European Journal of Cardiovascular Medicine

The nitrogen containing heterocycles are of special interest because they constitute an important class of synthetic and natural products, many of which exhibit useful biological activities and unique electrical and optical properties. [1-5]

The pyrazole ring is one of the most important targets in the synthetic and medicinal chemistry because this ring is the key moiety in numerous biologically active compounds. Some of them, such as antipyrine,[6] phenylbutazone,[7] celecoxib,[8] Deracoxib,[9] SC-558,[10] SC-560,[11] ramifenazone,[12] famprofazone,[13] are prominent COX-2 inhibitors and acting as an anti-inflammatory as well as analgesic agents. The number of drugs containing a pyrazole nucleus has increased significantly in the last 10 years. Some of the best-selling drugs in this class are ibrutinib, ruxolitinib, axitinib, niraparib and baricitinib, and are used to treat different types of cancers; lenacapavir to treat HIV; riociguat to treat pulmonary hypertension; and sildenafil to treat erectile dysfunction. Several aniline-derived pyrazole compounds have been reported as potent antibacterial agents with selective activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Many heterocyclic compounds are biosynthesized by plants and animals and are biologically active. The biological properties of heterocycles in general make them one of the prime interests of pharmaceutical industry and biotechnology industry.

Pyrazole derivatives have been reported to show a broad spectrum of biological activity including antimicrobial, [14] anti-inflammatory,[15] antituberculosis,[16] antiviral,[17] hypoglycemic,[18] anti-tumor,[19] antihypertensive[20] and vascular effect attributed to NO/cGMP mechanism [21] etc.

Chalcone is one of the major classes of natural product with wide spread distribution in fruit, vegetables, spices, tea and soya based foodstuff has been recently subjects of great interest for their interesting pharmacological activities.[22] Majority of synthesized chalcones and chalcones isolated from the natural product  are flavonoid and isoflavonoid precursors which are abundant in edible plants and display a wide spectrum of biological activities including antioxidant,[23-27] antibacterial,[28, 29] antileishmanial,[30-32] anticancer,[33-35] antiangiogenic,[36] anti-infective and anti-inflammatory activities.[37-41]

Based on these predictions, we have synthesized a series of new chalcones containing pyrazole scaffold by using poly(ethylene glycol) (PEG-400) as an efficient a green alternative reaction medium reaction medium through Claisen-Schmidt condensation method.

All the compounds and reagents were commercially available without pre-treatment. All solvents and chemicals were obtained from Merck, Spectrochem or Aldrich and are of analytical grade, and were used immediately after opening. TLC was performed on the glass-backed silica gel sheets (Silica Gel-60 GF254) and visualized in UV light (254 nm). Melting points were recorded in open capillary tubes and were found uncorrected. 1H NMR and 13C NMR spectra were recorded on a Bruker AV- 400 spectrometer in CDCl3 using TMS as an internal standard. Infrared spectra were recorded on Thermo scientific spectrometer. Elemental analyses were obtained using a Thermo Finnigan Flash EA 1112 as an instrument. Mass spectrum was recorded with an Advion mass spectrometer of Micromax Company.

General procedure for the synthesis of substituted acetophenone phenylhydrazone (1a-c)

Phenyl hydrazine (10 mmol) was added To a solution of substituted acetophenone (10 mmol) in 20 ml of methanol, phenyl hydrazine (10 mmol) was added at room temperature followed by the slow addition of conc. H₂SO₄ (2 drops). The reaction mixture was then refluxed for 2-3 hours. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mass is cooled to room temperature, the product precipitated out of the reaction mixture, which was filtered, washed with cold methanol (15 ml) and dried under vacuum to obtain pure substituted acetophenone phenylhydrazone 1a-c as a yellow solid.

General procedure for the synthesis of substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (2a-c)

To a solution of N, N-Dimethylformamide (30 mmol), the phosphorous oxychloride (30 mmol) was slowly added lot by lot at 0^oC for half an hour. To this reaction mixture (Vilsmier Haack reagent), the acetophenone phenylhydrazone formed above was then added and the reaction mixture allowed to stirr for 10 min at 0^oC and then heated to 70^oC for 5 hours. The progress of reaction was monitored by TLC. The reaction mixture was then cooled to room temperature, poured into the crushed ice and made it alkaline with cold and dil. NaOH and a solid precipitated out. The precipitate was filtered, washed with cold water (50 ml) to obtain the crude product as a yellow coloured solid 2a-c. The crude product was purified by recrystallisation from ethanol to obtain pure product.

General procedure for the synthesis of chalcones (4a-r)

The equimolar mixture of substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (1 mmol) and substituted acetophenones 3a-f (1 mmol) was dissolved in minimum amount of PEG-400. (10 ml). To this mixture sodium hydroxide (20%, 1 ml) was added slowly and the reaction mixture was stirred at room temperature for 2-3 h using magnetic stirrer. The completion of reaction was monitored by TLC. Then, the reaction mixture was poured slowly into ice-cold water with constant stirring, the product was precipitated out. The precipitate obtained was filtered, washed and dried. The crude product was recrystallised from ethanol to give pure pyrazole chalcones 4a-r.

CHARACTERISATION:

(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4a)

Yield: 84 %; MF: C₂₈H₂₆N₂O₅; Mol.Wt.: 470.52; Colour: Off white solid; MP:185 ºC.

IR (cm^-1): 2954, 2694, 1682, 1628, 1561, 1530, 1212, 1108, 698; ¹H NMR (400 MH_z, CDCl₃) δ: 3.95 (3H, s), 4.00 (3H, s), 4.01 (6H, s), 6.84 (d, 1H, J = 15 Hz, -CH=CH-), 7.01 (2H, s), 7.21 (m, 5H, N-ArH), 7.53 (d, 1H, J = 15Hz, -CH=CH-), 7.6 (d, 2H,ArH, J=8.1 Hz), 7.8 (d, 2H, ArH, J=8.1 Hz), 8.28 (s, 1H, H-pyrazole); ¹³C NMR (100 MH_z, CDCl₃) δ: 29.63, 41.77, 55.31, 56.27, 60.90, 75.76, 104.02, 114.12, 118.98, 120.23, 124.83, 125.23, 126.44, 126.56, 129.41, 139.77, 139.86, 151.08, 153.32, 156.55, 159.70; HRMS (ESI): m/z [M+H] calcd. For C₂₈H₂₇N₂O₅: 470.1820; found: 471.1806.

 (4-hydroxyphenyl)-3-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-one (4b)

Yield: 82 %; MF: C₂₅H₂₀N₂O₃; Mol.Wt.: 396.44; Colour: Faint yellow solid; MP:198 ºC;

IR (cm^-1): 3775, 2979, 2734, 1689, 1635, 1567, 1535, 1206,1110, 753; ¹H NMR (CDCl₃):  δ 3.87 (s, 3H, -OCH₃);, 6.85 (d, 1H, J = 15 Hz, -CH=CH-), 6.8-7.8 (m, 13H, Ar-H);  7.76 (d, 1H, J = 15Hz, -CH=CH-); 8.28 (s, 1H, H-pyrazole); 10.06 (s, 1H, D₂O exchangeable, -OH); HRMS (ESI): m/z [M+H] calcd. For C₂₅H₂₁N₂O₃: 397.1212; found: 397.1501.

(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(3-nitrophenyl)prop-2-en-1-one (4c)

Yield: 84 %; MF: C₂₅H₁₉N₃O₄; Mol.Wt.: 425.44; Colour: Yellow solid; MP:141 ºC;

IR (cm^-1): 1652, 1577, 1403, 1208, 823, 2983, 3115 cm ^-1; ¹H NMR (CDCl₃): δ 3.9 (s, 3H, -OCH₃); 7.2 (m, 5H, N-ArH); 7.30 (d, 1H, J=15 Hz, -CH=CH-); 7.5 (t, 2H, ArH, J=7.8 Hz); 7.6 (d, 2H,ArH, J=8.1 Hz,) 7.8 (d, 2H, ArH, J=8.1 Hz); 7.91 (d, 1H, J=15 Hz, -CH=CH-),8.0 (d, 2H, ArH); 8.34 (s, 1H, H-pyrazol); HRMS (ESI): m/z [M] calcd. For C₂₅H₁₉N₃O₄: 425.4130; found: 424.9986.

(2,4-difluorophenyl)-3-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-one (4e)

Yield: 84 %; MF: C₂₅H₁₈N₂O₂F₂; Mol.Wt.: 416; Colour: Off white solid; MP: 176-178^oC; IR (cm^-1): 1661, 1591, 1504, 1422, 1267, 860, 2917, 3127 cm ^-1; ¹H NMR (CDCl₃):  δ 3.88 (s, 3H, H-of Methoxy group); 7.21 (d, 1H, J = 16Hz, -CH=CH-); 6.87-7.90 (m, 12H, N-ArH); 7.35 (d, 1H, J = 16Hz, -CH=CH-); 8.33 (s, 1H, H-pyrazole); HRMS (ESI): m/z [M+H] calcd. For C₂₅H₁₈N₂O₂F₂: 417.0243; found: 417.1102.

(4-hydroxyphenyl)-3-(1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)prop-2-en-1-one (4h)

Yield: 84 %; MF: C₂₅H₂₀N₂O₂; Mol.Wt.: 380.44; Colour: Pale yellow solid; MP: 187 ^oC;

IR (KBr): 1658, 1599, 1524, 1492, 1230, 832, 2918, 3126 cm ^-1; ¹H NMR (CDCl₃):  δ 2.46 (s, 3H, CH₃); 6.89-7.90 (m, 13H, N-ArH); 7.35 (d, 1H, J = 16Hz, -CH=CH-), 7.87 (d, 1H, J = 16 Hz, -CH=CH-); 8.34 (s, 1H, H-pyrazole); 13.3 (s, 1H, D₂O exchangeable, -OH); ¹³C NMR (100 MH_z, CDCl₃) δ: 21.31, 42.03, 60.94, 75.82, 104.05, 119.06, 120.65, 124.84, 126.41, 126.62, 128.01, 129.43, 129.82, 138.17, 139.81, 139.90, 151.16, 153.34, 156.49; HRMS (ESI): m/z [M+H] calcd. For C₂₅H₂₁N₂O₂: 381.5801; found: 381.6001.

(2,4-difluorophenyl)-3-(1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)prop-2-en-1-one (4k)

Yield: 84 %; MF: C₂₅H₁₈N₂OF₂; Mol.Wt.: 400; Colour: Pale yellow solid; MP: 122-124^oC; IR (KBr): 1659, 1609, 1597, 1505, 1492, 1228, 828, 2922, 3125 cm ^-1; ¹H NMR (CDCl₃):  δ 2.4 (s, 1H, H-of Methyl group); 6.86-7.89 (m, 12H, N-ArH); 7.22 (d, 1H, J = 16 Hz, -CH=CH-); 7.37 (d, 1H, J = 16 Hz, -CH=CH-); 8.32 (s, 1H, H-pyrazole); HRMS (ESI): m/z [M+H] calcd. For C₂₅H₁₉N₂OF₂: 401.2101; found: 401.2087.

(4-bromophenyl)-3-(1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)prop-2-en-1-one (4l)

Yield: 89 %; MF: C₂₅H₁₉BrN₂O; Mol.Wt.: 443.34; Colour: Pale orange solid; MP: 144^oC;

IR (KBr): 1622, 1587, 1493, 1212, 821, 3055, 3114 cm ^-1; ¹H NMR (CDCl₃): δ 2.4 (s, 3H, -CH₃); 7.14-7.4 (m, 5H, N-ArH); 7.27 (d, 1H, J = 15 Hz, -CH=CH-); 7.51 (t, 2H, ArH, J = 7.8 Hz); 7.6 (d, 2H, ArH, J = 8.1 Hz); 7.8 (d, 2H, ArH, J = 8.1 Hz); 7.90 (d, 1H, J = 15 Hz, -CH=CH-); 8.0 (d, 2H, ArH); 8.35 (s, 1H, H-pyrazol); HRMS (ESI): m/z [M] calcd. For C₂₅H₁₉BrN₂O: 443.3412; found: 443.3398.

(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(4-hydroxyphenyl)prop-2-en-1-one (4n)

Yield: 89 %; MF: C₂₄H₁₇ClN₂O₂; Mol.Wt: 400.86; Colour: Pale yellow solid; MP: 153 ^oC;

IR (KBr): 1658, 1599, 1524, 1492, 1230, 832, 2918, 3126 cm ^-1; ¹H NMR (CDCl₃):  δ 6.89-7.90 (m, 13H, N-ArH); 7.35 (d, 1H, J = 16 Hz, -CH=CH-); 7.87 (d, 1H, J = 16 Hz, -CH=CH-); 8.34 (s, 1H, H-pyrazole); 10.35 (s, 1H, D₂O exchangeable, -OH); HRMS (ESI): m/z [M+H] calcd. For C₂₄H₁₈ClN₂O₂: 400.8565; found: 400.8196.

(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (4p)

Yield: 87 %; MF: C₂₅H₁₆ClF₃N₂O; Mol.Wt: 452.86; Colour: Off white solid; MP: 167 ^oC;

IR (KBr): 1653, 1581, 1489, 1200, 816, 3117, 3181 cm ^-1; ¹H NMR (CDCl₃):  δ 7.16 (t, 2H, ArH); 7.30 (d, 1H, J = 15 Hz, -CH=CH-); 7.36-7.54 (m, 5H, N-ArH); 7.65 (d, 2H, ArH, J = 8.1 Hz), 7.8 (d, 2H, ArH,J = 8.1 Hz); 7.84 (d, 1H, J = 15 Hz, -CH=CH-); 8.0 (d, 2H, ArH); 8.36 (s, 1H, H-pyrazol )

(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2,4-difluorophenyl)prop-2-en-1-oneCompound (4q)

Yield: 90 %; MF: C₂₄H₁₅N₂OF₂Cl; Mol.Wt: 420; Colour: Off white solid; MP: 140 ^oC; IR (KBr): 1660, 1611, 1596, 1505, 1492, 1229, 828, 2922, 3125 cm ^-1; ¹H NMR (CDCl₃):  δ, ,  6.88-7.91 (m, 12H, N-ArH); 7.24 (d, 1H, J = 16 Hz, -CH=CH-)7.76 (d, 1H, J = 16 Hz, -CH=CH-); 8.34 (s, 1H, H-pyrazole) ¹³C NMR (100 MH_z, CDCl₃) δ: 21.31, 29.67, 42.03, 56.30, 60.94, 75.82, 104.05, 119.06, 120.65, 124.84, 126.41, 126.62, 128.01,  129.43, 129.82, 138.17, 139.81, 139.90, 151.16, 153.34, 156.49; HRMS (ESI): m/z [M+H] calcd. For C₂₄H₁₆N₂OF₂Cl: 421.0180; found: 421.0311.

To achieve our aim and objective, we have synthesized various pyrazole substituted chalcone derivatives with electron withdrawing and electron donating substituent changing the position of the substituent. In the present investigation, the synthesis of pyrazole based chalcone derivatives 4a-r (Table 1) is achieved by using poly(ethylene glycol) (PEG-400) as an efficient reaction medium through Claisen-Schmidt condensation method. In general PEG is nontoxic, being used in food products, and cosmetics was potentially recyclable and was water miscible which facilitate its removal from reaction products.

The synthesis of pyrazole substituted chalcone derivatives were brought about by following the straight forward chemistry. Firstly, the substituted acetophenones treated with phenyl hydrazine in presence of catalytic amount of conc. H₂SO₄ under reflux condition in methanol gave acetophenone phenylhydrazones  which on Vilsmeier-Haack reaction when treated with Vilsmeier-Haack reagent (POCl₃ + DMF) gave 1, 3-diphenyl-1H-pyrazole-4-carbaldehydes (Pyrazole aldehydes). The equimolar amount of pyrazole aldehydes on Claisen-Schimdt condensation with various substituted acetophenones in presence of aqueous NaOH in PEG-400 gave chalcone in good to excellent yields.

This intermediates was confirmed by TLC and all the synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR and Mass Spectroscopy.

Reagents and conditions: (i) Ph–NHNH₂, conc.H₂SO₄, 70 ºC, 2-3 h;

     (ii) DMF, POCl₃, 80 ºC, 5 h;

     (iii) NaOH, PEG-400, stir at 40-50 ºC for 3-9 h

Table 1: Synthesized pyrazole chalcone derivatives (3a-r)

The IR spectrum of substituted pyrazole chalcone derivatives showed that, the absorption band observed at ~3200 cm^-1  due to Ar–H stretch and also at ~2800-3000 cm^-1 due to the –CH– stretch. The absorption band at ~1622-1690 cm^-1 due to >C=O stretch and at ~1560-1590 cm^-1 due to C=C stretching. The N–N stretch of pyrazole gives the absorption band at ~1200-1050 cm^-1

In the ¹H NMR spectra of (taken in 400 MHz in CDCl₃) pyrazole chalcone derivatives, the >CH=CH< protons of chalcones gives two doublets at δ ~ 6.8-7.3 and δ ~ 7.5-7.9 with same coupling constants. The aromatic protons resonated at δ ~ 6.8-8.0 ppm. The singlet at δ ~8.28 - 8.38 ppm is due to the deshielded aromatic proton of pyrazole. The characteristic signal of sp² hybridized carbon of pyrazole carbon appeared at δ ~103-109 ppm while all aromatic carbons resonated at δ ~ 100-175 ppm.

The mass spectrums of corresponding substituted pyrazole chalcone derivatives confirm their molecular formula and molecular weight.

As PEG is nontoxic, being used in food products, and cosmetics was potentially recyclable and also water miscible, we have devised a more versatile and convenient synthesis of pyrazole chalcones in PEG-400 which is becoming prominent and a benign alternative medium in synthetic chemistry by applying the principles of “Green Chemistry.” The combination of both the active scaffolds i.e. pyrazole moiety and chalcone, may provide synergistic effect to improve the pharmacological activity. Emerging analogs with unique physicochemical, pharmacokinetic, and pharmacodynamic properties could be useful scaffolds for future studies. The a, ß -unsaturated ketones (chalcones) are important and versatile intermediates for the preparation of various heterocycles suggesting the great utility of pyrazole chalcones as precursor for new heterocycle synthesis.

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