Synthesis and Characterization of Some New 2-Hydroxy-N-( 3-Trifluoromethyl-Phenyl )-Benzamide Derivatives

IOANA M.C. IENASCU1, ALFA X. LUPEA1*, IULIANA M. POPESCU2, STEFAN Th. TOMAS3, ALINA D. ZAMFIR4,5 1 Politechnica” University, Faculty of Industrial Chemistry and Environment Engineering, Department of Organic Chemistry, 2 P-þa Victoriei, 300006, Timisoara, Romania 2 Banat’s Agricultural Science University, Faculty of Agriculture, Department of Chemistry and Biochemistry, 119 Calea Aradului, 300645, Timisoara, Romania 3 “Politechnica” University, Faculty of Applied Chemistry and Material Sciences, Department of Organic Technology and Macromolecular Compounds, 149 Calea Victoriei, 71101, Bucharest, Romania 4 Mass Spectrometry Laboratory, National Institute for Research and Development in Electrochemistry and Condensed Matter, 1 Plautius Andronescu, 300224, Timiooara, Romania 5 ”Aurel Vlaicu” University of Arad, 77 Revoluþiei Blvd., 310130, Arad, Romania

Searching for novel biological active compounds with a better and more selective effect and lower toxicity remains a challenge for the pharmaceutical chemistry.
Salicylamide-O-acetic hydrazide and its hydrazones obtained with substituted benzaldehydes show antiinflammator y and analgesic activity superior to salicylamide itself and lower ulcerogenic activity [10,11].
In order to attain such active compounds, some orthosubstituted phenoxyalkanoic acids and their derivatives were synthesized and characterized [12,13].
The target of this work was to synthesize some novel compounds with o-hydroxibenzamidic structure, derivatives with potential antibacterial and antifungal activity, and their full characterization using physicochemical methods.
Melting points were determined with a Böetius Carl-Zeiss Jena apparatus.IR spectra in KBr pellets were recorded on a Jaskow FT/IR-430 apparatus and NMR spectra were recorded on "Bruker Avance DRX 400" instrument.Mass spectra were recorded on a high capacity ion trap, HCT Ultra PTM instrument (Bruker, Daltonics, Bremen), interfaced to a PC running the Compass TM 1.2.integrated software package, which includes the Hystar TM 3.2.37 module for instrument controlling and spectrum acquisition, Esquire Control TM 6.1.512and Data Analysis TM 3.4.179modules for storing the ion chromatograms and processing the MS data.
The obtaining pathways of the synthesized compounds are presented in figure 1.
1. Synthesis of the ethyl ester 1 [14].A mixture of 0.015 mol 2-hydroxy-N-(3-trifluoromethyl-phenyl)-benzamide obtained and purified according to reference 9, and 0.015 mol anhydrous potassium carbonate was refluxed in 80 mL ethyl-methylketone.Ethyl chloroacetate (0.015 mol) was added dropwise.The optimum molar ratio was amide:ester:K 2 CO 3 = 1:1:1.The mixture was stirred and heated on a steam bath for 5 h.After cooling at room temperature, the mixture was poured into water, and whirled intensively.The organic phase was separated and dried over MgSO 4 .After filtration and evaporation of the solvent in vacuum, the ester was crystallized.The solid ester was recrystallized from ethanol.
3. Synthesis of the hydrazones 3,4 [10].To a solution of 0.003 mol hydrazide in 30 mL ethanol, 0.003 mol of an appropriate benzaldehyde were added.The reaction mixture was refluxed for 5 h.The solid, obtained after cooling, was filtered off, washed with water and recrystallized from dimethylformamide.

Results and discussions
The synthesized compounds, presented in Table 1, are white crystalline substances (needels or prisms) and were obtained with yields ranged between 83-96%.
Yields, uncorrected melting points and spectral data of these compounds are presented in table 2.
The experimental results suggest that the 2-hydroxy-N-(3-trifluoromethyl-phenyl)-benzamide derivatives were readily separated and gave pure compounds.IR spectral data of the ethyl ester show the presence of an ether bond between phenolic hydroxyl and alkyl α-C atom of the ester by signals at 1226 cm -1 (ν as COC aromatic) and 1122 cm -1 (ν as COC alifatic).The carbonyl group of the ester (νC=O) appears at 1757 cm -1 , but in the IR spectra of the hydrazide this band is missing, proving the conversion of the ester into hydrazide.The signals corresponding to the vibrations of the amidic and hydrazidic group appear between 3290-3360 cm -1 (νNH) and 1660-1710 cm -1 (νC=O).
The obtained compounds were also analyzed by 1 H-NMR in DMSO and 13 C-NMR in CCl 3 .In order to facilitate the NMR data interpretation, in figure 2, the numbering of the aromatic rings is presented.The 1 H-NMR shifts of ethyl group from ester appear between 1.2-4.3ppm, that of the amidic group between 10.6-11.6 ppm, that of hydrazidic group, from both, hydrazides and hydrazones, between 9.0-12.2ppm, and that of iminic group between 8.7-8.9 ppm.The 13 C-NMR signals corresponding to both carbons from the hydrazidic and amidic groups appear between 163-170 ppm and those for the aromatic carbons between 113-156 ppm.
In order to obtain a full characterization of the synthesized compounds, MS analysis, using positive electrospray ionization (+ESI) technique, was performed.The compounds were dissolved in pure methanol, and both, +MS 1 and tandem mass spectra +MS n (n=2-6), were acquired.The MS 1 revealed the presence only of the peaks corresponding to the protonated and/or sodiated molecular ions: [M+H] + and [M+Na] + , whereas the fragmentation spectra clearly proved their structure.

Fig. 1 .
Fig. 1.The obtaining pathways of the synthesized compounds

Table 2
CHARACTERIZATION OF THE SYNTHESIZED COMPOUNDS

Table 1 THE
SYNTHESIZED COMPOUNDS