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Article

Green One Pot Solvent-Free Synthesis of Pyrano[2,3-c]-Pyrazoles and Pyrazolo[1,5-a]Pyrimidines

1
Chemistry Department, Faculty of Science, University of Kuwait, P.O. Box 5969, Safat, 13060 Kuwait
2
Chemistry Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
*
Author to whom correspondence should be addressed.
Molecules 2010, 15(9), 6619-6629; https://doi.org/10.3390/molecules15096619
Submission received: 26 July 2010 / Revised: 13 August 2010 / Accepted: 26 August 2010 / Published: 20 September 2010

Abstract

:
Pyrano[2,3-c]pyrazoles are obtained via mixing ethyl acetoacetate, hydrazine hydrate, aldehydes or ketones and malononitrile in the absence of solvent. These same products were also obtained by reacting arylidenemalononitriles 3 with 3-methyl-2-pyrazolin-5-ones. NOE difference experiments confirmed that these products exist solely in the 2H form. Similar treatments of 3-amino-2-pyrazolin-5-one with arylidene-malononitrile afforded adduct 6. Similarly mixing ethyl cyanoacetate, hydrazine hydrate, aldehydes, with malononitrile gave the same product 6. A novel synthesis of 4-oxo-4H-pyrano[2,3-c]pyrazole (8) could be achieved via reacting 3-methyl-2-pyrazolin-5-one with a mixture of cyanoacetic acid and acetic anhydride. Similar treatment of 3-aminopyrazole 11 with the benzylidene-malononitrile produced the pyrazolo[2,3-a]pyrimidines 12a,b.

Introduction

The considerable biological activities of 2-amino-4-substituted pyrano[2,3-c]pyrazole-3-carbonitriles 1, have stimulated considerable research directed for synthesis of derivatives of this ring system. These compounds were first obtained by H. Otto in 1974 [1] by adding malononitrile to 4-arylidene-3-methyl-2-pyrazolin-5-one. In 1981 [2] we reported alternate synthesis of this same product, via addition of arylidenemalononitrile to 3-methyl-2-pyrazolin-5-one and assigned the same structure, despite a claim to the contrary in a relatively recent citation of our work [3]. Since then numerous authors [4,5,6,7,8,9,10,11,12] have used this approach for the synthesis of a variety of derivatives of 1, although several have ignored our original synthesis [11,12]. Despite the fact that it could be established by X-ray that these compounds exist exclusively in the 2H form [5,6,7,8,9,10], several subsequent papers ignored this finding [11,13]. Recently we used NOE difference experiments to establish that these products also exist in the 2H form in DMSO solutions [14]. Recently derivatives of 1 have been obtained via direct one pot synthesis upon mixing ethyl acetoacetate, hydrazine hydrate, aromatic aldehydes and malononitrile [15,16,17,18]. We became interested to see if the multi-component synthesis of 1 can be extended to enable synthesis of other substituted pyranopyrazoles and if the products are obtained this way in yields comparable to those originally obtained. In the same time we have looked into a report in the literature [12] of the isolation of acyclic adducts 5 from reaction of 3-methyl pyrazoline-5-one 2 (R = CH3) and arylidene-malononitrile 3, as isolation of this product stands out as an oddity among plenty of reports indicating that derivatives of 1 are the only isolable products in these reactions [1,2,3]. We have also investigated the possible replacement of ethyl acetoacetate with ethyl cyanoacetate and 3-oxoalkanenitriles in the reported multi-component reaction. This work enabled us to introduce an efficient approach for the synthesis of pyranopyrazoles that could be shown via NOE difference experiments to exist in the 2H form. Moreover new syntheses of 1-substituted aminopyrazoline-5-ones and pyrazole[1,5-a]pyrimidines could be achieved. The one step synthesis approach seems to offer an attractive green methodology that saves both solvent and time compared to the multi-step approach.

Result and Discussion

Mixing equimolecular amounts of ethyl acetoacetate with hydrazine hydrate, benzaldehyde and malononitrile has produced 1a or 4a. This same product could be obtained in almost the same yield by reacting 2 and 3 in ethanol in the presence of chitosan or, as originally reported, in the presence of piperidine. Despite the recently claimed isolation of Michael adduct 5, this could not be repeated even when the reaction was conducted at room temperature for a short period. Only either unchanged starting materials or cyclic products were isolated. It is of value to report that after an induction period the reaction is exothermic and temperature control is somewhat difficult. Similarly when benzaldehyde was replaced with anisaldehyde or furfural in the above multi-component reaction pyranopyrazoles 4b and 4c were produced (Scheme 1). All these proved to exist, in contrast to literature reports for 4b and 4c, in the 2H form 4. These same pyranopyrazoles were also produced in the classical route via reaction of 2 and 3 (R1 = H) in the presence of chitosan or piperidine. 1H-NMR and 13C-NMR indicated the presence of one tautomer 4 (the 2H form). In addition, NOE difference experiments could readily confirm the predominance of form 4 as irradiating the CH3 signal at σ 1.9 ppm resulted in an enhanced NH signal at σ 12.17 ppm, in addition to aryl proton enhancement. Thus we conclude that the 2-H form is the predominant one and this is also supported by the previous X-ray investigations [5,6,7,8,9,10], although a fast tautomerization with the 1H form can't be excluded. We have found that a mixture of ethyl acetoacetate, hydrazine hydrate, malononitrile and acetophenone or acetone also affords pyranopyrazoles 4d,e also proven to exist in the 2H form as major product, as indicated (cf. Scheme 1).
Scheme 1. Proposed mechanism for the formation of 2-H-pyranopyrazoles 4a-e.
Scheme 1. Proposed mechanism for the formation of 2-H-pyranopyrazoles 4a-e.
Molecules 15 06619 g001
We have then looked into possible replacing ethyl acetoacetate by ethyl cyanoacetate hoping to obtain aminopyranopyrazoles, pyrazolopyrimidines or pyrazolopyridines. Although the goals were not met, the obtained results seem of value. A mixture of ethyl cyanoacetate, carbonyl compound, hydrazine hydrate and malononitrile was reacted to yield a product that could also be isolated from the reaction of 3-amino-2-pyrazoline-5-one with 3. Several structures seemed possible. Structure 7 could however be assigned to the reaction product based on 1H-NMR that revealed a CH2 singlet at σ 2.50 ppm which proved through HMBC to be linked to pyrazoline carbon at σ 41.39 ppm. It is thus assumed that initially an aminopyrazolone is formed that then reacted with an in-situ formed 3 to give adduct 7. In the cases of 7a-d, the adduct could not be isolated as it was auto-oxidized to 6.
Recently we reported that mixtures of cyanoacetic acid and acetic anhydride can effectively cyanoacylate electron rich aromatics in the absence or in presence of a catalyst [19]. Reaction of this mixture with 2 afforded also a cyanoacylated product. IR and 13C-NMR indicated involvement of cyano function in this product in a subsequent cyclization. Several structures seemed possible for this product (cf. structures 8, 10 in Scheme 3). 1H-NMR and 13C-NMR indicated the presence of only one tautomer 8 (in 2H form). Structure 8 could also be readily established based on NOE difference experiments as irradiating the Me protons at σ 2.26 ppm enhanced only the NH at σ 5.9 ppm while the NH2 protons were not affected, which excludes both structures 9 and 10, thus pointing out that the 2H form is the predominant one; this is also supported by the previous X-ray investigations [5,6,7,8,9,10]. However again the rapid tautomerization to the 1H form 9 can't be excluded.
Scheme 2. Multi-component reaction of aminopyrazolone with arylidene-malononitrile.
Scheme 2. Multi-component reaction of aminopyrazolone with arylidene-malononitrile.
Molecules 15 06619 g002
Scheme 3. Synthesis of 6-Amino-3-methyl-2H-pyrano[2,3-c]pyrazol-4-one 8.
Scheme 3. Synthesis of 6-Amino-3-methyl-2H-pyrano[2,3-c]pyrazol-4-one 8.
Molecules 15 06619 g003
We have previously reported that 11a reacts with 3a to yield 12a [20]. We now report that 12b could be directly formed via a mixture of 13b, hydrazine hydrate, benzaldehyde, and malononitrile. Although the two reactions may also yield 14, the 7-amino structure is established based on 15N HMBC where the NH2 protons showed a cross peak with sp3 hybridized N-atom. This methodology has been extensively utilized recently to establish structures of the reaction products of α,β-unsaturated nitriles with aminopyrazoles (Scheme 4).
Scheme 4. Multi-component reaction of aminopyrazole 11 with benzylidene-malononitrile 3a.
Scheme 4. Multi-component reaction of aminopyrazole 11 with benzylidene-malononitrile 3a.
Molecules 15 06619 g004

Experimental

General

Melting points were recorded on a Gallenkamp apparatus and are uncorrected. Infrared spectra (KBr) were determined on a Perkin-Elmer 2000 FT-IR system. NMR measurements were determined on a Bruker DPX spectrometer, at 600 MHz for 1H-NMR and 125 MHz for 13C-NMR, in DMSO-d6 as solvent and using TMS as internal standard. Mass spectra were measured on MS 30 and MS 9 (AEI) spectrometers, with EI 70 eV. Elemental analyses were measured by means of LECO CHNS-932 Elemental Analyzer. Copies of original data can be provided upon request.

Synthesis of pyranopyrazoles 4a-e

Method A

A mixture of ethyl acetoacetate (1.30 g, 10 mmol), hydrazine hydrate (1.00 mL, 80%), malononitrile (0.66 g, 10 mmol), carbonyl compound (benzaldehyde, p-methoxybenzaldehyde, furfural, acetophenone or acetone, 10 mmol), was mixed in presence of 5 drops of triethylamine. The mixture was refluxed for 6 h. The crude product was cooled and collected by filtration. Then, the product was recrystallized from ethanol to give the corresponding pyranopyrazoles 4a-e.

Method B

A mixture of pyrazolone (0.98 g, 10 mmol) and a carbonyl compound (benzaldehyde, p-methoxybenzaldehyde, furfural, acetophenone or acetone) arylidene (10.0 mmol) was mixed with 5 drops of triethylamine. The mixture was refluxed for 6 h. The crude product was purified as mentioned in method A.
6-Amino-3-methyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4a). White powder (m.p. 245 °C, literature [2] m.p. 245–246 °C), (2.06 g, % yield = 82); IR (KBr): υ = 3372 (groups of NH, NH2), 2190.74 (CN) cm-1; 1H-NMR: δ = 1.78 (s, 3H, CH3), 5.18 (s, 1H, C-4 pyran), 6.89 (s, 2H, NH2), 7.16–7.33 (m, 5H, phenyl), 12.11 (s, 1H, NH); 13C-NMR: δ = 9.8 (CH3), 36.2 (pyran C), 57.2 (C-CN), 120.8 (CN), 126.8, 127.5, 128.4, 135.6, 144.5 (aromatic carbons); MS, m/z (%), 252.1 (23),175.1 (M+, 100); Anal. Calcd. for C14H12N4O: C, 66.65; H, 4.79; N, 22.21. Found: C, 66.50; H, 4.65; N, 22.05.
6-Amino-4-(4-methoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4b). White powder (m.p. 210 °C, literature [2] m.p. 212 °C), (2.50 g, % yield = 88.8); IR (KBr):υ = 3483.78 (NH2), 3255.25 (NH), 2191.7 (CN) cm-1; 1H-NMR: δ = 1.79 (s, 3H, CH3), 3.73 (s, 3H, O-CH3), 4.54 (s, 1H, C-4 pyran), 6.83 (d, 2H, J = 8.2 Hz, p-anisyl-H), 6.88 (d, 2H, J = 8.2 Hz, p-anisyl-H), 7.07 (s, 2H, NH2), 12.08 (s, 1H, NH); 13C-NMR: δ = 9.8 (CH3), 35.4 (pyran C), 54.9 (CH3-O), 57.6 (ethylene C), 117.8 (CN), 105.64, 110.24, 113.74, 136.48, 142.28, 154.74, 155.72 (furan and pyrazole carbons) 160.67 (ethlyene C); MS, m/z (%), 175.1 (M+, 100), 282.1 (40); Anal. Calcd. for C15H14N4O2: C, 63.82; H, 5.10; N, 19.85. Found: C, 63.16; H, 4.89; N, 19.74.
6-Amino-4-(furan-2-yl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4c). White powder (m.p. 219 °C, literature [21] m.p. 218 °C), (2.08 g, % yield = 86); IR (KBr): υ = 3357.5 (NH2), 3315.0 (NH), 2187.8 (CN) cm-1; 1H-NMR: δ = 1.98 (s, 3H, CH3), 4.78 (s, 1H, C-4 pyran), 5.96 (s, 2H, NH2), 6.18 (d, 1H, J = 1.6 Hz, C-3 furan), 6.37 (dd, 1H, J = 1.6, J = 3.2 Hz, C-4 furan), 7.53 (d, 1H, J = 3.2 Hz, C-5 furan), 12.16 (s, 1H, NH); 13C-NMR: δ = 9.58 (CH3), 29.81 (C-4, pyran), 53.96 (C-3 pyran), 95.11 (C-3 furan), 105.64 (C-4 furan), 110.24 (C-4 pyrazoles), 120.60 (CN), 135.83 (C-3 pyrazole), 142.28 (C-5 furan), 154.81 (C-5 pyrazole), 155.72 (C-2 furan), 161.48 (C-2 pyran); MS, m/z (%), 242 (M+, 100), 175.1 (86); Anal. Calcd. for C12H10N4O2: C,59.50; H, 4.16; N, 23.13. Found: C, 59.39; H, 4.02; N, 22.97.
2-[1-(3-Methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)-1-phenyl-ethyl]-malononitrile (4d). Pale yellow crystals (m.p. 200 °C, literature [22] 200 °C), (1.40 g, % yield = 53); IR (KBr): υ = 3380, 3320, 3190 (NH and NH2), 2189 (CN) cm-1; 1H-NMR: δ = 1.76 (s, 6H, two CH3), 6.78 (s, 2H, NH2), 7.17–7.33 (m, 5H, phenyl), 12.12 (s, 1H, NH); 13C-NMR: δ = 10.1 (CH3), 27.2 (CH3), 37.4 (C-4 pyran), 64.5 (C-3 pyran), 102.5 (C-5 pyran), 118.9 (CN), 126.1, 126.4, 128.0 (aromatic carbons), 134.9 (C-6 pyran), 147.3 (C-1 phenyl), 153.9 (C-5 pyrazole), 159.9 (C-2 pyran); MS, m/z (%), 266.1 (M+, 7), 251.1 (100); Anal. Calcd. for C15H14N4O: C, 67.65; H, 5.30; N, 21.04. Found: C, 67.46; H, 5.24; N, 20.81.
6-Amino-3,4,4-trimethyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4e). Pale yellow powder (m.p. 175 °C), (1.86 g, % yield = 91); IR (KBr):υ = 3472.2 (NH), 3240 (NH2), 2185.9 (CN) cm-1; 1H- NMR: δ = 1.17 (s, 6H, two CH3), 2.24 (s, 3H, CH3), 6.65 (s, 2H, NH2), 12.05 (s, 1H, NH); 13C-NMR: δ = 11.27 (CH3), 30.60 (two CH3, pyran), 63.96 (C-4 pyran), 102.67 (C-3 pyran), 120.41 (C-4 pyrazole), 135.30 (CN), 135.35 (C-3 pyrazole), 154.15 (C-5 pyrazole), 160.41 (C-2 pyran); MS, m/z (%), 204.1 (M+, 7), 189.1 (100); Anal. Calcd. for C10H12N4O: C, 58.81; H, 5.92; N, 27.43. Found: C, 58.76; H, 5.86; N, 27.39.

Reaction of 3-amino-5-pyrazolone with arylidene-malononitriles 3

Method A

A mixture of ethyl cyanoacetate (1.13 g, 10 mmol), hydrazine hydrate (1.00 mL, 80%), malononitrile (0.66 g, 10.0 mmol) and carbonyl compound (benzaldehyde, p-methoxybenzaldehyde, furfural, acetaldehyde or acetone, 10.0 mmol) was refluxed in presence of 5 drops of triethylamine. The crude product was cooled and collected by filtration. Then, recrystallized from ethanol to give the pyrazolopyrimidine and acyclic addition products 6a-d and 7e, respectively.

Method B

A mixture of 3-amino-5-pyrazolone (0.99 g, 10 mmol) and a carbonyl compound (benzaldehyde, p-methoxybenzaldehyde, furfural, acetaldehyde or acetone) arylidene (10.0 mmol) was refluxed for 3 h in presence of 5 drops of triethylamine. The crude product was purified as in method A.
7-Amino-2-oxo-5-phenyl-1,2-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile (6a). Pale yellow crystals (m.p. 288 °C), (1.4 g, % yield = 56); IR (KBr): υ = 3244.7 (br. bands, NH, NH2), 2217.7 (CN), 1599.7 (CO) cm-1; 1H-NMR: δ = 2.50 (s, 2H, pyrazole CH2), 7.48–7.57 (m, 5H, phenyl), 8.49 (s, 2H, NH2); 13C-NMR: δ = 41.4 (C-4 pyrazolone), 74.3 (C-CN), 116.3 (CN), 115.5, 127.9, 128.6, 130.2, 134.6, 156.7 (aromatic carbons), 159.2 (C-NH2), 159.6 (C=O); MS, m/z (%), 251.1 (M+, 100); Anal. Calcd. For C13H9N5O: C, 62.15; H, 3.61; N, 27.87. Found: C, 61.80; H, 3.52; N, 27.68.
2-[(3-Amino-5-oxo-4,5-dihydropyrazol-1-yl)-(4-methoxyphenyl)-methylene]-malononitrile (6b). White powder (m.p. 314 °C), (1.65 g, % yield = 59); IR (KBr): υ = 3396.0, 3319.8 (NH2), 2215.8 (two CN), 1640 (C=O) cm-1; 1H-NMR: δ = 3.85 (s, 3H, CH3), 5.65 (s, 2H, CH2), 7.09 (d, 2H, J = 8 Hz, p-anisyl H), 7.47 (d, 2H, J = 8 Hz, p-anisyl H), 8.44 (s, 2H, NH2); 13C-NMR: δ = 55.3 (CH2, pyrazolone), 74.2 (C(CN)2), 86.2 (CH3), 116.9 and 117.6 (Two CN), 113.9, 126.4, 129.8, 156.6, 159.2 (aromatic carbons), 159.3 (C=O), 160.7 (C=C, aliphatic), 153.39 (C-3 pyrazole), 162.35 (C-5 pyrazoles); MS, m/z (%), 281.1 (M+, 100); Anal. Calcd. For C14H11N5O2: C, 59.78; H, 3.94; N, 24.90; Found: C, 59.74; H, 3.89; N, 24.49.
2-[(3-Amino-5-oxo-4,5-dihydropyrazol-1-yl)-furan-2-yl-methylene]-malononitrile (6c). White powder (m.p. 320 °C), (1.28 g, % yield = 53); IR (KBr): υ = 3279.36 (br. Bands, NH, NH2), 2210 (CN), 1601.6 (CO) cm-1; 1H NMR (DMSO-d6): δ = 5.65 (s, 2H, CH2 pyrazolone), 6.82 (d, 1H, J = 1.8 Hz, C-3 furan), 7.34 (dd, 1H, J = 1.8 Hz, J = 3.1 Hz, C-4 furan), 8.08 (d, 1H, J = 3.1 Hz, C-5 furan), 8.45 (s, 2H, NH2); 13C NMR (DMSO-d6): δ = 72.4 (CH2 pyrazolone), 84.5 (C(CN)2), 114.5 (C-3 furan), 117.7 (C-4 furan), 118.2 (CN), 118.5 (CN), 146.7 (C-5 furan), 147.1 (C-3 pyrazoles), 148.1 (C-2 furan), 159.1 (C=O), 161.4 (C=C(CN)2); MS, m/z (%), 241.0 (M+, 100), 197.0 (36); Anal. Calcd. For C11H7N5O2: C, 54.77; H, 2.93; N, 29.03. Found: C, 54.57; H, 2.84; N, 28.69.
2-[1-(3-Amino-5-oxo-4,5-dihydropyrazol-1-yl)-ethylidene]-malononitrile (6d). White powder (m.p. 320 °C), (1.18 g, % yield = 63); IR (KBr):υ = 3316 (br. bands, NH, NH2), 2221.6 (two CN), 1651.7 (C=O) cm-1; 1H-NMR: δ = 2.35 (s, 3H, CH3), 5.55 (s, 2H, CH2), 8.36 (s, 2H, NH2); 13C- NMR: δ = 19.9 (CH3), 74.5 (CH2 pyrazoles), 86.7 (C(CN)2, 116.7, 117.1 (two CN), 156.4 (C-3 pyrazole), 158.1 (C-5 pyrazole), 159.1 (C=C(CN)2); MS, m/z (%), 189.1 (M+, 100), 160.1 (33); Anal. Calcd. For C8H7N5O: C, 50.79; H, 3.73; N, 37.02. Found: C, 50.49; H, 3.70; N, 36.72.
2-[1-(3-Amino-5-oxo-4,5-dihydropyrazol-1-yl)-1-methyl-ethyl]-malononitrile (7e). White powder (m.p. 202 °C), (1.33 g, % yield = 65); IR (KBr): υ = 3413.4, 3344.9 (NH2), 2252.5, 2174.4 (two CN), 1698.9 (C=O) cm-1; 1H-NMR: δ = 1.11 (s, 3H, CH3), 1.27 (s, 3H, CH3), 4.58 (s, 1H, CH(CN)2), 5.22 (s, 2H, CH2), 6.69 (s, 2H, NH2); 13C-NMR: δ = 24.1 (CH3), 26.5 (CH3), 32.5 (C(CN)2), 47.4 (CH2 pyrazole), 61.8 (C(CH3)2), 115.3, 117.5 (two CN), 153.4 (C-3 pyrazole), 162.4 (C-5 pyrazoles); MS, m/z (%), 205.1 (M+, 24), 190.1 (100); Anal. Calcd. For C9H11N5O: C, 52.67; H, 5.40; N, 34.13. Found: C, 52.48; H, 5.18; N, 33.68.

Cyanoacetylation of methylpyrazolone 2

A mixture of cyanoacetic acid (0.85 g, 10 mmol) and acetic anhydride (1.20 g, 10 mmol) was heated for 20 min. and then mixed with methylpyrazolone 2 (0.98 g, 10 mmol). The mixture was refluxed for 6 h. The crude product was treated with cold water and the solid product was then collected by filtration. The product was recrystallized from ethanol to give the corresponding pyranopyrazole 8.
6-Amino-3-methyl-2H-pyrano[2,3-c]pyrazol-4-one (8). Light brown crystals (m.p. 234 °C), (0.26 g, % yield = 15.5); IR (KBr): υ = 3337.2 (groups of NH, NH2), 1654.6 (C=O) cm-1; 1H-NMR: δ = 2.26 (s, 3H, CH3), 4.58 (s, 1H, pyran H), 5.91 (s, 1H, NH), 8.05 (s, 2H, NH2); 13C-NMR: δ = 14.3 (CH3), 65.9 (C=CNH2), 88.5, 150.5, 150.9, 150.9 (aromatic carbons), 152.3 (C-NH2), 158.1 (C=O); MS, m/z (%),165.1 (M+, 100), 98 (70); Anal. Calcd. For C7H7N3O2: C, 50.91; H, 4.27; N, 25.44; Found: C, 50.01; H, 4.13; N, 24.93.

Synthesis of pyrazolopyrimidines 12a,b

A mixture of oxoalkanenitriles 13a,b (10 mmol) hydrazine hydrate (1.00 mL, 80%), benzaldehyde (1.06 g, 10 mmol), and malononitrile (0.66 g, 10 mmol) was refluxed for 4 h. The solid product, so formed, was recrystallized from ethanol.
7-Amino-2,5-diphenylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (12a). Pale yellow solid (m.p. 253 °C), (% yield = 71); IR (KBr): υ = 3350 and 3325 (groups of NH, NH2), 2188.3 (CN), cm-1; 1H-NMR: δ = 5.38 (s, 2H, NH2), 6.92 (s, 1H, C-4, pyrazole), 7.12–7.68 (m, 10H, two phenyl); 13C-NMR: δ = 86.4 (C-CN), 92.6 (C-4, pyrazole), 117.6 (CN), 122.1, 124.7, 129.9, 130.5, 132.7, 139.6, 140.0, 142.4, 144.2 (aromatic carbons); MS, m/z (%), 311.1 (M+, 100), 77 (71); Anal. Calcd. For C19H13N5: C, 73.30; H, 4.21; N, 22.49; Found: C, 73.16; H, 4.13; N, 22.24.
7-Amino-2-(4-(dimethylamino)phenyl)-5-phenylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (12b). Pale yellow solid (m.p. 270 °C), (% yield = 75); IR (KBr): υ = 3340 and 3300 (groups of NH, NH2), 2183.0 (CN) cm-1; 1H-NMR: δ = 2.31 (s, 6H, two CH3), 5.27 (s, 2H, NH2), 7.18 (s, 1H, C-4, pyrazole), 7.21 (d, 2H, J = 8.0 Hz, p-aryl ring), 7.64 (m, 5H, phenyl), 7.84 (d, 2H, J = 8.0 Hz, p-aryl ring); 13C-NMR: δ = 37.6 (CH3), 82.9 (C-CN), 83.1 (C-4, pyrazole), 117.8 (CN), 113.5, 119.2, 121.4, 128.4, 128.8, 131.7, 132.4, 138.3, 139.6, 140.3, 143.6 (aromatic carbons); MS, m/z (%), 354.0 (M+, 100), 77 (38); Anal. Calcd. For C21H18N6: C, 71.17; H, 5.12; N, 23.71; Found: C, 69.94; H, 5.06; N, 23.31.

Conclusions

Efficient multi-component syntheses of pyrano[2,3-c]pyrazoles and pyrazolo[1,5-a] pyrimidines were achieved. The scope of these approaches is promising. The yields in multi-component synthetic approaches are almost the same as those utilizing our original synthetic approach but they are greener, avoiding use of solvent, separation and purification steps. Chitosan could be used as a catalyst, thus replacing the homogeneous catalysis of our original syntheses.

Supplementary Materials

Supplementary File 1

Acknowledgements

The support of this work was received from University of Kuwait by research grant (SC04/06) and the facilities of Analab/SAF by research grant (GC01/01), (GC01/03) and (GS03/01) are gratefully acknowledged.

References

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  • Sample Availability: Samples of the compounds 4, 6, 8 and 12a,b are available from the authors.

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MDPI and ACS Style

Al-Matar, H.M.; Khalil, K.D.; Adam, A.Y.; Elnagdi, M.H. Green One Pot Solvent-Free Synthesis of Pyrano[2,3-c]-Pyrazoles and Pyrazolo[1,5-a]Pyrimidines. Molecules 2010, 15, 6619-6629. https://doi.org/10.3390/molecules15096619

AMA Style

Al-Matar HM, Khalil KD, Adam AY, Elnagdi MH. Green One Pot Solvent-Free Synthesis of Pyrano[2,3-c]-Pyrazoles and Pyrazolo[1,5-a]Pyrimidines. Molecules. 2010; 15(9):6619-6629. https://doi.org/10.3390/molecules15096619

Chicago/Turabian Style

Al-Matar, Hamad M., Khaled D. Khalil, Aisha Y. Adam, and Mohamed H. Elnagdi. 2010. "Green One Pot Solvent-Free Synthesis of Pyrano[2,3-c]-Pyrazoles and Pyrazolo[1,5-a]Pyrimidines" Molecules 15, no. 9: 6619-6629. https://doi.org/10.3390/molecules15096619

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