Scholarly article on topic 'Ionic liquid 1-butyl-3-methylimidazolium bromide: A green reaction media for the efficient synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-ones/thiones using phthalimide-N-sulfonic acid as catalyst'

Ionic liquid 1-butyl-3-methylimidazolium bromide: A green reaction media for the efficient synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-ones/thiones using phthalimide-N-sulfonic acid as catalyst Academic research paper on "Chemical sciences"

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{"1-Butyl-3-methylimidazolium bromide ([Bmim][Br])" / "Phthalimide-N-sulfonic acid (PISA)" / 1-Phenyl-3-methyl-1H-pyrazole-5(4H)-one / "Pyrazolo[3 / 4-d]pyrimidine"}

Abstract of research paper on Chemical sciences, author of scientific article — S.P.N. Sudhan, R. Nasir Ahmed, H. Kiyani, S. Sheik Mansoor

Abstract A simple, green and environmentally benign procedure was developed for the one pot synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one/thiones using catalytic amount of phthalimide-N-sulfonic acid (PISA) in 1-butyl-3-methylimidazolium bromide ([Bmim][Br]) ionic liquid via the three-component reaction of 1-phenyl-3-methyl-1H-pyrazole-5(4H)-one, aromatic aldehyde and urea/thiourea. [Bmim][Br] as reaction media offers several advantages including non-toxic, non-corrosive, shorter reaction times, high yield of the products, mild reaction conditions as well as simple experimental and isolation procedures.

Academic research paper on topic "Ionic liquid 1-butyl-3-methylimidazolium bromide: A green reaction media for the efficient synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-ones/thiones using phthalimide-N-sulfonic acid as catalyst"

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Original article

Ionic liquid 1-butyl-3-methylimidazolium bromide: a green reaction media for the efficient synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazo-lo[3,4-d]pyrimidine-6-ones/thiones using phthalimide-N-sulfonic acid as catalyst

S.P.N. Sudhan, R. Nasir Ahmed, H. Kiyani, S. Sheik Mansoor

PII: DOI:

Reference:

S1319-6103(16)30055-2 http://dx.doi.org/10.1016/joscs.2016.07.001 JSCS 828

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Journal of Saudi Chemical Society

Received Date: Revised Date: Accepted Date:

15 May 2016 3 July 2016 6 July 2016

Please cite this article as: S.P.N. Sudhan, R. Nasir Ahmed, H. Kiyani, S. Sheik Mansoor, Ionic liquid 1-butyl-3-methylimidazolium bromide: a green reaction media for the efficient synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-ones/thiones using phthalimide-N-sulfonic acid as catalyst, Journal of Saudi Chemical Society (2016), doi: http://dx.doi.org/10.1016/jjscs.2016.07.001

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Title Page

Ionic liquid l-butyl-3-methylimidazolium bromide : a green reaction media for the efficient synthesis of 3-methyl-l,4-diphenyl-l,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-ones/thiones using phthalimide-M-sulfonic acid as

catalyst

S. P. N. Sudhana, R. Nasir Ahmeda, H. Kiyanib, S. Sheik Mansoora

1. S.P.N. Sudhan, M.Sc.,

Research Scholar

eem Co

715-364 Da

yntheti

aResearch Department of Chemistry, Bioactive Organic Molecule Synthetic Unit, C. Abdul Hakeem College (Autonomous), Melvisharam - 632 509, Tamil Nadu, India

School of Chemistry, Damghan University, 36715-364 Damghan, Iran e-mail: smansoors2000@yahoo.co.in

C. Abdul Hakeem College, Melvisharam - 632 509, Tamil Nadu, India

2. R. Nasir Ahmed, M.Sc., M.Phil.,

Research Scholar C. Abdul Hakeem College, Melvisharam - 632 509, Tamil Nadu, India

3. Dr. H. Kiyani, Ph.D.,

Associate Professor School of Chemistry,

Damghan University, 36715-364 Damghan, Iran

4. Dr. S. Sheik Mansoor, Ph.D., * (Corresponding Author)

Associate Professor

Research Department of Chemistry,

C. Abdul Hakeem College,

Melvisharam - 632 509, Tamil Nadu, India

Phone: +919944093020

e-mail: smansoors2000@yahoo.co.in

Ionic liquid 1-butyl-3-methylimidazolium bromide : a green reaction media for the efficient synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-ones/thiones using phthalimide-N-sulfonic acid as catalyst

S. P. N. _ N. H. Kiyani", S. _

aResearch Department of Chemistry, Bioactive Organic Molecule Synthetic Unit, C. Abdul Hakeem College (Autonomous), Melvisharam - 632 509, Tamil Na bSchool of Chemistry, Damghan University, 36715-364 Damghan, Iran e-mail: smansoors2000@yahoo. co. in

Abstract

A simple, green and environmentally benign procedure was developed for the one pot synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one/thiones using catalytic amount of phthalimide-N-sulfonic acid (PISA) in 1-butyl-3-methylimidazolium bromide ([Bmim][Br]) ionic liquid via the three-component reaction of 1-phenyl-3-methyl-1H-pyrazole-5(4H)-one, aromatic aldehyde and urea/thiourea. [Bmim][Br] as reaction media offers several advantages including non-toxic, non-corrosive, shorter reaction times, high yield of the products, mild reaction conditions as well as simple experimental and isolation procedures. Keywords: 1-butyl-3-methylimidazolium bromide ([Bmim][Br]); phthalimide-N-sulfonic acid (PISA); 1-phenyl-3-methyl-1H-pyrazole-5(4H)-one; pyrazolo[3,4-d]pyrimidine

1. Introduction

The elimination of volatile organic solvents in organic synthesis is the most important goal in green chemistry. Ionic liquids (ILs) are an excellent alternative to substitute volatile organic solvents in more environmental friendly technologies. ILs are growingly popular because they

have been recognized as important novel solvents showing specific properties including high heat capacity, high density, extremely low volatility, non-flammability, high thermal stability, and wide temperature range for liquid state. They are also known as environmentally benign catalysts and much attention has currently been focused on organic reactions in the presence of these compounds as catalysts or solvents [1-5].

The development of simple routes toward making widely used organic compounds from readily available reagents and compounds is one of the major tasks in organic synthesis. Multi-component condensation reactions (MCRs) occupy an advantageous position among other reactions, because of high atom economy, high yields, convergent character and simplicity of procedures [6,7]. Therefore, the discovery and development of novel MCRs is one of the goals of chemistry research group

Pyrazoles are novel class of heterocyclic compounds possessing wide variety of application in the pharmaceutical industries [8]. Derivatives of pyrazoles are found to show good antibacterial [9], anti-inflammatory [10], antitumor and anti-HCV [11], anticancer, radioprotective [12] and anti-convulsant activity [13]. The structural diversity and biological importance of pyrimidines have made them attractive targets for synthesis over many years [1416]. Fused pyrimidine derivatives have shown diverse biological activities. Among them, pyrazolo[3,4-d]pyrimidines as purine analogs have attracted considerable interest due to their remarkable pharmacological properties [17]. Pyrazolo[3,4-d]pyrimidines exhibit antimicrobial

activity [18], antiviral activity [19], anti-tumor activity [20], adenosine A2A receptor antagonists [21], reactive oxygen species in human breast adenocarcinoma cells [22], anti-proliferative activity [23], antitumor and anti-leukemia activity [24], anti-mycobacterial [25] and CK1 inhibitors [26].

During the last few years, synthesis of pyrazolo[3,4-d]pyrimidines has received great interest. A recent literature survey indicated that the synthesis of the pyrazolo[3,4-d]pyrimidine derivatives have been conducted using molecular iodine [27], heteropolyacids [28,29], microwave-assisted reaction [30,31] and Vilsmeier-type reagents [32]. A series of 3-amino-6-aryl-2-phenylpyrazolo[3,4-d]pyrimidine derivatives were prepared through an efficient and environmentally friendly reaction between 4-amino-6-aryl-2-phenylpyrimidine-5-carbonitrile derivatives and hydrazine hydrate [33]. A variety of pyrazolo[3,4-d]pyrimidine-6(7H)-thione derivatives were easily synthesized in the presence of catalytic amount of p-toluene sulfonic acid (p-TSA) in 1-butyl-3-methylimidazolium bromide ionic liquid [34]. The reaction of phenylisothiocyanate, 5-methyl-1H-pyrazol-3-amine, and aldehyde were used for the synthesis of pyrazolo[3,4-d]pyrimidine-6(7H)-thiones. In the presence of p-TSA under solvent-free conditions, the yield of the final product was not high, mainly because the reaction mixture could not be stirred well. In order to improve the yield, the ionic liquid [Bmim][Br]was used as solvent. The results indicated that the reaction proceed efficiently by using p-TSA in [Bmim][Br], and the desired product was obtained in excellent yield. However, the major drawback of these procedures includes long reaction times, low to moderate yields, large excess of a strong Br0nsted acid and limited number of reactants and partial structural diversity of products. Consequently, designing a new synthetic pathway to obtain these structurally complex heterocycles is of great interest in the modern drug discovery.

In recent years phthalimide-N-sulfonic acid (PISA) has drawn much interest in different organic reactions due to its experimental simplicity. PISA has been used as a catalyst for the solvent-free synthesis of 5-alkenyl-2,2-butylidene-1,3-dioxane-4,6-diones under ultrasonic irradiation [35], synthesis of 3,4-dihydropyrimidin-5(1#)-ones/thiones under solv ent-free conditions [36] and for the solvent-free synthesis of 2-(2-oxo-2H-chromen-3-yl)-4-aryl-indeno [ 1,2-b]pyridine-5-ones [37].

In continuation of our previous research in heterocyclic synthesis [38-42], herein, we wish to report a novel and straightforward synthetic pathway to access fused 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-ones/thiones by the three-component reaction of 1-phenyl-3-methyl-1H-pyrazole-5(4#)-one, aromatic aldehyde and urea/thiourea in the presence of catalytic amount of PISA in [Bmim][Br] ionic liquid at 80 °C (Scheme 1).

Recently, one pot synthesis of 7-phenyl-1,4,6,7-tetrahydrothiazolo[5,4-d]pyrimidine-2,5-diones via a multicomponent reaction between thiazolidine-2,4-dione, aromatic aldehyde and urea analogues is described. The ionic liquid has been used as a solvent as well as catalyst for this reaction [43]. 2. Experimental

2.1 Chemicals and apparatus

Chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies. All

yields refer to isolated products unless otherwise stated. H-NMR (500 MHz) and C-NMR (125 MHz) spectra were obtained using Bruker DRX- 500 Avance at ambient temperature, using TMS as internal standard. FT-IR spectra were obtained as KBr discs on Shimadzu spectrometer. Mass spectra were determined on a Varion - Saturn 2000 GC/MS instrument. Elemental analysis were measured by means of Perkin Elmer 2400 CHN elemental analyzer flowchart.

2.2 Preparation of phthalimide -N-sulfonic acid

Phthalimide-N-sulfonic acid (PISA) as a stable reagent is easily prepared [36] as reported previously by the reaction of potassium phthalimide with chlorosulfonic acid (Scheme 2). 2, ^ ^ * * « of t^14^1«57-.^ pyrazolo[3,4-d]pyrimidin-6-one/thiones (4a-n)

A mixture of 1-phenyl-3-methyl-1H-pyrazole-5(4H)-one 1 (1 mmol), urea/thiourea 3 (1.2 mmol) was stirred for 5 min at 80 °C. Then, aldehyde 2 (1 mmol) and PISA (0.1 mmol), [Bmim][Br] (0.4 g) were added and the mixture was heated at 80 °C for 0.8 - 1.0 h. After completion of the reaction (monitored by TLC, eluent: n-hexane/ethyl acetate, 2:1), the mixture was cooled to room temperature, washed with water (25 mL) and the residue was purified by recrystallization from EtOH to afford the pure products. If necessary, the product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate, 3:1). The PISA used for the transformation was recovered and used for the further reactions. 2.4 Spectral data for the synthesized compounds (4a-n)

2.4.1 3-Methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (4a)

IR (KBr): 3344, 3206, 2972, 1671, 1566, 1446, 794 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.22 (s, 3H, CH3-3), 5.52 (s, 1H, CH-4), 6.81-7.15 (m, 5H, Ar-H), 7.35-7.52 (m, 5H, Ar-H), 8.17 (s, 1H, NH-5), 9.26 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) d: 11.9, 43.6, 104.7, 118.2, 126.1, 126.4, 127.5, 128.0, 128.4, 129.5, 138.9, 143.0, 148.9, 151.1, 167.0 ppm; MS (ESI): m/z 305 (M+H)+. Anal. Calcd. for C18H16N4O (%): C, 71.05; H, 5.26; N, 18.42. Found: C, 71.01; H, 5.22; N, 18.38.

2.4.2 3-Methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-thione (4b)

IR (KBr): 3353, 3192, 2970, 1571, 1363, 1250, 778 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.28 (s, 3H, CH3-3), 5.50 (s, 1H, CH-4), 6.79-7.14 (m, 5H, Ar-H), 7.30-7.49 (m, 5H, Ar-H), 8.14 (s, 1H, NH-5), 9.27 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 11.7, 44.1,

105.0, 118.8, 126.3, 126.6, 127.7, 128.2, 128.6, 128.9, 139.4, 143.1, 148.7, 150.7,

166.6 ppm;

MS (ESI): m/z 321 (M+H) . Anal. Calcd. for C18H16N4S (%): C, 67.50; H, 5.00; N, 17.50. Found: C, 67.41; H, 5.01; N, 17.44.

2.4.3 3-Methyl-1-phenyl-4-(4-chlorophenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-

IR (KBr): 3353, 3216, 2979, 1668, 1577, 1448, 788 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.18 (s, 3H, CH3-3), 5.48 (s, 1H, CH-4), 6.84-7.11 (m, 5H, Ar-H), 7.29 (d, 2H, J = 8.4 Hz, ArH), 7.59 (d, 2H, J = 8.4 Hz, ArH), 8.12 (s,1H, NH-5), 9.21 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.5, 43.7, 105.3, 118.6, 126.2, 126.7, 127.3, 128.3, 128.8, 129.3, 139.5, 142.5, 149.0, 150.5, 166.5 ppm; MS (ESI): m/z 339 (M+H)+. Anal. Calcd. for C^H^ClW (%): C, 63.82; H, 4.43; N, 16.55. Found: C, 63.71; H, 4.33; N, 16.56.

2.4.4 3-Methyl-1-phenyl-4-(4-chlorophenyl)-1,4,5,7-tetrahydro-pyrazolo[ 3,4-d]pyrimidin-6-thione(4d)

IR (KBr): 3349, 3194, 2978, 1575, 1360, 1243, 774 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.20 (s, 3H, CH3-3), 5.46 (s, 1H, CH-4), 6.85-7.09 (m, 5H, Ar-H), 7.34 (d, 2H, J = 8.2 Hz, ArH), 7.54 (d, 2H, J = 8.2 Hz, ArH), 8.19 (s,1H, NH-5), 9.22 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.0, 44.2, 104.8, 118.0, 126.4, 126.8, 127.4, 128.4, 128.7, 129.2, 139.3, 142.7, 149.1, 151.0, 167.1 ppm; MS (ESI): m/z 355 (M+H)+. Anal. Calcd. for C^H^Cl^S (%): C, 60.94; H, 4.23; N, 15.80. Found: C, 60.88; H, 4.17; N, 15.77.

2.4.5 3-Methyl-1-phenyl-4-(4-fluorophenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (4e)

IR (KBr): 3357, 3205, 2981, 1665, 1569, 1449, 783 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.19 (s, 3H, CH3-3), 5.51 (s, 1H, CH-4), 6.88-7.08 (m, 5H, Ar-H), 7.36 (d, 2H, J = 8.2 7.55 (d, 2H, J = 8.2 Hz, ArH), 8.15 (s,1H, NH-5), 9.21 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.1, 43.8, 104.9, 117.9, 126.2, 126.6, 127.5, 128.5, 128.9, 129.4, 138.8, 143.2, 148.8, 151.3, 166.9 ppm; MS (ESI): m/z 323 (M+H)+. Anal. Calcd. for C18H 15FN4O (%): C, 67.01; H, 4.66; N, 17.39. Found: C, 66.94; H, 4.60; N, 17.31.

2.4.6 3-Methyl-1-phenyl-4-(4-fluorophenyl)-1,4,5,7-tetrahydro-pyrazolo[ 3,4-d]pyrimidin-6-thione (4f)

IR (KBr): 3361, 3197, 2975, 1569, 1371, 1248, 773 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.24 (s, 3H, CH3-3), 5.56 (s, 1H, CH-4), 6.91-7.13 (m, 5H, Ar-H), 7.28 (d, 2H, J = 8.0 Hz, ArH), 7.50 (d, 2H, J = 8.0 Hz, ArH), 8.21 (s,1H, NH-5), 9.25 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 11.8, 43.9, 105.2, 118.1, 126.4, 126.7, 127.7, 128.0, 128.4, 128.7, 138.8, 142.7, 148.7, 150.5, 166.8 ppm; MS (ESI): m/z 339 (M+H)+. Anal. Calcd. for C18H15FN4S (%): C, 54.15; H, 3.76; N, 14.00. Found: C, 54.10; H, 3.72; N, 13.92.

2.4.7 3-Methyl-1-phenyl-4-(4-nitrophenyl)-1,4,5,7-tetrahydro-pyrazolo[ 3,4-d]pyrimidin-6-one (4g)

IR (KBr): 3361, 3200, 2982, 1661, 1570, 1452, 790 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.21 (s, 3H, CH3-3), 5.44 (s, 1H, CH-4), 6.85-7.12 (m, 5H, Ar-H), 7.37 (d, 2H, J = 8.1 Hz, ArH), 7.57 (d, 2H, J = 8.1 Hz, ArH), 8.16 (s,1H, NH-5), 9.24 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 11.6, 43.6, 105.3, 118.3, 126.3, 126.8, 127.4, 128.2, 128.5, 128.9, 139.5,

142.2, 149.2, 150.8, 166.4 ppm; MS (ESI): m/z 350 (M+H)+. Anal. Calcd. for C18H15N5O3 (%): C, 61.89; H, 4.30; N, 20.06. Found: C, 61.84; H, 4.25; N, 20.01.

2.4.8 3-Methyl-1-phenyl-4-(4-nitrophenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-thione (4h)

IR (KBr): 3358, 3203, 2973, 1574, 1369, 1254, 772 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.19 (s, 3H, CH3-3), 5.47 (s, 1H, CH-4), 6.94-7.06 (m, 5H, Ar-H), 7.33 (d, 2H, J = 8.2 Hz, ArH), 7.53 (d, 2H, J = 8.2 Hz, ArH), 8.20 (s,1H, NH-5), 9.21 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.1, 43.9, 105.4, 118.6, 126.2, 126.6, 127.6, 128.3, 128.5, 129.2, 139.4, 143.0, 149.1, 150.7, 167.2 ppm; MS (ESI): m/z 366 (M+H)+. Anal. Calcd. for C18H15N5O2S (%): C, 59.18; H, 4.11; N, 15.34. Found: C, 59.11; H, 4.10; N, 15.25.

2.4.9 3-Methyl-1-phenyl-4-(4-bromophenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (4i)

IR (KBr): 3355, 3199, 2974, 1671, 1568, 1454, 792 cm1; NMR (500 MHz, DMSO-d6): 8 2.26 (s, 3H, CH3-3), 5.40 (s, 1H, CH-4), 6.93-7.05 (m, 5H, Ar-H), 7.36 (d, 2H, J = 8.1 Hz, ArH), 7.52 (d, 2H, J = 8.1 Hz, ArH), 8.16 (s,1H, NH-5), 9.24 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.0, 44.2, 105.0, 118.7, 126.4, 126.7, 127.5, 128.3, 128.6, 128.9, 138.9, 143.0, 148.8, 151.1, 166.8 ppm; MS (ESI): m/z 383.5 (M+H)+. Anal. Calcd. for C^H^Br^O (%): C, 56.41; H, 3.92; N, 14.62. Found: C, 56.33; H, 3.90; N, 14.57.

2.4.10 3-Methyl-1-phenyl-4-(4-bromophenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-thione (4j)

IR (KBr): 3357, 3195, 2973, 1565, 1368, 1251, 776 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.23 (s, 3H, CH3-3), 5.43 (s, 1H, CH-4), 6.80-7.02 (m, 5H, Ar-H), 7.27 (d, 2H, J = 8.2 Hz, ArH), 7.51 (d, 2H, J = 8.2 Hz, ArH), 8.12 (s,1H, NH-5), 9.19 (s, 1H, NH-7) ppm; 13C NMR (125

n-6-one

MHz, DMSO-d6) S: 12.4, 44.4, 104.8, 117.9, 126.1, 126.7 127.4, 128.4, 128.7, 129.4, 138.9, 142.6, 149.1, 150.5, 166.7 ppm; MS (ESI): m/z 399.7 (M+H)+. Anal. Calcd. for C^H^Br^S (%): C, 54.15; H, 3.76; N, 14.00. Found: C, 54.08; H, 3.71; N, 14.01.

2.4.11 3-Methyl-l-phenyl-4-(3-nitrophenyl)-l,4,5,7-tetrahydro-py

IR (KBr): 3352, 3198, 2975, 1673, 1574, 1449, 785 cm1; XH NMR (500 MHz, DMSO-d6): 8

2.17 (s, 3H, CH3-3), 5.54 (s, 1H, CH-4), 6.95-7.12 (m, 5H, Ar-H), 7.31-7.53 (m, 4H, Ar-H), 8.11 (s, 1H, NH-5), 9.21 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 11.5, 44.3,

105.3, 118.3, 126.3, 126.5, 127.7, 128.5, 128.7, 129.3, 139.3, 142.7, 149.1, 150.4, 166.6 ppm; MS (ESI): m/z 350 (M+H)+. Anal. Calcd. for C18H15N5O3 (%): C, 61.89; H, 4.30; N, 20.06. Found: C, 61.77; H, 4.31; N, 20.00.

2.4.12 3-Methyl-1-phenyl-4-(3-nitrophenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-thione (4l)

IR (KBr): 3363, 3211, 2977, 1570, 1370, 1247, 778 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.19 (s, 3H, CH3-3), 5.46 (s, 1H, CH-4), 6.89-7.09 (m, 5H, Ar-H), 7.39-7.58 (m, 4H, Ar-H),

8.18 (s, 1H, NH-5), 9.23 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 11.9, 44.2,

105.4, 118.7, 126.2, 126.4, 127.3, 128.2, 128.6, 128.9, 139.5, 143.1, 148.9, 150.7, 166.4 ppm; MS (ESI): m/z 366 (M+H)+. Anal. Calcd. for C18H15N5O2S (%): C, 59.18; H, 4.11; N, 15.34. Found: C, 59.11; H, 4.03; N, 15.31.

2.4.13 3-Methyl-1-phenyl-4-(3-bromophenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (4m)

IR (KBr): 3358, 3211, 2981, 1669, 1576, 1446, 779 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.22 (s, 3H, CH3-3), 5.44 (s, 1H, CH-4), 6.91-7.08 (m, 5H, Ar-H), 7.40-7.57 (m, 4H, Ar-H),

idin-6-

8.15 (s, 1H, NH-5), 9.19 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 11.8, 43.8, 105.5, 118.5, 126.4, 126.8, 127.4, 128.4, 128.8, 129.4, 139.6, 143.1, 149.0, 151.2, 167.2 ppm; MS (ESI): m/z 383.5 (M+H)+. Anal. Calcd. for C^H^Br^O (%): C, 56.41; H, 3.92; N, 14.62. Found: C, 56.34; H, 3.90; N, 14.55.

2.4.14 3-Methyl-1-phenyl-4-(3-bromophenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimid thione (4n)

IR (KBr): 3349, 3197, 2972, 1573, 1367, 1254, 769 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.29 (s, 3H, CH3-3), 5.48 (s, 1H, CH-4), 6.92-7.10 (m, 5H, Ar-H), 7.32-7.54 (m, 4H, Ar-H), 8.18 (s, 1H, NH-5), 9.26 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.1, 43.7, 104.9, 118.2, 126.1, 126.6, 127.7, 128.3, 128.6, 129.5, 139.4, 142.8, 149.3, 151.3, 166.6 ppm; MS (ESI): m/z 399.5 (M+H)+. Anal. Calcd. for C^H^Br^S (%): C, 54.15; H, 3.76; N, 14.00. Found: C, 54.13; H, 3.78; N, 13.88.

2.4.15 3-Methyl-1-phenyl-4-(4-methylphenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (4o)

IR (KBr): 3353, 3213, 2984, 1668, 1573, 1443, 773 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.10 (s, 3H, CH3), 2.19 (s, 3H, CH3-3), 5.43 (s, 1H, CH-4), 6.89-7.15 (m, 5H, Ar-H), 7.34 (d, 2H, J = 8.4 Hz, ArH), 7.55 (d, 2H, J = 8.4 Hz, ArH), 8.11 (s,1H, NH-5), 9.25 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.7, 18.9, 43.9, 105.5, 118.7, 126.3, 126.8, 127.5, 128.4, 128.9, 129.5, 139.6, 142.6, 149.2, 150.7, 166.8 ppm; MS (ESI): m/z 319 (M+H)+. Anal. Calcd. for C19H18N4O (%): C, 71.70; H, 5.66; N, 17.61. Found: C, 71.63; H, 5.63; N, 17.57.

2.4.16 3-Methyl-1-phenyl-4-(4-methylphenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-thione (4p)

IR (KBr): 3355, 3199, 2975, 1576, 1365, 1245, 776 cm-1; NMR (500 MHz, DMSO-dô): 5 2.07 (s, 3H, CH3), 2.22 (s, 3H, CH3-3), 5.49 (s, 1H, CH-4), 6.80-7.10 (m, 5H, Ar-H), 7.25 (d, 2H, J = 8.4 Hz, ArH), 7.51 (d, 2H, J = 8.4 Hz, ArH), 8.07 (s,1H, NH-5), 9.24 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.4, 19.2, 43.4, 105.2, 118.4, 126.1, 126.6, 127.2, 128.2, 128.6, 129.1, 139.3, 142.3, 149.0, 150.3, 166.3 ppm; MS (ESI): m/z 335 (M+H)+. Anal.

razolo[3,

Calcd. for C19H18N4S (%): C, 68.26; H, 5.39; N, 16.77. Found: C, 68.16; H, 5.31; N, 16.71.

2.4.17 3-Methyl-1-phenyl-4-(4-methoxyphenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (4q)

IR (KBr): 3350, 3216, 2989, 1664, 1574, 1448, 779 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.21 (s, 3H, CH3-3), 3.67 (s, 3H, OCH3), 5.40 (s, 1H, CH-4), 6.78-7.00 (m, 5H, Ar-H), 7.24 (d, 2H, J = 8.2 Hz, ArH), 7.45 (d, 2H, J = 8.2 Hz, ArH), 8.10 (s,1H, NH-5), 9.17 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.3, 44.3, 53.7, 104.5, 117.7, 126.0, 126.5 127.3, 128.3, 128.5, 129.3, 138.7, 142.4, 149.0, 150.1, 166.1 ppm; MS (ESI): m/z 335 (M+H)+. Anal. Calcd. for C19H18N4O2 (%): C, 68.26; H, 5.39; N, 16.77. Found: C, 68.20; H, 5.36; N, 16.75.

2.4.18 3-Methyl-1-phenyl-4-(4-methoxyphenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-

'h'"ne <4r>

IR (KBr): 3358, 3198, 2977, 1572, 1360, 1247, 778 cm-1; 1H NMR (500 MHz, DMSO-d6): 8 2.27 (s, 3H, CH3-3), 3.60 (s, 3H, OCH3), 5.49 (s, 1H, CH-4), 6.88-7.13 (m, 5H, Ar-H), 7.34 (d, 2H, J = 8.2 Hz, ArH), 7.57 (d, 2H, J = 8.2 Hz, ArH), 8.17 (s,1H, NH-5), 9.22 (s, 1H, NH-7) ppm; 13C NMR (125 MHz, DMSO-d6) S: 12.6, 44.7, 54.1, 104.7, 117.7, 126.4, 126.9 127.5, 128.5, 128.9, 129.7, 138.9, 142.9, 149.5, 150.7, 167.1 ppm; MS (ESI): m/z 351 (M+H)+. Anal. Calcd. for C19H18N4OS (%): C, 65.14; H, 5.14; N, 16.00. Found: C, 65.07; H, 5.10; N, 16.02.

3. Results and discussion

To obtain the optimum conditions for the synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one, the reaction of 1-phenyl-3-methyl-1H-pyrazole-5(4#)-one 1, benzaldehyde 2 and urea 3 was chosen as a model reaction.

Initially, a systematic study was carried out for catalytic evaluation of P preparation of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one at a temperature of 80 °C (Table 1). Our studies showed that in the presence of PISA under solventfree conditions, the yield of the final product was not high, mainly because the reaction mixture could not be stirred well. In order to improve the yield, the ionic liquid [Bmim][Br] was used as solvent. The results indicated that the reaction proceed efficiently by using PISA in [Bmim][Br], and the desired product was obtained in excellent yield (Table 1, entry 2). A comparison of catalytic activity of Br0nsted and Lewis acids was examined in the model reaction under the optimal reaction conditions, showing the highest catalytic activity of PISA (Table 1, entries 3-7).

Screening of the reaction conditions was established suitable solvents, the temperature as well as the amount of catalyst for the desired model reaction (Table 2). It was exciting that the chosen solvents such as ethanol (EtOH), N,N-dimethylformamide (DMF), acetonitrile (CH3CN), chloroform (CHCl3), 1,4-dioxane, [HNEt3][Ac], [Bmim][Cl], [Bmim]BF4, [Bmim]PF6, [Bmim][Br] etc. were suitable for the model reaction (Table 2, entries 1-10). Ionic liquid [Bmim][Br] proved to be the best among them (Table 2, entry 10). It is noteworthy that no reaction was occurred in the absence of the catalyst even after a long time (7 h, Table 2, entry 11). Lower yield was obtained when the same reaction carried out with lower amount of the catalyst (Table 2, entries 12-14). Further, an increase in the amount of the catalyst no improvement could be observed in the yield of the product (Table 2, entries 15-16). Lowering the temperature to 50 °C, 60 °C and 70 °C, decreased the conversion to 51%, 66% and 79%

ISA for the

respectively (Table 2, entries 17 - 19). Notably, higher temperature (90 °C) makes no obvious difference in the yield of the product (Table 2, entry 20). Overall, we found that, in the presence of 10 mol% of PISA in [Bmim][Br] at 80 °C the product was formed in excellent yield. Thus, we selected the optimized reaction condition to examine the universality of this catalyst's

application with different electron rich and deficient substrates. Various substituted aromatic aldehydes, 1-phenyl-3-methyl-1H-pyrazole-5(4#)-one, and urea/thiourea undergo the reaction in the presence of catalytic amount of PISA (10 mol%) in [Bmim][Br] at 80 oC to furnish the corresponding 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-

one/thiones (Scheme 1). The results of this study are summarized in Table 3. It was indicated that both electron deficient and electron rich aromatic aldehydes worked well, giving high yields of the product in shorter reaction time. The reusability of the catalyst is one of the most important benefits and makes it useful for commercial applications. Thus the recovery and reusability of PISA were investigated. The PISA used for the transformation was recovered and used for further reactions and gave good yield for further reactions as shown in Figure 1.

A plausible mechanism for the formation of products 4 is shown in Scheme 3. Initially, with the aid of PISA in the presence of [Bmim][Br], intermediate 5 is formed through condensation of 5-methyl-2-phenyl-2H-pyrazol-3-ol 1b and aromatic aldehyde 2. Addition of urea/thiourea 3 to the intermediate 5 gives intermediate 6. Then, the intermediate 6 undergo heterocyclization and isomerization to furnish the corresponding 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one/thiones product 4 (Scheme 3).

4. Conclusions

In summary, we have developed a direct and efficient method for the preparation of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one/thiones using catalytic amount

of phthalimide-N-sulfonic acid (PISA) in 1-butyl-3-methylimidazolium bromide ionic liquid. The simplicity of the procedure, eco-friendly, non-volatile, easy handling are the advantages of these methods. These methods not only afford the products in excellent yields but also avoid the problems associated with pollution.

upport.

oid the

Acknowledgments

The author Mansoor is grateful to the management of C. Abdul Hakeem College (Autonomous), Melvisharam-632 509 (Tamil Nadu), India for facilities and suppc

zolium

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ro-thia

H2N X 2 3

X = O, S

N-SO3H HsC R

[Bmim][Br] 80 oC

N N X H

.......

X=O, S

Scheme 1 Synthesis of various 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one/thions

\ / CH2Cl2

* + ClSO3H -/ \

\ 0oC, r.t.,

G^n^o 2.5 h O N O

I O=S=O

yj + kci

Potassium phthalimide Phthalimide-N-sulfonic acid (PISA)

Scheme 2 Preparation of phthalimide-N-sulfonic acid /

1 -Phenyl-3-methyl-1H-pyrazole-5(4H)-one

5-Methyl-2-phenyl-2H-pyrazole-3-ol

n-sq3h q

[Bmim][Br]

NN i h

-H2O N

1 vqh H2N

N "O 1

Scheme 3 A plausible mechanism for the formation of the 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one

100 98 96 H 94 92 H 90 88 86 84 82 H 80

Reuasbility of catalyst

Number of runs

Figure 1 Recyclability of the catalyst: PISA catalyst could be reused four times without any loss of its activity

catalyst: P /

Table 1 Evaluation of catalytic activity of different catalysts for the synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one in [Bmim][Br] at

80 oCa

Catalyst

(mol %)

Time (h)

PISA PISA InCl3 BiCl3

Sulfamic acid

Cu(OTf)2

aReaction conditions: 1-phenyl-3-mi mmol), urea (1.2 mmol) at 80 bIsolated yield. cWithout [Bmim][Br

ethyl-1H-

pyrazole-5(4#)-one (1 mmol), benzaldehyde (1

Table 2 Synthesis of 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-6-one in the presence of PISA as catalyst in different reaction conditionsa

Solvent

mol %) Temperature (oC) Time (h) Yield

1 <%>b

10 11 12

1,4-Dioxane

[HNEt3][Ac]

[Bmim][Cl]

[Bmim]BF4

[Bmim]PF6

[Bmim][Br]

[Bmim][Br]

[Bmim][Br]

[Bmim][Br

[Bmim][Br]

[Bmim][Br]

[Bmim][Br]

[Bmim][Br]

[Bmim][Br]

[Bmim][Br]

[Bmim][Br]

Reflux Reflux Reflux Reflux Reflux 80 80 80 80

5.0 5.0

4 8 12 14 10 10 10 10

80 80 80 80 80 80 80 50 60 70 90

4.0 2.0 2.0 2.0 2.0 1.0 7.0 1.8 1.5 1.2 1.0 1.0 2.5 2.0 1.5 1.0

43 36 42

78 80 77 94

41 64 80 93 93 51 66

aReaction conditions: 1-phenyl-3-methyl-1H-pyrazole-5(4^)-one (1 mmol), benzaldehyde (1 mmol) and urea (1.2 mmol).

Isolated yield.

Table 3 Synthesis of various 3-methyl-1,4-diphenyl-1,4,5,7-tetrahydro-pyrazolo [3,4-d]pyrimidine-6-one/thiones in [Bmim][Br] in the presence of PISA (10 mol %)a

ield (%)b

Entry Aldehyde Urea/Thiourea

Product

Time (h) Yiel

s' nh2

Nx /CH3

<x""nh2

s' nh2

Nx /CH3

-NH S 4d

.N XH3 ^N V^ 3

HN ^ NH 4

N V^ 3

s^"nh2

HN )-<( ?—F

y nh 4

-N --CH

J >-( \—N(

Nv /CH

-NH O 4i

-N CH3

o s'^ nh2

HN S 4j

/N CH3

11 CHO O NH2

O 4k no2 1.0

12 CHO s nh2

^ NH , S 4l NO2

CHO <X"NH2

k /N. ^n' y 'CH3

HN V -O

^ NH \=/

0 4m Br

CHO o "NH2

18 CHO s nh2

-NH S 4r

aReaction conditions: 1-phenyl-3-methyl-1H-pyrazole-5(4#)-one (1 mmol), benzaldehyde (1 mmol) and urea (1.2 mmol).

Isolated yield.