Insights on the Chemical Behavior of Ethyl Cyanoformate: Dipolarophile, Cyano or Ethoxycarbonyl Source

Abstract

Imidazo[1,2-a]pyridines (azaindolizines) 1a-k have been designed and easily synthesized by the [3 + 2] cycloaddition reaction between cycloimmonium salts and ethyl cyanoformate used as dipolarophile. The behavior of the latter in cycloaddition reactions has been studied using different pyridinium, (iso)quinolinium or benzimidazolium salts and demonstrated the substrate-dependent reactivity, and the observation in many cases of its reaction as a cyano or an ethoxycarbonyl donor reagent. New chemical platforms have been identified thanks to the different reactivity of ethyl cyanoformate. Final molecules were subjected to a biological evaluation on ESKAPE pathogens (five bacteria: Escherichia coli, Klebsiella pneumoniae (MDR), Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus (MRSA) and two fungi: Cryptococcus neoformans (H99) and Candida albicans). Azaindolizines 1b and 1e displayed antifungal activity on Candida albicans and ylide 11 inhibited both fungi Candida albicans and Cryptococcus neoformans. These results open the way for the development of analogues with improved antifungal activity.

1,3-Dipolar cycloaddition of cycloimmonium salts and 4-(trimethylsilyl)-3-butyn-2-one to access new functionalized indolizines with potential cytostatic activity

“…The loss of the nitrogen substituent of the intermediate ylide formed in situ was previously observed by performing a [3+2] cycloaddition reaction of a quinolinium salt with ethyl cyanoformate. 23 In this case, upon loss of the benzoyl group of salt 13m , the only regioisomer observed and isolated corresponded to the 1-trimetylsilyl-2-acetylindolizine, contrary to what was observed on derivatives bearing a 3-benzoyl group on the indolizine core.…”

“…Pyridinium, quinolinium and isoquinolinium salts 13a,b,d-g,i-l,n had the same physicochemical properties as described previously in the literature. 3,4,[16][17][18][19][20][21][22][23] Next, the [3+2] dipolar cycloaddition of all salts 13a-m with 4-(trimethylsilyl)-3-butyn-2-one 1 furnished target compounds 10a-m along with trimethylsilyl-substituted derivatives 14, 15 and 16 (Scheme 1 and Table 1). As previously reported on the dipolar cycloaddition of diazoalkanes with TMS-alkynes, the regioselectivity was altered by the presence of the bulky trimethylsilyl group in the current cycloaddition reaction with cycloimmonium salts.…”

“…in 20 mL acetone and the mixture was stirred at reflux for 4 h. The obtained precipitate was filtered and washed with acetone to afford the pure expected salts 13a-n. Pyridinium, quinolinium and isoquinolinium salts 13a,b,d-g,i-l,n had the same physicochemical properties as described previously in the literature. 3,4,[16][17][18][19][20][21][22][23] 1-(2-(4-Cyanophenyl)-2-oxoethyl)-4-methylpyridin-1-ium bromide (13c)…”

“…Pyridinium, quinolinium and isoquinolinium salts 13a,b,d–g,i–l,n had the same physicochemical properties as described previously in the literature. 3,4,16–23…”