Electro-organic synthesis of dibenzylaminodioxocyclohexa-dienecarboxylic acids

Electrochemical oxidation of dihydroxybenzoic acids 1a – c has been studied in the presence of dibenzylamine ( 3 ) as nucleophile in water/acetonitrile (90:10) solution using cyclic voltammetry and controlled-potential coulometry. The quinones 2a–c derived from dihydroxybenzoic acids participate in Michael addition reactions with dibenzylamine ( 3 ), and via ECE mechanism convert to the corresponding (dibenzylamino)dioxocyclohexadienecarboxylic acids 5a–c .


Introduction
Alkylaminoquinones are of considerable interest because they exhibit antitumor and antimalarial activities 1,2 and many of them are also involved in enzyme inhibition and DNA cross-linking. 3,2-Benzoquinone derivatives have been less extensively studied than the 1,4-benzoquinone derivatives because they are more difficult to prepare.2,4,5 The importance of amino derivatives of quinones has encouraged us to study 6 and synthesize 7 a number of these compounds.However, no report has been published so far about the chemical or electrochemical synthesis of (dibenzylamino)dioxocyclohexadienecarboxylic acids.Therefore, we have investigated the electro-oxidation of ortho and para dihydroxybenzoic acids in the presence of dibenzylamine as N-nucleophile.The present work has led to the development of a facile and environmentally friendly electrochemical method for the synthesis of some new (dibenzylamino)dioxocyclohexadienecarboxylic acids in a two-compartment cell with high atom economy and good yields.

Electrochemical study of 2,3-dihydroxybenzoic acid (1a)
Cyclic voltammograms of 2,3-dihydroxybenzoic acid (1a) in the absence and in the presence of dibenzylamine (3) in water/acetonitrile mixture (90:10, v/v) containing 0.2 M phosphate buffer (pH 7.0) are shown in Figure 1.The cyclic voltammogram of 1a in the absence of dibenzylamine (3) (curve a) shows one anodic peak (A 1 ) at 0.28 V and the corresponding cathodic peak (C 1 ) at 0.22 V, which correspond to the transformation of 2,3-dihydroxybenzoic acid (1a) to related obenzoquinone (5,6-dioxocyclohexa-1,3-dienecarboxylic acid, 2a) and vice versa within a quasireversible two-electron process. 8At this condition, the peak-current ratio (I p C1 /I p A1 ) is nearly unity; this can be considered as a criterion for the stability of o-benzoquinone 2a produced at the surface of the electrode under the experimental conditions.In other words, hydroxylation 9 or dimerization 10 reactions are too slow to be observed on the time scale of cyclic voltammetry.Figure 1 (curve b) shows the first cycle voltammogram obtained for a 1 mM solution of 1a in the presence of 1 mM dibenzylamine (3).The voltammogram exhibits two cathodic peaks C 1 (0.18 V versus SCE (Saturated Calomel Electrode)) and C 0 (0.03 V versus SCE).In the second cycle, a new peak (A 0 ) appears with an E p value of 0.01 V versus SCE.This new peak is related to oxidation of intermediate 4a.
Controlled-potential coulometry was performed in water/acetonitrile mixture (90:10, v/v) (phosphate buffer, c = 0.2 M, pH = 7.0) containing 0.30 mmol of 2,3-dihydroxybenzoic acid (1a) and 0.30 mmol of dibenzylamine (3) at peak A 1 potential.Cyclic voltammetric analysis carried out during the electrolysis shows the progressive formation of new anodic peak (A 0 ), parallel to the disappearance of the A 1 peak (Figure 2).The anodic peak (A 1 ) and cathodic peak (C 1 ) disappear when the charge consumption becomes about 4e -per molecule of 1a.
These observations are indicative of an ECE (Electron transfer-Chemical reaction-Electron transfer) mechanism 11 and allows to propose the pathway for the electro-oxidation of 2,3-dihydroxybenzoic acid (1a) in the presence of dibenzylamine (3) (Scheme 1).Accordingly, the 1,4-addition (Michael) reaction of dibenzylamine (3) to the o-benzoquinone derivative 2a leads to intermediate 4a.The oxidation of 4a is easier than the oxidation of 1a by virtue of the presence of more electron-donating groups.Since E The 1,4-addition (Michael) reaction of dibenzylamine (3) to the ortho-quinone intermediate 2a can conceivably occur at C-2 and C-3 resulting in products 5a or 6a, respectively (Figure 3).The 1 H NMR spectrum of the isolated product displays two doublet peaks with vicinal coupling constants (δ 6.50 and 6.76) in support of structure 5a.

Conclusions
This work reports the electro-oxidation of dihydroxybenzoic acids (1) in water/acetonitrile solution to the corresponding quinones 2, which in turn, add dibenzylamine (3) to form (dibenzylamino)dioxocyclohexadienecarboxylic acids 5. The advantage of dibenzylamine (3) as a bulky nucleophile is the formation of monoamino-substituted benzoquinones as final products (Schemes 1 and 3).The present work has led to the development of a one-pot electrolytic method for the synthesis of new (dibenzylamino)dioxocyclohexadienecarboxylic acids 5a-c as final products, in good yields.

Experimental Section
General Procedures.Cyclic voltammetry, controlled-potential coulometry and preparative electrolysis were performed using an Autolab model PGSTAT 20 potentiostat/galvanostat.The working electrode used in the voltammetry experiment was a glassy carbon disc (1.8 mm ARKAT diameter) and a platinum wire was used as the counter electrode.The working electrode used in controlled-potential coulometry and macro-scale electrolysis was an assembly of four carbon rods (6 mm diameter and 4 cm length) and large platinum gauze constituted the counter electrode.In controlled-potential coulometry, the counter electrode compartment was separated from the working electrode with porous membrane electrode shape that involving counter electrode.The working electrode potentials were measured versus SCE (all electrodes were obtained from AZAR Electrodes).All experiment was carried out at a temperature of 25 ± 1 °C.Melting points of all synthesized compounds were determined in open capillary tubes and are uncorrected.IR spectra (KBr) were recorded on IFS66 Bruker FT-IR spectrometer. 1 H and 13 C, NMR spectra (DMSO-d 6 ) were recorded on JEOL JNM-EX90A spectrometer operating at 90 and 22.6 MHz, respectively and BRUKER DRX-500 AVANCE spectrometer at 500.1 and 125.8, MHz, respectively.Mass spectra were recorded on a QP-1100EX Shimadzu Mass spectrometer operating at an ionization potential of 70 eV.General procedure for the synthesis of (dibenzylamino)dioxocyclohexadienecarboxylic acids 5a-c.A solution of phosphate buffer (ca.80 mL; c = 0.2 M, pH = 7.0) in water/acetonitrile (90:10; 80 mL) solution containing dihydroxybenzoic acid (1a-c; 154.1 mg, 1 mmol) and dibenzylamine (3; 197.3 mg, 1 mmol) was electrolyzed in a two-compartment cell at 0.3 V vs. SCE.The electrolysis was terminated when the current decreased by more than 95%.The process was interrupted during the electrolysis and the graphite anode was washed in acetone in order to reactivate it.After electrolysis, the precipitated solid was collected by filtration.The products were purified by column chromatography (silica gel; chloroform for 5a,b, chloroform/ether for 5c).After purification, the products were characterized by UV, IR, 1 H NMR, 13 C NMR and MS.2-(Dibenzylamino)-5,6-dioxocylohexa-1,3-dienecarboxylic acid (5a).The product 5a was obtained as violet crystals, (208.4 mg, 60% yield); mp 170-172 °C.

2 ,
the occurrence of solution electron transfer (Scheme 2) is possible.So, we think that both mechanisms (ECE and Disp (disproportionation)) are participating in electrochemical oxidation of benzoic acid derivatives in the presence of dibenzylamine.

1 H
NMR singlet peaks (δ 5.40 and 5.80) provide evidence of product structure 5b resulting from the 1,4-addition of dibenzylamine (3) at C-6 of intermediate 4b.Electrochemical study of 2,5-dihydroxybenzoic acid (1c)Under the same conditions the electrochemical oxidation of 2,5-dihydroxybenzoic acid (1c) in the presence of dibenzylamine (3) was performed using cyclic voltammetry.In comparison with the cyclic voltammogram of 1a the p-benzoquinone intermediate 2c formed by oxidation of 1c is less reactive toward the Michael addition reaction.A decreased peak current ratio (I p A1 /I p C1 )