Tandem Cyclization of a Bispyridinium Chloride: Facile Synthesis of Substituted Indolizines

Abstract

Functionalized indolizines were prepared by a one-pot cascade reaction from bispyridinium salts. This mild experimental procedure allowed the isolation of the product in very good yield. Combination of the indolizine derivative with electrophiles confirmed the reactivity of the C₃ ring carbon and allowed the bromination, formylation, hydroxymethylation, and dimerization of the indolizine scaffold.

Key words

pyridinium salt - bispyridinium salt - intramolecular cyclization - indolizines - electrophilic aromatic substitution

• References and Notes

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• 16 Synthesis of 1,1′-(2-Amino-1-cyanoprop-1-ene-1,3-diyl)bis(4-methylpyridin-1-ium) Chloride (2b) This dimer was synthesized according to previously reported procedures¹⁵ and isolated as a brown solid in 77% yield.
• 17 General Experimental Procedure for the Synthesis of N-(1-Cyanoindolizin-2-yl)acetamide (10) Acetic anhydride (5.30 mmol, 500 μL) was added to dipyridinium salt 2 (0.29 mmol), followed by Et₃N (0.60 mmol, 83 μL). A beige suspension was obtained, and the reaction mixture was heated at 50 °C for 21 h. H₂O (5 mL) was added to the suspension. The solid was filtered and washed with H₂O, leading to the pure product 10.
• 18 Experimental Procedure for the Synthesis of N-(1-Cyano-3-formylindolizin-2-yl)acetamide (11) A solution of POCl₃ (268 mg, 1.75 mmol, 160 μL) and DMF (1 mL) was stirred in an ice bath for 1 h. Then, 400 μL of this solution was added to a solution of N-(1-cyanoindolizin-2-yl)acetamide (10a, 106 mg, 0.530 mmol) in CH₂Cl₂ (4 mL), and the reaction mixture was stirred in an ice bath for 75 min and then at r.t. for 35 min. The remaining and previously prepared solution of POCl₃ and DMF was added, and stirring at r.t. was continued for 19 h. A sat. solution of NaHCO₃ (4 mL) was added to the reaction mixture, kept stirring in an ice bath, followed by addition of CH₂Cl₂ (4 mL) and H₂O (4 mL). The grey suspension was stirred for 20 min, and then the grey solid was filtered and washed with H₂O, leading to a pure product identified as N-(1-cyano-3-formylindolizin-2-yl)acetamide (11; 86.0 mg, 0.379 mmol; 72%).
• 19 Experimental Procedure for the Synthesis of N-(3-Bromo-1-cyanoindolizin-2-yl)acetamide (12) N-(1-cyanoindolizin-2-yl)acetamide 10a (101 mg, 0.508 mmol) was added to a solution of NBS (139 mg, 0.781 mmol) in CH₂Cl₂ (3 mL) leading to a red solution. The reaction mixture was stirred at r.t. for 30 min, and the solvent was evaporated using the rotary evaporator. H₂O (2 mL) was added to the red solid, and the reaction mixture was stirred for 10 min at r.t. The brown solid was filtered and washed with H₂O, leading to a pure product identified as N-(3-bromo-1-cyanoindolizin-2-yl)acetamide (12; 99.3 mg, 0.357 mmol; 70%).
• 20 Experimental Procedure for the Synthesis of N,N′-[methylenebis(1-cyanoindolizine-3,2-diyl)]diacet-amide (13) N-(1-Cyanoindolizin-2-yl)acetamide 10a (91.7 mg, 0.461 mmol) was added to formaldehyde (37% aq solution, 112 mg, 1.38 mmol, 103 μL) in H₂O (0.2 mL) and MeCN (0.2 mL). The brown suspension was stirred in a H₂O bath at 40 °C for 20 h. The beige solid was filtered and washed with H₂O, leading to a pure product identified as N,N′-[methyl-enebis(1-cyanoindolizine-3,2-diyl)]diacetamide (13; 85.4 mg, 0.208 mmol; 90%).
• 21 Experimental Procedure for the Synthesis of N-[1-Cyano-3-(hydroxymethyl)indolizin-2-yl]acetamide (14) N-(1-cyanoindolizin-2-yl)acetamide 10a (90.8 mg, 0.456 mmol) was added to formaldehyde (37% aqueous solution, 0.114 g; 1.41 mmol; 105 μL) in an aqueous solution of Na₂CO₃ (0.05 M, 0.2 mL) and acetonitrile (0.2 mL). The brown suspension was stirred in a water bath at 40 °C for 2 h. The beige solid was filtered and washed with water, leading to a pure product identified as N-[1-cyano-3-(hydroxymethyl)indolizin-2-yl]acetamide (14; 70.2 mg, 0.306 mmol; 67%).