One Pot, Four-Component for the Synthesis of Pyrano Pyrazole Derivatives using TBAHS as Green Catalyst and their Biological Evaluation

 

Vijay N. Bhosale¹* Gopinath S. Khansole², Jaman A. Angulwar³, Sunil S. Choudhare¹,

Ashok R. Karad¹, Navanand B. Wadwale¹

¹P.G. Research Centre, Department of Chemistry, Yeshwant Mahavidyalaya, Nanded (M.S.) India.

²Department of Chemistry, D.A.B.N. Arts & Science College, Chikhali, Sangli (M.S.) India.

³Department of Chemistry, Dayanand Science College, Latur (M.S.) India.

 

ABSTRACT:

A green, efficient and simple procedure has been developed for the synthesis of Pyrano [2,3-c] Pyrazoles  from a  one pot four component  condensation of ethylacetoacetate, malononitrile, hydrazine hydrate and different substituted aromatic aldehydes using  Tetrabutyl ammonium hydrogen sulphate (TBAHS) as green catalyst in ethanol-water. The synthesized Pyrano [2,3-c] Pyrazoles  were screened for their Antioxidant activity. These newly synthesized compounds were evaluated by their   using various spectroscopic techniques and also elemental analysis.

 

 

 

INTRODUCTION:

Multicomponent Reactions (MCRs) are very proficient in the synthesis of organic molecule^1-3. In this protocol single step reaction gives magnificent yield without any isolation of intermediate and intimately associated with the principals of green chemistry.⁴

 

Pyranopyrazole derivatives has vital role in the class of organic compounds because of their broad spectrum of biological as well as pharmacological importance. The pyranopyrazole moieties of the drug with wide medicinal application such as antimicrobial^5-6, antitumor⁷, antipyretic⁸, anti-inflammatory⁹, antidepressant¹⁰, anti hypertensive¹¹, and peptide deformylase inhibitor¹². Moreover, Dihydropyrano [2,3-c] pyrazole showed hypotensive and  hypoglycemic  agents¹³, mollusicidal activity¹⁴ and as well as a screening hit for Chkl kinase inhibitor¹⁵.

 

Chemists have reported various methods for the synthesis of Pyrano pyrazole derivatives. Various method of four component synthesis by using Thiamine hydrochloride (VB₁)¹⁶, CsF¹⁷, ZnO nanoparticle¹⁸, CAPB¹⁹, NaHSO₃ using ultrasound mediated²⁰   and molecular iodine non recoverable²¹ also have been reported. Overall, all these reported methods are effective but requires long time, expensive catalyst. So in order to overcome problem, keeping green approach in mind, in this present investigation we have reported synthesis of the pyranopyrazole derivatives by simple, efficient and ecofriendly method. We have synthesized pyranopyrazoles derivatives   by using tetrabutyl ammonium hydrogen sulphate (TBAHS) as a green catalyst.

 

Acidic TBAHS act as a phase transfer catalyst (PTC) and it perform much organic transformation under mild condition. Thus new route utilizing a MCR protocol, for the synthesis of Pyrano [2,3-c] Pyrazoles  can attacks considerable attention in the search of method for rapid entry of these heterocycles. Consequently, we thought that there is scope for further innovation towards milder reaction condition, short reaction time and better yield in choosing TBAHS for this multicomponent reaction (MCRs).

 

 

RESULT AND DISCUSSION:

As a Initial steps, we have focused on model reaction (Scheme 1) by refluxing equimolecular amount of ethylacetoacetate (1) (3.0 mmol), hydrazine hydrate (80%) (2) (3.0 mmol), malononitrile (3) (3.0 mmol), and different substituted aromatic aldehydes (4) (3.0 mmol) in ethanol-water (1:1) buy using Tetrabutyl ammonium hydrogen sulphate (TBAHS) (20 mol%) for one and half  hour at 50⁰C which results in the formation of compound 5b with 85% yield (Table 1, entry 7). The investigating the effectiveness of different polar and non polar solvent using catalytic amount of TBAHS (20 mol%). Solvent optimization clearly suggested that ethanol-water is the best solvent for the desired transformation due to fast reaction rate and high yield (Table1, entry 7). The other polar protic solvents gives moderate yield (Table1, entry 6).while other aprotic solvent like DCM,THF, Acotonitrile, and toluene displayed slow reaction rates leading lower yield (Table1, entry 1-4). Also, carried out the model reaction using different stoichiometric amount of TBAHS catalyst. The catalyst screening result are summarized in Table 2. It was observed that the excellent yield was achieved by using 20 mol% of TBAHS (Table 2, entry 6).

 

After optimization the reaction condition, the scope of the method was investigated with a series of substituted aromatic aldehydes and the result are summarized in Table 3. With the presence of both electron-poor and electron-rich  substituents in the ortho-, meta-, or para-positions, the reaction proceeded fairly well and afforded with desired product give Pyrano [2,3-c] pyrazoles with high of yields (Table 3, entries 5b-c, 5g ,5i and 5m-n ), but the electron rich  benzaldehydes like (Table 3, entries 5d-f, 5k , and 5o) it gives Pyrano [2,3-c] pyrazoles with good yield.

 

These synthesized products (5a-o) were completely characterized from IR, ¹H-NMR, Mass and ¹³C-NMR spectroscopic technique and also elemental analysis. We proposed tentative plausible mechanism for the formation of Pyrano [2,3-c] pyrazoles (5a-o) in the presence of TBAHS. The overall, mechanism takes place according to Knoevenagels-Micheal reaction (Scheme-II).

 

 

 

Table 1. Optimization of the reaction conditions using different solvents.^[a]

Entry	Solvent	Reaction Time (h)	Yield (%)[b]
1	DCM	7.0	30
2	THF	6.5	35
3 4	Acetonitrile Toluene	6.0 5.5	40 45
5	Ethanol	3.0	65
6 7	Water Ethanol-Water	3.0 2.0	70 85

^[a] Reaction conditions: Ethylacetoacetate (1) (3.0 mmol), hydrazine hydrate (80%) (2) (3.0 mmol), malononitrile (3) (3.0 mmol), and different substituted aromatic aldehydes (4) (3.0 mmol) in Ethanol-Water and TBAHS were refluxed at 50.

 ^[b] Isolated yields.

 

 

Table 2: Optimization Study for the amount of TBAHS.^[a]

Entry	Catalyst (mole %)	Temperature (0C)	Reaction Time (h)	Yield %[b]
1	01	50	2.0	30
2	02	50	2.0	50
3	05	50	2.0	60
4	10	50	2.0	60
5	15	50	2.0	70
6	20	50	2.0	85
7	25	50	2.0	85

^[a] Reaction conditions: Ethylacetoacetate (1) (3.0 mmol), hydrazine hydrate (80%) (2) (3.0 mmol), malononitrile (3) (3.0 mmol), and different substituted aromatic aldehydes (4) (3.0 mmol) in Ethanol-Water and TBAHS were refluxed at 50.

 ^[b] Isolated yields.

 

Table 3. Synthesis of pyrano [2,3-c] pyrazoles derivatives .^[a]

Entry	Ar	Time (Hrs)	Yield%[a]	M.P. (0C)
				Found	Lit.Ref
5a	C6H5	2.5	68	243-245	244-24522
5b	4’-OCH3 -C6H4	2.0	85	208-210	209-21122
5c	4’-CH3 -C6H4	2.0	80	206-208	205-20723
5d	4’-Br  -C6H4	3.0	70	179-181	177-17924
5e	4’-Cl -C6H4	3.5	70	233-235	234-23523
5f	4’-NO2 -C6H4	4.0	60	248-250	251-25223
5g	4’-OH -C6H4	2.0	75	221-223	223-22525
5h	4’-F -C6H4	3.5	65	172-174	170-17123
5i	4’-OCH3, 3’-OCH3-C6H3	2.0	82	310-312	311-31323
5j	4’- OCH3 ,3’-OH-C6H3	2.0	82	242-244	244-24622
5k	3’- Br -C6H4	3.5	66	221-223	223-22523
5l	3’- NO2 -C6H4	4.5	56	193-195	190-19226
5m	3’- OH -C6H4	2.0	72	223-225	221-22327
5n	2’- OH -C6H4	2.0	65	205-206	207-20928
5o	2’- Cl -C6H4	3.5	68	142-144	143-14528
[a] Reaction conditions: Ethylacetoacetate (1) (3.0 mmol), hydrazine hydrate(80%) (2) (3.0 mmol),  malononitrile (3) (3.0 mmol), and different substituted aromatic aldehydes (4) (3.0 mmol) in Ethanol-Water and TBAHS were refluxed at 50℃. [b] Isolated yields.

 

 

EXPERIMENTAL:

Melting points were determined on electro-thermal melting point apparatus and are uncorrected. IR (KBr) spectra were recorded using Perkin-Elmer FTIR spectrophotometer. Mass spectral data were recorded on liquid chromatography mass spectrometer (Shimadzu 2010Ev) using ESI probe. The ¹H and ¹³C NMR spectra were recorded on spectrometer at 300MHz using TMS as an internal standard. All the reactions were monitored by thin layer chromatography, carried out on 0.25 mm thick silica gel-G plate using iodine vapour for detection.

General procedure for the synthesis of 4-substituted derivatives of 4- phenyl Pyrano [2,3-c] pyrazoles (5a-5o):

A mixture of ethylacetoacetate (1) (3.0 mmol), hydrazine hydrate (80%) (2) (3.0 mmol),   malononitrile (3) (3.0 mmol), was refluxed independently with different substituted aromatic aldehydes (4) (3.0 mmol) in presence of Tetrabutyl ammonium hydrogen sulphate (TBAHS) (20 mol%)as a green catalyst  in ethanol-water as solvent for two  hours at 50⁰C. After completion of the reaction (monitored by TLC), the product obtained was filtered, and recrystallized from ethanol (5ml) to give the pure products of 5(a-o), (Table 3).

 

Spectral Characterization of Representative Compounds.

6-amino-1,4-dihydro-3-methyl-4-phenylpyrano[2,3-c]pyrazole-5-carbonitrile (5a):

Yellow solid, IR (KBr / cm^-1 ) 3410,3340 (-NH₂), 3120(-NH) , 2190 (–CN) , 1665 (C=N), 1270(-C-O-C-) ; ¹H NMR (300MHz, DMSO-d_{6 /} ppm ) δ 1.72(s,3H); 4.7 (s,1H,-CH);  6.80(s,br, 2H); 7.10-7.40 (m,5H, Ar-H); 12.06(s,1H,-NH); EI-MS (m/z: RA %): 253 (M^+. +1, 100%). Elemental analysis calculated data for C₁₄H₁₂N₄O; C, 66.65; N, 22.11. Found: C, 66.63; N, 22.09.

 

6-amino-1,4-dihydro-4-(4-methoxyphenyl)-3-methylpyrano[2,3-c]pyrazole-5-carbonitrile (5b):

Yellow solid, IR (KBr/ cm^-1 ) 3460 , 3250 (-NH₂), 3110 (-NH) , 2192 (–CN), 1655 (C=N), 1250 (-C-O-C-) ; ¹H NMR (300MHz, DMSO-d_{6 /} ppm ) δ 1.70 (s,3H); 3.7 (s,3H, Ar–OCH₃ ); 4.5(s,1H,-CH); 7.0 (s,br,2H); 7.0 -6.8 (m,4H, Ar-H); 12.0(s,1H,-NH); EI-MS (m/z: RA %): 283  (M^+. +1, 100% ). ¹³C NMR (300 MHz, DMSO–d6 / ppm ) δ: 36.8, 55.5, 99.2, 114.0, 120.1,127.2, 129.6, 144.2, 159.0.  Elemental analysis calculated data for C₁₅H₁₄N₄O₂ ; C, 63.82 ; N, 19.82. Found: C, 63.79; N, 19.80.

 

6-amino-1,4-dihydro-3-methyl-4-p-tolylpyrano[2,3-c]pyrazole-5-carbonitrile(5c):

Yellow solid,  IR (KBr/ cm^-1 ) 3317 , 3409 (-NH₂), 3190 (-NH) , 2190 (–CN) 1647 (C=N), 1157 (-C-O-C-) ; ¹H NMR (300MHz, DMSO-d_{6 /} ppm ) δ 1.77 (s,3H);  2.26 (s,3H, Ar–OCH₃ );  4.54(s,1H,-CH); 6.8 (s,br,2H); 7.02 -7.12 (m,4H, Ar-H); 12.07 (s,1H,-NH); EI-MS (m/z: RA %): 267  (M^+. +1, 100% ). Elemental analysis calculated data for C₁₅H₁₄N₄O  ; C, 67.65 ; N, 21.40. Found: C, 67.63; N, 21.38.

 

6-amino-4-(4-bromophenyl)-1,4-dihydro-3-methylpyrano[2,3-c]pyrazole-5-carbonitrile(5d):

White solid, IR (KBr/ cm^-1 ) 3474 , 3325 (-NH₂), 3190 (-NH) , 2192 (–CN) 1658 (C=N), 1157 (-C-O-C-) ; ¹H NMR (300MHz, DMSO-d_{6 /} ppm ) δ 1.7 (s,3H);  4.6 (s,1H,-CH);  6.93 (s,br,2H); 7.12 -7.52 (m,4H, Ar-H); 12.14 (s,1H,-NH); EI-MS (m/z: RA %): 330(M^+. ) 332  (M^+. +1, 100% ). ¹³C NMR (300 MHz, DMSO–d6 / ppm ) δ: 35.0, 56.0, 97.2, 119.0, 120.1, 131.0, 143.0, 154.0, 160.0.  Elemental analysis calculated data for C₁₅H₁₄ BrN₄O  ; C, 50.77 ; N, 16.92. Found: C, 50.75; N, 16.90.

 

 

 

6-amino-4-(4-chlorophenyl)-1,4-dihydro-3-methylpyrano[2,3-c]pyrazole-5-carbonitrile(5e):

White solid, IR (KBr / cm^-1 ) 3409 , 3305 (-NH₂), 3174 (-NH) , 2187 (–CN) 1647 (C=N), 1184 (-C-O-C-) ; ¹H NMR (300MHz, DMSO-d_{6 /} ppm ) δ 1.79 (s,3H); 4.63 (s,1H,-CH); 6.93 (s,br,2H); 7.18 -7.20 (m,4H, Ar-H); 12.14 (s,1H,-NH); EI-MS (m/z: RA %): 287(M^+. ) 288 (M^+. +1, 100% ). Elemental analysis calculated data for C₁₅H₁₄ ClN₄O ; C, 58.65 ; N, 19.54. Found: C, 58.63; N, 19.54.

 

BIOLOGICAL EVALUATION:

Antioxidant Activity:

a)     DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging assay :

DPPH (1, 1-diphenyl-2-picrylhydrazyl) radical scavenging assay was proceed by reported method. Take 1 ml (1 mM) of the test sample is added to equimolar quantity of 0.1 mM solution of DPPH in ethanol. After incubation at room temperature for 25 min, then the DPPH reduction was takes places and measured by Reading the absorbance at 517 nm. Ascorbic acid (1mM) used as reference compound.

 

The compound 5 (d, f, k, l and o), (Table 4) showed remarkable antioxidant activity against DDPH radical scavenging activity with reference of ascorbic acid.

 

b)     OH radical scavenging assay:

Hydroxy radicals scavenging activity was measured with Fenton’s reaction (Rollet –Labelle et al., 1998). The reaction mixture contained 60 µl of FeCl₂ (1mM), 90 µl of 1,10-phenanthroline (1mM), 2.4 ml of phosphate buffer (pH 7.8),150 µl of 0.17M H₂O₂ and 1.5 ml of individual newly synthesized organic compounds (1mM). The reaction mixture was kept at room temperature for 5 minutes incubation and the absorbance was recorded at 560 nm using UV-Visible spectrophotometer. Ascorbic acid (1mM) was used as the reference compound. The OH radical scavenging activity, the OH radical in which oxygen species are most reactive. The effective OH radical stabilizing potential observed strong absorption maximum at 560 nm using standard Ascorbic acid (89.5 ± 0.021) drug.

 

The compound 5(d, f, k and l), (Table 4) showed remarkable antioxidant activity against OH radical scavenging activity with reference of ascorbic acid.

 

Table 4: Antioxidant activity of tested compounds (5a-5o.)

Entry	Compound Code	% Radical scavenging activity
		DPPH radical scavenging	OH radical scavenging
01	5a	55.7 ± 1.03	53.2 ± 1.39
02	5b	68.5 ± 0.79	60.3 ± 2.20
03	5c	60.2 ± 0.54	65.2 ± 1.30
04	5d	80.1 ± 1.50	80.2 ± 1.28
05	5e	79.1 ± 0.72	73.6 ± 0.69
06	5f	86.5 ± 1.68	89.2 ± 1.40
07	5g	50.2 ± 0.32	55.2 ± 1.66
08	5h	60.4 ± 0.66	65.2 ± 2.00
09	5i	58.2 ± 1.44	49.2 ± 0.80
10	5j	61.2 ± 0.08	45.2 ± 2.10
11	5k	89.5 ± 2.68	85.2 ± 0.28
12	5l	82.8 ± 1.04	86.2 ± 0.10
13	5m	44.0 ± 0.30	55.8 ± 2.11
14	5n	58.1 ± 1.60	59.2 ± 1.80
15	5o	80.7 ± 1.70	76.2 ± 2.60
16	Ascorbic Acid (Standard)	91.4 ± 0.021	89.5 ± 0.021

 

CONCLUSION:

The method we used for the synthesis of 4-substituted derivatives of Pyrano [2,3-c] pyrazoles derivatives with by using PTC catalyst Tetrabutyl ammonium hydrogen sulphate (TBAHS) is efficient method. The product can be easily isolated by simple workup technique, requires ambient reaction condition, short time, less expensive and give excellent yield. Among these synthesized compounds few compounds shows potent antioxidant activity.

 

ACKNOWLEDGMENTS:

Authors are grateful to thanks Principal, Yeshwant Mahavidyalaya, Nanded for providing laboratory facilities, UGC, New Delhi (File no.41-230/2012) (SR) for financial support and Director, Indian Institute of Chemical Technology, Hyderabad for providing spectra.

 

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Received on 14.08.2017         Modified on 19.09.2017

Accepted on 11.10.2017         © AJRC All right reserved