A Surprising Substituent Effect Provides a Superior Boronic Acid Catalyst for Mild and Metal‐Free Direct Friedel–Crafts Alkylations and Prenylations of Neutral Arenes

Abstract

The development of more general and efficient catalytic processes for Friedel-Crafts alkylations is an important objective of interest toward the production of pharmaceuticals and commodity chemicals. Herein, 2,3,4,5-tetrafluorophenylboronic acid was identified as a potent air- and moisture-tolerant metal-free catalyst that significantly improves the scope of direct Friedel-Crafts alkylations of a variety of slightly activated and neutral arenes, including polyarenes, with allylic and benzylic alcohols. This method also provides a simple alternative for the direct installation of prenyl units commonly found in naturally occurring arenes. Alkylations with benzylic alcohols occur under exceptionally mild conditions.

Synthesis of N-Arylpyrazoles by Palladium-Catalyzed Coupling of Aryl Triflates with Pyrazole Derivatives

“…Purification of the crude material by silica gel column chromatography (hexane/AcOEt = 91:9) afforded 5.88 g of 4-methyl-2-(3-methylbut-2-en-1-yl)­phenol (33.4 mmol, 84% yield) as a colorless oil. The analytical data for 4-methyl-2-(3-methylbut-2-en-1-yl)­phenol are in good agreement with those reported in literature …”

“…The analytical data for 4-methyl-2-(3-methylbut-2-en-1-yl)phenol are in good agreement with those reported in literature. 20 Preparation of 4-Methyl-2-(3-methylbut-2-en-1-yl)phenyl Trifluoromethanesulfonate (1d). To a solution of 4-methyl-2-(3methylbut-2-en-1-yl)phenol (0.798 g, 4.53 mmol) and 0.6 mL of pyridine in 20 mL of dichloromethane at 0 °C was added Tf 2 O (1.57 g, 5.56 mmol) dropwise, and the mixture was stirred for 4.5 h at room temperature.…”

Brønsted Acid and H‐Bond Activation in Boronic Acid Catalysis

“…Electronically deactivated alcohol 2 c needed a stronger Brønsted acid but its transformation could still be effectively catalyzed by H 2 SO 4 (entry 2.6). Previously, the possibility of Brønsted acid catalysis was ruled out on the basis of: 1) the lack of reactivity of 2 b with CF 3 CO 2 H and 2) the fact that a different boronic acid ( B2 ), which has a comparable p K a in H 2 O and DMSO to the catalyst used ( B1 ), does not facilitate the reaction in HFIP/MeNO 2 . However, as the data provided in Figure emphasized, B2 and CF 3 CO 2 H do not produce a suitably strong Brønsted acid in HFIP/MeNO 2 and thus are not suitable points of reference.…”

Recent Advances in Direct Catalytic Dehydrative Substitution of Alcohols

“…Another Ca(NTf 2 ) 2 -catalyzed transformation was also reported in 2015 by the Gandon group, who disclosed the dehydrative addition of cinnamyltype boronic acids to allylic alcohols under mild conditions ( Table 3, entry 6). 67 In 2015 Hall and co-workers reported the use of a novel tetrafluorophenyl boronic acid as a catalyst for activation of allylic alcohols in Friedel-Crafts reac-tions 68 that proved to be more active than previous iterations of related catalyst architectures when used under a new set of reaction conditions. 69,70 Although more widely developed for the substitution reactions of pre-activated allylic alcohol derivatives such as allylic acetates and allylic carbonates, 71 the direct substitution of allylic alcohols via the formation of an intermediate metal π-allyl species has also been widely explored (Scheme 3).…”

“…In addition, substrates bearing chelating functionalities such as basic amines are often incompatible as they sequester the acidic catalyst. Indeed, in Hall's recent report, 68 attempted use of N-Boc phenylalanine methyl ester as a Friedel-Crafts nucleophile resulted in 0% conversion. This lack of reactivity is attributed to catalyst inhibition by the basic amino ester moiety.…”