C−H Activation and Cross‐Coupling of Acyclic Aldonitrone

Abstract

Palladium‐catalyzed activation of C(sp2)−H bond in a readily E,Z‐isomerizable aldonitrone, bearing an ester group at the C terminus, enabled its cross‐coupling with a variety of aryl and heteroaryl bromides to give ketonitrones, including products with functional groups not compatible with the classical nitrone synthesis via condensation with hydroxylamines. The reactions proceeded with very high (usually complete) E selectivity. The key to obtaining good yields of the cross‐coupling products was the use of sterically hindered carboxylic acid as additive and non‐polar solvent (toluene), in which the starting nitrone exists mainly as E isomer. Further use of the obtained ketonitrones in dipolar cycloaddition or nucleophilic addition has also been demonstrated.

Palladium Catalysis: Dependence of the Efficiency of C−C Bond Formation on Carboxylate Ligand and Alkali Metal Carboxylate or Carboxylic Acid Additive. Part A: the C(sp2)−C(sp2), C(sp2)−C(sp3) and C(sp3)−C(sp3) Bonds

“…Loska and co-workers disclosed in 2021 that addition of bromobenzene to N-(2-ethoxy-2oxoethylidene)methanamine oxide using Pd(OAc) 2 / PPh 3 catalyst and K 2 CO 3 in toluene required carboxylic acid additive. [40] Its structure had a dramatic effect on the efficiency (Scheme 5a), the best result arising with the bulky tri(cyclohexylmethyl)acetic acid previously used by Tsuji, Fujihara and co-workers (see below). [41] The high selectivity towards the E cross-coupling product as well as the determinant role of the carboxylate ligand led Loska's team to assume a mechanism involving coordination of the nitrone oxygen to the phenylpalladium complex as depicted in 5bA (Scheme 5b).…”

“…Loska and co‐workers disclosed in 2021 that addition of bromobenzene to N ‐(2‐ethoxy‐2‐oxoethylidene)methanamine oxide using Pd(OAc) 2 /PPh 3 catalyst and K 2 CO 3 in toluene required carboxylic acid additive [40] . Its structure had a dramatic effect on the efficiency (Scheme 5a), the best result arising with the bulky tri(cyclohexylmethyl)acetic acid previously used by Tsuji, Fujihara and co‐workers (see below) [41] .…”

Palladium-Catalyzed Access to Benzocyclobutenone-Derived Ketonitrones via C(sp2)–H Functionalization

“… 20 We have recently disclosed a Pd-catalyzed reaction for the C–H activation of aldonitrones bearing an ester group to access various aryl ketonitrones ( Scheme 1 A). 21 In this approach, a reaction pathway has been proposed in which the nitrone oxygen atom serves as the directing group, facilitating the cross-coupling process. Accordingly, our envisioned strategy toward benzocyclobutenone-derived nitrones, which we term benzocyclobutenitrones (BCBn), is based upon palladium-catalyzed cyclization of bromoaryl-substituted aldonitrones ( Scheme 1 C).…”

“…Their efficiency in the formation of four-membered rings of BCBs via C­(sp 3 )–H activation is well-documented. ,, Concerning coupling of two C­(sp 2 ) carbon atoms, the 2010 seminal report of Martin et al indicated that benzocyclo­butenones could be obtained by simple palladium-catalyzed cyclization of haloaryl-containing aldehydes (Scheme B) . We have recently disclosed a Pd-catalyzed reaction for the C–H activation of aldonitrones bearing an ester group to access various aryl ketonitrones (Scheme A) . In this approach, a reaction pathway has been proposed in which the nitrone oxygen atom serves as the directing group, facilitating the cross-coupling process.…”