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

Abstract

•Access to a wide range of linear alcohols and arylated alkanes•Compatible with aliphatic and electronically deactivated epoxides•No pre-activation required for primary aliphatic alcohols•Hexafluoroisopropanol is key to the reactivity Substitution reactions are a common way to couple two molecular fragments at a sp3-hybridized carbon atom. The pre-activation of one or both coupling partners is typically required, which adds additional chemical steps and generates waste at each stage. Efforts to develop catalytic substitution reactions of arenes that bypass pre-activation, starting from common feedstocks, such as alcohols or epoxides, have been limited to specific structural subclasses. We report the discovery of catalytic conditions for the direct substitution of arenes with numerous classes of alcohols and epoxides that were not previously accessible, allowing for one-step access to branched alcohols and complex arylated products. Furthermore, since the products of epoxide substitution are alcohols, this discovery enables the direct bis-substitution of epoxides with two different arenes in one pot. Alcohols and epoxides are arguably ideal electrophiles for the Friedel-Crafts alkylation, since they are widely available, require no pre-activation, and produce no stoichiometric waste beyond water. However, neither primary aliphatic alcohols nor most classes of terminal epoxides are compatible with existing intermolecular Friedel-Crafts methodologies, and sequential Friedel-Crafts reactions starting from epoxides consequently remain underexplored. Here, we report that these limitations are easily overcome using Brønsted acid catalysis in hexafluoroisopropanol (HFIP) as a solvent. Electron-poor aromatic epoxides and aliphatic epoxides undergo stereospecific arylation to give an alcohol which, depending on the reaction conditions, can partake in a second nucleophilic substitution with a different arene in one pot. Phenyl ethanols react through a phenonium intermediate, whereas simple aliphatic alcohols participate in a rare intermolecular SN2 Friedel-Crafts process, delivering linear products exclusively. This work provides an alternative to metal-catalyzed cross-couplings for accessing important scaffolds, widening the range of applications of the Friedel-Crafts reaction. Alcohols and epoxides are arguably ideal electrophiles for the Friedel-Crafts alkylation, since they are widely available, require no pre-activation, and produce no stoichiometric waste beyond water. However, neither primary aliphatic alcohols nor most classes of terminal epoxides are compatible with existing intermolecular Friedel-Crafts methodologies, and sequential Friedel-Crafts reactions starting from epoxides consequently remain underexplored. Here, we report that these limitations are easily overcome using Brønsted acid catalysis in hexafluoroisopropanol (HFIP) as a solvent. Electron-poor aromatic epoxides and aliphatic epoxides undergo stereospecific arylation to give an alcohol which, depending on the reaction conditions, can partake in a second nucleophilic substitution with a different arene in one pot. Phenyl ethanols react through a phenonium intermediate, whereas simple aliphatic alcohols participate in a rare intermolecular SN2 Friedel-Crafts process, delivering linear products exclusively. This work provides an alternative to metal-catalyzed cross-couplings for accessing important scaffolds, widening the range of applications of the Friedel-Crafts reaction. Epoxides and primary aliphatic alcohols both represent important building blocks in synthetic chemistry,1Weissermel K. Arpe H.-J. Industrial Organic Chemistry.Fourth Edition. Wiley-VCH Verlag GmbH, 2008Google Scholar the former especially serving as a gateway to densely functionalized molecules in medicinal chemistry, crop science, and material science.2Yudin A.K. 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Soc. 2020; 142: 8090-8096https://doi.org/10.1021/jacs.0c02095Google Scholar phenonium ion without pre-activation of the alcohol. Simple aliphatic alcohols can also undergo a Friedel-Crafts reaction through a rare intermolecular SN2-type mechanism, as supported by density functional theory (DFT) calculations. This broad-reaching (>160 examples) expansion of the Friedel-Crafts reaction, thus, allows the user to re-evaluate the reactivity of primary aliphatic alcohols, epoxides, and related compounds toward new synthetic applications. We commenced our investigations by studying the monoarylation of highly electron-deficient styrene oxides, which are notoriously challenging to functionalize. Following a large survey of reaction conditions, notably Lewis and Brønsted acid catalysts (see Table S1), we observed that the reaction between (pentafluorophenyl)ethylene oxide and m-xylene (5 equiv) provided the target product 3 in 97% yield at room temperature in 6 h by conducting the reaction in HFIP (0.4 M) in the presence of TfOH (5 mol %) as a catalyst (Scheme 2). A similar reactivity was obtained by using the promoter system Bi(OTf)3/nBu4NPF679Qin H. Yamagiwa N. Matsunaga S. Shibasaki M. Bismuth-catalyzed intermolecular hydroamination of 1,3-dienes with carbamates, sulfonamides, and carboxamides.J. Am. Chem. Soc. 2006; 128: 1611-1614https://doi.org/10.1021/ja056112dGoogle Scholar instead of TfOH under otherwise identical reaction conditions (96% yield). The reaction could also be performed at higher concentration (1 M), albeit with lower selectivity. More common solvents (dichloromethane, 1,2-dichloroethane, toluene, and nitromethane) led to a significant decrease in yield (<55%) because of the oligomerization of the substrate, highlighting the critical role of HFIP in the transformation. Of note, reducing the number of equivalents of m-xylene caused the ring-opening of the epoxide by HFIP to become a competitive side reaction. a[1a] = 0.2 M. bRegioisomers were separated by flash column chromatography. cBi(OTf)3/nBu4NPF6 (5 mol %) as the catalyst. dUsing TfOH (0.1 mol %). eDiarylated product detected but not isolated (22% yield determined by 1H NMR using hexamethyldisiloxane as an external standard). fDiarylated product 107 isolated in 34% yield. gDiarylated product 120 isolated in 13% yield. h[1x] = 0.2 M.iDiarylated product 121 isolated in 8% yield. Mes = 1,3,5-trimethylphenyl. TMP = 1,3,5-trimethoxyphenyl. With optimized conditions in hand, we first explored the scope of (pentafluorophenyl)ethanol synthesis from styrene oxide 1a using an array of aryl and heteroaryl nucleophiles. The transformation was compatible with a wide range of mono- to tetrasubstituted arenes, incorporating either electron-donating or electron-withdrawing substituents to afford the corresponding products 3–29 in 42%–97% yields. The steric hindrance exhibited by the various functional groups on the nucleophile did not hamper the reactivity, as nearly quantitative yields was achieved in most cases (up to 96%). Although the reaction with 1,3,5-triethylbenzene as a nucleophile produced a mixture of mono- and diarylated products 8 and 84 in a 1:1.25 ratio, conducting the reaction at 0°C enabled the selective formation of 8 in 96% yield. The same applied to mesitylene (9, 95%). Moreover, the reaction could be extended to less electron-rich nucleophiles, such as benzene (18), fluorobenzene (19), and bromobenzene (20), providing arylated compounds in 53%–84% yields. On the other hand, 1,4-difluorobenzene (21) was not sufficiently reactive due to its reduced nucleophilicity. In this case, the epoxide underwent oligomerization and nucleophilic ring-opening by HFIP. Lower reaction concentrations (0.2 M) improved the yield up to 90% in the case of benzene adduct 18, in agreement with previous studies that identified the key role of H-bonded solvent clusters in Lewis and Brønsted acid-catalyzed reactions in HFIP.53Pozhydaiev V. Power M. Gandon V. Moran J. Lebœuf D. Exploiting hexafluoroisopropa