Unlocking the Friedel-Crafts arylation of primary aliphatic alcohols and epoxides driven by hexafluoroisopropanol

•Access to a wide range of linear alcohols and arylated alkanes•Compatible with aliphatic electronically deactivated epoxides•No pre-activation required for primary alcohols•Hexafluoroisopropanol is key the reactivity Substitution reactions are common way couple two molecular fragments at sp3-hybridized carbon atom. The one or both coupling partners typically required, which adds additional chemical steps generates waste each stage. Efforts develop catalytic substitution arenes that bypass pre-activation, starting from feedstocks, such as epoxides, have been limited specific structural subclasses. We report discovery conditions direct numerous classes epoxides were not previously accessible, allowing one-step access branched complex products. Furthermore, since products epoxide alcohols, this enables bis-substitution different in pot. Alcohols arguably ideal electrophiles Friedel-Crafts alkylation, they widely available, require no produce stoichiometric beyond water. However, neither nor most terminal compatible existing intermolecular methodologies, sequential consequently remain underexplored. Here, we these limitations easily overcome using Brønsted acid catalysis hexafluoroisopropanol (HFIP) solvent. Electron-poor aromatic undergo stereospecific arylation give an alcohol which, depending on reaction conditions, can partake second nucleophilic arene Phenyl ethanols react through phenonium intermediate, whereas simple participate rare SN2 process, delivering exclusively. This work provides alternative metal-catalyzed cross-couplings accessing important scaffolds, widening applications reaction. Epoxides represent building blocks synthetic chemistry,1Weissermel K. Arpe H.-J. Industrial Organic Chemistry.Fourth Edition. Wiley-VCH Verlag GmbH, 2008Google Scholar former especially serving gateway densely functionalized molecules medicinal chemistry, crop science, material science.2Yudin A.K. 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Simple SN2-type mechanism, supported density functional theory (DFT) calculations. broad-reaching (>160 examples) reaction, thus, allows user re-evaluate toward applications. commenced our investigations studying monoarylation electron-deficient notoriously functionalize. Following large survey (see Table S1), observed (pentafluorophenyl)ethylene oxide m-xylene (5 equiv) provided target product 3 97% yield room temperature 6 h conducting (0.4 M) presence TfOH mol %) 2). similar was obtained Bi(OTf)3/nBu4NPF679Qin Yamagiwa Matsunaga Shibasaki Bismuth-catalyzed hydroamination 1,3-dienes carbamates, sulfonamides, carboxamides.J. 2006; 128: 1611-1614https://doi.org/10.1021/ja056112dGoogle instead otherwise identical (96% yield). performed higher concentration (1 M), albeit lower selectivity. More (dichloromethane, 1,2-dichloroethane, toluene, nitromethane) led significant decrease (<55%) because oligomerization substrate, highlighting critical transformation. Of note, reducing number equivalents caused become competitive side a[1a] = 0.2 bRegioisomers separated flash column chromatography. cBi(OTf)3/nBu4NPF6 dUsing (0.1 %). eDiarylated detected isolated (22% determined 1H NMR hexamethyldisiloxane external standard). fDiarylated 107 34% yield. gDiarylated 120 13% h[1x] M.iDiarylated 121 8% Mes 1,3,5-trimethylphenyl. TMP 1,3,5-trimethoxyphenyl. With optimized hand, first explored scope (pentafluorophenyl)ethanol 1a array heteroaryl nucleophiles. transformation mono- tetrasubstituted arenes, incorporating electron-donating substituents afford corresponding 3–29 42%–97% yields. steric hindrance exhibited various nucleophile did hamper reactivity, nearly quantitative yields achieved cases (up 96%). Although 1,3,5-triethylbenzene produced mixture diarylated 8 84 1:1.25 ratio, 0°C 96% same applied mesitylene (9, 95%). Moreover, extended less nucleophiles, (18), fluorobenzene (19), bromobenzene (20), providing 53%–84% other 1,4-difluorobenzene (21) sufficiently its reduced nucleophilicity. case, underwent HFIP. Lower concentrations (0.2 improved up 90% case adduct 18, agreement previous identified H-bonded clusters HFIP.53Pozhydaiev hexafluoroisopropa