Palladium-catalyzed decarboxylative, decarbonylative and dehydrogenative C(sp²)–H acylation at room temperature

Abstract

Over the past few decades, an impressive array of C-H activation methodology has been developed for organic synthesis. However, due to the inherent inertness of the C-H bonds (e.g. ∼110 kcal mol for the cleavage of C(aryl)-H bonds) harsh reaction conditions have been realized to overcome high energetic transition states resulting in a limited substrate scope and functional group tolerance. Therefore, the development of mild C-H functionalization protocols is in high demand to exploit the full potential of the C-H activation strategy in the synthesis of a complex molecular framework. Although, electron-rich substrates undergo electrophilic metalation under relatively mild conditions, electron-deficient substrates proceed through a rate-limiting C-H insertion under forcing conditions at high temperature. In addition, a stoichiometric amount of toxic silver salt is frequently used in palladium catalysis to facilitate the C-H activation process which is not acceptable from the environmental and industrial standpoint. We report herein, a Pd(ii)-catalyzed decarboxylative C-H acylation of 2-arylpyridines with α-ketocarboxylic acids under mild conditions. The present protocol does not require stoichiometric silver(i) salts as additives and proceeds smoothly at ambient temperature. A novel decarbonylative C-H acylation reaction has also been accomplished using aryl glyoxals as acyl surrogates. Finally, a practical C-H acylation via a dehydrogenative pathway has been demonstrated using commercially available benzaldehydes and aqueous hydroperoxides. We also disclose that acetonitrile solvent is optimal for the acylation reaction at room temperature and has a prominent role in the reaction outcome. Control experiments suggest that the acylation reaction via decarboxylative, decarbonylative and dehydrogenative proceeds through a radical pathway. Thus we disclose a practical protocol for the sp C-H acylation reaction.

Photoredox‐Catalyzed Tandem Demethylation of N,N‐Dimethyl Anilines Followed by Amidation with α‐Keto or Alkynyl Carboxylic Acids

“…Unless otherwise stated, all commercial reagents were used without additional purification. The starting materials α‐oxocarboxylic acid; alkynyl carboxylic acid; and metal‐photocatalysts were prepared using literature reported method.…”

Recent Progress in Palladium‐Catalyzed Radical Reactions

“…reported a palladium‐catalyzed ortho ‐ sp 2 C−H acylation of electron‐deficient 2‐arylpyridine derivatives 246 via decarboxylation, dehydrogenation or decarbonylation, providing the acylation products 248 in moderate to good yields (Scheme 69). [52] These transformations exhibited excellent functional group tolerances. Reactions of phenylglyoxylic acids bearing electron‐withdrawing or electron‐donating groups proceeded smoothly to furnish the corresponding product.…”

Pd(II)-Catalyzed C-H Acylation of (Hetero)arenes—Recent Advances

“…The formation of an acyl radical intermediate is proposed in all cases. Generally, good yields of 6 are obtained, although aldehydes required longer reaction times (36 h) ( Scheme 2 c) [ 13 ]. Interestingly, when 2-pyrimidine was used as directing group instead, mixtures of mono- and diacylated products were obtained.…”