Selective C–H fluoroalkylation of azines enabled by tailored phosphorus-based reagents

The installation of –CF3 or –CF2H groups into compounds can impact important biologically relevant properties. In a recent paper published in Nature, McNally, Paton, and co-workers introduce novel phosphine-based reagents that allow for the conversion variety complex azines through C–H functionalization directly their fluoroalkylated derivatives. Incorporation drug molecules often improve pharmacokinetic properties, including permeability, stability, affinity.1Müller K. Faeh C. Diederich F. Fluorine pharmaceuticals: looking beyond intuition.Science. 2007; 317: 1881-1886Crossref PubMed Scopus (4537) Google Scholar Consequently, development reaction methods enable di- trifluoromethylation—especially at aryl heteroaryl Csp2 centers—has become major area research. Substitution reactions on functionalized C–X substrates—most typically by transition metal-mediated -catalyzed methods—represent one valuable strategy this regard.2Cho E.J. Senecal T.D. Kinzel T. Zhang Y. Watson D.A. Buchwald S.L. palladium-catalyzed trifluoromethylation chlorides.Science. 2010; 328: 1679-1681Crossref (587) Complementarily, fluoroalkylation provides an attractive alternative bypasses need prefunctionalization converts substrate bond C–CF2X (X = H F) product. co-workers3Zhang X. Nottingham K.G. Patel Alegre-Requena J.V. Levy J.N. Paton R.S. McNally A. Phosphorus-mediated sp2-sp3 couplings azines.Nature. 2021; https://doi.org/10.1038/s41586-021-03567-3Crossref (18) described elegant main-group-based simple one-pot transformation with exceptional selectivity C4 position pyridines. This work exemplifies innovative advance main group reagent design enables new mechanistic approach to fluoroalkylation, substantial potential medicinal agrichemical research development. One overarching consideration across all concerns provenance moieties.4Caron S. Where does fluorine come from? A review challenges associated synthesis organofluorine compounds.Org. Process Res. Dev. 2020; 24: 470-480Crossref (77) Indeed, simplest notional precursors, namely fluoroform (HCF3) difluoromethane (H2CF2), are gaseous limited reactivity be difficult handle lab scale. based heavier elements p-block have long productive history. There three classes such trifluoromethylating spanning nucleophilic, radical, electrophilic reactivities (Scheme 1A). predominant exemplar nucleophilic class is Ruppert-Prakash (TMS-CF3 [1]), Si(IV)-based commonly employed as CF3− precursor. Kanai has applied TMS-CF3 donor along B(C6F5)3 activator effect trilfluoromethylation azines, albeit demonstration scope.5Nagase M. Kuninobu 4-Position-selective perfluoroalkylation perfluoroarylation six-membered heteroaromatic compounds.J. Am. Chem. Soc. 2016; 138: 6103-6106Crossref (78) Langlois (2) sulfinate-based readily handled under ambient conditions radical CF3⋅ source, especially conjunction photoredox catalysis. attributed facile one-electron oxidation S(IV) center facilitates both SO2 gas liberation, enabling Minisci-type nitrogen-containing heterocycles good chemoselectivity but variable regioselectivity efficiency.6Nagib MacMillan D.W.C. Trifluoromethylation arenes heteroarenes means catalysis.Nature. 2011; 480: 224-228Crossref (956) Among most tunable I(III) developed Togni (3 4) S(IV)/Se(IV)-based Umemoto (5 6), which benefit from divergent redox properties atoms provide access useful modes trifluoromethylation.7Barata-Vallejo Lantaño B. Postigo Recent advances reagents.Chemistry. 2014; 20: 16806-16829Crossref (264) newly work, phosphorus-based (7 8) add growing palette group-based reactivity. Phosphines 7 8 isoelectronic Umemoto’s sulfur (5), periodic shift left makes accessible two-electron P(III)/P(V) couple. Furthermore, nonbonding phosphorus lone pair retains measure nucleophilicity despite inductive –CF2X substituent, further electron-donating ancillary substituents compensate electron-withdrawal CF2X moiety center, empowering it serve effective nucleophile. With deft mastery relationships molecular tuning, wholly mode group-mediated made accessible. As prior group, leverage technique phosphorylation π-deficient involving treatment azine phosphine presence trifluoromethanesulfonic anhydride (Tf2O).8Hilton M.C. Dolewski R.D. Selective pyridines via heterocyclic phosphonium salts.J. 13806-13809Crossref (103) Although not ultimately incorporated products, Tf2O-activating plays critical 2-fold role success method: N-triflation first activates toward attack excellent pyridines; then, resulting Meisenheimer-type intermediate undergoes deprotonative rearomatization triflyl serves electron sink. Overall, process results swift (<1 h time) mild (room temperature) formation fluoroalkylphosphonium salt (9) parent azine. While structurally related ions been previously utilized Lewis acid9Fasano V. LaFortune J.H.W. Bayne J.M. Ingleson M.J. Stephan D.W. Air- water-stable acids: P-trifluoromethyl cations.Chem. Commun. (Camb.). 2018; 54: 662-665Crossref transfer reagents,10Ran Lin Q.-Y. Xu X.-H. Qing F.-L. Visible light induced oxydifluoromethylation styrenes difluoromethyltriphenylphosphonium bromide.J. Org. 81: 7001-7007Crossref (90) aqueous Brønsted acids (either TfOH HCl) alcohol solutions induces remarkable contractive Csp2–Csp3 ligand coupling forge target heteroaryl-CF3 Density functional theory calculations validate unimolecular nature C–C rationalize observed among other possible processes. pentacoordinate P(V) (10) implicated key intermediate, apical CF3 bearing partial negative charge α-migration ipso carbon equatorial pyridyl substituent positive virtue its protonation acidic conditions. Notably, entire synthetic sequence (from C–CF3 product) was found amenable procedure, thus demonstrating practicality current method. strength method resides broad scope, summarized Scheme 1C. Given prevalence scaffolds myriad marketed drugs preclinical candidates, efficient selective likely interest chemistry community. high tolerance make desirable late-stage modifications advanced drug-like structures, feasibility demonstrated pharmaceutical agrochemicals pyriproxyfen (12), loratadine (13), imatinib (14), etoricoxib (15) analogs. welcome aspects discovery many, although certain remaining opportunities might noted. At present, must independently prepared multistep then stoichiometric quantities; mass atom efficiency therefore low. possibility developing catalytic regeneration commercially available precursor would principle circumvent these challenges. Also, pyridine necessity, since decomposition relies activation pyridinic nitrogen atom. extension “simple” obvious, feature hardly restrictive given azacycles bioactive compounds. summary, beautiful example allows direct exceptionally scope selectivity. tools form bespoke fluoroalkylphosphines expands synthetically fluoroalkylations exercising underdeveloped elements. successful application should chemists significantly greater ability tailor trifluoromethylated late stages route.