fluorination-borylation strategies from practical use (Fig. 1a).
Thus, the development of regioselective installation of fluoroalkyl and boronated functionalities to unactivated hydrocarbons in the absence of transition-metal catalysts represents great challenge.
Due to the complexity of radical process incorporating C-C and C-B bonds formation, several issues need to be addressed, including the reactivities of carbon and boron-centered radicals, the regioselectivity of the radical additions to unsymmetrical alkynes, and stereoselectivity towards E/Z vinylboronates. Typically, a radical borylation process [25][26][27][28][29][30][31][32] often employs Lewis basic solvents/mediators such as DMAc 33,34 , DMF 19,35 , phthalimide 36 , and pyridine 37,38 for the activation of diboron reagents via homolytic cleavage of B-B bonds (Fig. 1b). However, the exogenous Lewis base-activated diboron species inevitably deplete CF 3 radicals that generated promptly from the trifluromethylating reagents, unable to engage in the desired trifluoromethylborylation sequence (for DFT calculation details, see Supplementary Fig. 18). Inspired by recent radicalinduced difunctionalization strategies 39,40 , we intend to design an integrated reagent that progressively releases CF 3 radical for alkene/ alkyne addition, and the endogenous Lewis basic residue subsequently activates the B-B bond for further borylation (Fig. 1c).
Trifluoromethanesulfinate-derived fluorinating reagents have been devised and adopted for direct functionalization of alkenes, alkynes, and arenes 41 . In contrast, the highly hydroscopic and corrosive trifluoromethanesulfonic anhydride (Tf 2 O) as a trifluoromethyl source is rarely explored. For its strong electrophilic nature, triflic anhydride is commonly used as an alcohol and amine protecting agent [42][43][44] . Qing and co-workers 45 have described a triflated pyridine intermediate (Tf − Py + ·OTf − ) that generated in situ for trifluoromethylated arenes and alkynes. However, the strong electron-withdrawing triflate-derived pyridinium complex is preferably dissociated and unattainable in solid or liquid phase. We speculated that a more basic N-heterocycle such as imidazole could harness the highly reactive Tf 2 O to assemble a bench-stable redoxactive reagent. The positive charge of the resulting imidazolium trifluoromethanesulfonate can be delocalized on both nitrogen. Through the cleavage of the stabilized N-S bond (BDE ≈ 70 kcal mol −1 ) 46 , this cationic complex undergoes SET process to generate CF 3 SO 2 radical. Meanwhile, as a Lewis base, the imidazole residue can further activate the diboron reagents towards homolytic cleavage of the diboron reagent 20,[34][35][36][37][38][39] . Herein, we have synthesized a dual functional reagent IMDN-SO 2 CF 3 1a-1g, a scalable and airstable crystalline salt for a sequential radical fluoroalkylationborylation of unsaturated hydrocarbons (Fig. 1d). First, under the irradiation, Ir(III)* can reduce the cationic reagent 1 to a neutral radical I and releases CF 3 radical, SO 2 , and imidazole. Then the addition of ·CF 3 to the alkyne regioselectively furnishes vinylic radical II. Subsequent addition of vinyl radical II to B 2 cat 2 affords a Z-vinyl diboron radical III. The control of stereoselectivity is governed by steric repulsion between the trifluoromethyl group and the boronates. The following activation of diboron by the Lewis basic imidazole forms a highly reactive B-N heteroleptic intermediate IV, which leads to the carboborylation product 3 and imidazolestabilized boryl radical V. Finally, photo-oxidation of V followed by coupling with − OTf affords boryl imidazolium salt VI and regenerates Ir(III) (Fig. 1e). These proposed intermediates and selectivities are supported by DFT calculations (see Supplementary  Figs. [16][17][18][19] This photoinduced cascade radical difunctionalization offers a concise and applicable protocol for constructing highly regio-and stereoselective fluorine-substituted vinylboronates and vicinal fluoroalkyl boronates.
Other diboron reagents, such as bis(pinacolato)diboron (B 2 pin 2 ) and bis(neopentylglycolato)-diboron (B 2 neop 2 ), did not provide the corresponding borylated products (entries 9-10). Addition of excess bases such as imidazole and pyridine resulted in much lower yields (entries [11][12]. Substrate scope with respect to the alkynes. Using 2 mol% of fac-Ir(ppy) 3 , IMDN-SO 2 CF 3 (1a) (2.5 equiv), and B 2 cat 2 (2.5 equiv) at ambient temperature, a range of alkyens underwent fluoroalkylation-borylation with good efficiency. As shown in Fig. 2, the reaction can be performed at a gram scale to give 3a in 61% yield and high stereoselectivity. Aromatic alkynes with electro-donating or electro-withdrawing substituents afford the desired products 3b-3j in good to excellent yields (60-93%) with high regio-and stereoselectivity (Z:E > 20:1). Functionalities including halides (3b, 3m, 3n), nitrile (3d), ester (3g), and boronate (3j) are tolerated. Naphthyl-and thienylsubstituted alkynes also readily transformed into the Z-products 3h and 3i in good yields. The reaction could also be applied to alkynyl deuterium to produce the (Z)-selective deuterated vinylboronates 3k-3n in 52-72% yields. An attempt of more challenging internal alkyne substrate resulted in the tetrasubstituted olefin in high regio-and stereoselectivity (3o, 45%). For further investigation of the reaction scope, different fluoroalkylating reagents 1i-1l have been synthesized and applied to the   standard cabonborylation conditions. Perfluoro-butyl (1i), hexyl (1j), and octanyl (1k) reagents could furnish the corresponding products 3q-3s in good yields (81-87%). Using a perhalogenated ether-derived sulfonate (1l), the vinylboronate 3t was formed in high yield. To demonstrate the scalability of such radical carboborylation protocol, the reaction was carried out on 10 mmol scale to afford 3a in 61% yield with equally high Z/E ratio. Under the standard reaction conditions, alkyl-substituted alkynes could not transform to the desired products. DFT calculations illustrate that the energy barrier of CF 3 radical addition to aliphatic alkynes is higher than that to aromatic alkynes. Furthermore, a competing pathway of CF 3 radical addition to B 2 cat 2 leads to other trifluoromethylated products. Therefore, an excess amount of alkyl alkyne substrate is needed to facilitate the main reaction pathway. By using four equivalents of the alkyne, the borylated product 3p can be obtained in 26% yield. For internal aliphatic alkynes, the computed barrier with the CF 3 radical is much higher than that for the reaction of B 2 Cat 2 with the CF 3 radical. Therefore, no desired product is obtained using internal aliphatic alkynes as substrate.
Synthetic applications. The synthetic utility of the method was demonstrated in a number of transformations of the highly functionalized alkylboronates and alkenylboronates 20,52,53 (Fig. 4).

Discussion
In summary, we have described an air-stable redox-active reagent IMDN-SO 2 R F 1 with high reactivity and scalability. A key design feature of this dual functional imidazolium sulfonate reagent is the cationic nature that favors the progressive formation of fluoroalkyl radicals by SET reduction under photocatalytic conditions. Meanwhile, the in situ-generated Lewis basic imidazole residue promotes the B-B bond cleavage. The integrated reagent is applicable to regulate the reaction sequence of carbon and boron-centered radicals to access various fluorine-bearing vinylboronates and alkylboronates with high stereo-and regioselectivities. Further study of this reagent is underway in our laboratory.

Methods
General procedure for the synthesis of imidazolium salts 1. To a one-necked 1000 mL flask equipped with a magnetic stirrer, the corresponding imidazole (100 mmol), Et 3 N (150 mmol), and 600 mL DCM were added. The flask was then cooled in an ice bath, and 130 mmol ( General procedure for the synthesis of alkylboronates 5. Under argon, to a solution of 1 (0.50 mmol, 2.5 equiv), B 2 Cat 2 (0.6 mmol, 3.0 equiv) and fac-Ir(ppy) 3 (2 mol%) in 1:1 MeCN/acetone (0.2 mL) was added Et 3 B (0.6 mmol, 3.0 equiv, 1 mol/L in THF) and corresponding alkenes 4 (0.2 mmol) at room temperature. After that, the tube was exposed to 30 W blue LEDs at room temperature for 30 h until the reaction was completed as monitored by TLC or GC-MS analysis. A solution of pinacol (142 mg, 1.2 mmol) in Et 3 N (1.1 mL) was added to the mixture. After 1 h, the reaction mixture was evaporated in vacuo. The product was purified by flash column chromatography on silica gel with n-pentane/ethyl acetate as eluent to give the alkylboronates 5.

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