Synthesis of gem-Difluoroalkenes via Nickel-Catalyzed Allylic

Letter Cite This: ACS Catal. 2018, 8, 9245−9251

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Synthesis of gem-Difluoroalkenes via Nickel-Catalyzed Allylic Defluorinative Reductive Cross-Coupling Yun Lan, Feiyan Yang, and Chuan Wang* Department of Chemistry, Center for Excellence in Molecular Synthesis, Hefei National Laboratory for Physical Science at the Microscale, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China

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S Supporting Information *

ABSTRACT: In this protocol, we report an allylic defluorinative reductive cross-coupling reaction for C−C bond formation. Under the Ni-catalysis the challenging C(sp3)−F bond cleavage of trifluoromethyl-substituted alkenes was achieved with easily accessible primary, secondary and tertiary alkyl halides as the coupling partners and Zn-powder as reducing agent. This process provides an efficient and convenient entry to gem-difluoroalkenes bearing various sensitive functional groups under mild reaction conditions. Moreover, this method proves to be suitable for late-stage functionalization of multifunctional complex molecules. KEYWORDS: gem-difluoroalkenes, C−F bond activation, β-F elimination, reductive cross-coupling, Ni-catalysis Scheme 1. Methods for the Synthesis of gemDifluoroalkenes

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rganofluorine compounds are widely used in medicinal and agrochemistry because of their unique stability, reactivity, and biological properties.1 Among numerous fluorine-containing functional groups, the gem-difluoroalkene moiety is an intriguing structural motif owing to its presence in a series of biologically active compounds2 and its great potential in drug discovery, as the gem-difluoroalkene moiety is known to serve as a carbonyl bioisostere with less susceptibility to in vivo metabolism leading to improved pharmaceutical performance.3 Moreover, gem-difluoroalkenes are also precursors for synthesis of versatile fluorine-containing molecules including monofluoroalkenes, gem-difluorocyclopropanes as well as compounds incorporating a difluoromethyl group.4 Consequently, great efforts have been made to develop efficient methods to construct the gem-difluoroethylene motif and two conventional strategies have been established.5−7 Difluoroolefination of carbonyl5 or diazo compounds6 employing difluorocarbene precursors or difluoromethyl sulfones offers a general method for preparation of gem-difluoroalkenes (Scheme 1A). However, in this case good results are often limited to less-bulky substrates, such as aldehydes and acetophenone derivatives. In the second approach, direct coupling of trifluoromethyl alkenes with a broad range of nucleophiles including Grignard reagents, organolithiums and other reactive organometallics provides various gem-difluoroalkenes as products following the β-fluorine-elimination mechanism (Scheme 1B).7 Apparently, most reactions in this category are conducted under harsh conditions and thus suffer from the low functional group tolerance and the resulting narrow substrate scope. Notably, Ichikawa et al. reported a Nicatalyzed alkenylation of trifluoromethyl olefins to access diverse gem-difluoroalkenes avoiding the use of pregenerated organometallics.7k However, the products afforded in this reaction are limited to dienes. Recently, photocatalysis also © XXXX American Chemical Society

finds applications in the synthesis of gem-difluoroalkenes (Scheme 1C).8 For instance, Molander et al. developed a photocatalytic defluorinative alkylation of trifluoromethyl Received: July 16, 2018 Revised: August 26, 2018 Published: September 4, 2018 9245

DOI: 10.1021/acscatal.8b02784 ACS Catal. 2018, 8, 9245−9251

Letter

ACS Catalysis alkenes and through this radical reaction diverse gemdifluoroalkenes bearing sensitive functional groups were prepared with high efficiency.8b On the other side, Ni-catalyzed reductive cross-coupling has attracted increasing attention in the organic community owing to its high functional group tolerance and the avoidance of using pregenerated organometallics.9,10 However, allylic defluorinative reductive cross-coupling11 for C−C bond formation remains elusive mainly due to the high energy of the C(sp3)-F cleavage and the shielding effect of the three F atoms.12 Herein, we reported the first Ni-catalyzed allylic defluorinative cross-coupling of trifluoromethyl alkenes with an array of alkyl halides providing an efficient access to diverse gem-difluoroalkenes bearing various sensitive functional groups under mild reaction conditions (Scheme 1D). For optimization of the reaction conditions we utilized a trifluoromethyl-substituted alkene 1a and cyclohexyl iodide (2a) as standard substrates (Table 1). Systematic screening of

5 and 6). Replacing Zn by Mn as reductant resulted in the complete loss of reactivity (entry 7). When NiCl2·glyme, Ni(acac)2, and Ni(COD)2 were used as catalysts, the product was obtained with reduced efficiency (entries 8−10). Performing the reaction without CsF as an additive led to a slight decrease of the yield (entry 11). The use of cosolvent consisting of DMA and THF turned out to be crucial for this reaction, since significant decrease of the yields was observed in the case of either DMA or THF as solvent (entries 12 and 13). Lowering the reaction temperature gave rise to detrimental effect on the reaction outcome (entry 14). Furthermore, this coupling reaction proved to be sensitive to air, evidenced by the dramatic diminish of efficiency when the reaction was carried out without inert protective gas (entry 15). With the optimum reaction conditions in hand, we next started to investigate the substrate spectrum of this Nicatalyzed allylic defluorinative cross-coupling reaction. First, we reacted diverse aryl and heteroaryl substituted trifluoromethyl alkenes 1a−q with cyclohexyl iodide (2a). Generally, all the reactions proceeded smoothly affording the products 3a−q with high efficiency (Table 2). It is noteworthy that our

Table 1. Variation of the Reaction Parametersa

Table 2. Evaluation of the Substrate Scope by Varying the Structure of Trifluoromethyl Alkenesa

entry

variation from standard conditions

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

none no ligand no catalyst 0.2 equiv Zn instead of 2 equiv Zn L2 instead of L1 L3 instead of L1 Mn instead of Zn NiCl2·glyme instead of NiBr2·glyme Ni(acac)2 instead of NiBr2·glyme Ni(COD)2 instead of NiBr2·glyme no CsF DMA instead of DMA/THF THF instead of DMA/THF reaction at 25 °C reaction under air

99 (97c,d) 0 0 16 73 45 0 94 traces 90 93 68 49 90 52

a

Unless otherwise noted, the reactions were performed on a 0.2 mmol scale of trifluoromethyl alkene 1a using 2 equiv cyclohexyl iodide (2a), 10 mol % catalyst, 10 mol % ligand, 2 equiv reductant, and 1 equiv CsF in 2 mL of solvent (THF/DMA = 4:1) at 40 °C. bYields determined by 19F-NMR spectroscopy using 4-fluoroanisole as an internal standard. cPerformed on a 0.5 mmol scale of 1a. dIsolated yield.

ligands, Ni-salts, reducing agents, solvents and temperature afforded the best reaction conditions, under which the desired product 3a was obtained in an excellent yield (entry 1). We discovered that in the absence of either nickel catalyst or the terpyridine ligand L1, no reaction occurred (entries 2 and 3). The use of a lower amount of Zn powder as reductant led to a remarkable loss in yield (entry 4).The reactions employing other ligands such as the related terpyridine L2 and bis(pyridine) L3, furnished the product in lower yields (entries

a

Unless otherwise noted, the reactions were performed on a 0.5 mmol scale of trifluoromethyl alkenes 1a−q using 2 equiv cyclohexyl iodide (2a), 10 mol % NiBr2·glyme, 10 mol % ligand L1, 2 equiv Zn, and 1 equiv CsF in 2 mL solvent (THF/DMA = 4:1). bPerformed on a 5.0 mmol scale of 1a with 2.5 mol % NiBr2·glyme and 2.5 mol % ligand L1 at 50 °C. 9246

DOI: 10.1021/acscatal.8b02784 ACS Catal. 2018, 8, 9245−9251

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ACS Catalysis

tertiary, secondary and primary alkyl halides turned out to be suitable substrates for this defluorinative cross-coupling furnishing the desired products 4a−p in moderate to excellent yields. Notably, in the cases of primary iodides the reactions were conducted under modified reaction conditions using 10 mol % 1,10-phenanthroline as ligand, MeCN as solvent, and 1 equiv K2HPO4·3H2O as additive. Again, good compatibility of a broad range of functional groups such as ether (4e and 4g), ester (4b and 4d), aldehyde (4f), ketone (4h), carbamate (4i− k), and acetal (4m) was observed, evidencing that our method possesses significant advantages over the traditional strategy using organometallics. Interestingly, in the case of 1,3dibromo-1-methylbutane as precursor, which bears both primary and tertiary alkyl bromide moiety, the compound 4c was yielded as the single product, presenting the high chemoselectivity of this synthetic protocol. To demonstrate the utility of our method, we decided to apply it in the late-stage functionalization of structurally complex multifunctionalized molecules. As shown in Table 4,

reductive strategy demonstrated high tolerance of a wide range of functional groups including amino (3e and 3f), hydroxyl (3g), carbonyl (3h), sulfonyl (3i), and amide group (3j and 3k), which are vulnerable in the presence of organometallics. Furthermore, this method is also suitable for bromosubstituted precursor 1l, which is prone to undergo Nipromoted reductive homo- or cross-coupling. Moving beyond the styrene system, heterocycles, such as quinoline, pyrimidine, and pyridine, were also competitive substrates under the reductive conditions furnishing the products 3m−q in good to high yields. Moreover, we also performed the reaction using the trifluoromethyl alkene 1a with cyclohexyl iodide (2a) on a gram-scale. In this case, the catalyst loading could be reduced to 2.5 mol % and the product 3a was still obtained in a 98%, promising the practical use of this method in a large-scale synthesis. The generality of this protocol was then examined by varying the structure of alkyl halides 2 (Table 3). Various Table 3. Evaluation of the Substrate Scope by Varying the Structure of Alkyl Halides.a

Table 4. Late-Stage Functionalizationsa

a

Unless otherwise noted, the reactions were performed on a 0.5 mmol scale of 1 using 2 equiv of 2, 10 mol % NiBr2·glyme, 10 mol % ligand L1, 2 equiv of Zn, and 1 equiv of CsF in 2 mL of solvent (THF/ DMA= 4:1). bReaction time: 24 h. cReactions performed on a 0.2 mmol scale. dReactions performed in MeCN using 10 mol % 1,10phenanthroline as ligand and 1 equiv of K2HPO4·3H2O as additive.

several alkyl iodides bearing natural product- or drug-scaffold were reacted with various trifluoromethyl alkenes under the standard reaction conditions. To our delight, all these reactions proceeded smoothly furnishing the products 5a−e in moderate to high yields. To shed a light on the mechanism of this Ni-catalyzed reaction, we conducted a series of control experiments (Scheme 2). First, t-BuZnBr was used as the reactant instead of the mixture of tBuBr and zinc. In this case the desired product 4a was also obtained, albeit in lower yield. When pmethoxy benzaldehyde was added to the reaction mixture, the defluorinative cross-coupling reaction delivered only traces of the product 4a (Scheme 2A). In contrast, under the reductive

a

Unless otherwise noted, the reactions were performed on a 0.5 mmol scale of trifluoromethyl alkenes 1 using 2 equiv of alkyl halides 2, 10 mol % NiBr2·glyme, 10 mol % L1, 2 equiv of Zn, and 1 equiv of CsF in 2 mL solvent (THF/DMA = 4:1). bReactions performed in MeCN using 10 mol % 1,10-phenanthroline as ligand and 1 equiv of K2HPO4·3H2O as additive.

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DOI: 10.1021/acscatal.8b02784 ACS Catal. 2018, 8, 9245−9251

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ACS Catalysis Scheme 2. Control Experiments for the Ni-Catalyzed Allylic Defluorinative Cross-Coupling

Scheme 3. Proposed Mechanism for the Ni-Catalyzed Allylic Defluorinative Cross-Coupling

oxidative cyclization with the trifluoromethyl-substituted alkenes 1. The resulting three-membered ring Ni(II) complex II interacts with the alkyl halides (2) to generate a cage III consisting of a Ni(III) intermediate and an alkyl radical through a single electron transfer, which can rapidly combine with each other via reductive radical ring opening reaction. Subsequently, the afforded Ni(II) species IV undergoes βfluorine elimination to provide the corresponding gemdifluoroalkenes 3 as products. Finally, the initial Ni(0)−Ln complex I is regenerated for the next catalytic cycle through the reduction of the Ni(II)LnXF complex V by zinc powder. According to the previous reports, Ni-salts prove to be able to mediate radical conjugate addition to activated olefins by alkyl halides under reductive conditions.15 Therefore, likely is an alternative mechanism involving the initial generation of an alkyl radical through the interaction between Ni-catalyst and alkyl halides. The resultant alkyl radical performs addition to trifluoromethyl alkenes providing an electron-deficient α-CF3 radical, which is prone to undergo a single electron reduction to a carbanion. The subsequent E1cB elimination provides the gem-difluoroalkenes as products. In conclusion, we have developed an unprecedented nickelcatalyzed allylic defluorinative reductive cross-coupling reaction between trifluoromethyl-substituted alkenes and easily accessible alkyl halides, providing an efficient entry to synthesize a variety of functionalized gem-difluoroalkenes under basic-free mild conditions. Notably, this new method demonstrates high tolerance of a broad range of sensitive functional groups, enabling its application in the late-stage functionalization of structurally complex molecules. The preliminary mechanistic studies reveal that this Ni-catalyzed reaction proceeds in a radical reductive coupling pathway.

conditions the reaction still provided the gem-difluoroalkene 4a in a 90% yield in the presence of p-methoxy benzaldehyde (Scheme 2B). We also performed a competitive reaction using both an organozinc compound and an alkyl bromide as reactants, which provided the product deriving from the alkyl halide as the major product.13 The results shown above indicate that the Negishi cross-coupling with in situ formed organozincs cannot be ruled out, but is probably not the main reaction pathway of the studied reaction.13 Next, this crosscoupling reaction was conducted in the presence of a radical scavenger (TEMPO or BHT) and in both cases the reaction was completely shut down implying that a radical key intermediate might be involved (Scheme 2C). Furthermore, we performed a radical clock experiment using a cyclopropyl substituted styrene 6 under the standard reaction conditions providing the ring-opened product 7 in 32% yield. This result also revealed the existence of a free alkyl radical in this catalytic reaction (Scheme 2D). Next, a stoichiometric reaction of the trifluoromethyl alkene 1a with Ni(COD)2 was conducted. The reaction was complete within 2 h and the 19F-NMR spectroscopy indicated the formation of a F-species containing a CF3-group, which is likely a nickelacyclopropane intermediate according to the previous reports.7k,14 Subsequent addition of cyclohexyl iodide to the reaction mixture in the absence of reductant furnished the product 3a in 46% (Scheme 2E). This result suggests that this Ni-catalyzed reaction is likely initiated by the interaction of trifluoromethyl alkenes with the in situ generated Ni(0) species and does not require Zincmediated intermediate reduction to achieve the final product. On the basis of the experimental results aforementioned and the previous reports, we proposed a radical-type mechanism for this Ni-catalyzed allylic defluorinative cross-coupling reaction (Scheme 3). Initially, Ni(0)−Ln complex I is formed under the reductive reaction conditions, followed by the

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ASSOCIATED CONTENT

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.8b02784. Representative experimental procedures and necessary characterization data for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chuan Wang: 0000-0002-9219-1785 9248

DOI: 10.1021/acscatal.8b02784 ACS Catal. 2018, 8, 9245−9251

Letter

ACS Catalysis Notes

(5) For recent examples on gem-difluoroolefination of carbonyl compounds, see: (a) Nowak, R.; Robins, M. J. New Methodology for the Deoxygenative Difluoromethylenation of Aldehydes and Ketones; Unexpected Formation of Tetrafluorocyclopropanes. Org. Lett. 2005, 7, 721−724. (b) Zhao, Y.; Huang, W.; Zhu, L.; Hu, J. Difluoromethyl 2-Pyridyl Sulfone: A New gem-Difluoroolefination Reagent for Aldehydes and Ketones. Org. Lett. 2010, 12, 1444−1447. (c) Zheng, J.; Lin, J.-H.; Cai, J.; Xiao, J.-C. Conversion between Difluorocarbene and Difluoromethylene Ylide. Chem. - Eur. J. 2013, 19, 15261−15266. (d) Zheng, J.; Cai, J.; Lin, J.-H.; Guo, Y.; Xiao, J.C. Synthesis and Decarboxylative Wittig Reaction of Difluoromethylene Phosphobetaine. Chem. Commun. 2013, 49, 7513−7515. (e) Thomoson, C. S.; Martinez, H.; Dolbier, W. R., Jr. The Use of Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate as the Difluorocarbene Source to Generate an in situ Source of Difluoromethylene Triphenylphosphonium Ylide. J. Fluorine Chem. 2013, 150, 53−59. (f) Li, Q.; Lin, J.-H.; Deng, Z. Y.; Zheng, J.; Cai, J.; Xiao, J.-C. Wittig gem-Difluoroolefination of Aldehydes with Difluoromethyltriphenylphosphonium Bromide. J. Fluorine Chem. 2014, 163, 38−41. (g) Gao, B.; Zhao, Y.; Hu, M.; Ni, C.; Hu, J. gem-Difluoroolefination of Diaryl Ketones and Enolizable Aldehydes with Difluoromethyl 2-Pyridyl Sulfone: New Insights into the Julia−Kocienski Reaction. Chem. - Eur. J. 2014, 20, 7803−7810. (h) Wang, X.-P.; Lin, J.-H.; Xiao, J.-C.; Zheng, X. Decarboxylative Julia−Kocienski gem-Difluoro-Olefination of 2-Pyridinyl Sulfonyldifluoroacetate. Eur. J. Org. Chem. 2014, 2014, 928−932. (i) Aikawa, K.; Toya, W.; Nakamura, Y.; Mikami, K. Development of (Trifluoromethyl)zinc Reagent as Trifluoromethyl Anion and Difluorocarbene Sources. Org. Lett. 2015, 17, 4996−4999. (j) Gao, B.; Zhao, Y.; Hu, J.; Hu, J. Difluoromethyl 2-Pyridyl Sulfone: A Versatile Carbonyl gem-Difluoroolefination Reagent. Org. Chem. Front. 2015, 2, 163−168. (k) Krishnamoorthy, S.; Kothandaraman, J.; Saldana, J.; Prakash, G. K. S. Direct Difluoromethylenation of Carbonyl Compounds by Using TMSCF3: The Right Conditions. Eur. J. Org. Chem. 2016, 2016, 4965−4969. (6) For selected examples on gem-difluoroolefination of diazo compounds, see: (a) Hu, M.; He, Z.; Gao, B.; Li, L.; Ni, C.; Hu, J. Copper-Catalyzed gem-Difluoroolefination of Diazo Compounds with TMSCF3 via C−F Bond Cleavage. J. Am. Chem. Soc. 2013, 135, 17302−17305. (b) Hu, M.; Ni, C.; Li, L.; Han, Y.; Hu, J. gemDifluoroolefination of Diazo Compounds with TMSCF3 or TMSCF2Br: Transition-Metal-Free Cross-Coupling of Two Carbene Precursor. J. Am. Chem. Soc. 2015, 137, 14496−14501. (c) Zheng, J.; Lin, J.-H.; Yu, L.-Y.; Wei, Y.; Zheng, X.; Xiao, J.-C. Cross-Coupling between Difluorocarbene and Carbene-Derived Intermediates Generated from Diazocompounds for the Synthesis of gem-Difluoroolefins. Org. Lett. 2015, 17, 6150−6153. (d) Zhang, Z.; Yu, W.; Wu, C.; Wang, C.; Zhang, Y.; Wang, J. Reaction of Diazo Compounds with Difluorocarbene: An Efficient Approach towards 1,1-Difluoroolefins. Angew. Chem., Int. Ed. 2016, 55, 273−277. (7) For selected examples on synthesis of gem-difluoroalkenes via βF elimination with various nucleophiles, see: (a) Hiyama, T.; Obayashi, M.; Sawahata, M. Preparation and Carbonyl Addition of γ,γ-Difluoroallylsilanes. Tetrahedron Lett. 1983, 24, 4113−4116. (b) Fuchikami, T.; Shibata, Y.; Suzuki, Y. Facile Syntheses of Fluorine-Containing α,β-Unsaturated Acids and Esters from 2Trifluoromethylacrylic Acid. Tetrahedron Lett. 1986, 27, 3173− 3176. (c) Bégué, J.-P.; Bonnet-Delpon, D.; Rock, M. H. A Concise Synthesis of Functionalised gem-Difluoroalkenes, via the Addition of Organolithium Reagents to α-Trifluoromethylstyrene. Tetrahedron Lett. 1995, 36, 5003−5006. (d) Bégué, J.-P.; Bonnet-Delpon, D.; Rock, M. H. Addition of Organolithium Reagents to α(Trifluoromethyl)styrene: Concise Synthesis of Functionalised gemDifluoroalkenes. J. Chem. Soc., Perkin Trans. 1 1996, 1409−1413. (e) Ichikawa, J.; Fukui, H.; Ishibashi, Y. 1-Trifluoromethylvinylsilane as a CF2C−−CH2+ Synthon: Synthesis of Functionalized 1,1Difluoro-1-alkenes via Isolable 2,2-Difluorovinylsilanes. J. Org. Chem. 2003, 68, 7800−7805. (f) Ichikawa, J.; Ishibashi, Y.; Fukui, H. A Novel Synthesis of Functionalized 1,1-Difluoro-1-alkenes via Isolable 2,2-Difluorovinylsilanes. Tetrahedron Lett. 2003, 44, 707−710.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by “1000-Youth Talents Plan” starting up funding, National Natural Science Foundation of China (Grant No. 21772183), as well as by the University of Science and Technology of China.

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REFERENCES

(1) (a) Organofluorine Chemistry, Principles and Commercial Applications, in Topics in Applied Chemistry; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Springer Press: New York, 1994. (b) Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications; Kirsch, P., Ed.; WileyVCH: Weinheim, Germany, 2004. (c) Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881−1886. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320−330. (e) Hagmann, W. K. The Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359− 4369. (f) Kirk, K. L. Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments. Org. Process Res. Dev. 2008, 12, 305−321. (g) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed. Wiley-Blackwell: Chichester, UK, 2009. (h) Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications, 2nd ed.; Kirsch, P., Ed.; Wiley-VCH: Weinheim, 2013. (i) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315−8359. (j) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. Chem. Rev. 2016, 116, 422−518. (k) Liu, Q.; Ni, C.; Hu, J. China’s Flourishing Synthetic Organofluorine Chemistry: Innovations in the New Millennium. Natl. Sci. Rev. 2017, 4, 303−325. (2) (a) Bobek, M.; Kavai, I.; De Clercq, E. Synthesis and Biological Activity of 5-(2,2-Difluorovinyl)-2’-deoxyuridine. J. Med. Chem. 1987, 30, 1494−1497. (b) Pan, Y.; Qiu, J.; Silverman, R. B. Design, Synthesis, and Biological Activity of a Difluoro-Substituted, Conformationally Rigid Vigabatrin Analogue as a Potent γ-Aminobutyric Acid Aminotransferase Inhibitor. J. Med. Chem. 2003, 46, 5292−5293. (c) Altenburger, J.-M.; Lassalle, G. Y.; Matrougui, M.; Galtier, D.; Jetha, J.-C.; Bocskei, Z.; Berry, C. N.; Lunven, C.; Lorrain, J.; Herault, J.-P.; Schaeffer, P.; O’Connor, S. E.; Herbert, J.-M. SSR182289A, a Selective and Potent Orally Active Thrombin Inhibitor. Bioorg. Med. Chem. 2004, 12, 1713−1730. (d) Messaoudi, S.; Tréguier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.; De Losada, J. R.; Liu, J.-M.; Bignon, J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. Isocombretastatins A versus Combretastatins A: The Forgotten isoCA-4 Isomer as a Highly Promising Cytotoxic and Antitubulin Agen. J. Med. Chem. 2009, 52, 4538−4542. (3) (a) Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529−2591. (b) Magueur, G.; Crousse, B.; Ourévitch, M.; BonnetDelpon, D.; Bégué, J.-P. Fluoro-artemisinins: When a gem-Difluoroethylene Replaces a Carbonyl Group. J. Fluorine Chem. 2006, 127, 637−642. (c) Leriche, C.; He, X.; Chang, C.-w.; Liu, H.-w. Reversal of the Apparent Regiospecificity of NAD(P)H-Dependent Hydride Transfer: The Properties of the Difluoromethylene Group, A Carbonyl Mimic. J. Am. Chem. Soc. 2003, 125, 6348−6349. (4) For reviews on synthesis of gem-difluoroalkenes and their applications in organic synthesis, see: (a) Chelucci, G. Synthesis and Metal-Catalyzed Reactions of gem-Dihalovinyl Systems. Chem. Rev. 2012, 112, 1344−1462. (b) Zhang, X.; Cao, S. Recent Advances in the Synthesis and C-F Functionalization of gem-Difluoroalkenes. Tetrahedron Lett. 2017, 58, 375−392. 9249

DOI: 10.1021/acscatal.8b02784 ACS Catal. 2018, 8, 9245−9251

Letter

ACS Catalysis

Coupling of Alkyl Halides with Aryl Acid Chlorides. Org. Lett. 2012, 14, 3044−3047. (e) Everson, D. A.; Jones, B. A.; Weix, D. J. Replacing Conventional Carbon Nucleophiles with Electrophiles: NickelCatalyzed Reductive Alkylation of Aryl Bromides and Chlorides. J. Am. Chem. Soc. 2012, 134, 6146−6159. (f) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Catalytic Asymmetric Reductive Acyl CrossCoupling: Synthesis of Enantioenriched Acyclic α,α-Disubstituted Ketones. J. Am. Chem. Soc. 2013, 135, 7442−7445. (g) Correa, A.; Martin, R. Ni-Catalyzed Direct Reductive Amidation via C−O Bond Cleavage. J. Am. Chem. Soc. 2014, 136, 7253−7256. (h) Zhao, C.; Jia, X.; Wang, X.; Gong, H. Ni-Catalyzed Reductive Coupling of Alkyl Acids with Unactivated TertiaryAlkyl and Glycosyl Halides. J. Am. Chem. Soc. 2014, 136, 17645−17651. (i) Ackerman, L. K. G.; Lovell, M. M.; Weix, D. J. Multimetallic Catalysed Cross-Coupling of Aryl Bromides with AarylTriflates. Nature 2015, 524, 454−457. (j) Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J. Cobalt Co-Catalysis for Cross-Electrophile Coupling: Diarylmethanes from Benzyl Mesylates and Aryl Halides. Chem. Sci. 2015, 6, 1115−1119. (k) Kadunce, N. T.; Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-Coupling between Heteroaryl Iodides and αChloronitriles. J. Am. Chem. Soc. 2015, 137, 10480−10483. (l) Wang, X.; Wang, S.; Xue, W.; Gong, H. Nickel-Catalyzed Reductive Coupling of Aryl Bromides with Tertiary Alkyl Halides. J. Am. Chem. Soc. 2015, 137, 11562−11565. (m) Arendt, K. M.; Doyle, A. G. Dialkyl Ether Formation by Nickel-Catalyzed Cross-Coupling of Acetals and Aryl Iodides. Angew. Chem., Int. Ed. 2015, 54, 9876−9880. (n) Konev, M. O.; Hanna, L. E.; Jarvo, E. R. Intra- and Intermolecular Nickel-Catalyzed Reductive Cross-Electrophile Coupling Reactions of Benzylic Esters with Aryl Halides. Angew. Chem., Int. Ed. 2016, 55, 6730−6733. (o) Liu, J.; Ren, Q.; Zhang, X.; Gong, H. Preparation of Vinyl Arenes by Nickel-Catalyzed Reductive Coupling of Aryl Halides with Vinyl Bromides. Angew. Chem., Int. Ed. 2016, 55, 15544−15548. (p) Zhang, P.; Le, C.; MacMillan, D. W. C. Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling. J. Am. Chem. Soc. 2016, 138, 8084− 8087. (q) Wang, X.; Nakajima, M.; Serrano, E.; Martin, R. NiCatalyzed Carboxylation of Unactivated Alkyl Chlorides with CO2. J. Am. Chem. Soc. 2016, 138, 15531−15534. (r) Hansen, E. C.; Pedro, D. J.; Wotal, A. C.; Gower, N. J.; Nelson, J. D.; Caron, S.; Weix, D. J. New Ligands for Nickel Catalysis from Diverse Pharmaceutical Heterocycle Libraries. Nat. Chem. 2016, 8, 1126−1130. (s) Woods, B. P.; Orlandi, M.; Huang, C.-Y.; Sigman, M. S.; Doyle, A. G. NickelCatalyzed Enantioselective Reductive Cross-Coupling of Styrenyl Aziridines. J. Am. Chem. Soc. 2017, 139, 5688−5691. (t) Lu, X.; Wang, Y.; Zhang, B.; Pi, J.-J.; Wang, X.-X.; Gong, T.-J.; Xiao, B.; Fu, Y. Nickel-Catalyzed Defluorinative Reductive Cross-Coupling of gemDifluoroalkenes with Unactivated Secondary and Tertiary Alkyl Halide. J. Am. Chem. Soc. 2017, 139, 12632−12637. (u) Chen, F.; Chen, K.; Zhang, Y.; He, Y.; Wang, Y.-M.; Zhu, S. Remote Migratory Cross-Electrophile Coupling and Olefin Hydroarylation Reactions Enabled by in Situ Generation of NiH. J. Am. Chem. Soc. 2017, 139, 13929−13935. (v) Ai, Y.; Ye, N.; Wang, Q.; Yahata, K.; Kishi, Y. Zirconium/Nickel-Mediated One-Pot Ketone Synthesis. Angew. Chem., Int. Ed. 2017, 56, 10791−10795. (w) Peng, L.; Li, Z.; Yin, G. Photochemical Nickel-Catalyzed Reductive Migratory CrossCoupling of Alkyl Bromides with Aryl Bromides. Org. Lett. 2018, 20, 1880−1883. (x) Hofstra, J. L.; Cherney, A. H.; Ordner, C. M.; Reisman, S. E. Synthesis of Enantioenriched Allylic Silanes via NickelCatalyzed Reductive Cross-Coupling. J. Am. Chem. Soc. 2018, 140, 139−142. (y) Yan, X.-B.; Li, C.-L.; Jin, W.-J.; Guo, P.; Shu, X.-Z. Reductive Coupling of Benzyl Oxalates with highly Functionalized Alkyl Bromides by Nickel Catalysis. Chem. Sci. 2018, 9, 4529−4534. (z) Sheng, J.; Ni, H.-Q.; Zhang, H.-R.; Zhang, K.-F.; Wang, Y.-N.; Wang, X.-S. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Monofluoroalkyl Halides for Late-Stage Monofluoroalkylation. Angew. Chem., Int. Ed. 2018, 57, 7634−7639. (11) To the best of our knowledge, only Ichikawa, Nadano, and Ito reported a Pd-catalyzed intramolecular reductive allylic defluorinative cross-coupling for C-N bond formation Ichikawa, J.; Nadano, R.; Ito,

(g) Ichikawa, J.; Mori, T.; Iwai, Y. A New Class of Substrates for the Nucleophilic 5-endo-trig Cyclization, 1-Trifluoromethylvinyl Compounds: Syntheses of Indoline and Pyrrolidine Derivatives. Chem. Lett. 2004, 33, 1354−1355. (h) Miura, T.; Ito, Y.; Murakami, M. Synthesis of gem-Difluoroalkenes via β-Fluoride Elimination of Organorhodium(I). Chem. Lett. 2008, 37, 1006−1007. (i) Ichikawa, J.; Iwai, Y.; Nadano, R.; Mori, T.; Ikeda, M. A New Class of Substrates for Nucleophilic 5-endo-trig Cyclization, 2-Trifluoromethyl-1-alkenes: Synthesis of Five-Membered Hetero- and Carbocycles That Bear Fluorinated One-Carbon Units. Chem. - Asian J. 2008, 3, 393−406. (j) Fuchibe, K.; Takahashi, M.; Ichikawa, J. Substitution of Two Fluorine Atoms in a Trifluoromethyl Group: Regioselective Synthesis of 3-Fluoropyrazoles. Angew. Chem., Int. Ed. 2012, 51, 12059−12062. (k) Ichitsuka, T.; Fujita, T.; Ichikawa, J. Nickel-Catalyzed Allylic C(sp3)−F Bond Activation of Trifluoromethyl Groups via β-Fluorine Elimination: Synthesis of Difluoro-1,4-dienes. ACS Catal. 2015, 5, 5947−5950. (l) Huang, Y. H.; Hayashi, T. Rhodium-Catalyzed Asymmetric Arylation/Defluorination of 1-(Trifluoromethyl)alkenes Forming Enantioenriched 1,1-Difluoroalkenes. J. Am. Chem. Soc. 2016, 138, 12340−12343. (m) Liu, Y.; Zhou, Y.; Zhao, Y.; Qu, J. Synthesis of gem-Difluoroallylboronates via FeCl2-Catalyzed Boration/β-Fluorine Elimination of Trifluoromethyl Alkenes. Org. Lett. 2017, 19, 946−949. (n) Yang, J.; Zhou, X.; Zeng, Y.; Huang, C.; Xiao, Y.; Zhang, J. Divergent Synthesis from Reactions of 2-Trifluoromethyl-1,3-conjugated Enynes with N-Acetylated 2-Aminomalonates. Org. Biomol. Chem. 2017, 15, 2253−2258. (o) Dai, W.; Lin, Y.; Wan, Y.; Cao, S. Cu-Catalyzed Tertiary Alkylation of α(Trifluoromethyl)styrenes with Tertiary Alkylmagnesium Reagents. Org. Chem. Front. 2018, 5, 55−58. (p) Wu, X.; Xie, F.; Gridnev, I. D.; Zhang, W. A Copper-Catalyzed Reductive Defluorination of βTrifluoromethylated Enones via Oxidative Homocoupling of Grignard Reagents. Org. Lett. 2018, 20, 1638−1642. (q) Kojima, R.; Akiyama, S.; Ito, H. A Copper(I)-Catalyzed Enantioselective γ-Boryl Substitution of Trifluoromethyl-Substituted Alkenes: Synthesis of Enantioenriched γ,γ-gem-Difluoroallylboronates. Angew. Chem., Int. Ed. 2018, 57, 7196−7199. (r) Wang, P.; Pu, X.; Zhao, Y.; Wang, P.; Li, Z.; Zhu, C.; Shi, Z. Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents. J. Am. Chem. Soc. 2018, 140, 9061−9065. (8) (a) Xiao, T.; Li, L.; Zhou, L. Synthesis of Functionalized gemDifluoroalkenes via a Photocatalytic Decarboxylative/Defluorinative Reaction. J. Org. Chem. 2016, 81, 7908−7916. (b) Lang, S.; Wiles, R. J.; Kelly, C. B.; Molander, G. A. Photoredox Generation of CarbonCentered Radicals Enables the Construction of 1,1-Difluoroalkene Carbonyl Mimic. Angew. Chem., Int. Ed. 2017, 56, 15073−15077. (9) For reviews on reductive cross-couplings, see: (a) Everson, D. A.; Weix, D. J. Cross-Electrophile Coupling: Principles of Reactivity and Selectivity. J. Org. Chem. 2014, 79, 4793−4798. (b) Moragas, T.; Correa, A.; Martin, R. Metal-Catalyzed Reductive Coupling Reactions of Organic Halides with Carbonyl-Type Compounds. Chem. - Eur. J. 2014, 20, 8242−8258. (c) Gu, J.; Wang, X.; Xue, W.; Gong, H. Nickel-Catalyzed Reductive Coupling of Alkyl Halides with Other Electrophiles: Concept and Mechanistic Considerations. Org. Chem. Front. 2015, 2, 1411−1421. (d) Weix, D. J. Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 1767−1775. (e) Richmond, E.; Moran, J. Recent Advances in Nickel Catalysis Enabled by Stoichiometric Metallic Reducing Agents. Synthesis 2018, 50, 499− 513. (10) For selected examples on reductive cross-couplings, see: (a) Everson, D. A.; Shrestha, R.; Weix, D. J. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2010, 132, 920−921. (b) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides. Org. Lett. 2011, 13, 2138−2141. (c) Wotal, A. C.; Weix, D. J. Synthesis of Functionalized Dialkyl Ketones from Carboxylic Acid Derivatives and Alkyl Halides. Org. Lett. 2012, 14, 1476−1479. (d) Wu, F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Ketone Formation via Mild Nickel-Catalyzed Reductive 9250

DOI: 10.1021/acscatal.8b02784 ACS Catal. 2018, 8, 9245−9251

Letter

ACS Catalysis N. 5-endo Heck-type cyclization of 2-(trifluoromethyl)allyl ketone oximes: synthesis of 4-difluoromethylene-substituted 1-pyrrolines. Chem. Commun. 2006, 42, 4425−4427. (12) For reviews on C−F bond cleavage in organic synthesis, see: (a) Burdeniuc, J.; Jedicka, B.; Crabtree, R. H. Recent Advances in C− F Bond Activation. Chem. Ber. 1997, 130, 145−154. (b) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119−2183. (c) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. C−F Bond Activation in Organic Synthesis. Functionalization of Fluorinated Molecules by TransitionMetal-Mediated C−F Bond Activation To Access Fluorinated Building Blocks. Chem. Rev. 2015, 115, 931−972. (d) Fujita, T.; Fuchibe, K.; Ichikawa, J. Transition Metal-Mediated and -Catalyzed C-F Bond Activation via Fluorine Elimination. Angew. Chem., Int. Ed. 2018, DOI: 10.1002/anie.201805292. (13) For reaction details, see Supporting Information, page 123. (14) Ichitsuka, T.; Fujita, T.; Arita, T.; Ichikawa, J. Double C-F Bond Activation through β-Fluorine Elimination: Nickel-Mediated [3 + 2] Cycloaddition of 2-Trifluoromethyl-1-alkenes with Alkynes. Angew. Chem., Int. Ed. 2014, 53, 7564−7568. (15) (a) Gong, H.; Andrews, R. S.; Zuccarello, J. L.; Lee, S. J.; Gagné, M. R. Sn-Free Ni-Catalyzed Reductive Coupling of Glycosyl Bromides with Activated Alkenes. Org. Lett. 2009, 11, 879−882. (b) Kim, H.; Lee, C. Nickel-Catalyzed Reductive Cyclization of Organohalides. Org. Lett. 2011, 13, 2050−2053. (c) Shrestha, R.; Weix, D. J. Reductive Conjugate Addition of Haloalkanes to Enones To Form Silyl Enol Ethers. Org. Lett. 2011, 13, 2766−2769.

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DOI: 10.1021/acscatal.8b02784 ACS Catal. 2018, 8, 9245−9251