Catalytic Friedel‐Crafts Reactions on Saturated Heterocycles and Small Rings for sp³‐sp² Coupling of Medicinally Relevant Fragments

Abstract

gem‐Diarylheterocycles display a wide range of biological activity. Here we present a systematic study into the formation of 4‐ to 6‐membered O‐ and N‐heterocycles and cyclobutanes bearing the diaryl motif through a catalytic Friedel–Crafts reaction from the corresponding benzylic alcohols. 3,3‐Diaryltetrahydrofurans, 4,4‐diaryltetrahydropyrans, 3,3‐diarylpyrrolidines, 4,4‐diaryl‐piperidines, as well as diarylcyclobutanes are examined, with results for 3,3‐diaryloxetanes and 3,3‐diarylazetidines presented for comparison. Three catalytic systems are investigated for each substrate [Ca(II), Li(I) and Fe(III)], across preinstalled aromatic groups of differing electronic character. In most cases examined, the diaryl product is obtained directly from the alcohol with good yields using the most appropriate catalyst system. In the absence of a nucleophile, the olefins from the 5‐ and 6‐membered substrates by elimination of water are obtained under the same reaction conditions.

Synthesis, Characterization, and Antimicrobial Activity Screening of Some Novel 3-(2-(3-(Substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline Derivatives as Potential Antimycobacterial Agents

“…Compound 4 upon aromatic nucleophilic substitution reaction with 2-bromo-1,3-difluorobenzene ( 5 ) gave 3-(2-bromo-3-fluorophenoxy)-8-fluoro-2-methylquinoline ( 6 ). The reaction of organolithium or organomagnesium compounds upon nucleophilic addition reaction with oxetan-3-one gave alcohol . 3-(2-Bromo-3-fluorophenoxy)-8-fluoro-2-methylquinoline ( 6 ) upon reaction with n -butyllithium followed by nucleophilic addition reaction with oxetan-3-one gave 3-(2-fluoro-6-((8-fluoro-2-methylquinolin-3-yl)­oxy)­phenyl)­oxetan-3-ol ( 7 ).…”

“…The reaction of organolithium or organomagnesium compounds upon nucleophilic addition reaction with oxetan-3-one gave alcohol. 39 3-(2-Bromo-3-fluorophenoxy)-8-fluoro-2-methylquinoline ( 6 ) upon reaction with n -butyllithium followed by nucleophilic addition reaction with oxetan-3-one gave 3-(2-fluoro-6-((8-fluoro-2-methylquinolin-3-yl)oxy)phenyl)oxetan-3-ol ( 7 ). Compound 7 upon nucleophilic substitution reaction 40 with substituted benzyl bromide ( 8a – i ) furnished 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline ( 9a – i ).…”

Computationally driven design of an artificial metalloenzyme using supramolecular anchoring strategies of iridium complexes to alcohol dehydrogenase

“…This compound was synthesised by adapting a previously described protocol. 54 To a Pd/C (1.3 eq., 46 mg, 0.43 mmol) powder purged under N 2 , the Cbz-protected ketodiol 29 was added (1 eq., 0.39 mmol, 172 mg) in methanol (6 mL). The solution was then flushed with H 2 gas and stirred under H 2 atmosphere (balloon) at room temperature for 24 h. The suspension was filtered through a Celite pad and washed with MeOH (2 × 5 mL).…”

Short Synthesis of Oxetane and Azetidine 3-Aryl-3-carboxylic Acid Derivatives by Selective Furan Oxidative Cleavage

“…We envisaged a route to the target acids through a mild oxidative cleavage of the corresponding furan derivative, accessible through a catalytic Friedel–Crafts reaction on the four-membered ring alcohols. We recently reported the catalytic formation of 3,3-diaryloxetanes, 3,3-diarylazetidines, and 1,1-diarylcyclobutanes, using lithium, calcium, and iron catalysis, respectively. These methods were found to be effective for the installation of a furan ring, with three individual examples reported.…”

“…Finally, the arylcyclobutane furan series 9 was synthesized using FeCl 3 as the optimal catalyst and 2-methylfuran as the nucleophile in the Friedel–Crafts reaction. Because of the increased stability of the cyclobutane carbocation intermediate, phenyl ( 9b ) and electron-withdrawing Cl and CF 3 groups ( 9c , 9d ) could be incorporated in addition to p -methoxybenzene ( 9a ). A higher catalyst loading proved optimal in the oxidative cleavage of the cyclobutane furan series, enabling the formation of products 11a–d in 55–100% yield.…”