Efﬁcient Synthesis and X-ray Structure of [1,2,4]Triazolo[4,3- a ]pyridines via Oxidative Cyclization Using N-Chlorosuccinimide (NCS)

: Triazolopyridines are a family of compounds that, owing to their biological activity, have many pharmaceutical applications. In this study, 3-(pyridine-4-yl)-[1,2,4]triazolo[4,3- a ]pyridine and 6-bromo-3-(pyridine-4-yl)-[1,2,4]triazolo[4,3- a ]pyridine were synthesized by using the chlorinated agent NCS for hydrazones under very mild conditions. The characterization of these compounds was achieved by 1H NMR, 13 C NMR, FTIR, MS and X-ray diffraction. The compound 3-(pyridine-4-yl)-[1,2,4]triazolo[4,3- a ]pyridine was crystallized in the monoclinic space group P 2 1 /c with a = 15.1413(12), b = 6.9179(4), c = 13.0938(8) Å, β = 105.102(6) ◦ , V = 1324.16(16)Å 3 , Z = 4, and R = 0.0337. Also compound 6-bromo-3-(pyridine-4-yl)-[1,2,4]triazolo[4,3- a ]pyridine was crystallized in the monoclinic space group P 2 1 /c with a = 14.3213(11), b = 6.9452(4) (4), c = 12.6860(8)Å, β = 100.265(6) ◦ , V = 1241.62(14)Å 3 , Z = 4, and R = 0.0561.

Therefore, it is desirable to develop complementary approaches for the fast and efficient synthesis of valuable 1,2,4-triazole-fused heterocycles. Using N-Chlorosuccinimide (NCS) as an oxidative cyclizing agent of 2-pyridylhydrazones opens the door to the development of a method to furnish [1,2,4]triazolo [4,3-a]pyrazines and pyrimidines. To the best of our knowledge, the synthesis of the target compounds is not known in the literature by using the chlorinated agent NCS for hydrazones under very smooth conditions.

Materials and Physical Measurements
All commercially available reagents and solvents were used without further purification. Melting points were measured in the open capillary tubes on a Boetius melting point apparatus. NMR spectra (400/100 MHz) were acquired on a Bruker Avance 600 spectrometer (Bruker, Billerica, MA, USA). The spectra were recorded for 1 H and 13 C NMR at room temperature. Chemical shifts were reported in ppm (ν) and J values in Hz. Multiplicity was designated as the singlet (s), doublet (d), triplet (t), and multiplet (m). Infrared spectra (IR) were registered using the Bruker Tensor-27 FT-IR Spectrometer. All spectra were recorded in the range of 400-4000 cm −1 at room temperature. TLC was carried out on silica gel plates (Merck, Darmstadt, Germany) using a mixture of dichloromethane and methanol as an eluent; visualization was accomplished with UV light.

General Procedure for Synthesis of Hydrazones
Compounds were prepared via condensation reaction of 4-pyridinecarboxaldehyde with corresponding hydrazines in ethanol, following a previously reported procedure for related systems [28]. Further, 0.05 mol of pyridine-4-aldehyde was added to a solution of 0.05 mol of the appropriate hydrazine in ethanol (20 mL) at room temperature. The reaction mixture was stirred until the completion of the reaction (by TLC). A pale yellow solid precipitated and was collected by filtration and recrystallized from hot ethanol.

General Procedure for Synthesis of [1,2,4]Triazolo[4,3-a]pyridines Derivatives
Synthesis of 3-(pyridin-4-yl)- [1,2,4]triazolo[4,3-a]pyridine 1 and 6-bromo-3-(pyridin-4yl)- [1,2,4]triazolo[4,3-a]pyridine 2 was as follows (Scheme 1): 10 mmol of the appropriate hydrazone was dissolved in a minimum amount of dry DMF (20 mL), the mixture was cooled in an ice bath, then 11 mmol of N-chlorosuccinimide (NCS) was added portion-wise to the reaction mixture. It is worth noting that the reaction is highly exothermic and should be handled with care [29,30]. The reaction mixture was stirred at 0 • C for about 1 h, then the reaction mixture was allowed to warm up to room temperature. After the completion of the reaction, as indicated by TLC, the yellow solid was collected by filtration and washed twice with petroleum ether. The resulting solid was dissolved in 50 mL of hot water and 10 mmol of Et 3 N was added drop-wise while cooling. Pale yellow plates were formed, filtered, and washed with cooled water to afford more than 90% product.

Crystal Structural Determination
Crystals of compounds 1 and 2 were obtained via recrystallization from a hot aqueous solution. The diffraction data were collected using MoK radiation ( = 0.71073 Å) at 193.00(10) K using a STOE IPDS2T-diffractometer. The structure was solved using the SHELXT crystallographic software package and refined through full-matrix, least-squares techniques on F2 by the SHELXL-2018 crystallographic software package [31]. Selected crystallographic data of compounds 1 and 2 are listed in Table 1. The supplementary crystallographic data for 1 and 2 were deposited at the Cambridge Crystallographic Data Center (CCDC) as 2049251 and 2049252, respectively.

Crystal Structural Determination
Crystals of compounds 1 and 2 were obtained via recrystallization from a hot aqueous solution. The diffraction data were collected using MoKα radiation (λ = 0.71073 Å) at 193.00(10) K using a STOE IPDS2T-diffractometer. The structure was solved using the SHELXT crystallographic software package and refined through full-matrix, least-squares techniques on F2 by the SHELXL-2018 crystallographic software package [31]. Selected crystallographic data of compounds 1 and 2 are listed in Table 1. The supplementary crystallographic data for 1 and 2 were deposited at the Cambridge Crystallographic Data Center (CCDC) as 2049251 and 2049252, respectively.

Chemistry
Herein we describe the use of N-chlorosuccinimid (NCS) as an efficient reagent for the synthesis of [1,2,4] triazolo[4,3-a]pyridine derivatives. While NCS is well known as a chlorinating agent of hydrazones and this is the first time we have explored its new function as a cyclizing agent for 2-pyridylhydrazones to achieve the target depicted in Scheme 1. It is worth mentioning that we use NCS as a chlorinating agent for hydrazones to furnish the corresponding hydrazonoyl chlorides, which usually react with arylacetonitriles to afford aminopyrazoles. However, in this case, the use of 2-hydrazinopyridin for preparing hydrazones and their treatment with NCS as a chlorinating agent did not yield the corresponding hydrazonoyl chloride. In fact, the compound isolated was 3-(pyridine-4yl) [

Chemistry
Herein we describe the use of N-chlorosuccinimid (NCS) as an efficient reagent for the synthesis of [1,2,4] triazolo[4,3-a]pyridine derivatives. While NCS is well known as a chlorinating agent of hydrazones and this is the first time we have explored its new function as a cyclizing agent for 2-pyridylhydrazones to achieve the target depicted in Scheme 1. It is worth mentioning that we use NCS as a chlorinating agent for hydrazones to furnish the corresponding hydrazonoyl chlorides, which usually react with arylacetonitriles to afford aminopyrazoles. However, in this case, the use of 2-hydrazinopyridin for preparing hydrazones and their treatment with NCS as a chlorinating agent did not yield the corresponding hydrazonoyl chloride. In fact, the compound isolated was 3-(pyridine-4yl) [1,2,4]
The title compounds 1 and 2 have an extensive network of hydrogen bonds. The parameters of H-bonds are given in Table 3.
There are three water molecules per unit cell with an extensive network of hydrogen bonds between water molecules, and also the molecule linked to water by O1W-H2W···N13 and O1W-H1W···N13 hydrogen bonds in 1 and 2, respectively, as shown in Figure 2. There are three water molecules per unit cell with an extensive network of hydrogen bonds between water molecules, and also the molecule linked to water by O1W-H2WN13 and O1W-H1WN13 hydrogen bonds in 1 and 2, respectively, as shown in Figure 2.

Conclusions
In summary, we have developed an efficient procedure for the oxidative cyclization of 2-pyridylhydrazones to achieve triazolopyridines. Synthesis of the desired products proceeds under very mild conditions and includes dehydrative cyclization upon treating with NCS in DMF at 0 °C. Access to the unprecedented cyclized product under the conditions applied makes this reaction an operationally very convenient and high yielding step for the synthesis of [1,2,4]triazolo [4,3-a] pyridines. To the best of our knowledge, usage of NCS as a cyclizing agent was not mentioned before in this context, the reaction is robust and the products can be isolated in excellent yields.

Conclusions
In summary, we have developed an efficient procedure for the oxidative cyclization of 2-pyridylhydrazones to achieve triazolopyridines. Synthesis of the desired products proceeds under very mild conditions and includes dehydrative cyclization upon treating with NCS in DMF at 0 • C. Access to the unprecedented cyclized product under the conditions applied makes this reaction an operationally very convenient and high yielding step for the synthesis of [1,2,4]triazolo [4,3-a] pyridines. To the best of our knowledge, usage of NCS as a cyclizing agent was not mentioned before in this context, the reaction is robust and the products can be isolated in excellent yields.