A convenient modified synthesis of 5-pyridinyl-1,3,4-thiadiazole-2-carboxamides

A general one-pot procedure is developed for the synthesis of 5-pyridinyl-1,3,4-thiadiazole-2-carboxamides by the reaction of pyridine carboxaldehydes with oxamic acid thiohydrazides.

In this work, we report a new general procedure for the synthesis of 1,3,4-thiadiazole-2-carboxamides substituted at the 5-position by a pyridin-2,3, or 4-yl group.

Results and Discussion
One of the known methods reported for the synthesis of 1,3,4-thiadiazoles is based on the oxidation of thiohydrazones produced by the reaction of thiohydrazides with aldehydes. 8Scheme 2. Synthesis of thiadiazoles from thiohydrazones.

Scheme 3. Synthesis of oxamic acid thiohydrazides.
We investigated the effect of solvents, catalysts, and temperature on the yield of thiadiazole 18g produced by the reaction of 4-pyridine carboxaldehyde 15c with availible oxamic acid N-phenyl-2thiohydrazide 14h.It was found that the reaction performed in different solvents (Table 1) does not stop at the formation of hydrazone 16g or the equilibrium tautomer form dihydrothiadiazole 17g, but immediately gives thiadiazole 18g after auto-oxidation step with air oxygen (Scheme 4).In inert atmosphere the performed reaction does not lead to unoxidized compound (hydrazone 16g or dihydrothiadiazole 17g).The difference between this reaction and the reaction of oxamic acid thiohydrazides with benzaldehydes described in our previous studies [10][11][12] lies in the fact that the latter reaction produces stable hydrazones, which can be transformed into thiadiazoles only after an additional oxidation step.Apparently, the electronwithdrawing nature of pyridine facilitates the formation of the dihydrothiazole moiety followed by oxidation to the thiadiazole ring.Therefore, the one-pot reaction of pyridine carboxaldehyde with oxamic acid thiohydrazide involves the formation of hydrazone, its cyclization to the dihydrothiazole moiety, and oxidation to the fully unsaturated thiadiazole ring with atmospheric oxygen.The best yields of 18g (80%) were achieved by refluxing pyridine carboxaldehyde with oxamic acid thiohydrazide in methanol or ethanol.
The use of different acids (acetic, sulfuric, p-toluenesulfonic acids) as catalysts in the reaction in alcohols did not lead to either an increase in the rate of the formation of thiadiazole or a higher yield of product.This is a general method, which can be applied to perform the reactions with three isomers of pyridine carboxaldehyde and prepare thiadiazoles containing different substituents in the carbamoyl moiety 18a-r.The yields of thiadiazoles are given in Table 2.The reaction was performed in ethanol for 12-24 h.The completion of the reaction was monitored by TLC.As can be seen in Table 2, the nature of oxamic acid thiohydrazides has no significant effect on the reaction rate.The rate of the formation of thiadiazole 18с from the 2-pyridinyl isomer is lower than that from the other two isomers due apparently to the slower oxidation step.The formation of 5-pyridin-2-yl-1,3,4thiadiazolecarboxamide 18с is accelerated by bubbling air, which facilitates the oxidation of intermediate dihydrothiadiazole 17с.

Conclusions
A convenient general one-pot method with auto-oxidation step for the synthesis of pyridinyl-1,3,4-thiadiazole-2-carboxamides was developed based on the reaction of pyridine carboxaldehydes (2,3, or 4 isomers) with the readily available oxamic acid hydrazides.This method allows the synthesis of 1,3,4-thiadiazoles containing different substituents at the 5-position, including the three isomers of pyridyl substituents, without isolation of the hydrazone intermediates.

Experimental Section
General.The 1 Н NMR spectra were recorded on a Bruker AM-300 (300 MHz) spectrometer in CDCl 3 and DMSOd 6 ; 13 С NMR spectra, on a Bruker AM-300 (75 MHz) spectrometer in CDCl 3 and DMSO-d 6 ; residual protons and the carbon atom of the solvent were used as the internal standard.Elemental analysis was performed on a Eurovector EA 3000 automated analyzer.The HRMS measurements were carried out on a Bruker micrOTOF II spectrometer using electrospray ionization (ESI).Melting points were measured on a Boetius hot-stage apparatus and are uncorrected.The reaction mixture analysis and purity of the products was controlled by TLC on Merck Silica gel 60 F254 UV-254 plates.α-Chloroacetamides 12a-m were prepared by a standard procedure 13 from chloroacetyl chloride and appropriate amines in dichloromethane.The synthesis of thiohydrazides 14g-m was described previously; 11,14 oxamic acid thiohydrazides 14a-f were synthesized by procedures described in the cited references., 100).

General procedure for the synthesis of thiadiazoles 18a-r
Pyridine carboxaldehydes 15 (0.5 mmol) was added dropwise to a hot solution of thiohydrazide 14 (0.5 mmol) in ethanol (20 mL).The mixture was refluxed for 24 h in open atmosphere.After completion of the reaction (TLC monitoring; CH 2 Cl 2 :EtOH, 9:1), the reaction mixture was allowed to stand at room temperature.The formed precipitate was filtered off and washed with cold ethanol.For compound 18j, the reaction mixture was bubbled with atmospheric air at room temperature for 24 h, and then the formed precipitate was filtered off.

Table 1 .
Effect of solvents on the yield of thiadiazole 18g Scheme 4. Reaction of pyridine carboxaldehydes 15a-c with thiohydrazides 14a-m.