Pyrroles intramolecular oxidative coupling

A)-Ketorolac 132, a nonsteroidal anti-inflammatory dmg (NSAID), was synthesized in a two-step procedure based on an intramolecular oxidative coupling of pyrrole at the C-2 position with a chiral sultam enolate 130 leading to dihydropyrrolizine 131 as a 4.5 1 mixture of epimers (Scheme 23). Subsequent benzoylation, performed on the crude... 

Scheme 30 Pd(II)-catalyzed intramolecular oxidative coupling of pyrrole derivatives...

Finally, the intramolecular coupling reaction between an olefin and a pyrrole ring has been examined (Scheme 40). In this example, a 66% isolated yield of the six-membered ring product was obtained. A vinyl sulfide moiety was used as the olefin participant and the nitrogen protected as the pivaloyl amide in order to minimize the competition between substrate and product oxidation. Unlike the furan cyclizations, the anodic oxidation of the pyrrole-based substrate led mainly to the desired aromatic product without the need for subsequent treatment with acid. 

Although conceptually similar, the direct coupling of carbonyl compounds with pyrroles (Scheme 141) using a Cu(ii) oxidant probably differs mechanistically from the intramolecular cyclization of pyrrole 718 to 2,3-dihydro-l//-pyrrolizine 719 (in 65% yield as a 4.5 1 mixture of diastereomers) using Fe(lll)-based oxidant (ferrocenium hexa-fluorophosphate) (Scheme 142) <2006ARK310>. 

Conditions first described by Fagnou were used to affect the C-H to C-H bond cyclization, which proceeded in 47% yield. Mechanistically the direct coupling reaction is thought to proceed via intramolecular nucleophilic attack of the pyrrole moiety onto the Pd(II) centre. It was postulated that the electron rich DavePhos ligand facilitates both oxidative addition and forms a more reactive cationic Pd(II) species by dissociation of the halide. Following a deprotonation step, reductive elimination of Pd(0) then resulted in formation of the biaryl bond, completing the core framework. Application of this direct palladium-catalyzed biaryl coupling facilitates a very efficient and concise synthesis of rhazinilam as a racemate. 

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