Synthesis of Some New 4 , 5-Substituted-4 H-1 , 2 , 4-triazole-3-thiol Derivatives

In this study appropriate hydrazide compounds, furan-2-carboxylic acid hydrazide (1) and phenylacetic acid hydrazide (2) were converted into 1,4-substituted thiosemicarbazides 4a-e and 5a-e and 4-amino-5-(furan-2-yl or benzyl)-4H-1,2,4-triazole3-thiols 7 and 10. The 1,4-substituted thiosemicarbazides were then converted into 5-(furan-2-yl or benzyl)-4-(aryl)-4H-1,2,4-triazole-3-thiols 8a-e and 9a-e. In addition, the azomethines 11a-d and 12a-d were prepared from the corresponding arylaldehydes and the 4-amino-5-(furan-2-yl or benzyl)-4H-1,2,4-triazole-3-thiols 7 and 10. The structures of all the synthesized compounds were confirmed by elemental analyses, IR, H-NMR and C-NMR spectra.


Introduction
Derivatives of 1,2,4-triazole are known to exhibit anti-inflammatory [1,2], antiviral [3], analgesic [4], antimicrobial [5][6][7], anticonvulsant [8] and antidepressant activity [9], the latter being usually explored by the forced swim test [10,11].Among the pharmacological profiles of 1,2,4-triazoles, their antimicrobial, anticonvulsant and antidepressant properties seem to be the best documented.New changing problems in plant protection technology have promoted research to discover more efficient pesticides.In particular the development of herbicides, now an unavoidable means to selectively control the growth of weeds, resulted in a whole range of azoles exhibiting high levels of activity, application flexibility, crop tolerance and low levels of toxicity to mammals.Triazoles play an important role among this class of heterocycles.A series of 1,2,4-triazole derivatives [11] have been patented and extensively employed in agriculture.We now report the synthesis of 20 original compounds derived from furan-2-carboxylic acid hydrazide and phenylacetic hydrazide with the purpose of investigating in the future their possible antibacterial and antifungal activity.

General
Melting points were determined in open capillary tubes on a digital Gallenkamp melting point apparatus and are uncorrected.The IR spectra were recorded for KBr disks with a Mattson 1000 FT-IR spectrometer. 1 H-NMR spectra were recorded on a FX 90 JEOL 90 MHz NMR, spectrometer in CDCl 3 + DMSO-d 6 with TMS as an internal standard.Elemental analyses were done on a LECO-CHNS-938.Starting materials were obtained from Fluka or Aldrich.
General Procedure for Preparation of  or (phenylacetyl)dithiocarbazates 3 and 6.
Carbon disulfide (0.15 mole) was added to a solution of potassium hydroxide (0.15 mole), absolute ethanol (200 mL) and the appropriate furan-2-carboxylic acid hydrazide (1) or phenylacetic acid hydrazide (2) (0.10 mole).This mixture was diluted with absolute ethanol (150 mL) and agitated for 12-18 hours.It was then diluted with dry ether (250 mL) and the products were filtered off and vacuum dried at 65 ºC.The salts prepared as described above were obtained in nearly quantitative yields and were used without further purification.

General procedure for Preparation of 4a-e, 5a-e.
A mixture of 1 (or 2) (0.01 mole) and the appropriate aryl isothiocyanate (0.01 mole) in dry C 6 H 6 was refluxed for 6 hours.The solid material obtained on cooling was filtered off and recrystallized from methanol.A suspension of the potassium salt 3 (or 6) (20 mmoles), 95 % hydrazine (40 mmoles) and water (2 mL) was refluxed with stirring for 0.5 to 1 hours.The color of the reaction mixture changed to green, hydrogen sulfide was evolved and a homogeneous solution resulted.A white solid was precipitated by dilution with cold water (100 mL) and acidification with concentrated hydrochloric acid.This product was filtered, washed with cold water (2x30 mL) and recrystallized from ethanol or ethanol-water.

General Procedure for the Preparation of Compounds 8a-e and 9a-e.
A stirring mixture of compound 4a (or 4b-e, 5a-e) (1 mmole) and sodium hydroxide (40 mg, 1 mmole, as a 2N solution) was refluxed for 4 hours.After cooling, the solution was acidified with hydrochloric acid and the precipitate was filtered.The precipitate was then crystallized from ethanol.

General Procedure for the Preparation of Compounds 11a-d and 12a-d.
A mixture of 7 (or 10) (0.01 mole) and the corresponding aryl aldehyde (0.01 mole) in ethanol (25 mL) was treated with concentrated HCl (0.5 mL) and refluxed for 2 hours.The reaction mixture on cooling was filtered and recrystallized from ethanol.