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Cu(II) Catalyzed Unsymmetrical Di-Oxidation of Gem- Difluoroalkenes to Generate Α,Α-Difluorinated-Α-Phenoxyketones, an Unstudied Substructure

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Cu(II) Catalyzed Unsymmetrical Di-Oxidation of Gem- Difluoroalkenes to Generate Α,Α-Difluorinated-Α-Phenoxyketones, an Unstudied Substructure Cu(II) Catalyzed Unsymmetrical Di-oxidation of gem- Difluoroalkenes to Generate α,α-Difluorinated-α-Phenoxyketones, an Unstudied Substructure Suvajit Koley, [a] Kaylee T. Cayton, [b] Gisela A. González-Montiel,[b] M. Ramu Yadav,[c] Douglas L. Orsi,[d] Paul Ha-Yeon Cheong,*[b] and Ryan A. Altman*[a] [a] Dr. S. Koley, Dr. R. A. Altman Department of Medicinal Chemistry and Molecular Pharmacology; Department of Chemistry Purdue University West Lafayette, IN 47907 (USA) E-mail: [email protected] [b] K. T. Cayton, G. A. González-Montiel, Dr. P. H.-Y. Cheong Department of Chemistry Oregon State University 153 Gilbert Hall, Corvallis, OR 97331 (USA) [c] Dr. M. R. Yadav Department of Chemistry Indian Institute of Technology Delhi MS-723, Hauz Khas, New Delhi-110016 (India) [d] Dr. D. L. Orsi Broad Institute of Harvard and MIT Cambridge, MA 02142 (USA) Supporting information for this article is given via a link at the end of the document. Abstract: A Cu-based catalyst system convergently couples gem- conformers versus the parent alkyl-aryl ethers that preferentially difluoroalkenes with phenols under aerobic conditions to deliver α,α- reside in the plane of the arene,[23] and versus trifluoromethyl-aryl difluorinated-α-phenoxy ketones, an unstudied hybrid fluorinated ethers that reside orthogonally to the plane of the arene.[24] functional group. Composed of α,α-difluorinated ketone and α,α- Interestingly, despite the individual significance of the α,α- difluorinated ether moieties, these have only once been previously difluoroketone and α,α-difluoroalkyl ethers components, the reported as a synthetic intermediate en route to pharmacologically hybrid α,α-difluorinated-α-phenoxy-ketone functional group has active compounds. Computational predictions and later experimental only been reported once as a synthetic intermediate (Scheme corroboration suggest that the sp3-hybridized hydrate adduct of the 1A);[25] the lack of synthetic strategies for accessing α,α- phenoxy-substituted fluorinated ketone is energetically accessible. difluorinated-α-phenoxy ketones precludes evaluation of the The more facile conversion between ketone and hydrate forms properties of the functional group, and also impedes its use in suggest that covalent inhibition of proteases and other enzymes may medicinal chemistry and chemical biology. Herein, we report the be possible. Further functionalization of the ketone group enables synthesis and physicochemical characterization of the α,α- access to other useful fluorinated functional groups. difluorinated-α-phenoxy-ketone functional group, and predict its utility (computationally and experimentally) in biological and medicinal chemistry. Introduction Results and Discussion Fluorinated organic compounds are of great importance in many fields such as medicine, agrochemistry, and material To access α,α-difluorinated-α-phenoxy-ketones, we science[1–10]. Among all the fluorinated building blocks, α,α- envisioned exploiting the unique reactivity of readily available difluoroketones are important substructures for medicinal gem-difluorinated alkenes,[26–28] specifically a sequence involving chemistry, as well as synthons for accessing other fluorinated nucleophilic attack of the electrophilic difluorinated center and substructures.[11] This group readily rehybridizes from an sp2- subsequent oxidation (Scheme 1B). However, transition metal- hybridized keto form to an sp3-hybridzed form, which can interact catalyzed reactions of gem-difluoroalkenes typically proceed with aspartyl proteases through noncovalent hydrogen-bonding through β-fluoro anionic or β-fluoro metal intermediates that are interactions, with serine proteases through reversible covalent both prone to undergo β-fluoride elimination and generate interactions by forming stable tetrahedral adducts,[12–14] and also monofluoroalkene products; in contrast, “fluorine-retentive” with non-protease targets.[15,16] Therefore, this substructure has catalytic functionalization reactions of gem-difluorinated drawn significant attention of synthetic and medicinal chemists.[17] alkenes[29] are rare.[30–32] To overcome the challenge of β-fluoride Separately, α,α-difluoroalkyl ethers display a wide range of elimination, we hypothesized that radical (one-electron) applications in pharmaceuticals,[18] agrochemicals[19] and material functionalization of the gem-difluorinated alkene would avoid chemistry.[20,21] For example, α,α-difluoroalkyl ethers can enhance anionic intermediates and subsequent β-fluoride elimination. metabolic stability[18] and control molecular conformation.[22,23] Applied to the preparation of α,α-difluorinated-α-phenoxy ketones, Due to the small rotational barrier around the ArO–CF2R bond, addition of a phenoxy radical to the gem-difluorinated alkene difluorinated phenyl ethers can access a wide range of 1 would provide a α,α-difluorinated-α-phenoxy radical, which might as no product formed under an atmosphere of N2 (entry 12), be trapped under oxidative conditions to deliver the though under an atmosphere of air, a low yield of desired product unsymmetrically dioxygenated target substructure (Scheme 1C). was obtained along with the undesired secondary alcohol. A) Inspiration for a Hybrid Functional Group Table 1: Optimization of reaction conditions for the synthesis of α,α- α,α-Difluorinated Ketones difluorinated-α-phenoxy-ketone.[a] F F F F 1 H O or ROH 1 R 2 R 2 MeO Cl 20% CuCl2 R2 R F 10% TerPy Cl Cl (RO)HO OH + HO F F F F O Ar + Ar F DCB:DMSO (3 : 1) O O α,α-Difluorinated-α-Phenoxyketones Cl • Inhibition of Proteases 100 ºC, O2, 24 h O Cl OH Cl • Readily Rehybridize to Hydrate Form F F 1 2 3ab 4ab R1 Ar O Entry Deviation from the original Conversion Yield[b] (%) O condition (%) α,α-Difluorinated Ethers • Unstudied Hybrid Functional Group 3ab 4ab F F • No General Preparation? • Physical and Medicinal Properties? R3 O • Use as Synthetic Intermediate? 1 None 100 87 - • Extensive Use in Medicinal Chemistry • Slow Metabolism 2 Co(acac)2 instead of CuCl2 100 3 70 • Adopt Many Conformations 3 CuCl instead of CuCl2 100 73 - B) Nucleophilic Addition and Oxidation Strategy Desired F [O] Nu Bipyridine instead of R1 4 100 78 - F Terpyridine O F F Nu– Nu 1 R1 1,10-Phenanthroline R F 5 100 68 - δ+ F Undesired instead of Terpyridine F Elimination R1 Nu 10% CuCl2 instead of 20% 6 100 77 - CuCl2 C) Radical Pathway to Avoid β-Fluoride Elimination (Our Approach) 20% Terpyridine F F F F F 7 100 81 - Ar 1 instead of 10% Terpyridine 1 •O R1 Ar R Ar R O O F • [O] O 8 Using DCB as only solvent 100 30 - 9 Using DMSO as only solvent 33 2 - Scheme 1. Construction of α,α-difluorinated-α-phenoxy ketones by Cu- catalyzed oxidation of gem-difluoroalkenes. 10 80 °C instead of 100 °C 31 30 - 11 120 °C instead of 100 °C 100 77 - Routine synthetic optimization identified an optimal Cu-based Reaction under N2 atmosphere 12 6 - - catalyst system for reacting gem-difluoroalkenes with phenols to instead of O2 atmosphere produce α,α-difluorinated-α-phenoxy ketone 3ab selectively, Reaction under air atmosphere while avoiding formation of a related alcohol-containing side 13 69 34 10 instead of O2 atmosphere product 4ab. Notably, the combination of 20% CuCl2 and 10% 2,2',6',2"-terpyridine in a mixed solvent system of DCB/DMSO [a] Standard conditions: 1 (1.0 equiv., 0.10 mmol), 2 (3.0 equiv., 0.30 mmol), (1:1) under O2 at 100 °C afforded the desired ketone product in DCB (0.30 mL), DMSO (0.10 mL), 24 h under an atmosphere of O2. [b] in 87% yield (Table 1, entry 1; See Supporting Information for Determined by 19F NMR analysis of the crude reaction mixture using a,a,a- more optimization details). Interestingly, these oxidative Cu(II)- trifluorotoluene (TFT) as a standard. catalyzed oxidative conditions delivered the ketone-derived The generality and scope of the developed protocol were product, in contrast to a recently published Co(II/III)-based explored utilizing a wide range of electron-rich and -deficient gem- oxidative system that delivered alcohol-derived products (e.g. 4ab, [33] difluoroalkenes (1) and phenols (2), which generally afforded the entry 2). Further, use of CuCl instead of CuCl2 lowered the corresponding α,α-difluorinated-α-phenoxyketones 3 in good to conversion of substrates and delivered lower yield of ketone high yields (Tables 2–3). Numerous substituents like OR (R = (entry 3). Replacement of terpyridine with bipyridine or alkyl), SMe, alkyl, and halogen group on the gem-difluoroalkene phenanthroline provided lower yield of the desired product ring were compatible under standard conditions (Table 2, 3aa– (entries 4 and 5). Reactions run with lower loadings of CuCl2 3ap). Remarkably, an ortho-substituted gem-difluoroalkene also (10%) reduced the yield of ketone product, whereas an increase provided the corresponding α,α-difluorinated-α-phenoxyketones in ligand (20%), suppressed formation of the desired ketone in good yield (Table 2, 3al); whereas a bis-ortho-substituted gem- product (entries 6 and 7). Use of DCB alone in place of difluoroalkene only afforded trace amount of product (3ap), DCB:DMSO delivered low conversion and yield of 3ab, possibly [34,35] possibly due to the steric hindrance exerted by two ortho methyl due to the low solubility of O2 in the aromatic solvent (entry 8). groups. Importantly, gem-difluoroalkenes (1) bearing However, use of DMSO alone provided no yield of anticipated heteroaromatic groups, such as 3-pyrazolyl and 3-indolyl were product (entry 9). Elevating or lowering the reaction temperature tolerated under optimal conditions, with reactions
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