NHC catalysed direct addition of HMF to diazo compounds: synthesis of acyl hydrazones with antitumor activity

Abstract

Synthesis and evaluation of HMF derived N-acyl hydrazone with antitumor activity.

Activation of α‐Diazocarbonyls by Organic Catalysts: Diazo Group Acting as a Strong N‐Terminal Electrophile

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Fort he first time a-diazocarbonyls have been used as highly active N-terminal electrophiles in the presence of bicyclic amidine catalysts.The CÀNbond-forming reactions of active methylene compounds as Cnucleophiles with a-diazocarbonyls as N-terminal electrophiles proceed quickly under ambient conditions,i nt he presence of 1, 8-diazabicyclo-[5.4.0]undec-7-ene (DBU), because of the formation of the reactive N-terminal electrophilic intermediates.DBU activates both the active methylene and a-diazocarbonyl. [4] However,the utility of the electrophilic capability of their terminal nitrogen atom has rarely been studied, save for af ew reports on the use of highly reactive organolithium, Grignard reagents,o ra cyl anion equivalents as Cnucleophiles, [5] and NaH-mediated 1,3-aminoalkylation of a-aminoa-diazoesters to afford tetrasubstituted 1,2,3-triazolines,thus involving an intramolecular amination as the key step. a-Diazocarbonyls have been known since 1883 for the synthesis of ethyl diazoacetate (EDA), as reported by Curtius, and have attracted increasing interest because of their versatility.

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“…a-Diazocarbonyls have been known since 1883 for the synthesis of ethyl diazoacetate (EDA), as reported by Curtius, and have attracted increasing interest because of their versatility. [4][5][6][7] Thus,t he intermolecular nucleophilic attack on the terminal nitrogen atom of a-diazocarbonyls,b ya ctive methylenes such as Cnucleophiles,i su nfavored. [4] However,the utility of the electrophilic capability of their terminal nitrogen atom has rarely been studied, save for af ew reports on the use of highly reactive organolithium, Grignard reagents,o ra cyl anion equivalents as Cnucleophiles, [5] and NaH-mediated 1,3-aminoalkylation of a-aminoa-diazoesters to afford tetrasubstituted 1,2,3-triazolines,thus involving an intramolecular amination as the key step.…”

“…Importantly, this reaction is general for both active methylenes and adiazocarbonyls,a nd the activation mode will lead to new synthetic applications of a-diazocarbonyls. [4] However,the utility of the electrophilic capability of their terminal nitrogen atom has rarely been studied, save for af ew reports on the use of highly reactive organolithium, Grignard reagents,o ra cyl anion equivalents as Cnucleophiles, [5] and NaH-mediated 1,3-aminoalkylation of a-aminoa-diazoesters to afford tetrasubstituted 1,2,3-triazolines,thus involving an intramolecular amination as the key step. [1] These compounds have been extensively studied as metal carbene precursors, [2] 1,3-dipoles, [3] and Cnucleophiles.…”

“…[1] These compounds have been extensively studied as metal carbene precursors, [2] 1,3-dipoles, [3] and Cnucleophiles. [4][5][6][7] Thus,t he intermolecular nucleophilic attack on the terminal nitrogen atom of a-diazocarbonyls,b ya ctive methylenes such as Cnucleophiles,i su nfavored. [6] In general, the terminal nitrogen atom of a-diazocarbonyls is much less electrophilic than the neighboring nitrogen atom.…”

“…Among the solvents tested, DMF seemed to be the best choice.Asimilar result was obtained using DMSO as the solvent (entry 11). [1][2][3][4][5][6][7][8] Under the optimal reaction conditions ( Table 1, entry 3), the scope and generality of the reactions for active methylenes were examined and the results are summarized in Table 2. This above C À Nb ond-forming reaction is highly chemoselective and catalyst dependent (Table 1).…”