Green one pot solvent-free synthesis of pyrano[2,3-c]-pyrazoles and pyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.3390/molecules15096619

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 arylidenemalononitrile 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.

Full text of DOI:10.3390/molecules15096619

Molecules 2010, 15, 6619-6629; doi:10.3390/molecules15096619
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Green One Pot Solvent-Free Synthesis of Pyrano[2,3-c]-
Pyrazoles and Pyrazolo[1,5-a]Pyrimidines
Hamad M. Al-Matar 1,*, Khaled D. Khalil 2, Aisha Y. Adam 1 and Mohamed H. Elnagdi 1
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; E-Mail: h.almatar@ku.edu.kw.
Received: 26 July 2010; in revised form: 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.
Keywords: pyranopyrazole; multi-component synthesis; aminopyrazolinone; pyrazolo[1,5-
a]pyrimidine; cyanoacetic acetic anhydride; NOE difference experiments
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,

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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 [4-12] 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 [5-10], 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 [15-18]. 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 [1-3]. 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 [5-10],
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).

Molecules 2010, 15
Scheme 1. Proposed mechanism for the formation of 2-H-pyranopyrazoles 4a-e.
6621
O
O
CH2(CN)2
NH2.NH2.H2O
OEt
H3C
NH2
NH2
O
NC
R1
NC
R1
R1- CO - R2
O
R2
R2
N
NH
O
H3C
H3C
N
H
N
R1
CN
CN
1
4
+
NH
H3C
R2
N
4a, R1 = Ph, R2 = H
3
2
4b, R1 = 4-MeO-C6H4, R2 = H
4c, R1 = 2-furfuryl, R2 = H
4d, R1 = Ph, R2 = CH3
4e, R1 = R2 = CH3
3a, R1 = Ph, R2 = H
3b, R1 = 4-MeO-C6H4, R2 = H
3c, R1 = 2-furfuryl, R2 = H
3d, R1 = Ph, R2 = CH3
3e, R1 = R2 = CH3
NC
CN
R1
R2
O
NH
H3C
N
5
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
1
however be assigned to the reaction product based on H-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

Molecules 2010, 15
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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 [5-10].
However again the rapid tautomerization to the 1H form 9 can't be excluded.
Scheme 2. Multi-component reaction of aminopyrazolone with arylidene-malononitrile.
CH2(CN)2
NH2.NH2.H2O
NCCH2CO2Et
NH2
R1 -CO- R2
NH2
N
N
O
If R2 = H
O
N
N
CN
R1
R2
CN
CN
R1
NH2
CN
7
6
R1
CN
CN
7a, R1 = Ph, R2 = H
N
+
6a, R1 = Ph
O
7b, R1 = 4-MeO-C6H4, R2 = H
7c, R1 = 2-furfuryl, R2 = H
7d, R1 = CH3, R2 = H
R2
N
H
6b, R1 = 4-MeO-C6H4
6c, R1 = 2-furfuryl
6d, R1 = CH3
3
7e, R1 = R2 = CH3
3a, R1 = Ph, R2 = H
3b, R1 = 4-MeO-C6H4, R2 = H
3c, R1 = 2-furfuryl, R2 = H
3d, R1 = CH3, R2 = H
3e, R1 = R2 = CH3
Scheme 3. Synthesis of 6-Amino-3-methyl-2H-pyrano[2,3-c]pyrazol-4-one 8.
H
O
H2N
O
N
H2N
N
NH
N
Me
Me
O
O
NC - CH2 - COOH
Ac2O
O
8
2
9
H
O
N
N
Me
NH2
10
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.

Molecules 2010, 15
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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.
O
Ph - CHO
CN
NH2 -NH2.H2O
Ph
N
Ar
+
CN
CN
Ar
13a,b
13a, Ar = C6H5
N
N
CN
13b, Ar = p-(Me2)N-C6H4-
NH2
12a,b
NH2
NH2
N
Ar
N
N
3a
Ar
+
N
N
H
CN
Ph
11
14
11a, Ar = C6H5
11b, Ar = p-(Me2)N-C6H4-
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

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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,
13
NH2), 12.08 (s, 1H, NH); C-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
1
(NH and NH2), 2189 (CN) cm-1; H-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),

Molecules 2010, 15
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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),
1
1599.7 (CO) cm-1; H-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.

Molecules 2010, 15
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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),
1
1601.6 (CO) cm-1; H 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
1
(C=O) cm-1; H-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),
1
1698.9 (C=O) cm-1; H-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, %
1
yield = 15.5); IR (KBr): υ = 3337.2 (groups of NH, NH2), 1654.6 (C=O) cm-1; H-NMR: δ = 2.26
13
(s, 3H, CH3), 4.58 (s, 1H, pyran H), 5.91 (s, 1H, NH), 8.05 (s, 2H, NH2); C-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.

Molecules 2010, 15
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7-Amino-2,5-diphenylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (12a). Pale yellow solid (m.p. 253 °C),
1
(% yield = 71); IR (KBr): υ = 3350 and 3325 (groups of NH, NH2), 2188.3 (CN), cm-1; H-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
1
(CN) cm-1; H-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.
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
1. Otto, H.H. Synthesis of Some 4H-Pyrano[2.3-c]pyrazoles. Arch. Pharm. 1974, 307, 444-447.
2. Abdou, S.; Fahmy, S.M.; Sadek, K.U.; Elnagdi, M.H. Activated nitriles in heterocyclic synthesis:
A novel synthesis of pyrano[2,3-c]pyrazoles. Heterocycles 1981, 16, 2177-2180.
3. Shestopalov, A.M.; Emel'yanova Y.M.; Shestopalov, A.A.; Rodinovskaya, L.A.; Niazimbetova,
Z.I.; Evans, D.H. Cross-condensation of derivatives of cyanoacetic acid and carbonyl compounds.
Part 1: Single-stage synthesis of 1'-substituted 6-amino-spiro-4-(piperidine-4')-2H,4H-pyrano[2,3-
c]pyrazole-5-carbonitriles. Tetrahedron 2003, 59, 7491-7496.
4. Sharanin, Y.A.; Sharanina, L.G.; Puzanova, V.V. Nitrile cyclization reactions. VII. Synthesis of
6-amino-4-aryl-3-methyl-5-cyano-1H,4H-pyrazolo[3,4-b]pyrans. Zh. Org. Khim. 1983, 19, 2609.
5. El-Tamany, E.S.; El-Shahed F.A.; Mohamed B.H. Synthesis and biological activity of some
pyrazole derivatives. J. Serb. Chem. Soc. 1999, 64, 9-18.

Molecules 2010, 15
6628
6. Girgis, N.S.; Elgemeie, G.A.M.; Nawar, G.A.M.; Elnagdi, M.H. α, β -Unsaturated nitriles in
heterocyclic synthesis: The reaction of β -(2-furanyl)- and β -(2-thienyl)acrylonitrile with active
methylene reagents. Liebigs. Ann. Chem. 1983, 1468-1475.
7. Shestopalov, A.M.; Yakubov, A.P.; Tsyganov, D.V.; Emel'yanova, Y.M.; Nesterov, V.N.
Synthesis of substituted 6-amino-4-aryl-5-cyano-2H,4H-pyrano[2,3-c]pyrazoles. Crystal and
molecular structure of 6-amino-5-cyano-3-methyl-4-(2',4',6'-triethylphenyl)-2H,4H-pyrano[2,3-
c]pyrazole. Chem. Heterocycl. Compds. 2002, 38, 1180-1189.
8. Redkin, R.G.; Shemchuk, L.A.; Chernykh, V.P.; Shishkin, O.V.; Shishkina, S.V. Synthesis and
molecular structure of spirocyclic 2-oxindole derivatives of 2-amino-4H-pyran condensed with
the pyrazolic nucleus. Tetrahedron 2007, 63, 11444-11450.
9. Rodinovskaya, L.; Shestopalov, A.; Gromova, A.; Shestopalov, A. Substituted 4-(3-cyanopyridin-
2-ylthio)acetoacetates: New convenient reagents for the synthesis of heterocycles. Synthesis 2006,
2357-2370.
10. Rodinovskaya, L.A.; Gromova, A.V.; Shestopalov, A.M.; Nesterov, V.N. Synthesis of 6-amino-4-
aryl-5-cyano-3-(3-cyanopyridin-2-ylthiomethyl)-2,4-dihydropyrano[2,3-c]pyrazoles and their
hydrogenated analogs. Molecular structure of 6-amino-5-cyano-3-(3-cyano-4,6-dimethylpyridin-
2-ylthiomethyl)-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole. Russ. Chem. Bull. 2003, 52,
2207-2213.
11. Metwally, N.H.; Abdelrazek, F.M.; Sobhy, N.A. About the reaction of α -substituted
cinnamonitriles with 3-substituted and 1,3-disubstituted pyrazolin-5-ones. Afinidad 2005, 62, 616.
12. Abdelrazek, F.M.; Metz, P.; Metwally, N.H.; El-Mahrouky, S.F. Synthesis and molluscicidal
activity of new cinnoline and pyrano [2,3-c]pyrazole derivatives. Arch. Pharm. Chem. Life Sci.
2006, 339, 456-460.
13. Lehmann, F.; Holm, M.; Laufer, S. Three-component combinatorial synthesis of novel
dihydropyrano[2,3-c]pyrazoles. J. Comb. Chem. 2008, 10, 364-367.
14. Al-Matar, H.M.; Khalil, K.D.; Meier, H.; Kolshorn, H.; Elnagdi, M.H. Chitosan as heterogeneous
catalyst in Michael additions: The reaction of cinnamonitriles with active methylene moieties and
phenols. Arkivoc 2008, xvi, 288-301.
15. Vasuki, G.; Kumaravel, K. Rapid four-component reactions in water: Synthesis of
pyranopyrazoles. Tetrahedron Lett. 2008, 49, 5636-5638.
16. Gogoi, S.; Zhao, C. Organocatalyzed enantioselective synthesis of 6-amino-5-
cyanodihydropyrano[2,3-c]pyrazoles. Tetrahedron Lett. 2009, 50, 2252-2255.
17. Litvinov, Y.M.; Shestopalov, A.A.; Rodinovskaya, L.A.; Shestopalov, A.M. New Convenient
Four-Component Synthesis of 6-Amino-2,4-dihydropyrano[2,3-c]pyrazol-5-carbonitriles and
One-Pot Synthesis of 6′-Aminospiro[(3H)-indol-3,4′-pyrano[2,3-c]pyrazol]-(1H)-2-on-5′-
carbonitriles. J. Comb. Chem. 2009, 11, 914-919.
18. Nagarajan, A.S.; Reddy, B.S.R. Synthesis of substituted pyranopyrazoles under neat conditions
via a multicomponent reaction. Synlett 2009, 12, 2002-2004.
19. Khalil, K.D.; Al-Matar, H.M.; Al-Dorri, D.M.; Elnagdi, M.H. Studies with enaminones and
enaminonitriles: Synthesis of 3-aroyl- and 3-heteroaroylpyrazolo[1,5-a]pyrimidines. Tetrahedron
2009, 65, 9421-9427.

Molecules 2010, 15
6629
20. Anwar, H.W.; Fleita, D.H.; Kolshorn, H.; Meier, H.; Elnagdi, M.H. 2H-3-Pyrazolamines as
precursors for the synthesis of polyfunctionally substituted pyrazolo[1,5-a]pyrimidines.
ARKIVOC 2006, xv, 133-141.
21. Abdel Galil, F.M.; Abdel Motaleb, R.M.; Elnagdi, M.H. Nitriles in heterocyclic synthesis: The
reaction of acetophenonylidenemalononitrile with some active methylene reagents and
acrylonitrile derivatives. Anales de Quimica, Serie C: Quimica Organica y Bioquimica 1988, 84,
19-21.
Sample Availability: Samples of the compounds 4, 6, 8 and 12a,b are available from the authors.
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