Modular Access tometa-Substituted Benzenes via Mo-Catalyzed Intermolecular Deoxygenative Benzene Formation

Abstract

The substituted benzene derivatives are essential to organic synthesis, medicinal chemistry, and material science. However, the 1,3-di- and 1,3,5-trisubstituted benzenes are far less prevalent in small-molecule drugs than other substitution patterns, likely due to the lack of robust, efficient, and convenient synthetic methods. Here, we report a Mo-catalyzed intermolecular deoxygenative benzene-forming reaction of readily available ynones and allylic amines. A wide range of unsymmetric and unfunctionalized 1,3-di- and 1,3,5-trisubstituted benzenes were obtained in up to 88% yield by using a commercially available molybdenum catalyst. The synthetic potential of the method was further illustrated by synthetic transformations, a scale-up synthesis, and derivatization of bioactive molecules. Preliminary mechanistic studies suggested that this benzene-forming process might proceed through a Mo-catalyzed aza-Michael addition/[1,5]-hydride shift/cyclization/aromatization cascade. This strategy not only provided a facile, robust, and modular approach to various meta-substituted benzene derivatives but also demonstrated the potential of molybdenum catalysis in the challenging intermolecular deoxygenative cross-coupling reactions.

Molybdenum-catalyzed carbonyl–carbonyl olefination reaction for heterocycle syntheses

“…Based on the above experimental observations and the literature precedent, 11,12 a plausible reaction mechanism was proposed, as shown in Scheme 5. Firstly, the oxo-Mo-carbene complex I-2 is generated through CO double bond cleavage promoted by the Mo( ii )-complex ( M-1 ) that is proposed to form through the oxidation of Mo(CO) 6 by o -quinone.…”

“…The 2,3-diphenyl indole 2a was obtained in 70% yield in the presence of PPh 3 as a mild reductant and a Mo-catalytic system derived from commercially available Mo(CO) 6 and 3,5-di- tert -butyl- o -benzoquinone (entry 1). 11,12 Encouraged by these results, we carried out further optimization of the reaction conditions. Screening of reductants, molybdenum catalysts, and reaction temperature (entries 2–12) led to the identification of the optimal conditions as 1a in mesitylene, 10 mol% of Mo(CO) 6 , 10 mol% of o -quinone, 2 equiv.…”

“…The power of the molybdenum catalysis allows the carbonyl compounds to directly serve as carbene equivalents through catalytic deoxygenation, thus circumventing the use of hazardous diazo compounds. 11,12,21,22 Further studies on the reaction mechanism and the application of this protocol to the syntheses of bioactive molecules are ongoing in our laboratory.…”

“…As part of an ongoing research program focusing on Mo-catalyzed direct deoxygenative functionalization reactions of carbonyl compounds, 11–13 we recently reported a Mo-catalyzed intramolecular carbonyl–carbonyl olefination of α-ketoamides, 11 b in which the Mo-carbene species was proposed to be a plausible intermediate (eqn (1), Scheme 2C). 11,12,14 Interestingly, pyrrol-2-ones could also be easily obtained through a Mo-catalyzed intermolecular deoxygenative cross-coupling of 1,2-diketones with α-ketoamides. 11 b Meanwhile, Asako, Ilies et al described a Mo-catalyzed dimerization of aldehydes as well as intramolecular deoxygenative olefination of dicarbonyl compounds (eqn (2), Scheme 2C).…”

p-Cresol-Enabled Nickel-Catalyzed Intermolecular Redox-Economical Coupling of Allyl Alcohols with Alkynes through oxa-Nickelacycle

“…Alkenyl alcohols or amines are important building blocks and have been extensively employed in transition metal-catalyzed reactions . The advancement of these substrates for the creation of nickel ring intermediates will offer a novel avenue for their chemical conversion.…”