Synthesis of some new pyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.3184/030823408X287096

Pyrazolo[1,5-a]pyrimidines were synthesised from the the reaction of β-diketone, β-keto ester, 1,2-disubstituted acrylonitrile or sodium (3-oxocycloalkylidene) methenolate. Elemental analysis, spectral data and alternative synthesis route elucidated structures of the newly synthesised compounds.

Full text of DOI:10.3184/030823408X287096

26 RESEARCH PAPER
JANUARY, 26–31
JOURNAL OF CHEMICAL RESEARCH 2008
Synthesis of some new pyrazolo[1,5-a]pyrimidines
Sayed A. Ahmeda, Abdou O. Abdelhamidb*, Ahmed H. H. El-Ghandoura, Mahmoud A. Mohamedc
and Basant M. Mohameda
aDepartment of Chemistry, Faculty of Science, Beni-Suef University, Egypt
bDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
cDepartment of Textile, Faculty of Industrial Education, Beni-Suef University, Egypt
Pyrazolo[1,5-a]pyrimidines were synthesised from the the reaction of b-diketone, b-keto ester, 1,2-disubstituted
acrylonitrile or sodium (3-oxocycloalkylidene) methenolate. Elemental analysis, spectral data and alternative
synthesis route elucidated structures of the newly synthesised compounds.
Keywords: pyrazolo[1,5-a]pyrimidines
CH3
The importance of uracil and its annelated derivatives is well
recognised by synthetic1-6 as well as biological7-12 chemists.
Pyrazolo[3,4-d]pyrimidines constitute a class of naturally
occurring fused uracils that possess diverse biological
activities.13 Also, purines are widely used in the CNS
stimulation in vivo,14-30 antagonists, antiviral, antibacterial31
and in the treatment of gout.32
NH2
NH
N
AcOH
X
Y
(CH3CO)2CH2
+
N
CH3
N
N
Y
X
1a-d
2a-d
(1,2)a, X = 1,3-benzothiazol-2-yl, Y = methylthio
Results and discussion
(1,2)b, X = 1,3-benzothiazol-2-yl, Y = phenylamino
(1,2)c, X = 1,3-benzoimidazol-2-yl, Y = phenylamino
(1,2)d, X = cyano, Y =phenylamino
Treatment of 4-(1,3-benzothiazol-2-yl)-3-(methylthio)-1H-
pyrazol-5-amine (1a) with pentane-2,4-dione in boiling
acetic acid under reflux afforded 3-(1,3-benzothiazol-2-yl)-
5,7-dimethyl-2-(methylthio)pyrazolo[1,5-a]pyrimidine (2a)
(Scheme 1). The structure of 2a was established by elemental
analysis and spectral data. Thus, IR (cm-1) spectrum of 2a
revealed bands at 1617 (C=N) and 1594 (C=C). Its mass
spectrum showed peaks at m/z = 328 [M+ + 2, 18.7%], 327 [M+
+ 1, 33.3%], 326 [M+, 100.0%], 279 [M+-SCH3, 51.6%], 199
[M+-C5H7N, 14.6%], 146 [5.9%], 108 [35.21%]. Similarly,
pentane-2,4-dione reacted with 1b–d in boiling acetic acid to
give pyrazolo[1,5-a]pyrimidine derivatives 2b–d, respectively
(Scheme 1).
Analogously, 1a reacted with 1-phenylbutan-1,3-dione in
boiling acetic acid afforded product seemed to be 3-(1,3-
benzothiazol-2-yl)-7-methyl-2-(methylthio)-5-phenyl-
pyrazolo[1,5-a]pyrimidine3aortheisomer3-(1,3-benzothiazol-2-
yl)-5-methyl-2-(methylthio)-7-phenylpyrazolo[1,5-a]pyrimidine
4a (Scheme 2). The structure of the product was elucidated by
elemental analysis, spectral data and MO calculations.
Scheme 1
1
Thus, H NMR spectrum of compound 3a showed signals
at δ = 2.68 (s, 3H, CH3), 2.77 (s, 3H, SCH3), 6.87 (s, 1H,
pyrimidine H-5), 7.23–8.14 (m, 9H, ArHs). Structure 4a was
ruled out on the basis of MO calculation using Hyper-Chem
(semi-empirical method AM1) (Scheme 2).
Also, treatment of ethyl 3-oxobutanoate with 1a in boiling
acetic acid gave one isolable product which according to
TLC seemed to be 7-methyl-2-methylthio-5-oxo-3-(1,3-
benzothiazol-2-yl)pyrazolo[1,5-a]pyrimidine 5a or 5-methyl-
2-methylthio-7-oxo-3-(1,3-benzothiazol-2-yl) pyrazolo[1,5-a]
pyrimidine 6a (Scheme 3). The structure of the product was
confirmed by elemental analysis, spectral data, alternative
synthesis method and MO calculation. Thus, the IR (cm-1)
spectrum of compound 5a revealed bands at 3247 (NH),
1683(CO), 1619 (C=N) and 1577 (C=C). The 1H NMR
C6H5
N
X
N
CH3
N
NH2
NH
Scheme 1
C6H5COCH2COCH3
Y
3a-d
CH3
X
+
N
N
Y
X
N
C6H5
N
1a-d
(1,3)a, X = 1,3-benzothiazol-2-yl, Y = methyl tho
(1,3)b, X = 1,3-benzothiazol-2-yl, Y = phenylamino
(1,3)c, X = 1,3-benzoimidazol-2-yl, Y = phenylamino
(1,3)d, X = cyano, Y =phenylamino
Y
4a-d
Binding energy for 3a = -4812.563 kcal/mol
Heat of formation for 3a = 194.5587 kcal/mol
Binding energy for 4a = -4810.062 kcal/mol
Heat of formation for4a = 197.060 kcal/mol
Scheme 2
* Correspondent. E-mail: abdelhamid45@gmail.com
PAPER: 07/4947

JOURNAL OF CHEMICAL RESEARCH 2008 27
O
HN
NHCOCH2COCH3
NH2
NH
X
X
- H2O
- C2H5OH
N
NH
N
X
CH3
CH3COCH2COOC2H5
+
N
Y
N
Y
Y
5a-d
7a-d
1a-d
(1,5-7)a, X = 1,3-benzothiazol-2-yl, Y = methylthio
(1,5-7)b, X = 1,3-benzothiazol-2-yl, Y = phenylamino
(1,5-7)c, X = 1,3-benzoimidazol-2-yl, Y = phenylamino
(1,5-7)d, X = cyano, Y =phenylamino
CH3
HN
Binding energy for 5a = -3722.33 kcal/mol
Heat of formation for 5a =110.6034 kcal/mol
Binding energy for 6a = -3720.349 kcal/mol
Heat of formation for 6a = 112.5839 kcal/mol
X
N
O
N
Y
5a-d
Scheme 3
spectrum of compound 5a showed signals at δ = 2.49 (s, 3H,
CH3), 2.82 (s, 3H, SCH3), 5.82 (s, 1H, pyrimidine C-5), 7.36
(s, 1H, NH) and 7.38–7.95 (m, 4H, ArHs). Structure 6a was
rejected by MO calculations data using Hyper-Chem (semi-
empirical method AM1) (Scheme 3).
From the foregoing result the reaction occurred via the
intermediate 7a by elimination of ethanol. The latter was
readily cyclised to give 5a via elimination of one molecule of
water (Scheme 3). Thus, treatment of 1a with acetoacetanilide
in boiling acetic acid afforded a product identical in all aspects
(m.p., mixed m.p. and spectra) with 5a. Similarly, treatment of
1b–d with ethyl 3-oxobutanoate (or acetoacetanilide) in boiling
acetic acid gave pyrazolo[1,5-a] pyrimidines 5b–d, respectively.
Also, treatment of 1a with α-cyanocinnamonitrile in boiling
ethanol under reflux afforded 7-amino-3-(1,3-benzothiazol-
2-yl)-2-(methylthio)-5-phenylpyrazolo-[1,5-a]pyrimidine-6-
carbonitrile (11a) (Scheme 4).
Structure 11a was elucidated by elemental analysis, spectral
data and alternative synthesis method. Thus, IR revealed bands
1
at 3455, 3306 (NH2); 2187 (CN) and 1603 (C=C). H NMR
showed signals at δ = 2.68 (s, 3H, SCH3); 5.46 (s, 2H, NH2) and
7.21–8.34 (m, 9H, ArHs). Also, compound 12a, which prepared
via reaction of 1a with benzaldehyde in sodium ethoxide
solution, reacted with malononitrile in ethanol containing
catalytically amount of piperidine to give product identical in
all aspects (m.p., mixed m.p. and spectra) with 11a.
The reaction seemed to proceed through Michael
addition between 1a and benzylidenemalononitrile to give
intermediate 10a which underwent cyclisation via addition
of NH hydrogen to the nitrile function followed by
autoxidation to give the final product 11a. Also, treatment of
the appropriate arylidenemalononitrile with the appropriate
1a–d in ethanol and catalytically amount of piperidine to
give 11b–j.
NH2
N
CN
NH2
NCH(Ar)CH(CN)2
X
X
N
Ar
N
N
Y
Y
9
NH2
NH
X
ArCH=C(CN)2
+
NHCOCH2COCH3
N
Y
X
NH
N
1a-d
ArCHO
Ar
Y
10
N
X
NH
Ar
N
2
2
Y
N
CN
12a-j
Y
N
NH2
N
X
11a-j
(1,9-12)f, X = 1,3-benzothiazol-2-yl, Y = methylthio, Ar =4-CH3C6H4
(1,9-12)g, X = 1,3-benzothiazol-2-yl, Y = phenylamino, Ar =4-CH3C6H5
(1,9-12)h, X = 1,3-benzoimidazol-2-yl, Y = phenylamino, A r=4-CH3C6H4
(1,9-12)i, X = cyano, Y =phenylamino, Ar =4-CH3C6H4
(1,9-12)a, X = 1,3-benzothiazol-2-yl, Y = methylthio, Ar =C6H5
(1,9-12)b, X = 1,3-benzothiazol-2-yl, Y = phenylamino, Ar =C6H5
(1,9-12)c, X = 1,3-benzoimidazol-2-yl, Y = phenylamino, A r=C6H5
(1,9-12)d, X = cyano, Y =phenylamino, Ar = C6H5
(1,9-12)e, X = cyano, Y = methylthio, Ar = C6H5
(1,9-12)j, X = cyano, Y = methylthiol, Ar = 4-CH3C6H4
Scheme 4
PAPER: 07/4947

28 JOURNAL OF CHEMICAL RESEARCH 2008
Table 1 Characterisation data of the newly synthesised compounds
Compd.
no.
Mp./°C
solvent
Colour
Yield/%
Mol. formula
(M.Wt.)
Calcd./Found%
C
H
N
S
2a
249
Dioxan
211
Dioxan
243
Dioxan
266
Dioxan
239
Dioxan
203
EtOH
219
dil.AcOH
237
Yellow
89
Pale yellow
85
Pale yellow
85
White
87
Pale yellow
95
Yellow
93
Yellow
84
Yellow
96
Pale yellow
88
Pale yellow
82
White
83
White
89
Yellow
92
Yellow
95
Yellow
98
Pale yellow
87
Pale yellow
97
Yellow
83
Yellow
91
Yellow
90
Pale yellow
90
Pale yellow
89
Yellow
75
Pale yellow
65
Yellow
65
Yellow
85
Yellow
80
Yellow
70
Yellow
78
Yellow
70
C16 H14 N4 S2
326.44
C21 H17N5 S
371.47
C21H18N6
354.42
C15H13N5
263.30
C21H16N4S2
388.52
C26H19N5S
433.54
C26H20N6
416.9
C20H15N5
325.38
C15H12N4OS2
328.42
C20H15N5OS
373.44
C20H16N6O
356.39
C14H11N5O
265.28
C21H14N6S2
414.51
C26H17N7S
459.54
C26H18N8
442.49
C20H13N7
351.37
C15H10N6S
306.35
C22H16N6S2
428
C27H19N7S
473.54
C27H20N8
456.51
C21H15N7
365.40
C16H12N6S
320.38
C17H14N4S2
338.46
C18H16N4S2
352.48
C20H20N4S2
380.54
C22H17N5S
383.48
C23H19N5S
397.51
C25H23N5S
425.56
C22H18N6
366.43
C23H20N6
380.46
C25H24N6
408.51
C16H13N5
275.32
58.87
58.95
67.90
67.95
71.17
71.25
68.43
68.65
64.92
64.70
72.03
72.33
74.98
75.20
73.83
74.01
54.86
55.01
64.33
64.13
67.40
67.55
63.39
63.25
60.85
60.39
67.96
68.20
70.58
70.41
68.37
68.31
58.81
59.00
61.66
61.43
68.48
68.40
71.04
70.83
69.03
69.33
59.98
59.68
60.33
60.35
61.33
61.35
63.13
63.15
68.91
68.92
69.50
69.53
70.56
70.57
72.11
72.13
72.61
72.63
73.51
73.53
69.80
69.83
70.57
70.56
71.90
71.93
57.37
57.32
58.99
58.70
61.74
61.70
4.32
4.40
4.61
4.62
5.12
5.05
4.98
5.15
4.15
4.02
4.42
4.35
4.84
4.75
4.65
4.54
3.68
3.39
4.05
4.31
4.53
4.75
4.18
4.39
3.40
3.68
3.73
3.64
4.10
4.40
3.73
4.00
3.29
3.40
3.76
3.91
4.04
4.22
4.42
4.54
4.14
4.01
3.78
3.90
4.17
4.15
4.58
4.56
5.30
5.28
4.47
4.45
4.82
4.85
5.45
5.47
4.95
4.93
5.30
5.32
5.92
5.95
4.76
4.75
5.23
5.25
6.03
6.02
4.38
4.40
4.95
4.98
5.92
5.98
17.16
17.22
18.85
18.79
23.71
23.62
26.66
26.47
14.42
14.25
16.15
16.36
20.18
20.06
21.52
21.76
17.06
16.87
18.75
18.52
23.58
23.38
26.40
26.19
20.27
20.51
21.34
21.54
25.32
25.45
27.90
27.73
27.43
27.55
19.61
19.69
20.70
20.90
24.55
24.72
26.83
26.97
26.23
26.45
16.55
16.56
15.90
15.91
14.72
14.71
18.26
18.25
17.62
17.60
16.46
16.45
22.94
22.95
22.09
22.10
20.57
20.55
25.44
25.42
24.21
24.20
22.07
22.07
24.33
24.23
22.93
20.60
20.57
20.60
19.64
19.70
8.63
2b
8.72
2c
–
2d
–
3a
16.51
16.75
7.40
7.56
3b
3c
–
3d
Dioxan
259
–
5a
19.53
19.80
8.59
8.73
Dioxan
>300
DMF
>300
DMF
>300
DMF
>300
Dioxan
>300
Dioxan
>300
Dioxan
>300
Dioxan
275
EtOH
>300
Dioxan
>300
Dioxan
>300
Dioxan
>300
Dioxan
>300
AcOH
240
EtOH
240
EtOH
203
EtOH
>300
EtOH
285
EtOH
225
Dioxan
270
Dioxan
375
EtOH
233
EtOH
>300
Dioxan
215
5b
5c
–
5d
–
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
16a
16b
16c
16d
16e
16f
16g
16h
16i
16j
16k
16l
16m
16n
16o
15.47
15.31
6.98
6.71
–
–
10.47
10.70
14.96
15.27
6.77
6.95
–
–
10.01
9.85
18.95
18.97
18.19
18.20
16.85
16.60
8.36
8.38
8.07
8.05
7.54
7.52
–
–
–
–
–
Yellow
65
Yellow
80
Yellow
75
White
65
White
85
White
75
White
70
C17H15N5
289.34
C19H19N5
317.40
C11H10N4S
230.29
C12H12N4S
244.32
EtOH
215
Dioxan
160
EtOH
120
EtOH
115
Dioxan
–
13.92
14.00
13.12
11.80
11.77
11.80
C14H16N4S
272.37
PAPER: 07/4947

JOURNAL OF CHEMICAL RESEARCH 2008 29
Finally, treatment of sodium (2-oxocycloalkylidine)
methanolate 14 with the appropriate 3-aminopyrazoles
1a,b,d,e in the presence of piperidine acetate and acetic acid
afforded pyrazolo[1,5-a]pyrimidines 16a–o (Scheme 5).
The structure of the product 16a was confirmed by elemental
analysis and spectral data. Thus, IR spectroscopy revealed bands
at 1685 (C=N) and 1380 (CH3). Its mass spectrum showed
peaks at m/z = 340 [M+ +2, 28.4%], 339 [M+1, 46.4%], 338 [M+,
100.0%], 305 [M+-SH, 72.5%], 199 [17.3%], 148 [5.9%].
The reaction seemed to be via the initial nucleophilic attack
by the exocyclic amino group at the carbonyl group, which
formed in situ from 13a with water, followed by cyclisation
and elimination of one molecule of water leading to the
formation of the product 16a (Scheme 5). The suggestion of
the formation of the alternative isomeric product 18a is based
on the initial attack of endocyclic amino group at the formyl
group. The latter suggestion is excluded due to the higher
nucleophilicity of the exocyclic primary amino group than the
endocyclic amino group and our previously report.33
Table 2 Spectra of some selected synthesised compounds
Comp.
no.
Spectral data
2b
2c
2d
3b
3c
3d
5b
5c
5d
IR: 3067, 2960 (CH),1617 (C=N), 1594 (C=C) and 1370 (CH3). 1H NMR: 2.60 (s, 3H, CH3); 2.71 (s, 3H, CH3); 6.48 (s, 1H,
pyrimidine H-5); 7.02–8.00 (m, 9H, ArHs); 10.2 (s, 1H, NH).
IR (cm-1): 3384, 3281 (NHs) and 1596 (C=C). 1H NMR: insoluble Ms: 355 [M+ + 1, 24.7%]; 354 [M+, 100%] and 312[M+–C2H4N,
14.2%].
IR (cm-1): 3320 (NH); 2211 (C≡N); and 1605 (C=C). 1H NMR: 2.72 (s, 3H, CH3); 2.86 (s, 3H, CH3); 6.77 (s, 1H, pyrimidine H-5);
7.14–7.74 (m, 5H, ArHs) and 7.76 (s, 1H, NH).
IR: 3267 (NH) and 1599 (C=C). 1H NMR: 2.74 (s, 3H, CH3); 6.80 (s, 1H, pyrimidine C-5); 7.27–8.18 (m, 14H, ArHs) and 10.30
(s, 1H, NH).
IR: 3296, 3355 (NHs) and 1600 (C=C). 1H NMR: insoluble MS: 417 [M+ + 1, 92.2%], 416 [M+, 100.0%], 374 [M+–C2H4N,
51.7%], 298 [17.8%], 208 [65.5%].
IR: 3316 (NH); 2219 ((C≡N)) and 1601 (C=C). 1H NMR: 2.68 (s, 3H, CH3); 6.80 (s, 1H, pyrimidineH-5); 6.88–8.08 (m, 10H,
ArHs) and 8.20 (s, 1H, NH).
IR: 3425, 3259 (NHs); 1669 (CO); 1628 (C=N) and 1602 (C=C). 1H NMR: insoluble MS: 373 [M+, 100.0%], 340 [M+–CH5O,
12.8%], 173 [11.8%], 77 [19.8%].
IR: 3239, 3146, 3082 (NHs); 1666 (CO); 1601(C=N) and 1562 (C=C). 1H NMR: 2.42 (s, 3H, CH3); 5.76 (s, 1H, pyrimidine H-5);
6.90–7.68 (m, 9H, ArHs); 7.76 (s, br., 1H, NH) 7.79 (s, br., 1H, NH) and 10.34 (s, 1H, NH).
IR: 3411, 3297(NHs); 1669 (CO); 1624 (C=N) and 1597 (C=C). 1H NMR: 2.30 (s, 3H, CH3); 5.79 (s, 1H, pyrimidine H-5); 6.89–
7.76 (m, 5H, ArHs); 9.18 (s, 1H, NH) and 13.05 (s, br., 1H, NH).
11b
11c
IR: 3434, 3302, 3233 (NH, NH2); 2213 (CN); 1620 (C=N) and 1594 (C=C). 1H NMR: insoluble
IR: 3440, 3377, 3301 (NH, NH2); 2208 (CN); 1628 (C=N) and 1596 (C=C). 1H NMR): 6.99–8.07 (m, 14H, ArHs); 8.88 (s, 2H,
NH2); 10.57 (s, 1H, NH) and 11.65 (s, 1H, NH).
11d
11e
11f
IR: 3445, 3376, 3312 (NH, NH2); 2216, 2187 (CNs); 1663 (C=N) and 1604 (C=C). 1H NMR: 6.97–7.96 (m, 10H, ArHs); 8.99
(s, 2H, NH2) and 9.49 (s, 1H, NH).
IR: 3372, 3302 (NH2); 2219 (CN); 1644 (C=N) and 1599 (C=C). 1H NMR: 2.76 (s, 3H, SCH3) 7.60–7.80 (m, 5H, ArHs) and 9.28
(s, 2H, NH2).
IR: 3290, 3230 (NH, NH2); 2210 (CN); and 1595 (C=C). 1H NMR: insoluble MS: [M+ + 2, 28.4%], 429 [M+ + 1, 46.4%], 428 [M+,
45.6%], 382 [M+-CH3SH, 19.6%], 339 [M+ –(CH3SH + CN2H3)100.0%], 292 [57.6%] and 200 [13.3%].
IR: 3445, 3297, 3236 (NH, NH2); 2211 (CN); and 1592 (C=C). 1H NMR: insoluble
11g
11h
11i
IR: 3406, 3317, 3178 (NH, NH2); 2218 (CN); 1635 (C=N) and 1600 (C=C).
IR: 3450, 3369, 3312 (NH, NH2); 2187, 2216(CNs) and 1601(C=C). 1H NMR: 2.49 (s, 3H, CH3) 6.95–7.95 (m, 9H, ArHs); 8.95
(s, 2H, NH2) and 9.45 (s, 1H, NH).
11j
IR: 3374, 3301 (NH2); 2219 (CNs); 1646 (C=N) and 1592 (C=C). 1H NMR: 2.40 (s, 3H, CH3); 2.75 (s, 3H, SCH3); 7.34–7.77
(m, 4H, ArHs) and 9.12 (s, 2H, NH2).
16b
16c
16d
16e
16f
IR: 1420.3 (CH3). MS: 354 [M+ + 2, 11.7%], 353 [M+ + 1, 24.1%], 352 [M+, 100.0%], 319 [M+-SH, 66.7%]. 1H NMR: 1.6 (t, 2H,
CH2); 2.0 (m, 2H, CH); 2.5 (s, 3H, CH3); 2.8 (t, 2H, CH2); 3.2 (m, 2H, CH2); 7.2–8.2 (m, 5H, ArHs); 8.4 (s, 1H, pyrimidine H-4).
IR: 1422 (CH3). 1H NMR: 1.4 (m, 4H, 2CH2); 1.8 (m, 2H, CH2); 2.0 (m, 2H, CH2); 2.7 (s, 3H, CH3); 2.8 (t, 2H, CH2); 3.4 (t, 2H,
CH2); 7.2–8.2 (m, 5H, ArHs); 8.4 (s, 1H, pyrimidine H-4).
IR: 3379.1(NH). 1H NMR: 2.0 (t, 2H, CH2); 2.3 (m, 2H, CH2); 2.7 (t, 2H, CH2); 6.6–8.2 (m, 10H, ArHs); 10.25 (s, 1H, NH); 8.5
(s, 1H, pyrimidine H-4).
IR: 3278.8 (NH). 1H NMR: 1.9 (m, 2H, CH2); 2.8 (m, 2H, CH2); 3.3 (t, 4H, 2CH2); 7.0–8.2 (m, 10H, ArHs); 8.9 (s, 1H, pyrimidine
C-H); 10.2 (s, 1H, NH).
IR: 3268 (NH). 1H NMR: 1.5 (m, 2H, CH2); 1.8 (m, 2H, CH2); 2.1 (m, 2H, CH2); 2.8 (m, 2H, CH2); 3.1 (t, 2H, CH2); 3.4 (t, 2H,
CH2); 6.9–8.1 (m, 10H, ArHs); 8.4 (s, 1H, pyrimidine H-4); 10.3 (s, 1H, NH).
16g
16h
16i
IR: 3278.8, 3371.3 (NH). MS: 367 [M+ + 1, 25.6%], 366 [M+, 100.0%], 324 [M+-C3H6, 11.0%], 183 [15.0%]. 1H NMR: 2.3 (m, 2H,
CH2); 3.1 (t, 2H, CH2); 3.4 (t, 2H, CH2); 7.0–8.0 (m, 10H, ArHs); 8.4 (s, 1H, pyrimidine H-4); 9.9 (s, 1H, NH); 10.5 (s, H, NH).
IR: 3286.5, 3379.1 (NH). 1H NMR: 1.9 (m, 4H, 2CH2); 2.7 (t, 2H, CH2); 2.9 (t, 2H, CH2); 6.9–7.9 (m, 10H, ArHs); 8.1 (s, 1H,
pyrimidine C-H); 9.8 (s, 1H, NH); 10.3 (s, 1H, NH).
IR: 2923.9, 3375.2 (NH). MS: 409 [M+ + 1, 18.3%], 408 [M+, 100.0%]. 1H NMR: 1.5 (m, 4H, 2CH2); 1.8 (m, 2H, CH2); 2.0 (m, 2H,
CH2); 2.8 (t, 2H, CH2); 3.4 (t, 2H, CH2); 6.9–8.0 (m, 10H, ArHs); 8.2 (s, 1H, pyrimidine H-4); 9.8 (s, 1H, NH); 10.5 (s, H, NH).
IR: 2214.1 (CN); 3317.3 (NH). MS: 277 [M+ + 2, 1.5%], 276 [M+ + 1, 16.7%], 275 [M+, 100.0%], 65 [18.2%]. 1H NMR: 2.3
(t, 2H, CH2); 3.1 (t, 2H, CH2); 3.3 (t, 2H, CH2); 6.9–7.9 (m, 5H, ArHs); 8.6 (s, 1H, pyrimidine H-4); 9.5 (s, 1H, NH).
IR: 2206.4 (CN); 3325 (NH). MS: 290 [M+ + 1, 22.1%], 298 [M+, 100.0%], 65 [15.5%]. 1H NMR: 1.9 (m, 4H, 2CH2); 2.7 (t, 2H,
CH2); 2.9 (t, 2H, CH2); 6.9–7.8 (m, 5H, ArHs); 8.9 (s, 1H, pyrimidine H-4); 9.4 (s, 1H, NH).
IR: 2213.6 (CN); 3321.7 (NH). MS: 317 [M+, 100.0%], 274 [M+-C3H7, 14.7%], 65 [14.7%]. 1H NMR: 1.3 (m, 2H, CH2); 1.8
(m, 4H, 2CH2); 2.8 (m, 2H, CH2); 3 (t, 2H, CH2); 3.4 (t, 2H, CH2); 6.6–7.7 (m, 5H, ArHs); 8.2 (s, 1H, pyrimidine H-4).
IR: 1365 (CH3); 2083 (CN). MS: 232 [M+ + 2, 5.0%], 231 [M+ + 1, 15.5%], 230 [M+, 100.0%], 197[M+ -SH, 65.7%], 156 [M+ –C3H6
S, 31.2%], 65 [31.3%]. 1H NMR: 2.4 (m, 2H, CH2); 2.75 (s, 3H, CH3); 3.15 (t, 2H, CH2); 3.4 (t, 2H, CH2); 8.5 (s, 1H, pyrimidine H-4).
IR: 1357.8 (CH3); 2214.1 (CN). MS: 246 [M+ + 2, 6.4%], 245 [M+ + 1, 15.5%], 244 [M+, 100.0%], 211[M+–SH, 86.2%], 170 [M+–
C3H7 S, 48.2%], 143 [–CN, 15.6%], 77[43.7%], 52 [46.4%]. 1H NMR: 2.9 (m, 2H, CH2); 2.66 (s, 3H, CH3); 2.82 (t, 2H, CH2); 3.0
(t, 2H, CH2); 3.15 (m, 2H, CH2); 8.3 (s, 1H, pyrimidine H-4).
16j
16k
16l
16m
16n
16o
IR: 3285 (NH) and 1662 (CO). 1H NMR: 1.4 (m, 4H, 2CH2); 1.8 (m, 4H, 2CH2); 2.7 (s, 3H, CH3); 2.9 (t, 2H, CH2); 3.3 (t, 2H, CH2);
8.4 (s, 1H, pyrimidine H-4).
PAPER: 07/4947

30 JOURNAL OF CHEMICAL RESEARCH 2008
O
O
-
+
ONa
OH
H2O
H2O
n(H2C)
O
n(H2C)
O
n(H2C)
14b
1a-d
13
14a
pip. acetate/AcOH
1a-d
pip. acetate/AcOH
O
N
NH2
OH
H
N
X
N
n(H2C)
N
X
n(H2C)
N
Y
OH
17
Y
15
N
X
N
Y
N
N
N
n(H2C)
N
Y
X
18a-o
n(H2C)
16a-o
a; n = 5; X = 1,3-benzothiazol-2yl, Y = methylthio
b; n = 6; X = 1,3-benzothiazol-2-yl, Y = methylthio
c; n = 8; X = 1,3-benzothiazol-2-yl, Y = methylthio
d; n = 5; X = 1,3-benzothiazol-2-yl, Y = phenylamino
e; n = 6; X = 1,3-benzothiazol-2-yl, Y = phenylamino
f; n = 8; X = 1,3-benzothiazol-2-yl, Y = phenylamino
g; n = 5; X = 1,3-benzoimidazol-2-yl, Y = phenylamino
h; n = 6; X = 1,3-benzoimidazol-2-yl, Y = phenylamino
i; n = 8; X = 1,3-benzoimidazol-2-yl, Y = phenylamino
j; n = 5; X = CN, Y = phenylamino
k; n = 6; X = CN, Y = phenylamino
l; n = 8; X = CN, Y = phenylamino
m; n = 5; X = CN, Y = methylthio
n; n = 6; X = CN Y = methylthiol
o; n = 8; X = CN, Y = methylthio
Scheme 5
mixture was cooled. The resulting solid product was collected and
recrystallised from appropriate solvent to give 16a–o.
Experimental
All melting points were determined on an electrothermal apparatus
and are uncorrected. IR spectra were recorded (KBr discs) on a
Shimadzu FT-IR 8201 PC spectrophotometer. H NMR and spectra
were recorded in CDCl3 and (CD3)2SO solutions on a Varian Gemini
300 MHz spectrometer and chemical shifts are expressed in δ units
using TMS as an internal reference. Mass spectra were recorded on a
GC-MS QP 1000 EX Shimadzu. Elemental analyses were carried out
at the Microanalytical Center of the Cairo University.Aminopyrazoles
1a–e were prepared as previously reported.34,35
Received 30 November 2007; accepted 30 January 2008
1
Paper 07/4947
doi: 10.3184/030823408X287096
References
1
2
T.K. Bradshaw and D.W. Hutchinson, Chem. Soc. Rev., 1977, 6, 43.
E. Lunt, D.H.R Barton and W.D. Ollis (eds), Comprehensive organic
chemistry, Pergamon Press, Oxford, 1984, Vol. 4, p. 493.
D.J. Brown,A.R. Katritzky and C. Rees (eds), Comprehensive heterocyclic
chemistry, Pergamon Press, Oxford, 1984, Vol. 3, p. 57.
T. Sasaki, K. Minamoto, T. Suzuki and S. Yamashita, Tetrahedron, 1980,
36, 865 (1980).
D. Prajapati, P.J. Bhuyan and J.S. Sandhu, J. Chem. Soc., Perkin Trans. 1,
1988, 607.
P.J. Bhuyan, H.N. Borah and J.S. Sandhu, J. Chem. Soc., Perkin Trans. 1,
1999, 3083.
3
4
5
6
Synthesis of pyrazolo[1,5-a]pyrimidines (2, 3, 5) a–d
General procedure
Amixture of the appropriate aminopyrazoles 1a–e and the appropriate
pentane-2,4-dione, 1-phenylbutan-1,3-dione or ethyl-3-oxobutanoate
(acetoacetanilide) (5 mmol) in glacial acetic acid (15 ml) were
boiled under reflux for 3 h. The resulting solid was collected and
recrystallised from appropriate solvent to afford pyrazolo[1,5-a]
pyrimidines (2, 3, 5) a–e (Tables 2 and 3).
7
8
R. Marumoto and Y. Furukawa, Chem. Pharm. Bull., 1977, 25, 2974.
H. Griengel, E. Waneck, W. Schwarz, W. Streicher, B. Rosenwirth and
E. De. Clercq, J. Med Chem., 1987, 30, 1199.
Synthesis of pyrazolo[1,5-a]pyrimidines 11a–j
9
E. De. Clercq and R. Bernaertes, J. Biol. Chem., 1987, 262, 14905.
10 A.S. Jones, J.R. Sayers, R.T. Walker and E.De. Clercq, J. Med Chem.,
1988, 31, 268.
11 H. Mitsuya, R. Yarchoan and S. Broder, Science, 1990, 249, 1533.
12 R. Pontikis and C. Monneret, Tetrahedron Lett., 1994, 35, 4351.
13 E.Y. Sutcliffe, K.Y. Zee-Cheng, C.C. Cheng and R.K. Robins, J. Med.
Chem., 1962, 5, 588.
Method A: Equimolar amounts of aminopyrazoles 1a–e and α-cyano-
cinnamonitrile derivatives (0.005 mol) in ethanol (20 ml) containing
a catalytically amount of piperidine was heated under reflux for 4 h.
The resulting solids were collected and recrystallised from a suitable
solvent to give 11a–j.
Method B: A mixture of 1a, malonitrile and benzaldehyde
derivatives (0.005 mmol, each) were stirred for 3 h in the presence
of ethanol (15 ml) containing catalytical amount of piperidine at
room temperature to afford the solid product which collected and
recrystallised from a appropriate solvent to afford 11a–j.
14 G.B. Elion, S.W. Callahan, H. Nathan, S. Bieber, R.W. Rundles and
G.H. Hilching, Biochem. Pharmcol., 1963, 12, 85.
15 R.W. Rundles, J.W. Wyngarden, G.H. Hilching, G.B. Elion and
H.R. Silbermann, Trans. Assoc. Am. Physicians, 1963, 76, 126.
16 D.K. Kim, D.H. Ryu, N. Lee, J.Y. Lee, J. Kim, S. Lee, J.Y. Choi,
J.H. Ryu, N.H. Kim, G.J. Im, W.S. Choi and T.K. Kim, Bioorg. Med.
Chem., 2001, 9, 1895.
17 E.C. Moore and D. Pharm, J. Pharm. Soc. Wisconsin, 2000, Sep/Oct, 33.
18 E. Sanna, F. Busonero, G. Talani, M. Carta, F. Massa, M. Peis,
E. Maciocco and G. Biggio, Eur. J. Pharmacol., 2002, 451, 103.
19 M. Hurst and S. Noble, CNS Drugs, 1999, 11, 387.
20 Zaleplon (Sonata), new drug overview, AHFS Drug Inform., 1999, 28:
24, 92.
Synthesis of pyrazolo[1,5-a]pyrimidine derivatives 16a–o
General procedure
A mixture of sodium salt 1336-41 (0.01 mole) was refluxed with
amino pyrazols 1a–e in a solution of piperidine acetate [piperidine
(2.5 ml), water (5 ml) and acetic acid (2 ml)] for 10 minutes,
acetic acid (1.5 ml) was added to the above while boiling, then the
PAPER: 07/4947

JOURNAL OF CHEMICAL RESEARCH 2008 31
21 M. Scharf. Eur Neuropsychopharmacol., 1999, 9, (Suppl 5), 5360.
22 M.J.R. Mangano. Eur Neuropsychopharmacol., 1999, 9, (Suppl 5), 5362.
23 K.A. Moore, T.L. Zemrus, V. Ramcharitar, B. Levine and D.R. Fowler,
Forens. Scie. Int., 2003, 134, 120.
24 C.F.P. George, Lancet., 2001, 357, 1623.
25 J.K. Walsh and C.I. Engelhart, The direct economic Costs of insomnia in
the United States for 1995, 1999, 22, (Suppl 2), S186.
26 I. Eardley, ExP. Opin. Invert. Drugs, 1997, 6, 1803.
27 L. Garcia-Reboll, J.P. Mulhall and I. Goldstein, Drugs Aging, 1997,
11, 140.
28 M.C. Truss and C.G. Stief, Drugs Today, 1998, 34, 805.
29 B. Dumaitre and N. Dodic, J. Med. Chem., 1996, 39, 1635.
30 J. Foreman and I. Garland, Br. Med. J., 1976, 1, 820.
31 G.H. Elgemeie, S.E. Elezaby, H.A. Ali and A. Mansour, Bull. Chem. Soc.
Jpn., 1994, 67, 738.
32 S.A. Ahmed, A.M. Hussein, W.G.M. Hozayen, A.H.H. El-Ghandour and
A.O. Abdelhamid, J. Heterocyclic Chem., 2007, 44, 803.
33 C.R. Lefert, H. Siripumchidbouree, S. Hamspons, S. Workman, D. Sigee,
H.A.S. Epton and A. Harbour. J. Appl. Bact., 1955, 78, 97.
34 G.H. Elgemeie, A.H. Elghandour, A.M. Elzanate abd S.A. Ahmed,
J. Chem. Soc. Perkin Trans., 1, 1997, 3285.
35 G.H. Elgemeie, A.H. Elghandour, A.M. Elzanate and S.A. Ahmed,
J. Chem. Res. (S), 1998, 162.
36 V.P. Litvinov, Yu. A. Sharanin, L.A. Rodinov, V.N. Nesterov, V.E. Shkover
and Yu. T. Struchkov, Chem. Ser., 1989, 29, 327; Chem. Abstr., 1990, 113,
231238b.
37 L.A. Rodinovskaya, V.P. Promonenkov, Yu. A. Sharanin, V.I. Shevedor,
A.M. Shestopalov and V.P. Litvinov, Zh. Org. Khim., 1985, 21, 1578.
38 L.A. Rodinovskaya, V.P. Promonenkov, Yu. A. Sharanin, V.I. Shevedor,
A.M. Shestopalov and V.P. Litvinov, Chem. Abstr. 1986, 104, 19530k.
39 V.P. Litvinov, E.E. Apenova, Yu. A. Sharanin and A.M. Shestopalov,
Akad. Nauk. Sssr, Ser. Khim, 1984, 10, 2408.
40 L.A. Rodinovskaya, Yu. A. Sharanin, A.M. Shestopalov and V.P. Litvinov,
Khim. Geterotsikl. Soedin, 1988, 6, 805.
41 L.A. Rodinovskaya, Yu. A. Sharanin, A.M. Shestopalov and V.P. Litvinov,
Chem. Abstr., 1989, 110, 94943x.
PAPER: 07/4947