Synthesis of 4,5-dihydro-1H-pyrazole derivatives based on 3-acetyl-5-nitropyridines

Claisen–Schmidt-type aldol-crotonic condensation of 3-acetyl-5-nitropyridine derivatives with various aromatic aldehydes was used for the preparation of pyridylchalcones. Cyclization of the latter with hydrazine hydrate in acetic acid afforded the corresponding N-acetyl derivatives of 4,5-dihydro-1H-pyrazole.

Polyfunctional pyridines, including 3-acetylpyridines, are of particular interest as versatile objects for chemical modification (for example, in 4,5-dihydro-1H-pyrazoles) and subsequent study of the structure-activity relationship of the obtained compounds.
The presence of a nitro group in the molecule can increase its antibacterial activity. Previously, we have studied the antimicrobial and analgesic activity of α,γ-diketoacid derivatives synthesized from 3-acetyl-5-nitropyridine 4 [23].
To introduce a new pharmacophore 1H-pyrazole ring into the molecules of compounds 6a-6e and 7a-7e, a heterocyclization reaction with hydrazine hydrate in the presence of acetic acid was performed (Scheme 2).
In the case of 4,5-dihydro-1H-pyrazole 8b, which contains two acidophobic furan rings, the reaction is accompanied by much tarring. Nevertheless, it was possible to isolate the target product with a yield of 30%. It was purified by silica gel column chromatography. 4,5-Dihydro-1H-pyrazole 9b was also obtained in a low yield (30%), probably for the same reason: low stability of the furan ring when heated in acidic media. 4,5-Dihydro-1H-pyrazole derivatives 8a, 9a and 8c-8e, 9c-9e bearing aromatic substituents were isolated by treating the reaction mixtures with ice water and subsequent recrystallization from an appropriate solvent. Yields of the target compounds varied from 47 to 83% (Table 1).

Conclusion
In summary, a series of new potentially biologically active pyridylchalcone and 4,5-dihydro-1H-pyrazole derivatives was synthesized based on poorly studied 3-acetyl-5-nitropyridines 4 and 5. Moreover, it was shown that the presence of an acceptor nitro group in the pyridine nucleus greatly facilitates their chemical modification at the acetyl group. The presence of a furyl ring in the 4-position of 5-nitropyridine 4 leads to an increase in the yields of pyridylchalcones to almost quantitative, but significantly reduces the yields and complicates the subsequent isolation of the corresponding derivatives of 4,5-dihydro-1H-pyrazole. The obtained azachalcones and 4,5-dihydro-1H-pyrazole derivatives can be promising objects for search antibacterial agents. After reduction of the nitro group, the resulting amino derivatives of pyrazoles can exhibit excellent luminescent properties.

Experimental
IR spectra were recorded on an Infralum FT-801 spectrometer in KBr pellets. 1 H and 13 C NMR spectra were recorded on a Bruker DRX400 instrument (400 and 100 MHz, respectively) using CDCl 3 or DMSO-d 6 the internal standard was TMS or residual solvent signals (7.25 and 77.0 ppm in the case of CDCl 3 for 1 H and 13 C nuclei, respectively; 2.49 and 39.9 ppm 1 H and for 13 C nuclei in DMSO-d 6 ). Elemental analysis was performed on a Carlo Erba EA 1106 automatic CHN-analyzer. The reaction progress and purity of the obtained compounds were controlled by TLC on Sorbfil AF-A-UV plates, visualization in iodine vapor and under UV light. Melting points were determined using a Kofler hot bench.

General procedure for the synthesis of pyridylchalcones 6a-6e, 7a-7e
A solution of 0.2 g KOH (4 mmol) in 3 cm 3 H 2 O and 15 cm 3 EtOH was cooled in an ice bath (0-5 °C). Then, 3-acetyl-5-nitro-6-phenylpyridine 4 or 5 (4 mmol) in 1 cm 3 CH 2 Cl 2 was added, and the constantly stirred mixture was treated by dropwise addition of the appropriate aromatic aldehyde (4 mmol). A precipitate of pyridylchalcone 6a-6e, 7a-7e formed after 10 min. The mixture was stirred at room temperature for additional 3 h. Then, the precipitate is filtered, washed with a water-alcohol solution and dried in air. The crude product was purified by recrystallization from an appropriate solvent.