Modular synthesis of α-fluorinated arylmethanes via desulfonylative cross-coupling

α-Fluoromethylarenes are common substructures in pharmaceuticals and agrochemicals, with the introduction of fluorine often resulting in improved biological activity and stability. Despite recent progress, synthetic routes to α-fluorinated diarylmethanes are still rare. Herein we describe the Pd-catalyzed Suzuki-Miyaura cross-coupling of α-fluorinated benzylic triflones with arylboronic acids affording structurally diverse α-fluorinated diarylmethanes. The ease of synthesis of fluorinated triflones as the key starting materials enables powerful late-stage transformations of known biologically active compounds into fluorinated analogs.

T he strategic substitution of fluorine for hydrogen is an important strategy to improve the stability of materials and pharmaceuticals against metabolic or oxidative degradation ( Fig. 1a) [1][2][3][4][5][6] . Transition metal-catalyzed cross-coupling reactions of arene derivatives with fluorinated alkyl electrophiles or nucleophiles are among the most valuable methods to form aryl-fluoroalkyl bonds under mild conditions without the use of toxic or hazardous reagents [7][8][9][10][11] . However, despite these recent advances, α-fluorinated diarylmethanes are still prepared by classical methods including deoxyfluorination of diarylmethanols or diarylketone derivatives [12][13][14][15][16] . Important advances from the Zhang 17,18 and Szymczak 19 groups have begun to address these issues, but still require difluoromethylarenes as starting materials, which can be of limited availability (Fig. 1b, c). In an alternative approach, Chen has described the photolytic fluorination of benzylic C-H bonds, which enables the selective synthesis of mono-and difluorinated products 20 ; however, this reaction was demonstrated only for simple diphenylmethanes. Considering the potential importance of fluorinated molecules in drug discovery [21][22][23] , the modular and selective synthesis of α-fluorinated diarylmethanes from readily available reagents remains a real challenge. Routes that enable late-stage transformation of existing biomolecules are even more impactful [24][25][26][27][28] .
Sulfone derivatives are emerging as important electrophiles in transition-metal-catalyzed transformations 29 . Unlike other electrophiles, which serve only as a leaving group, the sulfonyl group also activates adjacent protons, enabling facile αfunctionalizations such as fluorination, in advance of any cross-coupling reactions. This enables the modular and straightforward synthesis of complex structures from simple, readily prepared starting materials. Utilizing this unique reactivity of sulfones, our group has developed Pd-and Ni-catalyzed reactions of benzylic sulfone derivatives that afford compounds which are difficult to prepare by other methods [30][31][32][33] . The Baran group has also employed this functional group to enable the Nicatalyzed radical cross-coupling of alkyl or fluoroalkylsulfones with arylzinc reagents (Fig. 1d) 34 .
We describe herein the Pd-catalyzed desulfonylative crosscoupling of α-fluorinated benzyltriflones with arylboronic acids, which enables the generation of a range of structurally diverse mono-and difluorinated diarylmethanes not described using the Baran approach (Fig. 1e). Notably, fluorinated benzyltriflone substrates were readily prepared by α-fluorination using an inexpensive fluorinating agent and mild base. This strategy takes advantage of the properties of the sulfone as an activator for fluorination and a leaving group for cross-coupling reactions.

Results
Optimization of desulfonylative coupling. Di-and monofluorinated starting materials 1 and 2 were readily prepared by the use of N-fluorobenzenesulfonimide (NFSI) as an inexpensive fluorinating agent. Difluorination was readily accomplished with excess NFSI and K 3 PO 4 , giving α-difluorobenzyltriflone 1 in high yield. Monofluoro derivatives 2 were prepared by deprotonation of benzyltriflones with one equivalent of NaHMDS followed by the addition of NFSI. These procedures enabled the facile synthesis of 1 and 2 bearing a variety of functional groups (see Supplementary Information).
Optimized conditions were found to be the following: the use of DavePhos as ligand, Pd(OAc) 2 as catalyst, K 3 PO 4 as base in THF at 60°C, which afforded 4aa in 90% isolated yield (   (Table 1, entries 4-7). The use of Na 2 CO 3 instead of K 3 PO 4 decreased the yield of product (Table 1, entry 8). The synthetically useful boronic acid pinacol ester was also applicable in this reaction (Table 1, entry 9). These conditions were less effective for electron-deficient substrates such as ester-substituted difluorobenzyltriflone 1b (Table 1, entry 10). However, di(1-adamantyl)-n-butylphosphine (P(Ad) 2 Bu) 17 was employed in DME at 90°C, and gave the crosscoupling product in good yield (Table 1, entry 11). The related αmonofluorobenzyltriflone 2a did give α-fluorodiarylmethane 10aa under standard conditions, but the yield was relatively low ( Table 1, entry 12). Anticipating that the presence of the acidic benzylic proton in 2a might be incompatible with strong base, we employed Na 2 CO 3 as a milder base, which gave the desired 10aa in 82% yield (Table 1, entry 13). In no case was benzotrifluoride, which can be potentially generated by the arylation of SO 2 -CF 3 bond, observed.
Substrate scope of desulfonylative Suzuki−Miyaura crosscoupling. With the optimized conditions for the cross-coupling in hand, we then investigated the substrate scope (Fig. 3).
First, we examined the reaction of 1a with a range of arylboronic acids. Arylboronic acids (3) bearing electrondonating and electron-withdrawing groups were well tolerated, and useful functional groups such as acetyl, cyano, formyl, ester, nitro, and vinyl groups were compatible, affording the corresponding products 4 in good yields. The sterically hindered o-tolylboronic acid (3j) displayed decreased reactivity, while πextended 1-naphthylboronic acid (3k) showed good reactivity. Although heteroarylboronic acids (3l−3n) were less reactive under standard conditions 35,36 , increasing the catalyst loading and reaction temperature improved product yields. Some πextended arenes (1b, 1c) and heteroarenes, such as indole (1d) and azole (1e), could be introduced in good yields. Gram-scale synthesis was successfully achieved in the preparation of 4bh.
Electron-deficient benzylic sulfones were smoothly reacted under the modified conditions (P(Ad) 2 Bu instead of DavePhos) as shown in Table 1. Under these conditions, sulfone substrates bearing ester (1f), cyano (1g), nitro (1h), benzoyl (1i), and benzyloxy (1j) groups underwent cross-coupling, affording the  Fig. 2 Substituent effect of sulfonyl group on desulfonylative cross-coupling reaction. Reactions were carried out on a 0.1 mmol scale. Yields were determined by GC using dodecane as an internal standard desired products. As an illustration of the ease with which heteroaromatics can be incorporated, α,α-difluorodi(heteroaryl) methane 4kn could be prepared in high yield. The present Pdcatalyzed cross-coupling is limited to benzylic substrates. Thus α,difluoroalkyltriflones such as 1,1-difluoro-3-phenylpropyl triflone are not viable substrates (see Supplementary Fig. 3).
Arylation of α-monofluorinated benzylic sulfones 2 also proceeded under the standard conditions, affording the corresponding monofluorinated diarylmethanes 10 in high yields. As in the difluorinated series, a variety of functional groups on sulfone and arylboronic acid substrates were compatible with this protocol (Fig. 3).
Desulfonylation of α-fluorobenzyl triflones 1 and 2. In addition to their use as partners in cross-coupling chemistry, 1 and 2 are also precursors to the pharmaceutically relevant difluoromethyland fluoromethylarenes (11, 12) (Fig. 4). Using typical procedures with Mg 37 or SmI 2 38 as reducing agents, desulfonylation proceeded smoothly to give the corresponding CF 2 H or CFH 2containing species in good yields. This desulfonylation approach is complimentary to other cross-coupling reactions using monoand difluoromethylating agents for the selective synthesis of mono-and difluoromethylarenes 39 .

Mechanistic investigations.
Experimental and theoretical studies were carried out to gain mechanistic insights into the desulfonylative cross-coupling reaction. Reaction mechanisms involving radical intermediates appear likely in cross-coupling reactions using fluoroalkyl halides 17 ; thus, we conducted preliminary experiments to determine whether similar radical species are generated in this case. When the reactions of 1a with 3a were conducted under standard conditions in the presence of typical radical inhibitors, such as TEMPO and BHT, or 1,4-dinitrobenzene as an electron-transfer inhibitor 40 , yields of 4aa were not significantly affected (Fig. 5a). This suggests that the present cross-coupling reaction does not likely involve the generation of free difluorobenzyl radical species in the catalytic cycle, and likely occurs via the similar catalytic cycle as the Suzuki−Miyaura cross-coupling reaction (see Supplementary Fig. 4).  Next, we explored the mechanism and the dramatic substituent effects of sulfonyl groups on the reactivity of cross-coupling by theoretical calculations. Gibbs free energies were obtained from single point calculations on optimized geometries with thermal correction and solvation effects considered. The energy profile is summarized in Fig. 5b for α,α-difluorobenzyltriflone 14 CF3 , α,αdifluorobenzyl phenyl sulfone 14 Ph , and 3,5-bis(trifluoromethy) phenyl difluorobenzyl sulfone 14 ArCF3 . The C-SO 2 activation step should occur through the formation of a η 2 -arene complex 15 between Pd(DavePhos) 13 and sulfones (14 CF3 , 14 Ph , or 14 ArCF3 ), and then the three-membered transition state (TS [15][16] to afford the Pd(II) complex.
Synthetic applications. A significant advantage of this method is that the triflyl group can be easily installed through the late-stage transformation of any benzylic methyl group or indeed any benzylic C-H group (Fig. 6a). For example, the methyl group on 6-methylflavone could be converted into the triflylmethyl group in two simple steps: benzylic bromination followed by S N 2 reaction with Langlois reagent (NaSO 2 CF 3 ) 41 . Subsequently, αfluorination selectively provides the fluorinated sulfone derivatives 17 and 18 (Supplementary Methods). The resulting triflones were reacted with phenylboronic acid 3a under standard reaction conditions to afford the cross-coupling products (19,20). The structure of 19 was unambiguously confirmed by X-ray crystallographic analysis. This sequential process enables the formal transformation of methyl group to arylfluoromethyl groups on arenes, highlighting potential application to late-stage transformation of biomolecules.
The CF 2 unit has recently attracted much attention as it functions as a bioisostere of carbonyl and ether functional groups to improve biological activity 42 . Thus, we demonstrated the practicality of the present cross-coupling reaction by synthesizing CF 2 analogs of biologically active molecules. Medarde reported that diarylketone 21 showed inhibitory activity against tubulin polymerization and has potent cytotoxicity against cancer cell lines 43 . Analog 22, in which the carbonyl unit is substituted with a CF 2 unit, was synthesized in excellent yield by the cross-coupling of α,α-difluoro-2-naphthylmethyl triflone 1c with 3,4,5-trimethoxylphenylboronic acid 3u (Fig. 6b).
ABT-518 has been developed as an inhibitor of matrix metalloproteinases, which are key species implicated in tumor growth and metastasis 44,45 . We have successfully prepared the analog of ABT-518 (26) in which the diarylether unit is replaced by a diarylCF 2 unit (Fig. 6c). The key intermediate α,αdifluorodiarylmethane 23 was synthesized from the crosscoupling of α,α-difluoro-4-methanesulfonylbenzyl triflone 1l and 4-(trifluoromethyl)methoxylphenylboronic acid 3v. According to the previous procedure, vinyl sulfone 25 could be isolated. Finally, the conjugated addition of hydroxylamine to 25 followed by N-formylation using formic acid-acetic anhydride mixture gave 26 in seven steps from 1l. These results illustrate that our robust method will expand the utility of CF 2 units as bioisosteres, which are difficult to introduce by existing methods, leading to accelerated generation of previously unknown pharmaceuticals.
In conclusion, we have established a versatile synthetic route for the synthesis of structurally diverse α-fluorinated and α,αdifluorinated molecules through the Pd-catalyzed Suzuki −Miyaura cross-coupling reaction of α-fluorinated benzyltriflones with arylboronic acids. In addition to cross-coupling, desulfonylation can be carried out to provide medicinally important fluoromethyland difluoromethylarenes in good yields. The ability to convert aromatic methyl groups to reactive sulfones is particularly exciting for late-stage functionalization approaches to the synthesis of fluorinated analogs of biomolecules. These reactions not only provide facile access to αfluorinated arylmethanes from stable and readily available

Methods
Cross-coupling of triflones 1 with arylboronic acids 3. A 10-mL sealable glass vessel containing a magnetic stirring bar was flame-dried under vacuum and filled with argon after cooling to room temperature. The tube was charged with Pd (OAc) 2 (2.2 mg, 0.01 mmol), DavePhos (11.8 mg, 0.03 mmol). The mixture was evacuated under vacuum and refilled with Ar. This cycle was repeated two additional times. Under an argon atmosphere, THF (0.4 mL) was added and the reaction was stirred at room temperature for 30 min. α,α-difluorobenzyltriflone 1 (0.2 mmol), arylboronic acid 3 (0.4 mmol), K 3 PO 4 (127 mg, 0.6 mmol), and THF (0.4 mL) were added, and the reaction was sealed and stirred at 60°C for 16 h. The reaction was then allowed to cool to room temperature, quenched with 3-4 drops of sat. NH 4 Cl aq and the mixture was passed through a pad of silica gel with copious washings with EtOAc (~10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (PTLC) or preparative recycling HPLC (GPC) to afford diaryl-α,αdifluoromethane 4.
Cross-coupling of triflones 2 with arylboronic acids 3. An oven-dried 1-dram vial equipped with a magnetic stirring bar was charged with Pd(OAc) 2 (3.3 mg, 0.015 mmol) and DavePhos (17.7 mg, 0.045 mmol). The vial was capped with a Teflon cap and dry THF (1.5 mL) was added, under argon. This mixture was stirred for 30 min. Another vial containing a stirring bar was charged with α-fluorobenzyl triflone 2 (0.3 mmol), base (0.9 mmol) and arylboronic acid 3 (0.6 mmol). The vial was sealed under argon atmosphere, and the solution containing the catalyst was added to it. The resulting mixture was heated at 60°C for 18-24 h, under stirring. After cooling to room temperature, the mixture was filtered through a plug of silica and washed with DCM/EtOAc (4:1). The crude product was purified by column chromatography or PTLC to afford diarylfluoromethane 10. a b c Fig. 6 Synthetic applications. a Sequential transformation of benzylic C-H bond of flavone derivatives. b Rapid preparation of the analog 22 bearing CF 2 unit as bioisosteres of carbonyl group. c Illustration of desulfonylative cross-coupling in the synthesis of the analog of ABT-518 (26) in which the diarylether unit is replaced by a diarylCF 2 unit