Transition metal catalyzed pyrrole synthesis

Synthesis of pyrroles, indoles, and carbazoles through transition-metal-catalyzed C—H functionalization 13AJ0466. 

Analogously to the precedent transition metal-catalyzed cycloisomerization of (Z)-pent-2-en-4-yn-l-ols like 113 into furan compounds (Scheme 8.45), Gabriele disclosed a general and a very convenient route leading to pyrroles 218 from nitrogen analogs of these reactive precursors (Scheme 8.81) [269]. Thus, di-, tri-, and tetra-substituted pyrroles 218 with different substitution patterns could be readily synthesized via the Cu(I)- or Cu(II)-catalyzed [270] cycloisomerization of (Z)-(2-en-4-ynyl)amines 217. The mechanism of this transformation is similar to that proposed for the transition metal-catalyzed synthesis of furans (Scheme 8.46). 

Schulte [285, 286] and later Chalk [287] described the Cu(I)-catalyzed synthesis of symmetrical 2,5-diarylpyrroles 261 from conjugated diynes 257 and primary amines 258. The reaction is believed to proceed via the transition metal-catalyzed hydroamination [33, 288-291] leading to tautomeric aminoenyne 259 or homopro-pargylic imine 260 intermediates, which further undergo 5-endo-dig cyclization to furnish pyrrole product 261 (Scheme 8.95). 

The reaction of isocyanide 42 and phenylacetylene (43) afforded pyrrole 44 under silver-catalyzed conditions. The pyrroles are formed regioselec-tively, in high yields, and with broad functional group tolerance. This represents the first example of the transition metal-catalyzed cycloaddition of isocyanides with unactivated terminal alkynes (13AG(I)6953). A similar system for the synthesis of substituted pyrroles was reported by Lei (13AG(1)6958). 

Another approach to pyrrole synthesis is based on transition metal catalyzed rearrangement of azirines [57]. 

Pyrroles, H.M.L. Davies. Synthesis of Porphyrins with Exocy-clic Rings from Cycloalkenopyrroles, T.D. Lash. Palladium-Catalyzed Coupling Reactions of Indoles, A.R. Martin and Q. Zheng. Cycloaddition Reactions of Indole Derivatives, U. Pindur. Transition-Metal Mediated Synthesis of Carbazole Derivatives, H. J. Knoiker. Synthesis of [b]-Annelated Indoles by Thermal Electrocyclic Reactions, S. Hibino and E. Sugi-no. Total Synthesis of (-) and ent (-) Duocarmycin SA, D.L. Boger. Index. I... 

The synthesis of bicyclo[3.2.1]octadienes 86 has been accomplished by refluxing divinyl-cyclopropanes 85 in xylene. Subsequent research led to the development of conditions employing a rhodium-catalyzed step for the synthesis of bridged systems via the cyclopropanation of cyclopentadienes, furans and pyrroles (see section on transition-metal-mediated rearrangements). 

The following section looks at how palladium-catalyzed C-H functionalization has been successfully applied in synthetic strategies enabling rapid and elegant routes to complex natural products containing the indole and pyrrole nucleus. There are a number of metal-mediated examples where stoichiometric quantities of transition metals are employed to affect the desired transformation however, there are very few cases of catalytic functionalization with in the context of complex molecule synthesis. 

A highly related method showed that pyrrole ring formation from 50 to produce indolizines 52 is promoted efficiently by various transition-metal catalysts, such as platinum(II) [17], indium(lll) [17], copper(I) [18,19], gold(I) [18], and silver(I) [18] (Scheme 19.11). It should be noted that these reactions were reported independently by the three research groups at nearly the same time [17-19]. The palladium-catalyzed two-component reaction of alkynylpyridines 53 with aryl halides is a convenient strategy for the synthesis of highly substituted fused pyrroles 55 [20]. 

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