Increasing Scope of Clickable Fluorophores: Electrophilic Substitution of Ylidenemalononitriles

Abstract

Recently, we demonstrated that ylidenemalononitriles (YMs) react with amines to form cyclic amidines and that the starting linear YMs are nonemissive in solution and the cyclic amidines are fluorescent. These turn-on systems were of interest to us because of their potential as biosensors and synthons for accessing functionalized pyridines. While our original method was promising, several limitations persisted, including access to more functionalized and polar-solvent-soluble structures as well as increased control over the rate of cyclization. Herein, we report a new approach that allows the electrophilic substitution of YMs. These substituted YMs exhibit faster turn-on rates, color tunability, access to polar-solvent-soluble species, and increased control over cyclization rate. This allowed us to significantly expand the fluorophore's chemical space.

Recent advances in the synthesis of cyclic compounds using α,α-dicyanoolefins as versatile vinylogous nucleophiles

“…A proposed reaction mechanism for the formation of products includes an initial nucleophilic substitution reaction, aza-Claisen rearrangement, intramolecular cyclization, dimethyl amine elimination, and aromatization (Scheme 45). 80 As the authors mentioned, the reactions yields were dependent on the steric hindrance of the R 2 substituent, and in the cases of less sterically bulky substituents, the desired enemalononitriles were obtained in significantly higher yields. 80 The McQuade research group also developed efficient approaches to produce functionalized enaminomalononitriles 169 and 171 using NCS and RSCl as strong electrophiles.…”

“…80 As the authors mentioned, the reactions yields were dependent on the steric hindrance of the R 2 substituent, and in the cases of less sterically bulky substituents, the desired enemalononitriles were obtained in significantly higher yields. 80 The McQuade research group also developed efficient approaches to produce functionalized enaminomalononitriles 169 and 171 using NCS and RSCl as strong electrophiles. The resulting substituted enaminomalononitriles reacted with both electrophiles and primary amines to yield pyridine derivatives (170, 172, and 173, Scheme 46) and cyclic amidine deriva-…”

“…This journal is © The Royal Society of Chemistry 2022 the elimination of dimethylamine to give nicotinonitrile 163 (Scheme 44). 80 Notably, the reaction of enaminomalononitriles 164 with allyl bromide 165 in MeCN at 125 °C under microwave irradiation yielded trace amounts of allyl-substituted pyridines 166. A proposed reaction mechanism for the formation of products includes an initial nucleophilic substitution reaction, aza-Claisen rearrangement, intramolecular cyclization, dimethyl amine elimination, and aromatization (Scheme 45).…”

“…The reaction is terminated by the elimination of dimethylamine to give nicotinonitrile 163 (Scheme 44). 80…”

“…A proposed reaction mechanism for the formation of products includes an initial nucleophilic substitution reaction, aza-Claisen rearrangement, intramolecular cyclization, dimethyl amine elimination, and aromatization (Scheme 45). 80…”