Peculiarities of the tandem reaction between cyanoacetylenic alcohols and aminobenzoic acids: Synthesis of 5,5-dialkyl-2-(3-aminophenyl)-4-oxo-4,5-dihydrofuran-3-carbonitriles

Tertiary cyanoacetylenic alcohols 1 reacting with 3-aminobenzoic acid (Et 3 N, MeCN, 20–25 °C, 28–30 h) afforded 5,5-dialkyl-2-(3-aminophenyl)-4-oxo-4,5-dihydrofuran-3-carbonitriles 2 (77– 85%). Under the same condition, 4-hydroxy-4-methylpent-2-ynenitrile 1a and 2-aminobenzoic acid gave 2-[(5-iminio-2,2-dimethyl-2,5-dihydrofuran-3-yl)amino]benzoate 4 (39%). With 4-aminobenzoic acid, alcohol 1a was almost quantitatively converted into the ester 5 .


Introduction
4-Oxo-4,5-dihydrofurans occur widely in nature 1 and are interesting pharmacological objects exhibiting anticancer, 2 antiulcer, 3 antiallergic 4 and antifungal 5 properties.Some their functional derivatives find application as non-steroidal anti-inflammatory drugs and analgetics 6 as well as for the treatment of metabolic disorders. 7Therefore, exploration of the chemistry and pharmacology of 4-oxo-4,5-dihydrofurans has progressed with vigor.Particular attention has been paid to the search for general and expedient syntheses of these important compounds and their controlled functionalization.1f Recently, we have briefly reported a novel general methodology for the synthesis of 5,5dialkyl-2-aryl-4-oxo-4,5-dihydrofuran-3-carbonitriles by the tandem reaction between cyanoacetylenic alcohols and substituted benzoic acids (Scheme 1). 8espite the large suite of substituted benzoic acids applied to this reaction, aminobenzoic acids have not been used, because when these were treated with cyanoacetylenic alcohols, 9 the reactions was shown to follow different courses.However, owing to the synthetic and pharmaceutical importance 10 of aminobenzoic acid derivatives (e.g., Novocain, Anaesthesin, Dicain, Novocainamide), additional effort to find conditions for the aminobenzoic acid-based synthesis of 3(2Н)-furanones was felt justified.Here, we present the results of this research.

Scheme 2
The formation of 2 is assumed 8 to proceed via the esters 3, which subsequently undergo Knoevenagel condensation.Catalysis by Et3N brings about cyclization, forming 4-oxo-4,5-dihydrofurans 2 instead of the esters 3 that have been previously observed. 9
The observed peculiarities of the reactivity of 2-, 3-, and 4-aminobenzoic acids toward cyanoacetylenic alcohols 1a-c are likely to be due to differences in the steric and electronic interaction between amino and carboxylic groups.For 2-aminobenzoic acid, the initial esterification should be significantly sterically hindered compared to its 3-and 4-isomers.Besides, the intramolecular H-bonding between NH2 and COOH groups may also slow down the ester formation.Consequently, this acid takes the alternative pathway of nucleophilic addition of the amino substituent to the triple bond.
The π-electron-donating effect of the amino substitutent toward the carboxylic group in 4aminobenzoic acid is expected to decrease the electrophilicity of the carbonyl group, and hence hampers the Knoevenagel condensation with the CH2CN moiety.This may explain the failure to form the 4-oxo-4,5-dihydrofuran derivative.

Experimental Section
General. 1 Н and 13 С NMR spectra of the products were recorded in (CD3)2CO on a Bruker DPX-400 spectrometer (400.13 and 100.62 MHz, respectively).IR spectra of KВr pellets were measured on a Bruker Vertex-70 instrument.Mass spectra were recorded on an Agilent 5975C spectrometer.Sample introduction was carried out via an Agilent 6890N gas chromatograph: the column was an HP-5MS (0.25 mm × 30 m ×0.25 μm); carrier gas helium, constant flow.All melting points were taken on a Kofler micro hot stage.The reaction was monitored by TLC on neutral Al2O3 (chloroform/benzene/ethanol, 20:4:1 as eluent).Aminobenzoic acids are commercial reagents (Merck).Cyanoacetylenic alcohols 1a-c were prepared according to a published method. 13Commercially available starting materials were used without further purification.