Pyrroles palladium-catalyzed cyclization

Category Ic cyclizations are rare for pyrroles. Palladium-catalyzed cyclizations of iV-allyl and N-vinyl-o-haloanilines are useful indole syntheses which are in category Ic. The ultimate starting material is usually an o-haloaniline (Scheme 32). 

Palladium-catalyzed cyclization of the oxime derivative 47 provided a good yield of the pyrrole 48 (Equation 9) <1999CL45>. Similar reactions have been observed in connection with cyclization studies of related ketone trimethylhydrazonium salts <2005H(65)273>. Photochemical radical cyclization of 7,5-unsaturated ketone oximes has been reported to produce 1-pyrrolines <2005TL2373>. Similar 0-acetyloximes may also be annulated to 1-pyrrolines by treatment with acetic acid in the presence of 1,4-cyclohexadiene and naphthalene-l,5-diol, possibly proceeding via a radical mechanism <2002CL144>. 

A route to pyrroles illustrated by the preparation of 292 involves initial treatment of the nitroketene-5, 5 -acetal 293 with an organometallic reagent, followed by conversion of the resulting alkene 294 to the enamine 295, and final annulation to the target heterocycle (Scheme 34) <1998T12973>. A related approach featuring constmction of /3-hydroxyenamines from 1,3-dicarbonyl compounds and /3-amino alcohols, and subsequent palladium-catalyzed cyclization to pyrroles, has been reported <1996TL9203>. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

A pyrrole synthesis leading to 20 has been achieved by a CuBr catalyzed cyclization of the intermediate imine 21, which was prepared over several steps from 1,3-hexadiyne (22) in a one-pot operation <02CHE748>. Aminomethyl substituted allenes have also been used for the synthesis of pyrroles by a palladium catalyzed annulation with aryl iodides <02H(57)2261>. 

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. 

Abstract An overview of recent transition metal-catalyzed syntheses of pyrroles and carbazoles is presented. The focus is on methods which have been applied to the preparation of biologically active namrally occurring pyrrole and carbazole alkaloids. For pyrroles, special attention is paid to silver(I)-catalyzed cyclization reactions. For carbazoles, iron(0)-mediated and palladium(0/ll)-catalyzed cychza-tion reactions are highlighted and their broad range of applications is discussed. 

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. 

A palladium-catalyzed oxidative cyclization of tertiary enamines 7 to pyrroles 8 using copper acetate was reported by Guan and co-workers. Trifluo-roacetic acid as a stoichiometric additive was proven to be integral to the improvement of yield. The mechanism is proposed to go through electrophilic paUadation on the C—H of a tertiary enamine under acidic conditions which tri ers a cascade to form pyrroles 8. This method was used to synthesize a range of differentially functionalized 1,3,4-tri-substituted pyrroles (14OL3360). 

While furans have been the main focus of palladium-catalyzed allene cycloisomerization, pyrroles can also be generated via reaction of allenyl-substituted amines. A number of metal catalysts have been reported to mediate the cyclization of these substrates to pyrrolines, however, the use of palladium catalysis can allow the concomitant incorporation of aryl functionality into the 3-position, as shown in Scheme 6.27. At elevated temperatures, oxidation of the pyrroline occurs to afford pyrroles [37]. 

Interestingly, this Heck-type palladium-catalyzed oxidative addition/insertion manifold can also be applied to the actual formation of the carbon-heteroatom bond. This was illustrated by Narasaka in the reaction of olefin-tethered oxime derivatives. This chemistry can be considered to arise from oxidative addition of the N—O bond to palladium (30) followed by the more classical olefin insertion and (3-hydride elimination, ultimately allowing the assembly of pyrroles (Scheme 6.58) [79]. The nature of the OR unit was found to be critical in pyrrole formation, with the pentafluorobenzoylimine leading to selective cyclization and rearrangement to the aromatic product. An analogous approach has also been applied to pyridines and imidazoles [80]. 

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