SYNTHESIS OF PYRAZOLE AND 1,3,4-OXADIAZOLE DERIVATIVES OF PHARMACEUTICAL POTENTIAL

Heterocyclic compounds are important molecules that serve as scaffolds or linkers for the core structure of numerous drug substances. In particular, pyrazole and 1,3,4-oxadiazole are compounds of great interest due to their comprehensive biological activities and interesting structural features. Here, we described an efficient and economical synthetic route leading to N -phenyl substituted pyrazole and 1,3,4-oxadiazole derivatives. Retrosynthetic disconnective analysis showed that the N -phenyl substituted pyrazole can be obtained from chalcone, accessible from the respective aldehyde, and acetophenone. The disubstituted 1,3,4-oxadiazole can be constructed from the respective aldehyde, which originates from pyrrole-containing compound, and formyl chloride. Based on our retrosynthetic analysis, N -phenyl substituted pyrazole was obtained by cyclization of the respective chalcone with phenylhydrazine to give pyrazoline which was in turn converted into pyrazole by oxidative aromatization. Potassium carbonate and a catalytic amount of molecular iodine were used to oxidatively cyclize semicarbazones into 1,3,4-oxadiazoles in a transition metal-free process. Novel pyrazole and 1,3,4-oxadiazoles with potential biological activity are investigated as antituberculosis, anticonvulsant, antidiabetic


Introduction
Heterocyclic compounds are widely spread in nature and vital in physiological processes.They exist as nucleic acids, plant alkaloids, anthocyanins, flavones, haem, chlorophyll, and other natural compounds.Additionally, vitamins, proteins, and hormones contain aromatic heterocyclic systems.Synthetically obtained heterocycles are used as agrochemicals and pharmaceuticals and play an important role in human life.Heterocycles have enormous potential as the most promising molecules for lead structures of new drug substances [1].

Syntheses
All reactions were carried out by standard syringe and septa technique under a nitrogen atmosphere.The solvents were purified, and dried before use by conventional methods.Column chromatography was performed on 60-120 or 230-400 mesh silica gel withethyl acetate (EtOAc) and hexane as eluents.The progress of all reactions was monitored by TLC on alumina sheets precoated with silica gel 60 F254 to a thickness of 0.5 mm.Spots were located using UV light or iodine vapors as the visualizing agent.Melting points were obtained by an open capillary method and are uncorrected.

Analytical data
The 1 H and 13 C NMR spectra were recorded in CDCl3 on 200 and 500 MHz spectrometers (Bruker Avance DPX200) and (Bruker Avance DRX500) at ambient temperature.Chemical shifts are reported in part per million (ppm) using tetramethylsilane (TMS) as an internal standard.The splitting pattern abbreviations are designated as singlet (s), doublet (d), double doublet (dd), triplet (t), quartet (q), and multiplet (m).

General procedure for the synthesis of the key intermediates 30a-f (exemplified by 30a)
A mixture of chalcone 28a (2.00 g, 5.95 mmol) and phenyl hydrazine hydrate (2.58 g, 17.86 mmol) in pyridine (20 mL) was refluxed for 15 hrs.Then the reaction mixture was cooled down, acidified with 1:1 HCl:H2O solution (20 mL), and stirred for 1 hr at 25 o C. The solid product was separated, filtered, and washed with a 10% NaHCO3 solution and water, filtered, dried, and the residue was purified by silica gel column chromatography using a mixture of ethyl acetate:petroleum ether (30:70) as eluent to afford pure compound 30a.

General procedure for the synthesis of the target compounds 31a-f (exemplified by 31a)
To a stirred solution of 30a (1.00 g, 2.35 mmol) in CH2Cl2 (5 mL) was added DDQ (0.80 mg, 3.52 mmol) at 0 o C. The mixture was stirred at 0 o C for 2 hrs and concentrated in vacuo.The crude product was purified by column chromatography over silica gel using a mixture of ethyl acetate:petroleum ether (20:80) to afford compound 31a.

General procedure for the synthesis of 1,3,4oxadiazoles 42a-c
To a stirred solution of semicarbazide hydrochloride (0.238 g, 2.13 mmol) and sodium acetate (0.175 g, 2.13 mmol) in H2O (1 mL), was added a solution of aldehyde 39a-c (0.500 g, 2.13 mmol) in MeOH (1 mL).After stirring at room temperature for 10 min, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in 1,4-dioxane (5 mL), followed by the addition of potassium carbonate (0.888 g, 6.417 mmol) and iodine (0.597 g, 2.35 mmol) in sequence.The reaction mixture was stirred at 80 o C until the conversion was complete (1-4.5 hrs).After cooling to room temperature, it was treated with 5% Na2S2O3 (20 mL) and extracted with MeOH:CH2Cl2 (5:95) (3 x 20 ml).The combined organic layer was dried over anhydrous sodium sulfate, and concentrated.The residue was purified by silica gel column chromatography using a mixture of ethyl acetate: petroleum ether (75:25) as eluent to afford the corresponding product.

Substances containing disubstituted pyrazole moiety
The target molecule 5 (Scheme 1), containing a pyrazole ring, can be obtained by reducing a pyrazoline derivative 6.This derivative can be disconnected to chalcone 7.Such a moiety has no suitable functional group for disconnection.Then, functional group interconversion is applied to obtain alcohol 8. Further disconnection leads to aldehyde 9 and acetophenone 10.Aldehyde 9 is disconnected to a pyrrole-containing compound 11 and formyl chloride 12. Finally, 11 is disconnected to hexane-2,5-dione (13) and p-chloroaniline (14).
The oxidative cyclization of 34 to give 1,3,4oxadiazole 35 was achieved by utilizing molecular iodine in the presence of potassium carbonate [52].
We have replaced the phenyl at the 2-position of 35 (Scheme 4) with the amine by using semicarbazide hydrochloride 40 (Scheme 5) to form a corresponding 1,3,4 oxadiazole framework 42a-c.
Firstly, substituted anilines 36a-c were converted into their corresponding N-substituted pyrroles 38a-c by the Paal-Knorr synthesis.In this process, the amines 36a-c were refluxed with 2,5-hexanodione (37) in the presence of dry acetic acid to afford the N-substituted pyrroles 38a-c in 90-92% yield.Secondly, these pyrroles were converted into substituted aldehydes 39a-c by the Vilsmeier-Haack reaction.In this process, pyrroles 38a-c were refluxed with POCl3 in DMF to give substituted aldehydes 39a-c in 80-86% yield.Next, the corresponding semicarbazones 41a-c (not isolated) were synthesized via the condensation of 39a-c and semicarbazide hydrochloride (40) in the presence of HOAc, MeOH, and H2O at room temperature.Finally, the oxidative cyclization of the formed semicarbazones 41a-c in the presence of iodine and potassium carbonate, as a weak base, in 1,4-dioxane gave the corresponding 5-substituted 2-amino-1,3,4-oxadiazoles 42a-c in a 60-62% yield.The structures of target oxadiazoles 42a-c were confirmed by 1 H and 13 C NMR, and IR.structural elucidation of oxadiazole 42a is discussed in detail.Oxadiazole 42a was acquired as a dark brown solid in 62% yield.The number and type of protons have been evaluated using the 1 H NMR. The signals of the deshielded aromatic protons present in 42a appeared at  7.43-7.22(m, 2H), 7.09-7.32(m, 2H), and 6.22 (brs, 1H).Also, the amine protons were observed at  5.42 (br s, 2H).The spectrum of 42a showed also two methyl signals in the aliphatic region which appeared at  2.28 (s, 3H) and 1.96 (s, 3H), respectively.Also, the carbon skeleton of 42a was systematically validated using the 13

Discussion
Our retrosynthetic disconnective analysis showed that the N-phenyl substituted pyrazole 5 can be obtained from chalcone 7, accessible from the respective aldehyde 9. 1,3,4-Oxadiazoles can be synthesized from the respective aldehyde 16, which originates from pyrrole-containing compound 19 and formyl chloride 20.Based on our retrosynthetic analysis, we used the existing methodologies to obtain novel N-substituted pyrazole 31a via pyrazoline 30a.Oxidative aromatization of pyrazoline derivative 30a treated with DDQ gave aromatic N-substituted pyrazole 31a.We have synthesized a series of chalcones 28a-f as advanced intermediates for N-substituted pyrazoles 31a-f.To prove the usefulness of the new intermediates, we transformed chalcone 28a into N-substituted pyrazole 31a.
Cyclization of benzoyl hydrazone 34 and its derivatives was reported in the synthesis of numerous 1,3,4-oxadiazoles [52] In our work, we have applied a scalable iodine-mediated process and noted that the oxidative C-O bond formation of the 5-substituted 2-amino-1,3,4-oxadiazoles 42a-c may be achieved by using a convenient inorganic base.Semicarbazones 41a-c derived from the related aldehydes 39a-c were easily transformed into the corresponding diazoles under sequential synthetic conditions without purification of the condensation intermediates.This adaptable and transition metal-free procedure enables the scalable and effective synthesis of a wide range of substituted diazole derivatives with a 2-amino group.In this cyclization, we have replaced the phenyl at the 2-position of 35 (Scheme 4) with the amine by using semicarbazide hydrochloride 40 (Scheme 5) to form a corresponding 1,3,4-oxadiazole framework 42a-c.
Evaluation of biological activity of our novel pyrazoles and 1,3,4-oxadiazoles as potential antituberculosis, anticonvulsant, antidiabetic, and anticancer agents, and tyrosinase inhibitors is underway in this laboratory.