Rhodium‐Catalyzed Directing‐Group‐Assisted Aldehydic C–H Arylations with Aryl Halides

Abstract

A rhodium‐catalyzed general protocol for the directing‐group‐assisted arylation of aromatic aldehydic C–H bonds was developed. This method involves either hydroxy‐ or amino‐group‐directed aldehyde C–H arylation with various aryl halides. A broad synthetic scope for the preparation of 2‐hydroxybenzophenones was established with electronically variant salicylaldehydes and aryl halides with chemo‐ and regioselective possibilities. The developed protocol was also applied in the synthesis of medicinally important 3‐salicyloylpyridines in high yields.

Continuous flow synthesis of diaryl ketones by coupling of aryl Grignard reagents with acyl chlorides under mild conditions in the ecofriendly solvent 2-methyltetrahydrofuran

“…Diaryl ketones are frequently used as core motifs for developing pharmaceutical agents. [1][2][3] They exist in numerous bioactive molecules ( Fig. 1), 1,4 such as the nonsteroidal anti-inammatory drug (NSAID) ketoprofen, 5 the broad-spectrum human anthelmintic mebendazole, 6 the classical lipid regulating agent feno-brate 7 and the therapeutically useful uricosuric agent benzbromarone (BBR) 8 (Fig.…”

Aerobic Copper‐Catalyzed Salicylaldehydic Cformyl−H Arylations with Arylboronic Acids

“…Because salicylaldehydes are versatile and available building blocks in organic synthesis, [9] much endeavor has been devoted to functionalizing the kind of aldehydes with various coupling partners via a direct C −H activation of aldehydes [10] . To date two main pathways have been applied to constructing the structure of 2‐hydroxybenzophenone via salicylaldehydic C formyl −H activation catalyzed by precious metal catalysts: 1) the arylation of o ‐hydroxybenzaldehydes with electrophiles (aryl halides) generally involving oxidative addition of aryl halides to metal species, followed by intramolecular C−H activation of the formyl group and reductive elimination to deliver the products; [7a–e] 2) the cross‐coupling between o ‐hydroxybenzaldehydes and nucleophiles (arylboronic acids or hypervalent iodines) [8] through direct C−H activation and transmetalation [8a, d, e] or nucleophilic addition and oxidation [8c] (Scheme 1 A).…”

“…The achievements of transition‐metal‐catalyzed functionalization of salicylaldehydes mainly benefit from the formation of noble metalcycle intermediates (e.g., rhodacycle and palladacycle) by coordination of the 2‐hydroxy group of salicylaldehydes to an active metal species (Scheme 1 B). The C formyl −H arylation, [7d, 8d, 11a] olefination [11b–j] and alkylation [11f, k–n] of salicylaldehydes catalyzed by rhodium involving rhodacycle intermediates as the key step were documented. With regard to palladium catalysis, five‐ [7a, b, 8a] and six‐membered [7c, 8c, 12] palladacycles have been reported, in which the former experiences the cleavage of aldehyde C−H bond and the latter does not.…”

Benzophenone: a ubiquitous scaffold in medicinal chemistry

“…24 Various other catalysts have also been used with different coupling partners and aldehydes to afford various unsymmetrical diaryl ketones. [25][26][27][28][29][30] In this area, transition-metal-catalyzed oxidative C-H acylation and decarboxylative acylation of unactivated sp 2 arene C-H bonds using different acyl sources, such as aldehyde, benzyl alcohol, benzylamine, toluene, and α-keto acids, has been recently developed. 31,32 Recently, a review on naturally occurring benzophenones, highlighting their biological activities, has been published; 1 however, a review on their synthetic analogues is lacking.…”