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...
Articles you may be interested inIn operando observation system for electrochemical reaction by soft X-ray absorption spectroscopy with potential modulation method Rev. Sci. Instrum. 85, 104105 (2014); 10.1063/1.4898054 Sonochemically precipitated spinel Co 3 O 4 and NiCo 2 O 4 nanostructures as an electrode materials for supercapacitor AIP Conf. Proc. 1512, 1216 (2013); 10.1063/1.4791488Pt metal-CeO 2 interaction: Direct observation of redox coupling between Pt 0 / Pt 2 + / Pt 4 + and Ce 4 + / Ce 3 + states in Ce 0.98 Pt 0.02 O 2 − δ catalyst by a combined electrochemical and x-ray photoelectron spectroscopy study An electrochemical robotic system using standard microtiter plates as reaction wells for potentiostatic and galvanostatic electrosynthesis and high-throughput electroanalysis was conceived and realized using stepmotor driven positioning stages in combination with a flexible software. Electrode bundles specifically adapted to the experimental needs are accurately positioned in the wells of a microtiter plate followed by the automatic performance of sequences of electrosynthetic or electroanalytical techniques. The system allows us to work under inert-gas atmosphere, in aqueous and organic solvents, and to add or remove solutions by means of integrated syringe pumps. A specifically developed script language permits the user to perform very complex experimental sequences in the different wells of the microtiter plate. The hardware and software features of the developed electrochemical robotic system, the design of suitable electrode arrangements for electrosynthesis and electroanalytical techniques, as well as the reproducibility in aqueous and organic electrolytes are described. The performance of the system is demonstrated by redox screening of a Ru-complex library and by electrosynthesis with in situ analysis of a compound library.
A library of 83 metalloporphyrins with varying substitution pattern at the meso-position of the porphyrins and different central metal ions in the core region has been synthesized in small quantities using a parallel synthesis strategy. By means of a specially designed electrochemical robotic device integrating a 96-well microtitre plate and an easily movable assembly of working, counter and reference electrodes, the different porphyrins were automatically applied in sequence to an in-well electrochemical preparation and testing of NO sensors. Screening the entire compound collection suggested initial considerations concerning the influence of varied functionalities of the metalloporphyrins on their electrocatalytic properties for the oxidation of NO and helped to identify the quality of the investigated catalyst candidates. As compared to manually performed quality tests, the proposed strategy of automation has advantages in convenience, rapidity and especially reproducibility avoiding any inaccuracies introduced by manually performing all steps of the complex sensor formation and testing sequence.
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