Iodine Mediated Base‐Controlled Regio‐Selective Annulation of 2‐(Pyridin‐2‐yl)acetate Derivatives with Acrylic Esters for the Synthesis of Indolizines

Abstract

An iodine mediated base‐controlled reaction between 2‐(pyridin‐2‐yl)acetate derivatives and acrylic esters has been developed for the selective synthesis of 1,3‐disubstituted indolizines and 1,2‐disubstituted indolizines. A single‐pot reaction of 2‐(pyridin‐2‐yl)acetate derivatives and acrylic esters in the presence of CsOAc delivers 1,3‐disubstitued indolizines, while KHCO3 promotes the formation of C3‐iodo indolizines, which could be further de‐iodinated in the presence of copper powder, affording 1,2‐disubstituted indolizines via a sequential stepwise fashion. A plausible reaction mechanism involving radical process has been proposed for this reaction. Pd‐catalzyed reaction of C3‐iodo indolizines with aryl boronic acids has been described.

Iodine-Catalyzed Synthesis of Substituted Furans and Pyrans: Reaction Scope and Mechanistic Insights

“…On the other hand, high-energy photoirradiation, with the intention to trigger iodine radical formation (entries 2–5, especially entry 4 where green light matched the homolytic cleavage energy of the I–I bond), significantly reduced reaction efficiency. While these results seemed to contradict each other, we encountered several literature examples where TEMPO or BHT reacted directly with I 2 in a range of oxidation or substitution reactions, which might interfere with our cyclization pathway. Moreover, it is also possible that BHT could trap the carbocation intermediate to form HI as well to further complicate the reaction.…”

Switching the reactivity of cyanomethylpyridinium salts in the 1,3-cycloaddition conditions with alkyl propiolates to cyanoindolizines or cyanoazaindolizinyl-indolizines

“…The methyl 3-cyano-7-methylindolizine-1-carboxylate has also been isolated in 86% yield by 1,3-dipolar cycloaddition of pyridinium N-ylide to methyl acrylate, followed by internal aromatization mediated by MnO2 (pathway 3, Scheme 1). Now, the ethyl 3-cyanoindolizine-1carboxylate has also been synthesized mainly through 1,3-cycloaddition reaction but using different catalysts and conditions (pathways 4, 6-9, Scheme 1): i) one-pot reaction of pyridine, bromoacetonitrile and ethyl acrylate in imidazolium-based ionic liquid [Omim]Br used to reinforce the final cycloaddition reaction by the noncovalent interactions between the ionic liquid and substrates at 110 °C (55% yield, pathway 4); 12 ii) reaction of pyridinium salt with ethyl acrylate in the presence of copper acetate monohydrate and sodium acetate in DMF at 80 °C (55% yield, pathway 6); 13 iii) reaction of pyridinium salt with ethyl acrylate in the presence of Na2CO3 in DMSO at rt, followed by the oxidation of the intermediate with chloranil and final acid treatment (58%, pathway 7); 14 iv) iodine-mediated cesium acetate-controlled annulation of ethyl 2-(pyridin-2-yl)acetate with acrylonitrile in DCE at 90 °C (42%, pathway 8); 15 and v) iodine-catalyzed intermolecular oxidative tandem cyclization reaction of acrylonitrile and ethyl 2-(pyridin-2-yl)acetate under metal-free conditions in the presence of TMEDA and TBHP in NMP at 120 °C (30%, pathway 9). 16 The only free carboxylic acid in the series of 3-cyanopyridine described in the literature is 3-cyanoindolizine-1carboxylic acid.…”

“…17,18 Scheme 1. Synthetic entries to target 3-cyanoindolizine derivatives reported in the literature 8,[10][11][12][13][14][15][16] and strategy applied in this study.…”

“…The general procedure B was used with 1.0 g (6.47 mmol) of 1-(cyanomethyl)pyridinium chloride 2a to obtain pure indolizine 3d with the same physico-chemical as previously reported. 28 White solid; 0.64 g (46% yield); mp (EtOAc/cyclohexane): 100-103 °C; Rf (EtOAc/cyclohexane 5/5) = 0.72. 1 H NMR (CDCl3, 500 MHz) δ (ppm): 1.38 (t, J = 7.0 Hz, 3H, CH3), 4.35 (q, J = 7.0 Hz, 2H, CH2), 7.00 (t, J = 7.0 Hz, 1H, ArH), 7.30 (td, J = 8.0, 1.0 Hz, 1H, ArH), 7.72 (s, 1H, ArH), 8.25-8.29 (m, 2H, ArH).…”

Copper-Catalyzed Bisannulations of Malonate-Tethered O-Acyl Oximes with Pyridine, Pyrazine, Pyridazine, and Quinoline Derivatives for the Construction of Dihydroindolizine-Fused Pyrrolidinones and Analogues

“…Due to the wide range of biological activities of the both heterocyclic architectures, the development of efficient methods to access such scaffolds has attracted wide attention. The main synthetic routes toward indolizines includes Chichibabin indolizine synthesis; 1,3-dipolar cycloaddition of pyridinium ylides with alkenes or alkynes; annulation of 2-alkylpyridines with alkenes, alkynes, or aldehydes; and intramolecular cycloisomerization of propargylic pyridines . You’s group developed a two-step synthesis of chiral dihydroindolizines through C -allylic nucleophilic substitution and a subsequent Ir-catalyzed N -allylic nucleophilic substitution of the pyridine derivatives .…”