Pyridone Directed Ru-Catalyzed Olefination of sp²(C–H) Bond Using Michael Acceptors: Creation of Drug Analogues

Abstract

Herein, the ruthenium-catalyzed regioselective sp 2(C–H) monoalkenylation of N-arylpyridones has been demonstrated, where the pyridone was utilized as a weakly coordinating directing group. Importantly, the current methodology has been effectively applied to the synthesis of many drug analogues such as pirfenidone, naproxen, ibuprofen, geraniol, umbelliferone, pregnenolone, and estrone. This methodology tolerates a wide range of functional groups and yields up to 93% yield. A six-membered ruthenium complex was also detected by HRMS.

Rh(III)-Catalyzed Weakly Coordinating 2-Pyridone-Directed Oxidative Annulation Using Internal Alkynes: A Reversal in Selectivity

“…12 In addition, Ravikumar's group developed 2-pyridone-directed alkenylation at the phenyl ring using acrylate as a coupling partner. 13 Intrigued by our previous studies of transition metalcatalyzed 2-pyridone functionalizations 3b,14 and weakly coordinating group-directed C−H bond functionalization, 15 we hypothesized that the carbonyl group in the 2-pyridone ring might play the role of an intrinsic directing group for the Satoh−Miura type annulation at the aryl ring with the internal alkynes. The selection of proper conditions might offer the desired annulated product.…”

“…Since the development of pioneering Rh­(III)-catalyzed oxidative annulation by Satoh and Miura’s group and You’s group, many transition metal-catalyzed oxidative annulations via C–H bond functionalizations have been developed. , Notably, the 2-pyridone ring of the N -aryl 2-pyridone moiety was functionalized through chelation or reactivity-guided C–H bond functionalizations . However, the weakly coordinating carbonyl-directed C–H bond functionalizations of the N -aryl/heteroaryl ring of these 2-pyridone scaffolds have rarely been explored. − In an important step forward, You’s group developed a Rh­(III)-catalyzed annulation of N -aryl 2-pyridone to furnish quinolizinones (Scheme a) . Recently, Xu, Lei, and Walsh’s group also reported a Rh­(III)-catalyzed rollover annulation of 1-(2-pyridyl)-2-pyridone using internal alkynes (Scheme b) .…”

“…Very recently, Koley’s group disclosed an interesting Ru­(II)-catalyzed alkenylation at the arene ring of N -aryl 2-pyridones using internal alkynes (Scheme c) . In addition, Ravikumar’s group developed 2-pyridone-directed alkenylation at the phenyl ring using acrylate as a coupling partner …”

Novel pirfenidone derivatives: synthesis and biological evaluation

“…For example, Ma et al 13 introduced alkoxy substituents that included terminal amines of different lengths at the C-4 position of the benzene ring to determine the influence of the size of the linker and different amines on the biological activity of the compound. Smruti Ranjan Mohanty et al 14 and Raziullah et al 15 used N -arylpyridone as a raw material for the Ru-catalyzed synthesis of pirfenidone allyl derivatives. Chenxi Gu et al 16 used pyridone compounds as raw materials to obtain pirfenidone amide derivatives.…”

Transformable Transient Directing Group-Assisted C(sp2)–H Activation: Synthesis and Late-Stage Functionalizations of o-Alkenylanilines

“…DGs are usually σ-coordinating functional groups that in combination with a transition metal control the site selectivity and activate the relatively strong C–H bonds by coordinating through the heteroatoms of DGs to the reactive metal catalysts. Transition metals like Pd, Rh, Ru, Co, Mn, etc., are being used for the activation of inert C–H bonds found in different organic moieties. The field of directed C–H bond activations has grown tremendously, and many chelating groups have been explored that can serve as auxiliaries .…”