Palladium-Catalyzed Arylation and Heteroarylation of Indolizines

Abstract

A highly effective protocol for palladium-catalyzed selective arylation and heteroarylation of indolizines at C-3 has been developed. Mechanistic studies unambiguously support an electrophilic substitution pathway for this transformation.Indolizines substituted at C-3 are very attractive heterocyclic units, as a number of representatives of this class 1 and, especially their partially or completely reduced analogues, indolizidine alkaloids 2 and related unnatural compounds, 3 exhibit important biological properties. As a part of our program on developing efficient methods toward differently substituted indolizines, we were particularly interested in elaborating efficient approaches toward C-3-arylated indolizines. To date, no general convenient methods for synthesis of C-3-arylated indolizines exist. 4 Scattered reports on synthesis of C-3-arylated indolizines via various modes of Chichibabin-type cyclocondensation 5 are limited to particular substitution patterns 6 and generally provide low to moderate yields of the products. 7 Other methods such as dipolar cycloaddition of pyridinium ylides with alkynes, 8 cyclopropenones, 9 or cyclopropenes 10 are limited to use of symmetric substrates, producing indolizines with two identical substituents at the pyrrole ring. Finally, synthesis of indolizines via cycloisomerization of alkynyl pyridines, 11,12 a method recently developed within our group, potentially can give access to 3-arylindolizines; however, it would require employment of rather expensive 3-aryl-1-propynes and, in this case, is unlikely to be considered as synthetically useful. Thus, we decided to explore the possibility of direct, last-stage methods of arylation of the indolizine core. Although analogous reactions on various heterocyclic systems such as furans, 13 thiophenes, 13a,14 pyrroles, 15 and indoles 16 have long been known, no reports on arylations involving indolizines have been reported to date. 17 Herein we report efficient palladium-catalyzed arylation and heteroarylation of indolizines, which allows for selective incorporation of aromatic or heteroaromatic substituent at the C-3 position of this heterocycle.Initial experiments revealed that indolizine 1a indeed underwent arylation in the presence of different palladium sources in DMSO; however, a 3-fold excess with respect to arylbromide © 2004 American Chemical Society Correspondence to: Vladimir Gevorgyan, vlad@uic.edu. Supporting Information Available: Detailed experimental procedures for preparation of and spectroscopic data for compounds 3aa-ed and 10. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2013 July 11. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript was required to attain high yields, and the reaction was rather sluggish, as it took 2 days for completion. Optimization experiments 18 indicated that arylation of indolizines proceeded much faster (1-3 h) in the presence of cataly...

Direct transition metal-catalyzed functionalization of heteroaromatic compounds

“…Detailed mechanistic studies (Schemes 3-6, Table 1) strongly supported an electrophilic mechanism for this transformation. 6 Sames reported a method for the selective C-2-arylation of N-substituted indoles 70 (Scheme 30). 44 Optimization of the reaction conditions and catalyst loads has identified an optimal protocol which allowed for up to good yields of arylated derivatives 71.…”

Direct Transition Metal Catalyzed Functionalization of Heteroaromatic Compounds

“…6 Indolizine, one of the most electron-rich heterocycles known, 7 was chosen for these studies. Experimental and theoretical studies were performed to evaluate possible involvement of any of the four mechanisms depicted in Scheme 3.…”

“…12 The possibility of involvement of this mechanism was originally proposed by Miura for the copper-assisted C-2 arylation of azoles, where arylation of "acidic" sites of the heterocycles was promoted by the addition of Cu salts. 3 However, addition of copper salts during the arylation of indolizine 6 resulted in greatly prolonged reaction times and reduced yields, thus, not supporting Path C. 6 Next, experimental and theoretical studies were performed to elucidate the possible involvement of the electrophilic aromatic substitution process (A). This mechanism has often been considered as the most probable mechanism for arylation of heterocycles.…”

“…6 To gather further support for electrophilic mechanism A, kinetic studies were performed (Table 1). 6 As expected for an electrophilic path, the EWG-substituted indolizine underwent the slowest arylation among tested substrates (Method I, Table 1). A similar trend of reactivity was observed in the Lewis acid-mediated Friedel-Crafts acylation of the same indolizines (Method II, Table 1), thus strongly supporting electrophilic nature of the arylation (Path A, Scheme 2).…”

Synthesis of 3-Unsubstituted Indolizines from Electron Deficient Alkenes under Transition Metal Free Conditions

“…其中, 3 位未取代的中氮茚不仅具有各种生物活 性(图 1), 同时因为其 3 位的电荷密度高, 还是一类重要 的合成中间体. 被用于合成 3-烯基中氮茚、3-芳基中氮 茚、3-酰基中氮茚、3-炔基中氮茚、环吖嗪类衍生物及 其他杂环化合物 [4] .…”