β-Amino-β-(pyrid-4-yl)acrylonitrile in heterocyclic synthesis: Synthesis of some new pyridine, pyridone, pyrazole, thiophene, fused pyrimidine and triazine derivatives

Article abstract of DOI:10.1016/S0040-4020(02)01220-6

β-Amino-β-(pyrid-4-yl)acrylonitrile reacts with various types of reagents with variable molar ratios under different conditions to yield pyridine derivatives and condensed heterocyclic compounds containing a pyridyl moiety.

Full text of DOI:10.1016/S0040-4020(02)01220-6

Tetrahedron 58 (2002) 9423–9429
b-Amino-b-(pyrid-4-yl)acrylonitrile in heterocyclic synthesis:
synthesis of some new pyridine, pyridone, pyrazole, thiophene,
fused pyrimidine and triazine derivatives
Said A. S. Ghozlana and Abu Zeid A. Hassanienb
,
*
aDepartment of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
bDepartment of Chemistry, Faculty of Education, Suez Canal University, Arish, Egypt
Received 6 June 2002; revised 5 September 2002; accepted 26 September 2002
Abstract—b-Amino-b-(pyrid-4-yl)acrylonitrile reacts with various types of reagents with variable molar ratios under different conditions to
yield pyridine derivatives and condensed heterocyclic compounds containing a pyridyl moiety. q 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
reaction of 1 with different types of aldehydes in AcOH
under reflux yielded 2:1 adducts formulated as pyridines
5a–d in good yield which are believed to be formed via
initial condensation of 1 with appropriate aldehydes 2a–f to
form the intermediates 3 which in turn react with another
mole of 1 to form intermediate diamines 4 which cyclized
via loss of NH3 and auto aromatization under the reaction
conditions. The structures of 5 were confirmed based on the
elemental analyses and spectral data. Thus, the IR spectrum
showed the absence of NH stretching and the presence of a
Substituted pyridines and condensed pyridines are
important as pharmaceuticals and agrochemicals,1–4 and
some 2-pyridone derivatives are also of considerable
biological importance as cardiotonic agents such as
milirinone5 (Fig. 1) and as potential HIV-1 specific
transcriptase inhibitors.5,6 In continuation of previous
work in developing syntheses of polyfunctionally substi-
tuted heteroaromatics,7–10 we report here several new
approaches to these derivatives using b-amino-b-(pyrid-4-
yl)acrylonitrile 1 as a precursor.
1
bands at 2208 cm21 for the cyano groups. The H NMR
spectrum of 5d revealed the presence of signals at 3.74–
3.88 ppm corresponding to 3-OCH3 groups and the absence
of the signal of the 4H-pyridine at 4.91. In addition, the
spectrum showed the presence of a singlet signal at d 7.27
corresponding to 2H-aromatic and two doublet signals at
8.05 and 8.91 corresponding to 3,5H- and 2,6H-pyridyl
protons, respectively. The mass spectrum of 5d is in
accordance with the proposed structure which showed a
molecular ion peak m/z¼449 (100%) corresponding to
the molecular formula C26H19N5O3. Similarly aldehydes
2a–c,e,f reacted with 1 to afford pyridine derivatives
5a–c,e,f (Scheme 1).
2. Results and discussion
The enaminonitrile 1 can be readily prepared and obtained
in excellent yield by reaction of acetonitrile with 4-cyano-
pyridine in the presence of potassium-t-butoxide.11 Now we
have found that compound 1 is an attractive starting material
for the preparation of pyridine derivatives. Thus, the
The efficiency of the above reactions prompted us to extend
this procedure to the synthesis of compounds containing two
pyridine units attached to a benzene ring. The reaction of 1
with terephthalaldehyde in a 4:1 molar ratio carried out in
AcOH afforded the desired 1,4-bis(pyridyl)-benzene deriva-
tive 6 in a moderate (52%) yield. Its structure was confirmed
by analytical and spectroscopic data which are similar to
those of 5a (Scheme 1).
Figure 1.
Keywords: b-amino-b-(pyrid-4-yl)acrylonitrile; enaminone; thiophene;
ethyl cyanoacetate.
Also, reaction of 1 with salicylaldehyde under the pre-
vious conditions gave a 1:2 adduct which is formulated as
*
Corresponding author; e-mail: abuzeid5@hotmail.com
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01220-6

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S. A. S. Ghozlan, A. Z. A. Hassanien / Tetrahedron 58 (2002) 9423–9429
Scheme 1.
Scheme 2.

S. A. S. Ghozlan, A. Z. A. Hassanien / Tetrahedron 58 (2002) 9423–9429
9425
Scheme 3.
2-(o-hydroxyphenyl)-4-(pyrid-4-yl)benzo[50.60]-4H-pyrano-
[2,3-d]pyrimidine 9. Compound 9 is assumed to be formed
via initial addition of salicylaldehyde with elimination of
1 mol of water to form the non-isolable intermediates 7 and
8. The latter intermediate 8 in turn, reacted with another
molecule of salicyaldehyde giving the cyclized product 9.
The structure of 9 was established based on its spectral data.
Thus, the IR spectrum (KBr) showed stretching bands at
3400 cm21 for OH and 1620 cm21 for CvN groups. The 1H
NMR spectrum revealed the presence of a singlet at
d¼4.95 ppm corresponding to 2H of 4H pyran, a multiplet
at d¼7.11–7.55 ppm due to the aromatic protons, doublets
at 8.43, 8.47 and 8.85 corresponding to the pyridyl protons
and a singlet at 12.79 corresponding to the phenolic OH.
Also, its mass spectrum revealed Mþ at m/z¼353 (100%)
corresponding to the molecular formula C22H15N3O2.
of 1 in a convenient route to polyfunctionally substituted
pyridine derivatives of an expected wide spectrum of
bioresponce.5,6 Thus, compound 1 reacted with an equi-
molar amount of a-cinnamonitriles 10a–f to provide
pyridine and pyridinone derivatives 12 and 13, respectively,
in acceptable yields.
Formation of 12 and 13 is assumed to proceed via an acyclic
intermediate 11 followed by intramolecular cyclization and
spontaneous autooxidation under the reaction conditions in
the case of 12 and elimination of ethanol in the case of 13
(Scheme 2). The structure of 12 and 13 were established on
the basis of elemental and spectroscopic studies.
Work was further extended to study the behavior of 1
towards the action of aryl and heterocyclic diazonium
chloride.12 Thus, compound 1 readily coupled with aromatic
diazonium salts 14 yielding the corresponding coupling
Next we investigated the applicability and synthetic potency

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S. A. S. Ghozlan, A. Z. A. Hassanien / Tetrahedron 58 (2002) 9423–9429
Scheme 4.
products that were assigned as the arylazo-enaminonitrile
derivatives 15 based on elemental analysis and spectral data.
But in the case of heterocyclic diazonium chlorides 16 the
pyrazolo[1,5-c][1,2,4]triazine derivatives 18a,b were
obtained via the non-isolable intermediates 17 by loss of
1 mol of ammonia. Similar cyclization reactions to form
pyrazolotriazine have been previously reported.13 – 15
Compound 15 reacted with hydrazine hydrate to afford
the aminopyrazole derivatives 19a,b. Compound 19a
reacted easily with an equimolar amount of both enami-
nones 20a,b and enaminonitrile 21a,b in ethanol with a
catalytic amount of piperidine to provide pyrazolo[1,5-a]-
pyrimidine derivatives7,16 22a,b and 23a,b, respectively
(Scheme 3).
4. Experimental
Melting points are uncorrected. IR spectra were recorded
with a Shimadzu FTIR-8201 PC spectrophotometer.
1H NMR spectra were obtained on a Varian Germini
200 MHz spectrometer in DMSO-d6 as solvent and TMS
as an internal reference Mass spectra were performed on
a Shimadzu GCMS-QP-1000 EX using the direct inlet
system and EIþQI MSLMRUPLR Microanalysis was
performed by the Microanalytical Unit at Cairo
University. Thin layer chromatography was carried out
on 5£20 cm plates coated with silica gel GF 254 type
60, mesh size 50–250. Compounds 111 and 1910 were
prepared according to the methods reported in the
literature.10,11
Moreover, the behavior of 1 towards the active methylene-
nitriles reagents was also investigated.15,17 Thus a mixture
of 1 and methylenenitrile 25a or b and elemental sulfur in
refluxing dioxane in the presence of a catalytic amount of
piperidine enabled the synthesis of 4-(5-amino-thiophen-3-
yl)pyridine derivatives 26a,b, in excellent yields. It is
believed that the reaction proceeds via the mechanistic path
illustrated in Scheme 4. The validity of structures 26a,b
were deduced from their correct elemental analysis and
compatible spectral data.
4.1. Preparation of b-amino-b-(pyrid-4-yl)acrylonitrile 1
The title compound was prepared according to reported
literature.11 (0.91 g, 63%) as colorless solid, mp 2028C.
[Found: C, 66.20; H, 4.82; N, 28.96. C8H7N3 requires C,
66.20; H, 4.80; N, 28.20; nmax [KBr] 3335, 2193 cm21; m/z
99 (34), 117 (100), 145 (49), found 145.14. C8H7N3 requires
145.14.
4.2. Preparation of pyridine derivatives 5a–f, 6 and 9
A solution of 1 (2.9 g, 0.02 mol) in glacial acetic acid
(30 mL) was treated with the appropriate aromatic or
heterocyclic aldehydes 2a–f (0.01 mol). The reaction
mixture was heated under reflux for 5–8 h and the solvent
was then evaporated in vacuo. The residue was triturated
with water, the solid product so formed was collected by
filtration and crystallized from ethanol.
3. Conclusion
In conclusion, we have investigated the applicability and
synthetic potency of b-amino-b-(pyrid-4-yl)acrylonitrile in
a convenient route to synthesize with a facile and simple
reaction conditions polyfunctionally substituted 4,20:60,400-
terpyridine derivatives 5 and 4,20-bispyridines 12 and 13 in
acceptable yield. Also, the behavior of 1 towards some aryl
(heterocyclic) diazonium chlorides was studied for pre-
paring condensed heterocyclic compounds containing
pyridine moiety such as pyrazolo[5,1-c][1,2,4]triazine
derivatives 18, pyrazolo[1,5-a]pyrimidines 22 and 23.
Similarly, the reactivity of 1 towards some active methyl-
enenitriles was studied to synthesize thiophene derivatives
26.
4.2.1. 3,5-Dicyano-4-phenyl-2,20:60,400-terpyridine (5a).
The title compound was obtained as white solid (2.58 g,
72%), mp 2568C. [Found: C, 76.80; H, 3.60; N, 19.40.
C23H13N5 requires C, 76.86; H, 3.64; N, 19.48; nmax [KBr]
3050, 2196, 1585 cm21; dH (DMSO-d6) 7.01–7.83 (m, 5H,
H-Ar), 8.35 (d, 4H, J¼6.0 Hz, 3,5H-pyridyl), 8.90 (d, 4H,
J¼6.0 Hz, 2,6H-pyridyl).

S. A. S. Ghozlan, A. Z. A. Hassanien / Tetrahedron 58 (2002) 9423–9429
9427
4.2.2. 3,5-Dicyano-4-(p-methoxyphenyl)-2,20:60,400-ter-
pyridine (5b). The title compound was obtained as pale
yellow solid (2.41 g, 62%), mp 2478C. [Found: C, 74.10; H,
3.80; N, 17.80. C24H15N5O requires C, 74.02; H, 3.88; N,
17.98; nmax [KBr] 2939, 2210 cm21; dH (DMSO-d6) 3.71
(s, 3H, OCH3), 7.01–7.73 (m, 4H, H-Ar), 8.31 (d, 4H, J¼
7.0 Hz, 3,5H-pyridyl), 8.83 (d, 4H, J¼7.0 Hz, 2,6H-
pyridyl).
m/z 51 (25), 28 (25), 130 (40), 235 (20), 353 (100), found
353.36 C22H15N3O2 requires 353.36.
4.3. Preparation of pyridine derivatives 12a–c and 13a–c
A solution of 1 (0.725 g, 0.005 mol) in absolute ethanol
(30 mL) was treated with the appropriate cinnamonitrile
derivatives 10a–f (0.005 mol) and a few drops of
triethylamine. The reaction mixture was refluxed for
7–10 h and the solvent was then evaporated in vacuo. The
residue was triturated with cold water and neutralized with
dilute hydrochloric acid. The solid obtained was collected
by filtration and crystallized from ethanol.
4.2.3. 3,5-Dicyano-4-(p-chlorophenyl)-2,20:60,400-terpyri-
dine (5c). The title compound was obtained as colorless
solid (2.36 g, 60%), mp 2808C. [Found: C, 70.20; H, 3.10;
N, 18.10, Cl, 9.0. C23H12N5Cl requires C, 70.16; H, 3.07, N,
17.78, Cl, 9.0; nmax [KBr] 3045, 2196 cm21; dH (DMSO-d6)
7.01–7.83 (m, 4H, H-Ar), 8.21 (d, 4H, J¼8.0 Hz, 3,5-H-
pyridyl), 8.63 (d, 4H, J¼8.0 Hz, 2,6-H-pyridyl); m/z 51
(35), 178 (28), 353 (62), 348 (42), 393 (100), 394 (65),
found 393.32 C23H12N5Cl requires 393.32.
4.3.1. 6-Amino-3,5-dicyano-4-phenyl-20,4-bispyridine
(12a). The title compound was obtained as pale violet
solid (1.83 g, 65%), mp 2708C. [Found: C, 72.90; H, 3.80;
N, 23.40. C18H11N5 requires C, 72.71; H, 3.72; N, 23.55;
n
max [KBr] 3320, 3290, 2219 cm21; dH (DMSO-d6) 7.10 (s,
4.2.4. 3,5-Dicyano-4-(3,4,5-trimethoxyphenyl)-2,20:60,400-
terpyridine (5d). The title compound was obtained as
yellow solid (2.46 g, 55%), mp 2588C. [Found: C, 69.50; H,
4.30; N, 15.80. C26H19N5O3 requires C, 69.47; H, 4.26; N,
15.58; nmax [KBr] 2949, 2208 cm21; dH (DMSO-d6) 3.74–
3.88 (m, 9H, 3OCH3), 7.27 (s, 2H, H-Ar), 8.05 (d, 4H, J¼
5.8 Hz, 3,5H-pyridyl), 8.91 (d, 4H, J¼5.6 Hz, 2,6H-
pyridyl); m/z 51 (25), 284 (100), 358 (30), 449 (98), found
449.46 C26H19N5O3 requires 449.46.
2H, NH2), 7.43–7.89 (m, 5H, H-Ar), 8.51 (d, 2H, J¼6.0 Hz,
3,5H-pyridyl), 8.93 (d, 2H, J¼6.0 Hz, 2,6H-pyridyl); m/z 51
(25), 158 (30), 250 (50), 297 (100), found 297.30 C18H11N5
requires 297.30.
4.3.2. 6-Amino-3,5-dicyano-4-(p-methoxyphenyl)-20,4-
bispyridine (12b). The title compound was obtained as
pale yellow solid (2.09 g, 64%), mp 2608C. [Found: C,
70.10; H, 3.90; N, 22.00. C19H13N5O requires C, 69.71; H,
4.00; N, 21.39; nmax [KBr] 3301, 3191, 2214, 1630 cm21
;
4.2.5. 3,5-Dicyano-4-(pyrid-3-yl)-2,20:60,400-terpyridine
(5e). The title compound was obtained as pale yellow
solid (2.08 g, 58%), mp 2828C. [Found: C, 73.20; H, 3.50;
N, 24.00. C22H12N6 requires C, 73.32; H, 3.35; N, 23.32;
nmax [KBr] 3038, 2225 cm21; dH (DMSO-d6) 5.6 (br, 1H,
4-H pyridyl), 8.05 (d, 5H, J¼6.0 Hz, 3,5H-pyridyl), 8.91 (d,
6H, J¼5.8 Hz, 2,6H-pyridyl).
4.2.6. 3,5-Dicyano-4-(thien-2-yl)-2,20:60,400-terpyridine
(5f). The title compound was obtained as yellowish green
solid (2.26 g, 62%), mp 2908C. [Found: C, 69.10; H, 3.20;
N, 19.30; S, 9.00. C21H11N5S requires C, 69.02; H, 3.03; N,
19.16; S, 8.77; nmax [KBr] 3038, 2190 cm21; dH (DMSO-d6)
7.2–7.3 (m, 1H, 4-H-theinyl), 7.3–7.83 (m, 2H, 3,5-H-
theinyl), 8.32 (d, 4H, J¼7.0 Hz, 3,5-H-pyridyl), 8.69 (d, 4H,
J¼7.0 Hz, 2,6-H-pyridyl); m/z 51 (30), 282 (100), 305 (48),
365 (40), found 365.40 C21H11N5S requires 365.40.
dH (DMSO-d6) 3.87 (s, 3H, OCH3), 7.14 (b, 2H, NH2),
7.59–7.79 (d, 4H, Ar-H), 8.35 (b, 2H, 3,5-H-pyridyl), 8.79
(d, 2H, J¼6.0 Hz, 2,6-H-pyridyl). m/z 51 (35), 142 (20), 270
(40), 296 (80), 327 (100), found 327.33 C19H13N5O requires
327.33.
4.3.3. 6-Amino-3,5-dicyano-4-(p-nitrophenyl)-2-(pyrid-
4-yl)pyridine (12c). The title compound was obtained as
pale brown solid (2.39 g, 70%), mp 2658C. [Found: C,
63.40; H, 3.10; N, 24.90. C18H10N6O2 requires C, 63.15; H,
2.94; N, 24.55; nmax [KBr] 3360, 3310, 2214 cm21; dH
(DMSO-d6) 6.93–7.71 (m, 6H, 4H-ArþNH2), 8.23 (d, 2H,
J¼7.0 Hz, 3,5-H-pyridyl), 8.64 (d, 2H, J¼7.0 Hz, 2,6-H-
pyridyl); m/z 51 (35), 184 (50), 276 (63), 342 (100), found
342.31 C18H10N6O2 requires 342.31.
4.3.4. 3,5-Dicyano-1H-4-(p-methoxyphenyl)-20,4-bispyri-
din-6-one (13a). The title compound was obtained as deep
yellow solid (1.80 g, 55%), mp 2638C. [Found: C, 69.60; H,
3.70; N, 17.10. C19H12N4O2 requires C, 69.50; H, 3.68; N,
17.06; nmax [KBr] 3050, 3210, 2218, 1710 cm21; dH
(DMSO-d6) 3.83 (s, 3H, OCH3), 7.13–7.89 (m, 4H,
H-Ar), 8.51 (d, 2H, J¼6.0 Hz, 3,5H-pyridyl), 8.91 (d, 2H,
J¼6.0 Hz, 2,6H-pyridyl), 9.1 (s, 1H, NH); m/z 51 (25), 118
(30), 218 (40), 256 (100), 328 (50), found 328.31
C19H12N4O2 requires 328.31.
4.2.7. Bis(3,5-dicyano-2,20:60,400-terpyrid-4-yl)benzene
(6). The title compound was obtained as yellow solid
(3.32 g, 52%), mp 2658C. [Found: C, 75.10; H, 3.30; N,
21.70. C40H20N10 requires C, 74.99; H, 3.14; N, 21.86; nmax
[KBr] 3042, 2225 cm21; dH (DMSO-d6) 7.01–7.50 (4H,
H-Ar), 8.02 (d, 8H, J¼5.8 Hz, 3,5-H-pyridyl), 8.815 (d, 8H,
J¼6.0 Hz, 2,6-H-pyridyl).
4.2.8. 2-(o-Hydroxyphenyl)-4-(pyrid-4-yl)benzo[50,60]-
4H-pyrano[2,3-d]pyrimidine (9). The title compound
was obtained as pale violet solid (2.22 g, 63%), mp
2458C. [Found: C, 74.60; H, 4.30; N, 11.70. C22H15N3O2
requires C, 74.77; H, 4.27; N, 11.89; nmax [KBr] 3400, 3030,
2927, 1620 cm21; dH (DMSO-d6) 4.95 (s, 2H, 4H-pyron),
7.11–7.55 (m, 8H, H-Ar), 8.45 (d, 2H, J¼8.0 Hz, 3,5-H-
pyridyl), 8.85 (br, 2H, 2,6-H-pyridyl), 12.79 (s, 1H, OH);
4.3.5. 3,5-Dicyano-1H-4-(p-nitrophenyl)-20,4-bispyridin-
6-one (13b). The title compound was obtained as pale
yellow solid (2.05 g, 60%), mp 2488C. [Found: C, 63.10; H,
2.70; N, 20.50. C18H9N5O3 requires C, 62.97; H, 2.64; N,
20.39; nmax [KBr] 3068, 3230, 2218, 1716 cm21; dH
(DMSO-d6) 7.78–8.08 (m, 4H, H-Ar), 8.49 (dd, 2H,
J¼8.0 Hz, 3,5-H-pyridyl), 8.84 (dd, 2H, J¼8.0 Hz,

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S. A. S. Ghozlan, A. Z. A. Hassanien / Tetrahedron 58 (2002) 9423–9429
2,6-H-pyridyl), 8.93 (s, 1H, NH) m/z 51 (50), 106 (15), 215
(22), 297 (100), 334 (50), 343 (80), found 343.29
C18H9N5O3 requires 343.29.
7.23–7.71 (m, 5H, H-Ar), 8.22 (d, 2H, J¼5.4 Hz, 3,5-H-
pyridyl), 8.87 (d, 2H, J¼6.0 Hz, 2,6-H-pyridyl).
4.4.5. Compound 19a. Compound 19a was prepared
according to reported literature.10
4.3.6. 3,5-Dicyano-1H-4-(3,4-dichlorophenyl)-20,4-bis-
pyridin-6-one (13c). The title compound was obtained as
pale yellow solid (3.04 g, 83%), mp 2388C. [Found: C,
59.10; H, 2.30; N, 15.60; Cl, 20.10. C18H8N4OCl2 requires
C, 58.88, H, 2.19; N, 15.25, Cl, 19.70; nmax [KBr] 3190,
3060, 2218, 1714 cm21, dH (DMSO-d6) 7.60–7.76 (m, 3H,
H-Ar), 7.81 (d, 2H, J¼6.0 Hz, 3,5-H-pyridyl), 8.89 (dd, 2H,
J¼6 Hz, 2,6-H-pyridyl), 8.91 (s, 1H, NH). m/z 51 (30), 148
(35), 265 (24), 367 (100), found 367.17 C18H8N4OCl2
requires 367.17.
The title compound was obtained as pale yellow solid
(1.87 g, 71%), mp 2958C. [Found: C, 64.10; H, 4.60; N,
31.90. C14H12N6 requires C, 63.67; H, 4.57; N, 31.79; nmax
[KBr] 3401, 3360, 3100, 1634 cm21; dH (DMSO-d6)
7.13–7.93 (m, 7H, NH2, 5H-Ar), 8.31 (d, 2H, J¼6.0 Hz,
3,5H-pyridyl), 8.94 (d, 2H, J¼6.0 Hz, 2,6H-pyridyl), 12.3
(br, 1H, NH); m/z 51 (70), 148 (60), 210 (25), 264 (100),
found 264.28 C14H12N6 requires 264.28.
4.4. Preparation of arylazo enaminonitrile derivatives
15a,b and pyrazolo[5,1-c][1,2,4]triazine derivatives
18a,b
4.4.6. Compound 19b. Compound 19b was prepared
according to reported literature.10
The title compound was obtained as yellow solid (1.88 g,
55%), mp 2908C. [Found: C, 49.30; H, 3.90; N, 28.90; S,
10.00. C14H13N7O2S requires C, 48.97; H, 3.81; N, 28.55; S,
9.33; nmax [KBr] 3438, 3301, 3190, 1631 cm21; dH (DMSO-
d6): 7.44–7.94 (m, 8H, 4H-ArþNH2), 8.15 (d, 2H, J¼
5.8 Hz, 3,5-H-pyridyl), 8.65 (d, 2H, J¼5.8 Hz, 2,6-H-
pyridyl), 12.50 (br, 1H, NH); m/z 51 (60), 131 (75), 184
(100), 265 (25), 343 (60), found 343.35 C14H13N7O2S
requires 343.35.
A solution of diazotized aromatic and heterocyclic amines
14a,b and 16a,b, respectively [prepared from the appro-
priate amines (0.01 mol) in hydrochloric acid and sodium
nitrite (0.01 mol)] was added to enaminonitrile 1 (1.45 g,
0.01 mol) in ethanol (50 mL) containing 1–2 g of sodium
acetate. The reaction mixture was then stirred in an ice bath
for 1–2 h. The solid so formed, was collected by filtration
and washed several times with water and recrystallized from
ethanol.
4.5. Preparation of pyrazolo [1,5-a]pyrimidine
derivatives 22a,b
4.4.1. 3-Amino-2-phenylazo-3-(pyrid-4-yl)acrylonitrile
(15a). The title compound was obtained as yellow solid
(2.24 g, 90%), mp 2268C. [Found: C, 67.50; H, 4.50; N,
28.20. C14H11N5 requires C, 67.45; H, 4.44; N, 28.08; nmax
[KBr] 3292, 3226, 2215, 1625 cm21; dH (DMSO-d6) 6.05
(s, 2H, NH2), 6.93–7.81 (m, 5H, H-Ar), 8.33 (d, 2H,
J¼8.0 Hz, 3,5-H-pyridyl), 8.78 (d, 2H, J¼8.0 Hz, 2,6-H-
pyridyl); m/z 51 (75), 77 (100), 172 (25), 249 (48), found
249.26 C14H11N5 requires 249.26.
A solution of 19a (1.32 g, 0.005 mol) and enaminones 20a
or b (0.005 mol) in ethanol/acetic acid (1:1) (30 mL) was
refluxed for 5–7 h. The solvent was removed by distillation
under reduced pressure and the resulting residue was left to
cool. The solid precipitate was collected and recrystallized
from ethanol.
4.5.1. 2-Phenyl-8-phenylazo-7-(pyrid-4-yl)pyrazolo[1,5-a]-
pyrimidine (22a). The title compound was obtained as
orange solid (1.69 g, 45%), mp 2388C. [Found: C, 73.20; H,
4.40; N, 22.20. C23H16N6 requires C, 73.32; H, 4.25;
N, 22.31; nmax [KBr] 3045, 1625 cm21; dH (DMSO-d6)
7.1–7.81 (m, 12H, 10H-Arþ2H pyrimidine), 8.12 (d, 2H,
J¼6.0 Hz, 3,5-H-pyridyl), 8.92 (d, 2H, J¼6.0 Hz, 2,6-H-
pyridyl); m/z 51 (25), 180 (30), 376 (100), found 376.40
C23H14N6 requires 376.40.
4.4.2. 3-Amino-2-(p-sulfonamidophenylazo)-3-(pryid-4-
yl)acrylonitrile (15b). The title compound was obtained
as orange solid (3.01 g, 92%), mp 2408C. [Found: C, 51.30;
H, 3.70; N, 25.70; S, 10.00. C14H12N6O2S requires C, 51.21;
H, 3.68; N, 25.59; S, 9.76; nmax [KBr] 3295–3226, 2214,
1652 cm21; dH (DMSO-d6) 6.10 (s, 2H, NH2). 7.10–7.68
(m, 6H, 4H-ArþNH2), 8.05 (d, 2H, J¼6.0 Hz, 3,5-H-
pyridyl), 8.92 (d, 2H, J¼5.8 Hz, 2,6-H-pyridyl).
4.4.3. 3-Cyano-8-methyl-7-phenyl-4-(pyrid-4-yl)pyra-
zolo[5,1-c][1,2,4]triazine (18a). The title compound was
obtained as brown solid (1.62 g, 52%), mp 2088C. [Found:
C, 69.40; H, 3.70; N, 26.90. C18H12N6 requires C, 69.22; H,
3.87; N, 26.90, nmax [KBr] 3035, 2973, 2220 cm21; dH
(DMSO-d6) 3.10 (s, 3H, CH3), 7.10–7.56 (m, 5H, H-Ar),
8.12 (d, 2H, J¼6.0 Hz, 3,5-H-pyridyl), 8.85 (d, 2H, J¼
6.0 Hz, 2,6-H-pyridyl), m/z 51 (30), 148 (22), 228 (40), 312
(100), found 312.32 C18H12N6 requires 312.32.
4.5.2. 2-(p-Tolyl)-8-phenylazo-7-(pyrid-4-yl)pyrazolo-
[1,5-a]pyrimidine (22b). The title compound was obtained
as orange solid (1.63 g, 42%), mp 2478C. [Found: C, 73.70;
H, 4.50; N, 21.40. C24H18N6 requires C, 73.82; H, 4.64; N,
21.52; nmax [KBr] 3035, 1635 cm21; dH (DMSO-d6) 2.21 (s,
3H, CH3), 7.01–7.89 (m, 11H, 9H-Arþ2H pyrimidine),
8.21 (d, 2H, J¼7.0 Hz, 3,5-H-pyridyl), 8.75 (d, 2H, J¼
7.0 Hz, 2,6-H-pyridyl); m/z 51 (25), 138 (25), 254 (40), 390
(100), found 390.44 C24H18N6 requires 390.44.
4.4.4. 3,7-Dicyano-8-phenyl-4-(pyrid-4-yl)pyrazolo[5,1-c]-
[1,2,4]triazine (18b). The title compound was obtained as
brown solid (1.38 g, 43%), mp 2848C. [Found: C, 67.10; H,
2.80; N, 30.50. C18H9N7 requires C, 66.86; H, 2.80; N,
30.32, nmax [KBr] 3045, 2220, 2192 cm21, dH (DMSO-d6)
4.6. Preparation of pyrazolo[1,5-a]pyrimidine
derivatives 23a,b
A suspension of 19a (1.32 g, 0.005 mol) and the appropriate
cinnamonitrile derivatives 21a,b (0.005 mol) in absolute

S. A. S. Ghozlan, A. Z. A. Hassanien / Tetrahedron 58 (2002) 9423–9429
9429
ethanol (30 mL) and a catalytic amount of piperidine (four
drops) were for 4–6 h. The solvent was concentrated under
reduced pressure then the reaction mixture was triturated
with cold water and the solid obtained was collected and
recrystallized from ethanol.
brown solid (1.22 g, 45%), mp 2428C. [Found: C, 57.10; H,
4.40; N, 16.00; S, 12.10. C13H11N5SO2 requires C, 56.93;
H, 4.37, N, 15.33; S, 11.69, nmax [KBr] 3403, 2204,
1705 cm21; dH (DMSO-d6) 1.20 (t, 3H, J¼7 Hz, CH3), 4.28
(q, 2H, J¼7 Hz, CH2), 6.91 (s, 2H, NH2), 8.49 (d, 2H,
J¼6.0 Hz, 3,5-H-pyridyl), 8.93 (d, 2H, J¼6.0 Hz, 2,6-H-
pyridyl), m/z, 51 (20), 115 (30), 165 (100), 288 (30), 273
(15), found 273.30 C13H11N3SO2 requires 273.30.
4.6.1. 4-Amino-3-cyano-2-phenyl-8-phenylazo-7-(pyrid-
4-yl)pyrazolo[1,5-a]pyrimidine (23a). The title compound
was obtained as pale brown solid (1.58 g, 38%), mp 3108C.
[Found: C, 69.10; H, 3.80; N, 27.30. C24H16N8 requires C,
69.22; H, 3.87; N, 26.90; nmax [KBr] 3313, 3228, 2212,
1644 cm21; dH (DMSO-d6) 7.10–7.74 (m, 10H, H-Ar), 8.03
(d, 2H, J¼8 Hz, 3,5-H-pyridyl), 8.41 (s, 2H, NH2), 8.83 (d,
2H, J¼8 Hz, 2,6-H-pyridyl); m/z 51 (33), 248 (30), 241 (17),
416 (100), found 416.43 C24H16N8 requires 416.43.
References
1. Lahaus, G.; Dittmar, W. S. Africa Patent 6906 036; Chem.
Abstr. 1988, 73, 720308.
2. Youngdale, G. A. US Patent 4288 440; Chem. Abstr. 1982, 96,
6596c.
4.6.2. 4-Amino-3-cyano-2-(p-chlorophenyl)-8-phenylazo-
7-(pyrid-4-yl)pyrazolo[1,5-a]pyrimidine (23b). The title
compound was obtained as brown solid (1.89 g, 42%), mp
3228C. [Found: C, 63.90; H, 3.20; N, 25.30; Cl, 8.10.
C24H15N8Cl requires C, 63.93; H, 3.35; N, 24.85; Cl, 7.86;
nmax [KBr] 3320, 3280, 2192, 1635 cm21; dH (DMSO-d6)
7.10–7.80 (m, 9H, H-Ar), 8.20 (d, 2H, J¼6.0 Hz, 3,5H-
pyridyl), 8.51 (s, 2H, NH2), 8.91 (d, 2H, J¼6.0 Hz, 2,6H-
pyridyl), m/z 51 (40), 153 (30), 245 (40), 314 (20), 451
(100), found 450.88 C24H15N8Cl requires 450.88.
3. Meyer, H.; Sitt, R.; Thomas, G.; Krause, H. P. Ger. Offen 3015
219, 1980; Chem. Abstr. 1982, 96, 6604d.
4. Worbel, J.; Li, Z.; Dietrich, A.; McCaleb, M.; Mihan, B.;
Sredy, J.; Sullivan, D. J. Med. Chem. 1998, 41, 1084.
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7. Hassanien, A. A.; Amr, A. E.; Ghozlan, S. A. S. J. Chin. Chem.
Soc. 2000, 47, 1273.
4.7. Preparation of aminothiophene derivatives 26a,b
8. Hassanien, A. A. Synth. Commun. 2000, 30/20, 3883.
9. Hassanien, A. A. Phosphorus Sulfur Silicon 1999, 155, 100.
10. (a) Hassanien, A. A.; Abdel Hafiz, I. S.; El-Nagdi, M. M.
J. Chem. Res. (S) 1999, 8, (M) 1999, 129. (b) Ghozlan, S. A. S.
Sulfur Lett. 1991, 13(1), 27.
To a solution of 1 (1.45 g, 0.01 mol) in dioxane (30 mL)
containing (0.2 mL) of piperidine, malononitrile (0.66 g,
0.01 mol) or ethyl cyanoacetate (1.13 g, 0.01 mol) and
elemental sulfur (0.32 g, 0.01 mol) were added. The
reaction mixture was refluxed for 4–5 h, then poured onto
cold water and neutralized by HCl. The solid so formed was
collected by filtration and crystallized from ethanol.
11. Yamagushi, Y.; Katsuyama, I.; Funabiki, K.; Matsui, M.;
Shibata, K. J. Heterocycl. Chem. 1998, 35, 805.
12. (a) Elnagdi, M. H.; Zayed, E. M.; El-Sayed Khalifa, M. A.;
Ghozlan, S. A. S. Monatsh. Chem. 1981, 112, 245. (b) Zayed,
E. M.; Ghozlan, S. A. S.; Ibrahim, A. A. H. Monatsh. Chem.
1984, 115, 431.
4.7.1. 4-[5-Amino-2,4-dicyano(thien-3-yl)pyridine (26a).
The title compound was obtained as dark brown solid
(0.94 g, 42%), mp 2638C. [Found: C, 58.60; H, 2.80; N,
25.10; S, 14.20. C11H6N4S requires C, 58.39; H, 2.66; N,
13. Elnagdi, M. H.; El-Moghayar, M. R. H.; Fleita, D. H.; Hafez,
E. A.; Fahmy, S. M. J. Org. Chem. 1976, 41(24).
14. Ghozlan, S. A. S.; Zayed, E. M.; El-Nagdi, M. H. Gazz. Chim.
Ital. 1983, 113.
24.76; S, 13.52; nmax [KBr] 3400, 3315, 2205, 3198 cm21
;
dH (DMSO-d6) 6.69 (s, 2H, NH2), 8.05 (d, 2H, J¼6.0 Hz,
3,5-H-pyridyl), 8.91 (d, 2H, J¼6.0 Hz, 2,6-H-pyridyl); m/z
60 (89), 110 (22), 164 (100), 226 (89), found 226.24
C11H6N6S requires 226.24.
15. Erian, A. W. Chem. Rev. 1993, 93, 1991 and references cited
therein.
16. (a) Al-Shiekh, M. A.; Al-Zaydi, K. M.; Hafez, E. A. J. Chem.
Res. (S) 2000, 5. (b) Al-Shiekh, M. A.; Al-Zaydi, K. M.;
Hafez, E. A. J. Chem. Res. (M) 2000, 173.
4.7.2. 4-[Ethyl 5-amino-2-cyano(thien-3-yl)]-4-carboxyl-
atepyridine (26b). The title compound was obtained as dark
17. Sabmis, R. W.; Rangnekar, D. W.; Sonawane, N. B.
J. Heterocycl. Chem. 1999, 36, 333.