Synthesis of Thiadiazoles and 1,2,4-Triazoles Derived from Cyclopropane Dicarboxylic Acid .

New heterocyclic derivatives of cyclopropane dicarboxylic acid comprising thiadiazole and 1,2,4-triazole moieties are reported. Reaction of 1,1-cyclopropane dicarboxylic acid (1) with thiosemicarbazide and phosphorous oxychloride resulted in 1,1-bis (2-amino-1,3,4-thiadiazol-5- yl)cyclopropane (2). Cyclopropane dicarboxylic acid thiosemicarbazide (6) was converted into 1,1-bis(3-thio-4H-1,2,4-triazol-5-yl) cyclo- propane (7) by ring closure in an alkaline medium. The thiadiazole 2 and the triazole 7 were converted into a variety of derivatives.


Introduction
Thiadiazoles, oxadiazoles and triazoles are five-membered rings associated with diverse biological and pharmacological properties [1]. For example, triazole derivatives are active as antibacterial, antiviral and insecticidal agents [2]. Substituted 1,2,4-triazoles have been associated with activities such as anti-inflammatory and diuretic agents and as plant grown regulators [3]. Esters of 1,1cyclopropane dicarboxylic acid are important insecticidal agents [4]. In continuation of our interest in the chemistry of 1,1-cyclopropane dicarboxylic acid, thiadiazole and 1,2,4-triazole derivatives of this acid have been prepared by conventional synthetic techniques.
Reaction of 7 with chloroacetic acid yielded 8 which on treatment with thionyl chloride and hydrazine hydrate afforded the acid hydrazide 9. Condensation with aromatic aldehydes in absolute ethanol gave the Schiff bases 10a-c. Introduction of a propynylic function by reaction with propargyl chloride in alkaline medium followed by the Mannich reaction with paraformaldehyde and secondary amines gave the Mannich bases 11a-c (Scheme 2, The structures of all derivatives of the thiotriazole 7 were proven on the basis of melting points (mp), thin layer chromatography (TLC) and spectral data. The IR spectra of compound 9 exhibited a C=O stretching vibration near 1675 cm -1 and NH,NH 2 stretching vibrations at 3180-3200 cm -1 .

General
Melting points were determined in open capillary tubes on a Gallenkamp melting point apparatus and are uncorrected. The IR spectra were recorded by KBr discs with a Pye-Unicam SP3-100 spectrometer. UV spectra were recorded with Hitachi 2000 spectrophotomer. 1 H-NMR spectra were recorded on a Hitachi -Perkin-Elmer 60 -MHz NMR spectrometer in CDCl 3 -DMSO-d 6 with TMS as an internal standard. Elemental analyses were done on a Carlo-Erba Analyzer type 1106. Starting chemical compounds were obtained from Fluka or Aldrich. Characterization data of the products is given in Tables 1 and 2.

Preparation of compounds 3a-c.
The corresponding aryl aldehyde (0.1 mole) was added to a stirred solution of compound 2 (0.1 mole) in absolute ethanol (30 mL) and the mixture was refluxed for 2 hours. After cooling the mixture was filtered and the solid recrystallized for methanol.

Preparation of Mannich bases 5a-c.
To a solution of compound 4 (0.025 mole) in dry dioxane (50 mL) was added paraformaldehyde (0.05 mole), the appropriate secondary amine (0.05 mole) and catalytic amount (0.05 g) of cuprous chloride. The reaction mixture was heated for 2 hours at 90 0 C. After cooling the mixture was filtered and poured on to ice-water and the precipitite was filtered and crystallized from chloroform.
A mixture of compound 1 (0.01 mole) and thionyl chloride (10 mL) was refluxed gently for 7 hours. Excess thionyl chloride was removed under vaccum to give red-brown oil of the acid chloride which was dissolved in dry benzene (25 mL) and thiosemicarbazide (0.02 mole) was added. The reaction mixture was refluxed for 2-3 hours. The product was filtered and recrystallized from ethanol .

Preparation of compound 8.
To a stirring solution of α-chloroacetic acid (0.01 mole ) in 10% sodium hydroxide (10 ml) was added a solution of compound 7 in 10% sodium hydroxide (10 ml) .The reaction mixture was refluxed for 3 hours . After cooling the solution was acidified with coc. HCl and the product was collected and recrystallized from ethanol.

Preparation of compound 9.
A mixture of compound 8 (0.002 mole) and thionyl chloride (8 mL) was refluxed for 2 hours. Excess thionyl chloride was removed in vacuo and the resulting acid chloride was crystallized from methanol. This was dissolved in pyridine (10 mL) and hydrazine hydrate (2 mL) was added dropwise with cooling. The reaction mixture was stirred overnight at room temperature then it was heated for 2 hours at 80 °C. Excess pyridine was removed in vacuo and product 9 was crystallized from ethanolwater . Preparation of Schiff bases 10 a-c.
These compounds were prepared following the same procedure used in preparation of compounds 3a -c.

Preparation of Mannich bases 11a-c.
These compounds were prepared by the same procedure used for compounds 5a-c.