Synthesis of diaryldifluoromethanes by Pd-catalyzed difluoroalkylation of arylboronic acids

Abstract

Diaryldifluoromethanes constitute a distinct class of fluorinated compounds in medicinal chemistry. But only limited methods to access this structural motif have been reported. Herein, we demonstrate the first example of Pd-catalyzed aryldifluoromethylation of arylboronic acids with readily available aryldifluoromethyl bromides. Because of its high efficiency, excellent functional group compatibility, and mild reaction conditions, this protocol provides a facile access to diaryldifluoromethanes. Preliminary mechanistic studies revealed that a Pd(0)L_n-initiated single electron transfer (SET) pathway is involved in the catalytic cycle.

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Fluorinated arenes are an important class of structural motif that is found in many pharmaceuticals, agrochemicals, and advanced materials due to the unique properties of the fluorine atom and/or the carbon–fluorine bond.¹ As a consequence, substitution of the hydrogen atom(s) in the parent molecules with the fluorine atom(s) is now a common strategy in drug discovery and development.² Among the fluorinated arenes, diaryldifluoromethanes, in which the methylene group (CH₂) is replaced by a difluoromethylene group (CF₂), represent an appealing type compounds because of their important applications in medicinal chemistry. For instance, Ledipasvir, a diaryldifluoromethane containing molecule, is an oral NS5A inhibitor for the treatment of hepatitis C virus (HCV) infection,³ and has been filed for approval by the FDA. To date, however, only limited methods have been reported to access diaryldifluoromethanes. The most common approach to such a fluorinated structural motif relies on deoxyfluorination of a carbonyl with dialkylaminosulfur trifluorides (i.e. DAST or DeoxoFluor).⁴ Despite the importance of such a process, to directly introduce a functionalized CF₂ group into organic molecules catalyzed by a transition metal would be an attractive alternative, as C–C bond formation catalyzed by transition-metals is a powerful strategy due to its broad substrate scope, high efficiency, and excellent functional-group compatibility. However, compared to transition-metal-catalyzed trifluoromethylation and fluorination of arenes,⁵ the difluoroalkylation of arenes through a similar strategy has been less studied,^6,7 although the CF₂ group plays an equally important role in medicinal chemistry and materials science.⁸ To the best of knowledge, there is no successful example that has been reported to prepare diaryldifluoromethanes catalyzed by a transition-metal. Therefore, it is highly desirable to develop an efficient reaction to access such a valuable structural motif.

As part of a systematic study on transition-metal-catalyzed reactions for the direct introduction of fluorinated moieties into organic molecules,^7,9 herein we describe the first example of synthesis of diaryldifluoromethanes through Pd-catalyzed cross-coupling between readily available aryldifluoromethyl bromides and arylboronic acids. The notable advantages of this protocol are its mild reaction conditions, excellent functional group compatibility, and operational simplicity, thus providing a facile access to a range of diaryldifluoromethanes of interest in drug discovery and development. Furthermore, to demonstrate the usefulness of this method, the late-stage aryldifluoromethylation of bioactive molecules has also been performed.

Initial studies focused on the Pd-catalyzed cross-coupling reaction of phenylboronic acid 2a with the readily available 4-(bromodifluoromethyl)-1,1′-biphenyl 1a¹⁰ in the presence of a variety of phosphine ligands (Table 1, entries 1–8). It was found that the choice of phosphine ligand was very critical to the reaction efficiency, and the bulky ligand cataCXium AHI [PAd₂(n-Bu)·HI]¹¹ was the optimal one, providing difluoromethylenated product 3a in 83% yield (determined by ¹⁹F NMR, Table 1, entry 6). This is probably because of formation of an active T-shaped palladium complex (Ph)(CF₂Ar)Pd[PAd₂(n-Bu)] that benefits the reductive elimination.¹² However, only a poor yield (27%) of 3a was obtained when XantPhos, which was previously demonstrated to be an excellent bisphosphine ligand for reductive elimination from fluoroalkyl palladium complexes,^7c,13 was employed (Table 1, entry 8). Encouraged by these results, several reaction parameters were examined to further optimize the reaction conditions (Table 1, entries 9–15, for details, see ESI†). It was revealed that K₂CO₃, 1,4-dioxane, and Pd(OAc)₂ were the optimal choices, leading to compound 3a in the best yield (91% upon isolation) when the ratio of ligand/Pd was decreased from 2/1 to 1/1 (Table 1, entry 10). Other bases, solvents, or palladium catalysts either afforded lower yields or showed no activity. The absence of palladium catalyst or ligand failed to provide the desired product, thus demonstrating that a Pd(0/II) catalytic cycle is involved in the reaction (Table 1, entries 16 and 17).

Table 1 Representative results for optimization of Pd-catalyzed cross-coupling of 1a with 2a^a

Entry	[Pd] (x)	L (y)	3a, Yield^b (%)
a Reaction conditions (unless otherwise specified): 1a (0.2 mmol, 1.0 equiv.), 2a (0.3 mmol, 1.5 equiv.), K2CO3 (2.0 equiv.), 1,4-dioxane (2 mL), 8 h. b Determined by ^19F NMR using PhCF3 as an internal standard and number in parentheses is isolated yield.
1	Pd(OAc)2 (5)	PPh3 (10)	27
2	Pd(OAc)2 (5)	P(o-OMePh)3 (10)	4
3	Pd(OAc)2 (5)	PCy3·HBF4 (10)	39
4	Pd(OAc)2 (5)	Pt-Bu3·HBF4 (10)	15
5	Pd(OAc)2 (5)	CyJohnPhos (10)	8
6	Pd(OAc)2 (5)	PAd2(n-Bu)·HI (10)	83
7	Pd(OAc)2 (5)	DPPE (10)	8
8	Pd(OAc)2 (5)	XantPhos (10)	27
9	Pd(OAc)2 (5)	PAd2(n-Bu)·HI (7.5)	89
10	Pd(OAc)2 (5)	PAd2(n-Bu)·HI (5)	97(91)
11	Pd(PPh3)4 (5)	PAd2(n-Bu)·HI (5)	Trace
12	Pd2(dba)3 (2.5)	PAd2(n-Bu)·HI (5)	34
13	Pd2(Allyl)2Cl2 (2.5)	PAd2(n-Bu)·HI (5)	56
14	Pd(PPh3)2Cl2 (2.5)	PAd2(n-Bu)·HI (5)	Trace
15	PdCl2(dppp) (2.5)	PAd2(n-Bu)·HI (5)	14
16	Pd(OAc)2 (5)	none	NR
17	None	PAd2(n-Bu)·HI(5)	NR

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Upon identification of viable reaction conditions, the substrate scope of this transformation was tested and representative results are illustrated in Table 2. Overall, aromatic boronic acids with either electron-rich or electron-deficient substituents underwent the present cross-coupling process with aryldifluoromethyl bromide 1a in moderate to high yields. A variety of important functional groups, such as the formyl, alkoxycarbonyl, enolizable ketone, and trimethylsilyl groups, were tolerated quite well (3l–p). The sterically hindered ortho-tolylboronic acid and its derivative were excellent substrates, and the cross-coupling with 1a proceeded with high efficiency (3d and 3e). Furthermore, other aryldifluoromethyl bromides were also applicable to the reaction and moderate yields were obtained (3r–u). However, it should be mentioned that in the cases of reactions of phenyldifluoromethyl bromide 1b with arylboronic acids, a significant amount of PhCF₂H was observed under standard conditions. We supposed that the formation of PhCF₂H could be ascribed to the reaction of solvent with PhCF₂˙ radical that was generated from 1b with Pd–PAd₂(n-Bu)–base. To our delight, when 1.0 equiv. of H₂O was added to the reaction, moderate yields of 3r and 3s were obtained. However, the role of H₂O in this reaction remains uncertain. Notably, aryl chloride was also compatible with the reaction conditions, thus providing a good opportunity for downstream transformations (3u).

Table 2 Pd-catalyzed aryldifluoromethylation of arylboronic acids 2 with aryldifluoromethyl bromides 1^a

a Reaction conditions (unless otherwise specified): 1 (0.4 mmol, 1.0 equiv.), 2 (0.6 mmol, 1.5 equiv.), K₂CO₃ (2.0 equiv.), 1,4-dioxane (4 mL), 8 h. All reported yields are isolated yields. b 1.0 equiv. of H₂O was used.

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The importance and usefulness of this method can also be highlighted by late-stage aryldifluoromethylation of bioactive molecules. As shown in Scheme 1, treatment of estrone-derived arylboronic acid 4 with the difluoroalkyl bromide 1a afforded difluoroalkylated compound 5 with high efficiency (79%). Similarly, the flavanone-derived arylboronic acid 6 also led to its corresponding difluoroalkylated product 7 in high yield (82%). In view of the fact that CF₂ can functionalize as a bioisostere of the oxygen atom or carbonyl group,¹⁴ and leads to profound changes in physical and biological properties of CF₂ containing molecules,⁸ we view these transformations as a highly valuable opportunity for application in drug discovery and development.

Scheme 1 Late-stage functionalization for synthesis of biologically active molecules.

To gain some mechanistic insight into the present reaction, radical inhibition experiments were conducted (Scheme 2). A significant decrease of the yields were observed when an electron transfer (ET) inhibitor (1,4-dinitrobenzene) was added to the reaction mixture of 1a and 2a in the presence of Pd(OAc)₂ (5 mol%), PAd₂(n-Bu)·HI (5 mol%), and K₂CO₃ in dioxane.¹⁵ Thus, these preliminary studies demonstrate that a single electron transfer (SET) pathway via an aryldifluoromethyl radical is involved in the catalytic cycle.

Scheme 2 Radical inhibition experiments.

To confirm that a free aryldifluoromethyl radical was generated during the reaction, a radical clock experiment was conducted (Scheme 3). When compound 8¹⁶ was treated with 1a under standard conditions, a ring-expanded product 9 was formed in 7% yield (determined by ¹⁹F NMR) along with 3% yield of protonated product 10 and 78% of starting material 1a unreacted. This finding demonstrated that a free radical was indeed generated during the reaction.

Scheme 3 Radical clock experiment.

On the basis of these results, a plausible reaction mechanism was proposed (Scheme 4). The reaction is initiated by a [PdL_n(0)]-promoted SET pathway to generate aryldifluoroalkyl radical (ArCF₂˙) A. A subsequently reacts with L_nPd(I)Br to produce Pd(II)-complex B. After transmetalation, a key intermediate C would be generated. As the final step of the catalytic cycle, reductive elimination of C affords diaryldifluoromethanes 3. However, for the detailed reaction mechanism remains a subject to be studied.

Scheme 4 Proposed reaction mechanism.

Conclusions

In conclusion, we have demonstrated the first example of palladium-catalyzed aryldifluoromethylation of arylboronic acids with readily available aryldifluoromethyl bromides. The utility of PAd₂(n-Bu)·HI is critical for the reaction efficiency. The reaction proceeds under mild reaction conditions with excellent functional group compatibility. Thus, these transformations provide a facile route for application in medicinal chemistry. Mechanistic studies revealed that a [Pd(0)L_n] promoted SET pathway via a free fluoroalkyl radical is involved in the reaction. Further studies to uncover the reaction mechanism as well as other derivative reactions are now in progress in our laboratory.

Acknowledgements

The National Basic Research Program of China (973 program (no. 2015CB931900)), the NSFC (nos 21425208, 21421002, 21172242, and 21332010), and SIOC are greatly acknowledged for funding this work.

Notes and references

1. For selected reviews, see: (a) B. E. Smart, J. Fluorine Chem., 2001, 109, 3; (b) P. Maienfisch and R. G. Hall, Chimia, 2004, 58, 93; (c) Special issue on “Fluorine in the Life Sciences”, ChemBioChem, 2004, 5, 557;; (d) D. O'Hagan, Chem. Soc. Rev., 2008, 37, 308.
2. For selected reviews, see: (a) K. L. Kirk, J. Fluorine Chem., 2006, 127, 1013; (b) J.-P. Begue and D. Bonnet-Delpon, J. Fluorine Chem., 2006, 127, 992; (c) K. Müller, C. Faeh and F. Diederich, Science, 2007, 317, 1881; (d) W. K. Hagmann, J. Med. Chem., 2008, 51, 4359; (e) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320.
3. J. O. Link, J. G. Taylor, L. Xu, M. Mitchell, H. Guo, H. Liu, D. Kato, T. Kirschberg, J. Sun, N. Squires, J. Parrish, T. Keller, Z.-Y. Yang, C. Yang, M. Matles, Y. Wang, K. Wang, G. Cheng, Y. Tian, E. Mogalian, E. Mondou, M. Cornpropst, J. Perry and M. C. Desai, J. Med. Chem., 2014, 57, 2033.
4. For selected examples of difluorination of carbonyl groups with fluorinated reagents, see: (a) W. J. Middleton and E. M. Bingham, J. Org. Chem., 1980, 45, 2883; (b) G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M. Prozonic and H. Cheng, J. Org. Chem., 1999, 64, 7048; (c) D. Solas, R. L. Hale and D. V. Patel, J. Org. Chem., 1996, 61, 1537; (d) S. Kobayashi, A. Yoneda, T. Fukuhara and S. Hara, Tetrahedron, 2004, 60, 6923; (e) T. Umemoto, R. P. Singh, Y. Xu and N. Saito, J. Am. Chem. Soc., 2010, 132, 18199; (f) A. L'Heureux, F. Beaulieu, C. Bennett, D. R. S. Clayton, F. LaFlamme, M. Mirmehrabi, S. Tadayon, D. Tovell and M. Couturier, J. Org. Chem., 2010, 75, 3401.
5. For selected reviews, see: (a) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470; (b) O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111, 4475; (c) C. Hollingworth and V. Gouverneur, Chem. Commun., 2012, 48, 2929; (d) T. Besset, C. Schneider and D. Cahard, Angew. Chem., Int. Ed., 2012, 51, 5048; (e) F.-L. Qing, Chin. J. Org. Chem., 2012, 32, 815; (f) X. Wang, Y. Zhang and J. Wang, Sci. Sin.: Chim., 2012, 42, 1417.
6. For transition-metal-catalyzed difluoroalkylation, see: (a) K. Araki and M. Inoue, Tetrahedron, 2013, 69, 3913; (b) S. Ge, W. Chaladj and J. F. Hartwig, J. Am. Chem. Soc., 2014, 136, 4149.
7. For our contribution to transition-metal-catalyzed difluoroalkylation, see: (a) Z. Feng, F. Chen and X. Zhang, Org. Lett., 2012, 14, 1938; (b) Z. Feng, Y.-L. Xiao and X. Zhang, Org. Chem. Front., 2014, 1, 113; (c) Z. Feng, Q.-Q. Min, Y.-L. Xiao, B. Zhang and X. Zhang, Angew. Chem., Int. Ed., 2014, 53, 1669; (d) Q.-Q. Min, Z. Yin, Z. Feng, W.-H. Guo and X. Zhang, J. Am. Chem. Soc., 2014, 136, 1230; (e) Y.-L. Xiao, W.-H. Guo, G.-Z. He, Q. Pan and X. Zhang, Angew. Chem., Int. Ed., 2014, 53, 9909; (f) Y.-B. Yu, G.-Z. He and X. Zhang, Angew. Chem., Int. Ed., 2014, 53, 10457; (g) Y.-L. Xiao, B. Zhang, Z. Feng and X. Zhang, Org. Lett., 2014, 16, 4822.
8. For selected reviews, see: (a) X.-L. Qiu, X.-H. Xu and F.-L. Qing, Tetrahedron, 2010, 66, 789; (b) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529; For selected papers, see: (c) C. S. Burgey, K. A. Robinson, T. A. Lyle, P. E. J. Sanderson, S. Dale Lewis, B. J. Lucas, J. A. Krueger, R. Singh, C. Miller-Stein, R. B. White, B. Wong, E. A. Lyle, P. D. Williams, C. A. Coburn, B. D. Dorsey, J. C. Barrow, M. T. Stranieri, M. A. Holahan, G. R. Sitko, J. J. Cook, D. R. McMasters, C. M. McDonough, W. M. Sanders, A. A. Wallace, F. C. Clayton, D. Bohn, Y. M. Leonard, T. J. Detwiler Jr., J. J. Lynch Jr., Y. Yan, Z. Chen, L. Kuo, S. J. Gardell, J. A. Shafer and J. P. Vacca, J. Med. Chem., 2003, 46, 461; (d) J. Li, S. Y. Chen, B. J. Murphy, N. Flynn, R. Seethala, D. Slusarchyk, M. Yan, P. Sleph, H. Zhang, W. G. Humphreys, W. R. Ewing, J. A. Robl, D. Gordon and J. A. Tino, Bioorg. Med. Chem. Lett., 2008, 18, 4072; (e) C. L. Lynch, C. A. Willoughby, J. J. Hale, E. J. Holson, R. J. Budhu, A. L. Gentry, K. G. Rosauer, C. G. Caldwell, P. Chen, S. G. Mills, M. MacCoss, S. Berk, L. Chen, K. T. Chapman, L. Malkowitz, M. S. Springer, S. L. Gould, J. A. DeMartino, S. J. Siciliano, M. A. Cascieri, A. Carella, G. Carver, K. Holmes, W. A. Schleif, R. Danzeisen, D. Hazuda, J. Kessler, J. Lineberger, M. Miller and E. A. Eminic, Bioorg. Med. Chem. Lett., 2003, 13, 119.
9. (a) C.-Y. He, S. Fan and X. Zhang, J. Am. Chem. Soc., 2010, 132, 12850; (b) X. Zhang, S. Fan, C.-Y. He, X. Wan, Q.-Q. Min, J. Yang and Z.-X. Jiang, J. Am. Chem. Soc., 2010, 132, 4506; (c) S. Fan, F. Chen and X. Zhang, Angew. Chem., Int. Ed., 2011, 50, 5918; (d) Z. Chen, C.-Y. He, Z. Yin, L. Chen and X. Zhang, Angew. Chem., Int. Ed., 2013, 52, 5813.
10. J. He and C. U. Pittman, Synth. Commun., 1999, 29, 855.
11. (a) A. Ehrentraut, A. Zapf and M. Beller, Synlett, 2000, 1589; (b) A. Zapf, A. Ehrentraut and M. Beller, Angew. Chem., Int. Ed., 2000, 39, 4153.
12. A. G. Sergeev, A. Spannenberg and M. Beller, J. Am. Chem. Soc., 2008, 130, 15549.
13. (a) V. V. Grushin and W. J. Marshall, J. Am. Chem. Soc., 2006, 128, 12644; (b) V. I. Bakhmutov, F. Bozoglian, K. Gómez, G. González, V. V. Grushin, S. A. Macgregor, E. Martin, F. M. Miloserdov, M. A. Novikov, J. A. Panetier and L. V. Romasho, Organometallics, 2012, 31, 1315.
14. (a) C. M. Blackburn, D. A. England and F. Kolkmann, J. Chem. Soc., Chem. Commun., 1981, 930; (b) G. M. Blackburn, D. E. Kent and F. Kolkmann, J. Chem. Soc., Perkin Trans. 1, 1984, 1119; (c) T. Kitazume and T. Kamazaki, Experimental Methods in Organic Fluorine Chemistry, Gordon and Breach Science, Tokyo, 1998.
15. For related radical inhibition experiments studies, see: (a) X.-T. Huang and Q.-Y. Chen, J. Org. Chem., 2001, 66, 4651; (b) R. N. Loy and M. S. Sanford, Org. Lett., 2011, 13, 2548.
16. J. E. Baldwin, Chem. Rev., 2003, 103, 1197.

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures, and analytical data for all new compounds. See DOI: 10.1039/c4qo00246f

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