Pyrrole oxidative coupling/cyclization

A Sml2-induced reductive cyclization of (V-(alkylketo)pyrroles provided an entry into medium ring 1,2-annelated pyrroles <06EJO4989>. An oxidative radical alkylation of pyrroles with xanthates promoted by triethylborane provided access to a-(pyrrol-2-yl)carboxylic acid derivatives <06TL2517>. An oxidative coupling of pyrroles promoted by a hypervalent iodine(III) reagent provided bipyrroles directly <060L2007>. 

Srinivasan found that the typical stoichiometric Pd(OAc)2 conditions effect cyclization of 2-(N-arylaminomethyl)indoles to aryl-fused p-carbolines in low yield [e.g., 51 to 52] [73]. Similar to the chemistry observed with N-(phenylsulfonyl)pyrrole, 1,4-naphthoquinone also undergoes Pd(OAc)2 oxidative coupling with A-(phenylsulfonyl)indole to give 53 in 68% yield [74],... 

There have also been several reports of the cyclization of diynes with amines under the influence of copper(I) chloride (equation 73) (65CB98, 70KGS125, 72TL3487). This is a potentially useful reaction for symmetrically substituted pyrroles, since symmetrical diynes can be obtained by oxidative coupling of alkynes. 

In a series of papers on the total syntheses of alkaloids, Baran and coworkers have recently reported that enolates of carbonyl compounds undergo oxidative coupling with indoles and pyrroles in the presence of oxidants such as copper(II) and iron(III) salts . A detailed study of the oxidative cyclization reported in equation 15 has shown that 26 is converted into 27 with the highest yields when Fe(acac)3 is the oxidant, presumably due to its high redox potential (+1.1 V vs. the ferrocenium/ferrocene couple in THF solution ), which is the most positive among all the oxidizing agents tested for the transformation. 

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>. 

A synthesis of the marine alkaloid (+)-dragmacidin F featured the oxidative cyclization of pyrrole 50 to give 51 in good yield [43], Further elaboration to the natural product involved a Suzuki coupling (Section 2.3.3). 

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. 

One of the most versatile approaches to highly functionalized carbazoles is the sequential palladium-catalyzed C-N/C-C coupling for assembly of the central pyrrole moiety. Many total syntheses of naturally occurring carbazole alkaloids are following this route. The initial C-N bond formation by a palladium(0)-cata-lyzed Buchwald-Hartwig amination of aryl halides or triflates 94 with arylamines 31 affords the diarylamines 95 (Scheme 24) [139,140]. Oxidative cyclization of the diarylamines 95 to the carbazoles 32 proceeds via a double C-H bond activation and is achieved in the presence of palladium(ll) compounds. 

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