Intramolecular Pd-Mediated Processes of Amino-Tethered Aryl Halides and Ketones:  Insight into the Ketone α-Arylation and Carbonyl-Addition Dichotomy. A New Class of Four-Membered Azapalladacycles

Abstract

An exploration of the scope and limitations of Pd(0)-catalyzed intramolecular coupling reactions of amino-tethered aryl halides and ketones has been conducted. Two different and competitive reaction pathways starting from omega-(2-haloanilino) alkanones, enolate arylation and addition to the carbonyl group, have been observed, while omega-(2-halobenzylamino) alkanones exclusively underwent the enolate arylation process. The dichotomy between ketone alpha-arylation and carbonyl-addition in the reactions of omega-(2-haloanilino) alkanones has been rationalized by the intermediacy of unprecedented four-membered azapalladacycles, from which X-ray data and chemical behavior are reported.

Control over the Chemoselectivity of Pd‐Catalyzed Cyclization Reactions of (2‐Iodoanilino)carbonyl Compounds

“…Interestingly, the use of xantphos and Cs 2 CO 3 as the base in the absence of phenol in THF afforded a nearly equimolecular mixture of alcohol 11 and ketone 20 (Table 2, entry 8). In contrast, the use of PPh 3 as the ligand under these same reaction conditions gives rise exclusively to the nucleophilic addition to the carbonyl group to give 11 (Scheme b) 3d. These results not only confirm the necessity of the phenoxy ligand to overcome the nucleophilic addition to the ketone carbonyl group and selectively promote the α‐arylation reaction, but also show that the ligand controls the reactivity of the ambiphilic σ‐arylpalladium(II) complexes.…”

“…This activation‐energy barrier would switch off the α‐arylation pathway, thus making the nucleophilic addition reaction the only possible mechanism. In contrast, the enolization reaction is much easier when ketones are the reactants (Scheme ) and, as a consequence, α‐arylation products can be produced 3d. 14…”

“…In sharp contrast to that observed with esters and amides, (2‐haloanilino)ketones show a remarkable structure‐dependent reactivity in the palladium‐catalyzed cyclization reactions because they undergo α‐arylation or nucleophilic addition to the carbonyl group depending on the length of the tether between the amino moiety and the ketone carbonyl bond (Scheme ) 3d. We recently carried out computational DFT studies on these compounds14 and concluded that the formation of transient four‐membered azapalladacyclic intermediates is essential to explain the experimentally observed reaction products.…”

Synthesis of fused indoles by sequential palladium-catalyzed Heck reaction and N-heteroannulation

“…21,22 It is not unlikely that the initial s-complex, formed by oxidative addition of palladium(0) into the aryl-bromine bond in 16, is coordinated to the pendant amine, forming a relatively stable complex. [23][24][25][26] This effectively removes palladium from the catalytic cycle, and the reaction is quenched. The amide 19, having a substantially lower ability to coordinate to the metal, cyclized to form the expected products 38 and 39.…”

Palladaphosphacyclobutenes as catalysts in Heck and Suzuki reactions

“…The most used palladaphosphacycles as catalysts are five-or six-membered rings. [2] Four-membered palladaphosphacycles are rather rare [3,4] since their poor stability leads to difficulties in preparation and isolation. Recently, we have successfully developed a method for the synthesis of palladaphosphacyclobutenes, which are air-and heat-stable.…”