The alkylation reaction of aromatic acidshydrazides with (±)-cis-3-dichloromethyl-1,2,2-trimethylcyclopentancarboxylic acid

The article describes the study of the alkylation reaction of aromatic acids hydrazides with (±)-cis-3-dichloromethyl-1,2,2-trimethylcyclopentancarboxylic acid. The acid mentioned is a new substance obtained by oxidative cleavage of racemic camphor in the tetrachloromethane medium according to the method described earlier and modified by us. As a result of alkylation of aromatic acids hydrazides, a series of 3-{[2-(R-carbonyl)hydrazinylidene]methyl}-1,2,2-trimethylcyclopentancarboxylic acids has been obtained with the yields of 77-88%. According to the data of 1H NMR spectra almost all products are E-isomers. The reaction of alkylation of anthranilic hydrazide proceeds with formation of the 1,2,3,4-tetrahydroquinazolin-4-one cycle and obtaining of (±)-cis-3-(3-аmіnо-1,2,3,4-tetrahydroquinazolin-4-оn-2-yl)-1,2,2-trimethylcyclopentancarboxylic acid. The composition of the compounds synthesized has been proven by elemental analysis , and their structure has been confirmed by 1H NMR spectroscopy. According to the results of PASS prediction the compounds synthesized are potential diuretic, antiviral and antibacterial agents. The synthetic studies conducted show the possibility of using (±)-cis-3-dichloromethyl-1,2,2-trimethylcyclopentancarboxylic acid as a building block for extension of a number of biologically active substances synthesized in our previous studies on the basis of (±)-cis-1,2,2-trimethylcyclopentan-1,3-dicarboxylic (camphoric) acid.

Acid 1 was obtained by oxidative cleavage of camphor under the action of alkali in the presence of tertbutanol in the carbon tetrachloride medium (Scheme 1). For the first time the synthesis of d-isomer of acid 1 from d-camphor was described by Meyers et al. [4,5], but the spectral characteristics of the acid were not given, and only chlorolactone was described among its derivatives. We have reproduced and optimized this method for racemic camphor. When carrying out the synthesis we excluded the stages of the solvent stripping and extraction of the product with diethyl ether, as well as reduced the number of tert-butanol used. As a result, (±)-acid 1 with the yield of 70% has been obtained, and it coincides with the results of authors [5].
Compound 1 is a white crystalline substance that dissolves in aqueous solutions of alkali and most organic solvents. In 1 H NMR spectrum of acid 1 the characteristic group of signals of the 1,2,2-trimethylcyclopentan fragment is present, the signal of the dichloromethyl group proton is observed as a doublet at 6.19 ppm. The mass spectrum of this compound does not have signals of a molecular ion. The heaviest ion has m/z -167. It is probably formed by cleavage of HCl with the lactone cycle closure and the subsequent cleavage of another chlorine atom.
There are almost no data published on the use of dichloromethyl aliphatic derivatives in the preparative organic synthesis. This fact can be explained by insufficient accessibility and low reactivity of these derivatives. Only the compounds with an activated dichloromethyl group, such as dichloromethyl ether [6] and dichloromethylphenylsulfoxide [7], were used.
The study of the dichloromethyl group reactivity of compound 1 was started from the alkylation reaction of aromatic acids hydrazides 2 (Scheme 2). The reaction was carried out in the aqueous-alcoholic solution in the presence of potassium carbonate. As a result, a series of 3-{[2-(R-carbonyl)hydrazinylidene] methyl}-1,2,2-trimethylcyclopentancarboxylic acids 3a-g (Scheme 2) with preparative yields was obtained. All acids 3a-g obtained are colourless crystalline compounds that are soluble in most organic solvents and practically insoluble in water. Proton signals of the expected structural fragments with the corresponding intensity and multiplicity were observed in 1 H NMR spectra of acids 3a-g, the chemical shift of the azometine group proton was about 7.7 ppm. The proton signal of the NH-group of compounds 3a-g was observed as one singlet, indicating that the products consisted of a single geometric isomer. The exception is acid 3b with the volumetric substituent -bromine in the ortho-position to the hydrazide group. The integrated intensity of two singlets of NH protons belonging to E-and Z-isomers of acid 3b is in the ratio of 2:1.
The geometric configuration of compounds 3a-g was determined on the example of acid 4c using the homonuclear Overhauser effect [8]. In Fig. the 1 H NMR spectrum of this compound is saturation of the signal of N=CH proton. As it can be seen, the singlet of the nearest NH proton (11.32 ppm) is characterized by the biggest integrated intensity indicating E-configuration of the compound studied. Four other signals belong to protons of CH, CH 2 and two CH 3 groups. It is obvious that for compounds 3(a-g) E-configuration is more favourable than Z-configuration since the cyclopentane fragment together with the carboxyl group can create steric hindrance for Z-configuration.
The PASS virtual screening [9] for compounds 3(a-g) was conducted. Among the aforementioned types of the biological activity studied for derivatives of camphor acid the diuretic activity is predicted for compounds 3(a-g) with the index P a in the range of 0.40-0.55. The anticonvulsant action (P a = 0.5-0.6) is expected for compound 3h and its virtual N-acyl derivatives. The cytoprotective and antiviral activities have the highest values of P a (~0.7) for compounds 3(a-g), whereas analysis of the literature data shows that hydrazones have antibacterial [10], antiprotozoal [11] and fungicidal [12,13] properties.

Experimental Part
According to the homonuclear Overhauser effect experiment the 1 H NMR spectra were recorded on a Varian Mercury VX-200 (200 MHz) spectrometer, the solvent was DMSO-d 6 with TMS as an internal standard. The mass spectra were obtained on a Varian 1200L spectrometer in full scanning mode in the range of 35-700 m/z and EI at 70 eV. Elemental analysis was performed on an EuroVector EA-3000 microanalyzer. Melting points were determined on a Kofler bench. The purity of the compounds synthesized was confirmed by TLC using Silufol UV 254 plates and the ethyl acetate -chloroform system (3:2 v/v) as an eluent.