Synthesis of fluorescent heterocycles via a Knoevenagel/[4 + 1]-cycloaddition cascade using acetyl cyanide

Abstract

A concise one-pot three-component reaction that affords fluorescent indolizines, benzo[d]pyrrolo[2,1-b]thiazoles, and pyrrolo[1,2-a]pyrazines is reported. The methodology involves the formation of a heterocyclic 1-aza-1,3-diene derived from a Knoevenagel condensation between an aldehyde and 2-methyl-ene-cyano aza-heterocycles, followed by [4 + 1] cycloaddition of acetyl cyanide behaving as a non-classical isocyanide replacement.

Sequential Knoevenagel [4+1] Cycloaddition–Condensation–Aza-Friedel–Crafts Intramolecular Cyclization: A 4-Center-3-Component Reaction Toward Tunable Fluorescent Indolizine Tetracycles

“…Comparing the fluorescence of the previously published amine 16a derived from 2-naphthaldehyde to the equivalent fully oxidized tetracyclic 15f , we observe that there is a decrease in excitation maxima (292–286 nm) and emission maxima (505–495 nm) and an increase in quantum yield more than 6-fold (0.02–0.13) . It is important to note that our previous work with fluorescence was measured in dimethylmethanamide (DMF), while herein, we utilize that DMSO and solvent may affect fluorescence.…”

“…It is important to note that our previous work with fluorescence was measured in dimethylmethanamide (DMF), while herein, we utilize that DMSO and solvent may affect fluorescence. Although solvent effects may be a factor, , we have consistently seen that these novel tetracyclic indolizines have magnitudes higher quantum yield and a range of fluorescent color versus our original work, a distinct improvement.…”

“…The reaction conditions were developed for the 4CR-3C reaction, building upon our previous reports for the synthesis of arrays of amino-indolizines using aromatic aldehydes. , Initial optimization efforts (Table ) evaluated the effects of molarity, time, cyanide source, and temperature on the model reaction between 2-cyanomethylpyridine 11 , 3-methoxybenzaldehyde 12a , and a cyanide source 13a or 13b to form ( E )-3-((3-methoxybenzylidene)­amino)-2-(3-methoxyphenyl)­indolizine-1-carbonitrile 14a . Encouragingly, utilizing TMSCN (70 °C, 8 h, entry 1) afforded 14a in a good, isolated yield of 65%.…”

“…One such MCR affords access to indolizines through a base-catalyzed 3-component reaction with isocyanides, aldehydes, and 2-cyanomethylpyridine via Knoevenagel condensation . In previous studies, we modified this reaction utilizing cyanides (acetyl cyanide, trimethylsilyl cyanide, TMSCN) to generate products with a functionalizable amine handle that exhibited fluorescence in one operation …”

The Kröhnke synthesis of benzo[a]indolizines revisited: towards small, red light emitters

“…Indolizines, although known since the 19 th century, [1][2][3][4] have always been overshadowed by regioisomeric indoles. Only during the last two decades was their chemistry rejuvenated, likely because of their potential as fluorophores, [5][6][7][8][9][10][11] which is especially strong for π-expanded indolizines. In recent years, multiple new methods for indolizine synthesis have been revealed, [12][13][14][15][16][17][18][19] nicely complementing older approaches.…”