Palladium Catalyzed Hydrodefluorination of Fluoro-(hetero)arenes

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Palladium Catalyzed Hydrodefluorination of Fluoro-(hetero)arenes Joseph J. Gair, Ronald L. Grey,* Simon Giroux, and Michael A. Brodney Vertex Pharmaceuticals Inc, 50 Northern Avenue, Boston, Massachusetts 02210, United States

Org. Lett. Downloaded from pubs.acs.org by IOWA STATE UNIV on 03/26/19. For personal use only.

S Supporting Information *

ABSTRACT: Palladium catalyzed hydrodefluorination was developed for fine-tuning the properties of fluoro-(hetero)aromatic compounds. The robust reaction can be set up in air, requires only commercially available components, and tolerates a variety of heterocycles and functionalities relevant to drug discovery. Given the prevalence of fluorine incorporation around metabolic hotspots, the corresponding deuterodefluorination reaction may prove useful for converting fluorinated libraries to deuterated analogues to suppress the oxidative metabolism by kinetic isotope effects.

F

chemists. Consider, for example, the hypothetical lead optimization campaign in Figure 1B; wherein, a fluorine atom was incorporated early in the campaign to improve metabolic stability at the expense of target binding affinity. On a more advanced scaffold (2), however, the vestigial fluorine may provide marginal metabolic benefit at the expense of affinity or solubility. To assess how fluorine impacts key metabolic and physiochemical properties, medicinal chemists typically prepare des-fluoro analogues (e.g., 3) via lengthy resynthesis. A direct method for late stage hydrodefluorination (HDF) of lead compounds would significantly accelerate this process. Additionally, given the complementary relationship between fluorination and deuteration as strategies for stabilizing metabolic soft spots (inductive/blocking effects vs kinetic isotope effects),11,15−20 a method for converting fluorine to deuterium would enable medicinal chemists to leverage routine fluorine scanning6,21−23 libraries to prepare deuterated analogs (Figure 1B, 3). The field of HDF reaction development has experienced rapid growth.24−27 Despite these advances, HDF methodology is not currently a routine tool in medicinal chemistry. Much of the ground-breaking work in HDF methodology was established with activated poly/per-fluorinated28−48 substrates or by gas chromatographic analysis49−63 of reactions with volatile substrates not conducive to product isolation. In cases where isolated yields have been provided for HDF of monofluoro-(hetero)arenes, the reported methods possess features that might hinder their uptake in medicinal chemistry, for example, use of custom synthesized catalysts,59 custom electrochemical setup,60 harsh/sensitive reductants,56 or stoichiometric transition metals.64 This work aims to harness the known reactivity of transition metal catalysts toward HDF to develop practical conditions for achieving high yielding defluorination of (hetero)aromatic compounds encountered in drug discovery.

ine tuning the physiochemical and metabolic properties of drug candidates by exchange of a hydrogen for a fluorine substituent is an indispensable strategy in drug discovery.1−10 Owing to its small size and high electronegativity, fluorine incorporation is a routine solution for improving the metabolic stability of lead compounds while introducing minimal steric perturbation.11−13 Beyond metabolic considerations, however, the effect of fluorine substitution on key physiochemical properties is often difficult to predict.1 In the development of dipeptidyl peptidase-4 inhibitors, for example, incorporation of fluorine at the 4 position of 1b (1b → 1c) gave a 1.5-fold boost in potency and the optimal fluorination pattern in the diabetes drug Sitagliptin (Figure 1A).5,14 In contrast,

Figure 1. (A) Importance of fluorine substitution in the discovery of Sitagliptin. (B) Hydrodefluorination as a tool for streamlining synthesis of desfluoro analogues.

fluorination at the 3 position (1b → 1a) resulted in a 30fold drop in potency and illustrates the potential for superfluous fluorine substituents to undermine physiochemical properties. Given the significant impact of H/F substitution in drug discovery, a method for removing fluorine substituents in advanced compounds would be a valuable tool for medicinal © XXXX American Chemical Society

Received: March 12, 2019

A

DOI: 10.1021/acs.orglett.9b00889 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

The reaction gave comparable conversions when sodium tertpentoxide, sodium tert-butoxide, and sodium hydride were employed as the base, but lithium and potassium salts gave reduced reactivity (SI Table 4). Sodium tert-pentoxide (NaOtAmyl) was used in the general reaction conditions rather than sodium tert-butoxide because of its higher solubility and commercial availability as a toluene stock solution. Given our reservations about possible complications from large excesses of alcohol, we were gratified to observe that excellent isolated yields could be obtained using as little as 3 equiv of either isobutanol or isopropanol (Table 1, entries 14 and 15). Although substrate 4a was conveniently defluorinated with either primary or secondary alcohols, it should be noted that optimal alcohol identity and alcohol loading is substrate dependent. Indazole 5, for example, was defluorinated much more efficiently with isobutanol than with isopropanol and suffered severe rate suppression in the presence of increasing alcohol concentration (Figure 2B and C).

Alkaline solutions of isopropanol have been a mainstay in HDF methodology for systems employing both heterogeneous49,51,57 and homogeneous59 palladium sources. From the outset, we sought to develop a method that did not require solvent quantities of alcohol because such conditions would likely lead to nucleophilic aromatic substitution with electrondeficient substrates and preclude selective deuterium labeling because of competing H/D exchange under similar conditions.57 Reaction development was therefore initiated using 20 volume percent alcohol solutions in toluene (Table 1). Table 1. Influence of Precatalyst and Alcohol on HDF

entry

Pd loading/source

alcohol

conversion

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

2% Pd black 2% XPhosPdG1 2% BrettPhosPdG1 2% BrettPhosPdG3 2% RuPhosPdG4 4% RuPhosPdG4 4% RuPhosPdG4 4% RuPhosPdG4 4% RuPhosPdG4 4% RuPhosPdG4 4% RuPhosPdG4 4% RuPhosPdG4 4% RuPhosPdG4 3% RuPhosPdG4 3% RuPhosPdG4

EtOH EtOH EtOH EtOH EtOH EtOH n PrOH n BuOH i BuOH i PrOH BnOH t BuOH t AmylOH i BuOHd i PrOHd

49%b 46%b 56%b 59%b 80%b 97%b 96%b 96%b 98%b 97%b 46%b 0%b 0%b 93%e 91%e

24 h. bConversion determined by peak areas of starting material and product separated by UHPLC (280 nm). c18 h. d3 equiv of alcohol. e Isolated yield.

Figure 2. (A) Reaction conditions for evaluating influence of alcohol identity on efficiency of HDF with indazole 5. Reaction progress versus time profiles for reactions conducted with varying loadings of (B) isobutanol and (C) isopropanol.

Both homogeneous and heterogeneous palladium sources were competent for HDF of substrate 4a (Table 1). It is plausible that homogeneous precatalysts decompose to heterogeneous active catalysts under the reaction conditions. The reaction mixture starts as a pale-yellow solution and gradually darkens (∼8 h) until the reaction is no longer visibly transparent, consistent with formation of palladium particles. RuPhos palladacycle generation 4 (RuPhosPdG4) was employed in the general reaction conditions because it afforded higher overall conversion (relative to both palladium black and other homogeneous precatalysts) and could be conveniently dispensed as a stock solution for rapid small scale reaction optimization (Table 1, entries 1−5 and SI Table 1). After establishing the utility of RuPhosPdG4 as an improved precatalyst for HDF, the reaction was evaluated for compatibility with various reductants, solvents, and bases. Excellent conversions were observed with several primary and secondary alcohols as terminal reductants (Table 1, entries 6− 11). Tertiary alcohols, on the other hand, gave no conversion to defluorinated products (Table 1, entries 12−13). Excellent conversions were observed for reactions conducted in toluene, cyclopentylmethyl ether, 2-methyltetrahydrofuran, isopropanol, and tert-pentanol (SI Table 3). No conversion was observed for reactions conducted in hexafluoro-isopropanol.

In contrast to 5, benzoic acid 6 showed minimal dependence on isobutanol loading, but achieved significant rate enhancements with increasing concentrations of isopropanol (SI Figure 11). While the mechanistic underpinnings of these differences are beyond the scope of this work, the practical conclusion for application of this methodology is that 3 equiv of isobutanol are a suitable (if not always optimal) starting point for a variety of substrates. Reaction efficiency can then be enhanced by optimizing alcohol identity and loading for individual fluoro(hetero)arenes. We thus set out to evaluate the scope of HDF using these general conditions with the expectation that the improved precatalyst and reduced alcohol loading would enable useful reactivity with an unprecedented range of fluoro(hetero)arenes. The general reaction conditions afforded useful to excellent yields of HDF on a diverse panel of fluoro-(hetero)aromatic scaffolds encountered in drug discovery (Figure 3). Hydrodefluorination was compatible with ortho, meta, and para fluoro-arenes (4, 7, and 8) as well as with crowded substrates bearing substituents at both carbons proximal to fluorine (5). The conditions are suitable for HDF of substrates bearing acidic and phenolic OH groups (6, 18, 26, 28) as well as NH moieties in amides (7 and 9), pyrazole (4), indazoles (5 and 12), imidazoles (15 and 16), azaindole (19), and secondary

a

B


Letter

Organic Letters

Figure 3. (A) General reaction conditions for HDF. (B) Substrate scope and isolated yields of HDF reactions using the general conditions except where noted otherwise (a 10 mol % Pd, b 3 mol % Pd, c 60 °C).

reaction was conducted in neat isopropanol (Figure 5 and SI Figure 43). However, when defluorination of 22b was conducted with 3 equiv of isobutanol, the desired HDF product was obtained in 72% isolated yield.

amines (23 and 27). The reaction is compatible with a variety of potentially coordinating heterocycles (in addition to those listed above) including tertiary anilines (8), benzimidazoles (10 and 11), benzotriazoles (17), (iso)quinolines (20, 21, 26), and pyridines (23−25). Given the scarcity of published HDF reactivity on heterocyclic scaffolds relevant to medicinal chemistry,53,62 the reported procedure constitutes a significant advance in HDF methodology as a tool for drug discovery. A notable limitation of using primary alcohols as terminal reductants is that aniline containing substrates (29 and 30) undergo efficient defluorination and unintended N-alkylation, likely via aldehyde byproducts from primary alcohol oxidation (Figure 3B and SI Figure 51−52). Although alcohol β-hydride elimination appears to serve as the terminal reductant for catalyst turnover, deuterium labeling experiments demonstrate that alcoholic β-hydrogens are not the primary direct source of hydrogen incorporated into the defluorinated product. For example, defluorination conducted in the absence of βdeuterides (neat CH3CH2OD) gave 70% deuterodefluorination as determined by 1H NMR (Figure 4). Importantly, this work provides an alternative to the widely reported49,51,57,59 use of neat isopropanol in HDF methodology and thereby enables HDF of electron-deficient heterocycles that are susceptible to nucleophilic aromatic substitution. Substrate 22b, for example, afforded the nucleophilic aromatic substitution product in 86% isolated yield when the

Figure 5. Reduced alcohol loading expands scope to substrates susceptible to nucleophilic aromatic substitution.

After demonstrating the improved scope of this method, we sought to leverage low alcohol conditions toward site specific deuterium labeling of metabolic hotspots while minimizing background H/D exchange. Modest deuterium labeling (70%) was achieved using only 3 equiv of isopropanol-d8 (Figure 6).

Figure 6. Demonstration of deuterodefluorination.

While this level of isotopic enrichment is not sufficient for large-scale production of deuterated therapeutics, it is relevant to preparation of deuterated analogues for applications in drug discovery including characterization of metabolite regiochemistry by HRMS65,66 and parsing metabolic mechanisms67 by competitive kinetic isotope effects. The method gave 91%

Figure 4. Deuterium labeling experiments to identify sources of H/D in HDF/DDF. C


Letter

Organic Letters

(3) Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881−1886. (4) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320−330. (5) Hagmann, W. K. The Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359−4369. (6) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001−2011). Chem. Rev. 2014, 114, 2432−2506. (7) 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. (8) Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822−5880. (9) Dimagno, S. G.; Sun, H. The Strength of Weak Interactions: Aromatic Fluorine in Drug Design. Curr. Top. Med. Chem. 2006, 6, 1473−1482. (10) Smart, B. E. Fluorine Substituent Effects (on Bioactivity). J. Fluorine Chem. 2001, 109, 3−11. (11) Stepan, A. F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A. S. Metabolism-Guided Drug Design. MedChemComm 2013, 4, 631−22. (12) O’Hagan, D.; Rzepa, H. S. Some Influences of Fluorine in Bioorganic Chemistry. Chem. Commun. 1997, 645−652. (13) O’Hagan, D. Understanding Organofluorine Chemistry. an Introduction to the C−F Bond. Chem. Soc. Rev. 2008, 37, 308. (14) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; et al. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-Amine: a Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes. J. Med. Chem. 2005, 48, 141−151. (15) Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani, A. A. Applications of Deuterium in Medicinal Chemistry. J. Med. Chem. 2019, DOI: 10.1021/acs.jmedchem.8b01808. (16) Russak, E. M.; Bednarczyk, E. M. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann. Pharmacother. 2019, 53, 211−6. (17) DeWitt, S. H.; Maryanoff, B. E. Deuterated Drug Molecules: Focus on FDA-Approved Deutetrabenazine. Biochemistry 2018, 57, 472−473. (18) Tung, R. D. Deuterium Medicinal Chemistry Comes of Age. Future Med. Chem. 2016, 8, 491−494. (19) Timmins, G. S. Deuterated Drugs: Where Are We Now? Expert Opin. Ther. Pat. 2014, 24, 1067−1075. (20) Gant, T. G. Using Deuterium in Drug Discovery: Leaving the Label in the Drug. J. Med. Chem. 2014, 57, 3595−3611. (21) Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst Sander, U.; D’Arcy, A.; Stihle, M.; Müller, K.; Diederich, F. A Fluorine Scan of Thrombin Inhibitors to Map the Fluorophilicity/Fluorophobicity of an Enzyme Active Site: Evidence for C−F···C−O Interactions. Angew. Chem., Int. Ed. 2003, 42, 2507−2511. (22) Morgenthaler, M.; Aebi, J. D.; Grüninger, F.; Mona, D.; Wagner, B.; Kansy, M.; Diederich, F. A Fluorine Scan of Non-Peptidic Inhibitors of Neprilysin: Fluorophobic and Fluorophilic Regions in an Enzyme Active Site. J. Fluorine Chem. 2008, 129, 852−865. (23) Giroud, M.; Harder, M.; Kuhn, B.; Haap, W.; Trapp, N.; Schweizer, W. B.; Schirmeister, T.; Diederich, F. Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds. ChemMedChem 2016, 11, 1042−1047. (24) Whittlesey, M. K.; Peris, E. Catalytic Hydrodefluorination with Late Transition Metal Complexes. ACS Catal. 2014, 4, 3152−3159. (25) Clot, E.; Eisenstein, O.; Jasim, N.; Macgregor, S. A.; McGrady, J. E.; Perutz, R. N. C−F and C−H Bond Activation of Fluorobenzenes and Fluoropyridines at Transition Metal Centers: How Fluorine Tips the Scales. Acc. Chem. Res. 2011, 44, 333−348.

deuterium labeling under conditions optimized to maximize deuteration (neat isopropanol-d8). Whereas simple arenes were suitable for deuterode fluorination with minimal H/D exchange (e.g., 8c), more activated substrates68 still underwent significant H/D exchange with as little as 3 equiv of reductant (e.g., 4a, SI Table 6, entry 1). Further development of site specific deuteration of metabolic hotspots via deuterodefluorination is ongoing in our laboratory. In summary, this work significantly expands the scope of HDF to (hetero)aromatic scaffolds that are frequently encountered in medicinal chemistry. The useful scope of this transformation can be attributed to several improvements upon reported methods for heterogeneous49,51,57 and homogeneous59 palladium catalyzed HDF. Our early reaction development demonstrated that soluble precatalysts can give greater overall catalytic efficiency than heterogeneous palladium sources (though the identity of the active catalyst is not clear). Moreover, by employing a small excess of alcoholic reductant, this method expands the scope of HDF to substrates with prohibitively low rates in alcoholic solvents (e.g., 5, Figure 2) and substrates that undergo nucleophilic aromatic substitution in the presence of concentrated alkaline alcohol (e.g., 22b, Figure 5). By avoiding solvent quantities of alcoholic reductant, the method provides a promising step toward minimizing background H/D exchange in deuterium labeling of metabolic hotspots. This simple procedure that is suitable for immediate implementation in drug discovery settings will serve as a valuable tool for testing the influence of fluorine substituents on physiochemical and metabolic properties via late-stage hydrodefluorination of drug candidates.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00889. Experimental details and NMR spectra (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ronald L. Grey: 0000-0001-8948-5056 Simon Giroux: 0000-0003-1499-2576 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank Barry Davis and Duncan Locke at Vertex Pharmaceuticals for high resolution mass spectrometry acquisition and analysis. We thank Frank Holland and Gregory May at Vertex Pharmaceuticals for assistance with challenging chromatographic separations.

■

REFERENCES

(1) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. Fluorine in Medicinal Chemistry. ChemBioChem 2004, 5, 637−643. (2) Kirk, K. L. Fluorine in Medicinal Chemistry: Recent Therapeutic Applications of Fluorinated Small Molecules. J. Fluorine Chem. 2006, 127, 1013−1029. D


Letter

Organic Letters (26) Amii, H.; Uneyama, K. C−F Bond Activation in Organic Synthesis. Chem. Rev. 2009, 109, 2119−2183. (27) Alonso, F.; Beletskaya, I. P.; Yus, M. Metal-Mediated Reductive Hydrodehalogenation of Organic Halides. Chem. Rev. 2002, 102, 4009−4092. (28) Tsuzuki, H.; Kamio, K.; Fujimoto, H.; Mimura, K.; Matsumoto, S.; Tsukinoki, T.; Mataka, S.; Yonemitsu, T.; Tashiro, M. Synthesis and NMR Study of [4,5,6,8-2H4][2.2]Metacyclophane. J. Labelled Compd. Radiopharm. 1993, 33, 205−212. (29) Maron, L.; Werkema, E. L.; Perrin, L.; Eisenstein, O.; Andersen, R. A. Hydrogen for Fluorine Exchange in C6F6 and C6F5H by Monomeric [1,3,4-(Me3C)3C5H2]2CeH: Experimental and Computational Studies. J. Am. Chem. Soc. 2005, 127, 279−292. (30) Beltrán, T. F.; Feliz, M.; Llusar, R.; Mata, J. A.; Safont, V. S. Mechanism of the Catalytic Hydrodefluorination of Pentafluoropyridine by Group Six Triangular Cluster Hydrides Containing Phosphines: a Combined Experimental and Theoretical Study. Organometallics 2011, 30, 290−297. (31) Chen, Z.; He, C.-Y.; Yin, Z.; Chen, L.; He, Y.; Zhang, X. Palladium-Catalyzed Ortho-Selective C−F Activation of Polyfluoroarenes with Triethylsilane: a Facile Access to Partially Fluorinated Aromatics. Angew. Chem., Int. Ed. 2013, 52, 5813−5817. (32) Senaweera, S. M.; Singh, A.; Weaver, J. D. Photocatalytic Hydrodefluorination: Facile Access to Partially Fluorinated Aromatics. J. Am. Chem. Soc. 2014, 136, 3002−3005. (33) Schwartsburd, L.; Mahon, M. F.; Poulten, R. C.; Warren, M. R.; Whittlesey, M. K. Mechanistic Studies of the Rhodium NHC Catalyzed Hydrodefluorination of Polyfluorotoluenes. Organometallics 2014, 33, 6165−6170. (34) Ekkert, O.; Strudley, S. D. A.; Rozenfeld, A.; White, A. J. P.; Crimmin, M. R. Rhodium Catalyzed, Carbon−Hydrogen Bond Directed Hydrodefluorination of Fluoroarenes. Organometallics 2014, 33, 7027−7030. (35) Cybulski, M. K.; Riddlestone, I. M.; Mahon, M. F.; Woodman, T. J.; Whittlesey, M. K. Stoichiometric and Catalytic C−F Bond Activation by the Trans-Dihydride NHC Complex [Ru(IEt2Me2)2(PPh3)2H2] (IEt2Me2 = 1,3-Diethyl-4,5-dimethylimidazol2-ylidene). Dalton Trans 2015, 44, 19597−19605. (36) McKay, D.; Riddlestone, I. M.; Macgregor, S. A.; Mahon, M. F.; Whittlesey, M. K. Mechanistic Study of Ru-NHC-Catalyzed Hydrodefluorination of Fluoropyridines: the Influence of the NHC on the Regioselectivity of C−F Activation and Chemoselectivity of C−F Versus C−H Bond Cleavage. ACS Catal. 2015, 5, 776−787. (37) Podolan, G.; Jungk, P.; Lentz, D.; Zimmer, R.; Reissig, H.-U. Studies on the Synthesis of Specifically Fluorinated 4-Amino- Pyridine Derivatives by Regioselective Nucleophilic Aromatic Substitution and Catalytic Hydrodefluorination. Adv. Synth. Catal. 2015, 357, 3215− 3228. (38) Liu, X.; Wang, Z.; Zhao, X.; Fu, X. Light Induced Catalytic Hydrodefluorination of Perfluoroarenes by Porphyrin Rhodium. Inorg. Chem. Front. 2016, 3, 861−865. (39) Matsunami, A.; Kuwata, S.; Kayaki, Y. Hydrodefluorination of Fluoroarenes Using Hydrogen Transfer Catalysts with a Bifunctional Iridium/NH Moiety. ACS Catal. 2016, 6, 5181−5185. (40) Krüger, J.; Leppkes, J.; Ehm, C.; Lentz, D. Competition of Nucleophilic Aromatic Substitution, Σ-Bond Metathesis, and synHydrometalation in Titanium(III)-Catalyzed Hydrodefluorination of Arenes. Chem. - Asian J. 2016, 11, 3062−3071. (41) Mai, V. H.; Nikonov, G. I. Hydrodefluorination of Fluoroaromatics by Isopropyl Alcohol Catalyzed by a Ruthenium NHC Complex. an Unusual Role of the Carbene Ligand. ACS Catal. 2016, 6, 7956−7961. (42) Cybulski, M. K.; McKay, D.; Macgregor, S. A.; Mahon, M. F.; Whittlesey, M. K. Room Temperature Regioselective Catalytic Hydrodefluorination of Fluoroarenes with Trans-[Ru(NHC)4H2] Through a Concerted Nucleophilic Ru−H Attack Pathway. Angew. Chem. 2017, 129, 1537−1541. (43) Chen, J.; Huang, D.; Ding, Y. Rhodium-Catalyzed OrthoSelective C-F Activation and Hydrodefluorination of Heterocycle-

Substituted Polyfluoroarenes: Dominated by Phosphine Ligands. ChemistrySelect 2017, 2, 1219−1224. (44) Cybulski, M. K.; Nicholls, J. E.; Lowe, J. P.; Mahon, M. F.; Whittlesey, M. K. Catalytic Hydrodefluorination of Fluoroarenes Using Ru(IMe4)2L2H2 (IMe4 = 1,3,4,5-Tetramethylimidazol-2ylidene; L2 = (PPh3)2, Dppe, Dppp, Dppm) Complexes. Organometallics 2017, 36, 2308−2316. (45) Kikushima, K.; Grellier, M.; Ohashi, M.; Ogoshi, S. TransitionMetal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate. Angew. Chem., Int. Ed. 2017, 56, 16191−16196. (46) Matsunami, A.; Kayaki, Y.; Kuwata, S.; Ikariya, T. Nucleophilic Aromatic Substitution in Hydrodefluorination Exemplified by Hydridoiridium(III) Complexes with Fluorinated Phenylsulfonyl1,2-diphenylethylenediamine Ligands. Organometallics 2018, 37, 1958−1969. (47) Jaeger, A. D.; Ehm, C.; Lentz, D. Organocatalytic C−F Bond Activation with Alanes. Chem. - Eur. J. 2018, 24, 6769−6777. (48) Cybulski, M. K.; Davies, C. J. E.; Lowe, J. P.; Mahon, M. F.; Whittlesey, M. K. C−F Bond Activation of P(C6F5)3 by Ruthenium Dihydride Complexes: Isolation and Reactivity of the “Missing” Ru(PPh3)3H(Halide) Complex, Ru(PPh3)3HF. Inorg. Chem. 2018, 57, 13749−13760. (49) Ukisu, Y.; Miyadera, T. Hydrogen-Transfer Hydrodehalogenation of Aromatic Halides with Alcohols in the Presence of Noble Metal Catalysts. J. Mol. Catal. A: Chem. 1997, 125, 135−142. (50) Young, R. J.; Grushin, V. V. Catalytic C−F Bond Activation of Nonactivated Monofluoroarenes. Organometallics 1999, 18, 294−296. (51) Aramendía, M. A.; Borau, V.; García, I. M.; Jiménez, C.; Marinas, A.; Marinas, J. M.; Urbano, F. J. Hydrogenolysis of Aryl Halides by Hydrogen Gas and Hydrogen Transfer Over PalladiumSupported Catalysts. C. R. Acad. Sci., Ser. IIc: Chim. 2000, 3, 465−470. (52) Desmarets, C.; Kuhl, S.; Schneider, R.; Fort, Y. Nickel(0)/ Imidazolium Chloride Catalyzed Reduction of Aryl Halides. Organometallics 2002, 21, 1554−1559. (53) Kuhl, S.; Schneider, R.; Fort, Y. Catalytic Carbon-Fluorine Bond Activation with Monocoordinated Nickel-Carbene Complexes: Reduction of Fluoroarenes. Adv. Synth. Catal. 2003, 345, 341−344. (54) Cellier, P. P.; Spindler, J.-F.; Taillefer, M.; Cristau, H.-J. Pd/CCatalyzed Room-Temperature Hydrodehalogenation of Aryl Halides with Hydrazine Hydrochloride. Tetrahedron Lett. 2003, 44, 7191− 7195. (55) Davies, C. J. E.; Page, M. J.; Ellul, C. E.; Mahon, M. F.; Whittlesey, M. K. Ni(I) and Ni(II) Ring-Expanded N-Heterocyclic Carbene Complexes: C−H Activation, Indole Elimination and Catalytic Hydrodehalogenation. Chem. Commun. 2010, 46, 5151− 5153. (56) Wu, J.; Cao, S. Nickel-Catalyzed Hydrodefluorination of Fluoroarenes and Trifluorotoluenes with Superhydride (Lithium Triethylborohydride). ChemCatChem 2011, 3, 1582−1586. (57) Sawama, Y.; Yabe, Y.; Shigetsura, M.; Yamada, T.; Nagata, S.; Fujiwara, Y.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Platinum on Carbon-Catalyzed Hydrodefluorination of Fluoroarenes Using Isopropyl Alcohol-Water-Sodium Carbonate Combination. Adv. Synth. Catal. 2012, 354, 777−782. (58) Xiao, J.; Wu, J.; Zhao, W.; Cao, S. NiCl2(PCy3)2-Catalyzed Hydrodefluorination of Fluoroarenes with LiAl(O-T-Bu)3H. J. Fluorine Chem. 2013, 146, 76−79. (59) Sabater, S.; Mata, J. A.; Peris, E. Hydrodefluorination of Carbon Fluorine Bonds by the Synergistic Action of a Ruthenium Palladium Catalyst. Nat. Commun. 2013, 4, 1−7. (60) Wu, W.-B.; Li, M.-L.; Huang, J.-M. Electrochemical Hydrodefluorination of Fluoroaromatic Compounds. Tetrahedron Lett. 2015, 56, 1520−1523. (61) Sabater, S.; Mata, J. A.; Peris, E. Immobilization of PyreneTagged Palladium and Ruthenium Complexes Onto Reduced Graphene Oxide: an Efficient and Highly Recyclable Catalyst for Hydrodefluorination. Organometallics 2015, 34, 1186−1190. E


Letter

Organic Letters (62) Xu, Y.; Ma, H.; Ge, T.; Chu, Y.; Ma, C.-A. Rhodium-Catalyzed Electrochemical Hydrodefluorination: a Mild Approach for the Degradation of Fluoroaromatic Pollutants. Electrochem. Commun. 2016, 66, 16−20. (63) Hokamp, T.; Dewanji, A.; Lübbesmeyer, M.; Mück-Lichtenfeld, C.; Würthwein, E.-U.; Studer, A. Radical Hydrodehalogenation of Aryl Bromides and Chlorides with Sodium Hydride and 1,4-Dioxane. Angew. Chem., Int. Ed. 2017, 56, 13275−13278. (64) Tashiro, M.; Nakamura, H.; Nakayama, K. Reductive Dehalogenation of Haloacetophenones with Raney Alloys in Alkaline Solution. Org. Prep. Proced. Int. 1987, 19, 442−446. (65) Chen, Y.; Tang, W. L.; Mou, J.; Li, Z. High-Throughput Method for Determining the Enantioselectivity of Enzyme-Catalyzed Hydroxylations Based on Mass Spectrometry. Angew. Chem., Int. Ed. 2010, 49, 5278−5283. (66) Andorfer, M. C.; Park, H. J.; Vergara-Coll, J.; Lewis, J. C. Directed Evolution of RebH for Catalyst-Controlled Halogenation of Indole C−H Bonds. Chem. Sci. 2016, 7, 3720−3729. (67) Cleland, W. W. The Use of Isotope Effects to Determine Enzyme Mechanisms. Arch. Biochem. Biophys. 2005, 433, 2−12. (68) Ahmed, B. M.; Mezei, G. Selective, Ambient-Temperature C-4 Deuteration of Pyrazole Derivatives by D2O. J. Org. Chem. 2018, 83, 1649−1653.

F


Palladium Catalyzed Hydrodefluorination of Fluoro-(hetero)arenes

Recommend Documents