Description:Background: Schiff's bases have received a lot of attention in the field of medicinal chemistry because of their diverse applications as catalysts, dyes, initiators in polymerization and bioactive agents (Polyhedron, 2009, 28, 3755-3758; Synth. React. Inorg. Met.-Org. Chem., 2000, 30, 625-636; Inorg. Chim. Acta, 1988, 151, 95-100; Met.-Based Drugs, 1995, 2, 297-309; ACS Omega, 2021, 6, 13704-13718). It has been well documented that pyrazole ring in free or fused state as a key component of Schiff base displayed a broad range of biological activities, including antibacterial, antiviral, antitubercular, anti-inflammatory, antioxidant, anticancer, antimalarial, and antileishmanial properties (Med. Chem. Lett., 2015, 25, 5540-5545; Bioorg. Med. Chem. Lett., 2015, 25, 5052-5057.; Archiv der Pharmazie, 2016, 349, 168-174; Med Chem Comm., 2016, 7, 832-836; Eur. J. Med. Chem., 2015, 90, 889-896; RSC Advances, 2015, 5, 94786-94795). As an illustration, pyrazole ring hybridisation with various scaffolds displayed significant in vivo and in vitro antimalarial activity, particularly for P. falciparum (Eur. J. Med. Chem., 2015, 94, 30-44; Eur. J. Med. Chem., 2019, 163, 353-366). Discovery of Cisplatin (Ann. Intern. Med., 1984, 100, 704-713) and Auranofin (U.S. Patent US4133952A1979; Curr. Med. Chem., 2016, 23, 3374-3403) was the harbinger in the field of metal-based drugs and still encouraging chemists to investigate metal complexes for the potential applications in the field of medicines (Dalton Trans., 2017, 46, 10758-10773). Copper-based compounds have recently gained significant attention in the field of inorganic synthesis, where scientists have developed Cu(II) complexes for a wide range of therapeutic purposes (Dalton Trans., 2017, 46, 10758-10773; Curr. Med. Chem., 2006, 13, 525-537; Appl. Organomet. Chem., 2020, 34, e5610; Arabian J. Chem., 2020, 13, 6379-6394; US Patent 7,128,923 B2, 2003) The revival is partially due to copper's inherent presence in numerous natural biological processes that can regulate copper levels and metabolize it significantly (Dalton Trans., 2017, 46, 10758-10773; ACS Omega, 2021, 6, 13704-13718). Here, we synthesized new 1,3,4-trisubstituted pyrazole-linked Schiff's bases and their Cu(II) complexes with an expectation to develop biologically active agents.
Detailed Description of the Invention:
Owing to huge synthetic and medicinal potential of Schiff's bases and their Cu(II) complexes and in continuation of our research work related to bioactive heterocycles, here pyrazole-linked Schiff's bases and their Cu(II) complexes have been synthesized. Schiff's base ligands (3a-e) were synthesized from pyrazole-4-carbohydrazide (1a-e) and DHA (2) by condensation method (Scheme-1) by refluxing reaction mixture at 85 ? for time T1 and cooled to room temperature. The crude white solid thus obtained was filtered and recrystallized from ethanol. Cu(II) complexes have synthesized by adding [Cu(NO3)2]•3H2O to ethanolic solution of Schiff's bases with constant stirring. Thereafter the mixture was refluxed for 2 h and further stirred with 450 rpm for 12 h at room temperature. Physical data of synthesized products are mentioned in Table-1.

Scheme-1: Synthesis of Schiff's base ligands and their Cu(??) complexes
Table-1: Reaction times and percentage yields of the synthesized compounds
Sr. No. Compd. Ar T1 (h) Yield (%) Color
M.pt.
(?)
1 3a p-FC6H4 5 72 White 185-188
2 3b p-ClC6H4 4 64 White 215-218
3 3c p-BrC6H4 5 68 White 185-190
4 3d p-MeC6H4 3 67 White 193-197
5 3e C6H5 2.5 85 White 190-193
6 4a p-FC6H4 2 82 Green 220-225
7 4b p-ClC6H4 2 84 Green 225-229
8 4c p-BrC6H4 2 88 Green 220-224
9 4d p-MeC6H4 2 87 Green 230-235
10 4e C6H5 2 85 Green 229-233

The synthesized compounds were characterized by analyzing their spectroscopic data. In FT-IR spectrum, a stretching band appeared at 1699-1702 and 1647 cm-1 confirmed the presence of more than one C=O functionality. In 1H NMR spectrum, appearance of a signal near d 9.14-9.20 ppm and 5.81-5.91 ppm due to pyrazole-5H and DHA proton also supports the formation of Schiff base ligands. In 13C NMR spectrum, chemical shift values at d 181 ppm, 169 ppm and 162 ppm indicate the presence of two carbonyl groups and azomethine moiety in all the synthesized compounds (3a-e) respectively. In case of 1H NMR spectra of all compounds, a signal appears in the range of d 2.14-2.16 and 2.64-2.67 ppm due to methyl proton attached to azomethine and DHA moiety, respectively.

Fig. 1. Crystal structure of compound Cu(II) complexes (4c)
The mass spectra show a well-defined molecular ion peaks at m/z 447.14 (3a), 463.11 (3b) 507.06 (3c) 443.18 (3d) 429.16 (3e) which are in agreement with the formula weight of the Schiff bases. For Single-Crystal X-ray Diffraction spectroscopy, crystals were developed by recrystalizing metal complexes in the mixture of DMF and EtOH. It has been observed that in the complex, ligand adopted a ?3 N:O:O coordination mode via the imine nitrogen, carbonyl oxygen and DHA oxygen atom while 4th sites are occupied by oxygen solvent molecule (DMF). Cu(II) ion in the complexes adopted square planar geometry with bond angles 88.60?, 93.85?, 83.18? & 94.08? (Fig. 1). It was observed that Cu-ODHA (1.885 Å) bond length found to be slightly shorter than Cu-N=C (1.905 Å), Cu-Osol. (1.968 Å) Cu-C=O (1.901 Å) bond lengths.

General procedure for the synthesis of Schiff base (3a-e) ligands
Schiff base (3a-e) ligands were synthesized by the reaction of pyrazole-4-carbohydrazide (1a-e) with DHA (2). Firstly, ethanolic solution of DHA (2, 1.2 mmol, 1eq) was added to an ethanolic solution of 3-(4-bromophenyl)-1-phenyl-1H-pyrazole-4-carbohydrazides (1c, 1.2 mmol, 1eq) under stirring. Then reaction mixture was refluxed at 85 ? for time T1 and cooled to room temperature. The crude white solid thus obtained was filtered and recrystallized from ethanol.
General procedure for the synthesis of Cu(II) Complexes (4a-e)
To an ethanolic solution of Schiff base ligand (3a-e), a hot ethanolic solution of [Cu(NO3)2]•3H2O was added with constant stirring at 450 rpm (metal-ligand ratio of 1 : 1). Thereafter, the mixture was refluxed for 2 h and further stirred at 450 rpm for 12 h at room temperature at 30?. The resulting green precipitates were filtered and dried. An ethanolic solution of the precipitates was kept at 20 ? for solvent evaporation, and triangular-shaped green crystals were obtained after 5 days.
Physical and characterization data of the synthesized compounds are given below
1) 3-(4-Flourophenyl)-N'-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)ethylidene)-1-phenyl-1H-pyrazole-4-carbohydrazides (3a): Colour: Off White, Yield: 68%, Observed melting point: 185-188?, FT-IR (KBr, cm-1): 3145 (OH str.); 3069 (NH str.); 1699 (C=O str.); 1648 (C=ODHA str.); 1593 (C=N str.). UV-vis (DMSO), ?(max): 270 nm (p ? p*); 370 nm (n ? p*). 1H-NMR (400 MHZ DMSO-d6, d ppm): 2.14 (s, 3H, CH3-C=N); 2.64 (s, 3H, CH3-DHA); 5.81 (s, 1HDHA); 7.28-7.32 (m, 2H, Flourophenyl-C3,5-H); 7.41-7.44 (m, 1H, N-phenyl-C4-H); 7.58-7.61 (m, 2H, N-phenyl-C3,5-H); 7.92-7.96 (m, 4H, Flourophenyl -C2,6-H, N-phenyl-C2,6-H); 9.14 (s, 1H, pyrazole-C5-H); 11.47 (s, 1H, NH,); 16.19 (s, 1H, OH). MS (EI) m/z: 447.14 [M+1]+.
2) 3-(4-Chlorophenyl)-N'-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)ethylidene)-1-phenyl-1H-pyrazole-4-carbohydrazides (3b): Colour: Off white, Yield: 67%, Observed melting point: 215-218? FT-IR (KBr, cm-1): 3178 (OH str.); 3072 (NH str.); 1699 (C=O str.); 1647 (C=ODHA str.); 1574 (C=N str.). UV-vis (DMSO), ?(max): 273 nm (p ? p*); 369 nm (n ? p*). 1H-NMR (DMSO-d6, d ppm): 2.15 (s, 3H, CH3-C=N); 2.66 (s, 3H, CH3-DHA); 5.91 (s, 1HDHA); 7.43-7.46 (m, 1H, N-phenyl-C4-H); 7.54-7.56 (m, 2H, Chlorophenyl -C3,5-H); 7.59-7.63 (m, 2H, N-phenyl-C3,5-H); 7.93-7.97 (m, 4H, Chlorophenyl -C2,6-H, N-phenyl-C2,6-H); 9.17 (s, 1H, pyrazole-C5-H); 11.47 (s, 1H, NH,); 16.23 (s, 1H, OH). MS (EI) m/z: 463.11/464.11 [M+1]+/ [M+2]+ (3:1).
3) 3-(4-Bromophenyl)-N'-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)ethylidene)-1-phenyl-1H-pyrazole-4-carbohydrazides (3c): Colour: Off White, Yield: 85%, Observed melting point: 185-190?, FT-IR (KBr, cm-1): 3145 (OH str.); 3069 (NH str.); 1699 (C=O str.); 1648 (C=ODHA str.); 1593 (C=N str.). UV-vis (DMSO), ?(max): 282 nm (p ? p*); 376 nm (n ? p*). 1H-NMR (DMSO-d6, d ppm): 2.16 (s, 3H, CH3-C=N); 2.67 (s, 3H, CH3-DHA); 5.93 (s, 1HDHA); 7.44-7.47(m, 1H, N-phenyl-C4-H); 7.55-7.71 (m, 4H, N-phenyl-C3,5-H, Bromophenyl-C3,5-H); 7.87-7.98 (m, 4H, Bromophenyl -C2,6-H, N-phenyl-C2,6-H); 9.18 (s, 1H, pyrazole-C5-H); 11.52 (s, 1H, NH,); 16.24 (s, 1H, OH). MS (ESI) m/z: 507.06/509.06 [M]+/ [M+2]+ (1:1).
4) 3-(4-Methylphenyl)-N'-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)ethylidene)-1-phenyl-1H-pyrazole-4-carbohydrazides (3d): Colour: Off White, Yield: 64%, Observed melting point: 193-197?, FT-IR (KBr, cm-1): 3150 (OH str.); 3070 (NH str.); 1701 (C=O str.); 1648 (C=ODHA str.); 1589 (C=N str.). UV-vis (DMSO), ?(max): 279 nm (p ? p*); 343 nm (n ? p*). 1H-NMR (DMSO-d6, d ppm): 2.14-2.64 (s, 9H, CH3); 5.89 (s, 1HDHA); 7.26-8.04 (m, 9H, Ar-H); 9.19 (s, 1H, pyrazole-C5-H); 11.48 (s, 1H, NH,); 16.20 (s, 1H, OH). MS (ESI) m/z: 443.18 [M+1]+.
5) N'-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)ethylidene)-1,3-diphenyl-1H-pyrazole-4-carbohydrazides (3e): Colour: Off white, Yield: 72%, Observed melting point: 190-193?, FT-IR (KBr, cm-1): 3106 (OH str.); 2957 (NH str.); 1670 (C=O str.); 1541 (C=ODHA str.); 1467 (C=N str.). UV-vis (DMSO), ?(max): 278 nm (p ? p*); 348 nm (n ? p*). 1H-NMR (DMSO-d6, d ppm): 2.14 (s, 3H, CH3-C=N); 2.63 (s, 3H, CH3-DHA); 5.90 (s, 1HDHA); 7.41-7.49 (m, 4H, phenyl-C3,5-H, N-phenyl-C3,5-H); 7.58-7.61 (m, 2H, N-phenyl-C4-H, phenyl-C4-H); 7.86-7.88 (d, 2H, N-phenyl-C2,6-H); 7.95-7.96 (d, 2H, phenyl -C2,6-H,); 9.14 (s, 1H, pyrazole-C5-H); 11.47 (s, 1H, NH,); 16.22 (s, 1H, OH). MS (ESI) m/z: 429.16 [M+1]+.
6) Cu(II) complex (4a): Colour: Green, Yield: 82%, Observed melting point: 220-225?, FT-IR:?max (KBr, cm-1): 1687 (C=O str.); 1588 (C=N str.); 1526 (C=N str.); 479 (M-N str.); 549 (M-O str.); UV-vis (DMSO), ?(max): 264 nm (p ? p*); 362 nm (n ? p*); 447 nm (2B1g ? 2E1g); 559 nm (2B1g ? 2A1g).
7) Cu(II) complex (4b): Colour: Green, Yield: 84%, Observed melting point: 225?-229?, FT-IR:?max (KBr, cm-1): 1677 (C=O str.); 1592 (C=N str.); 1541 (C=N str.); 474 (M-N str.); 560 (M-O str.); UV-vis (DMSO), ?(max): 264 nm (p ? p*); 363 nm (n ? p*); 449 nm (2B1g ? 2E1g); 559 nm (2B1g ? 2A1g).
8) Cu(II) complex (4c): Colour: Green, Yield: 88%, Observed melting point: 220-224?, FT-IR:?max (KBr, cm-1): 1677 (C=O str.); 1591 (C=N str.); 1541 (C=N str.); 479 (M-N str.); 549 (M-O str.); UV-vis (DMSO), ?(max): 264 nm (p ? p*); 362 nm (n ? p*); 447 nm (2B1g ? 2E1g); 558 nm (2B1g ? 2A1g).
9) Cu(II) complex (4d): Colour: Green, Yield: 87%, Observed melting point: 230-235?, FT-IR:?max (KBr, cm-1): 1699 (C=O str.); 1586 (C=N str.); 1550 (C=N str.); 478 (M-N str.); 549 (M-O str.); UV-vis (DMSO), ?(max): 264 nm (p ? p*); 365 nm (n ? p*); 451 nm (2B1g ? 2E1g); 550 nm (2B1g ? 2A1g).
10) Cu(II) complex (4e): Colour: Green, Yield: 85%, Observed melting point: 229?-233?, FT-IR:?max (cm-1): 1702 (C=O str.); 1583 (C=N str.); 1548 (C=N str.); 474 (M-N str.); 509 (M-O str.); UV-vis (DMSO), ?(max): 264 nm (p ? p*); 364 nm (n ? p*); 559 nm (2B1g ? 2A1g). , Claims:I/We claim:

1. The compound with formula-I and Formula-II where Ar may be C6H5, p-FC6H4, p-ClC6H4, p-BrC6H4, p-MeC6H4 and R is C6H5 and a process for the synthesis of 3-(Aryl)-N'-(1-(2-hydroxy-6-methyl-4-oxo-4H-pyran-3-yl)ethylidene)-1-phenyl-1H-pyrazole-4-carbohydrazides derivatives (Formula-I) comprising the steps of reacting substituted pyrazole-4-carbohydrazide (1.2 mmol, 1 equiv.) with DHA (1.2 mmol, 1 equiv.) in EtOH at 85 ? for 2-5 h. Cu(II) complexes (Formula-II) have synthesized by adding [Cu(NO3)2]•3H2O to ethanolic solution of Schiff's bases with constant stirring. Thereafter the mixture was refluxed for 2 h and further stirred with 450 rpm for 12 h at room temperature.

2. The process as claimed in claim 1, wherein the yield of 64-85% can be achieved