Synthesis of Tertiary Amides from Anionically Activated Aromatic Trifluoromethyl Groups

Abstract

In this paper, a novel synthesis of tertiary amides from anionically activated aromatic trifluoromethyl groups is presented. Anionically activated trifluoromethyl groups react with secondary amines under aqueous conditions to afford tertiary amides. The mechanism involves initial elimination of hydrogen fluoride by an E1cB mechanism to afford an electrophilic quinone methide- or azafulvene-type intermediate that reacts with secondary amines under aqueous conditions to afford the tertiary amide in good yield (up to 99%).

Model Experiments Implicate a Benzoquinoneketene Intermediate in LCP Synthesis

“…Dimer 1 (0.5 g, 1.7 mmol) was mixed with morpholine (0.23 g, 2.6 mmol) at 120 °C for 3 h. HBA was extracted 3× with hot water and rotary evaporated, leaving 4 and 7b (184 mg, 52.3%, mp 115–120 °C). 1 H and 13 C NMR spectra as reported …”

Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3

“…The precipitate was collected by filtration affording 2-(4-hydroxybenzamido)benzoic acid. 28 Secondarily, A dispersion of 2-(4-hydroxybenzamido)benzoic acid (1 equiv) and N,N 0 -dicyclohexylcarbodiimide (DCC, 1 equiv) in anhydrous methanol (10 ml) was stirred at room temperature for 1 h. 4-dimethylaminopyridine (DMAP, 0.5 equiv) was added and stirred at room temperature for 12 h, and gave 2-(4-hydroxybenzamido)benzoate esters. Finally, compounds 12-14 were synthesized through dissolving corresponding 2-(4-hydroxybenzamido)benzoate esters, respectively, in triethylamine/DCM (1:3) solution, and esterified through reacting with pivaloyl chloride for 2 h, and then purified by silica gel column chromatography using a mixture of n-hexane/ethyl acetate (2:1) solutions (Scheme 4).…”

Triple dehydrofluorination as a route to amidine-functionalized, aromatic phosphorus heterocycles

“…14 CF 3 groups of activated aromatic rings, for example, have been shown to degrade in the presence of amines and aqueous NaOH, resulting in amides. 15 The first step appears to be the formal addition of the N-H bond across the PQC double bond. 16 The following steps to the amidine substituent, however, could not be identified experimentally, as no other intermediate species were observed by means of NMR spectroscopy.…”

“…14 CF 3 groups of activated aromatic rings, for example, have been shown to degrade in the presence of amines and aqueous NaOH, resulting in amides. 15…”