Acetylacetaldehyde Dimethyl Acetal as Versatile Precursors for the Synthesis of Arylazonicotinic Acid Derivatives: Green Multicomponent Syntheses of Bioactive Poly-Heteroaromatic Compounds

Article abstract of DOI:10.1002/jhet.2673

A simple and efficient one-pot synthesis of interesting arylhydrazonals could be achieved via coupling of acetylacetaldehyde dimethyl acetal with aromatic diazonium salts. Dimroth type rearrangement was observed during the reaction of the arylhydrazonals with malononitrile or ethyl cyanoacetate leading to the formation of arylazonicotinic acid derivatives. The reaction of arylhydrazonals with malononitrile and aldehydes in the presence of DABCO afforded 4-styryl-1,2-dihydropyridine-3-carbonitrile whose structure was established by X-ray crystallography. Pyrazolyl-enaminone was accomplished and used as a scaffold to synthesize bioactive fused heterocyclic compounds such as 1,2,4-triazolo[1,5-a]pyrimidine 28, benzo[4,5]imidazo[1,2-a]pyrimidine 30 and pyrazole[1,5-a]pyrimidine derivatives 32.

Full text of DOI:10.1002/jhet.2673

Month 2016
Acetylacetaldehyde Dimethyl Acetal as Versatile Precursors for the
Synthesis of Arylazonicotinic Acid Derivatives: Green Multicomponent
Syntheses of Bioactive Poly-Heteroaromatic Compounds
*
Huwaida M. E. Hassaneen and Ismail A. Abdelhamid
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
*
E-mail: ismail_shafy@yahoo.com
Received January 29, 2016
DOI 10.1002/jhet.2673
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A simple and efficient one-pot synthesis of interesting arylhydrazonals could be achieved via coupling of
acetylacetaldehyde dimethyl acetal with aromatic diazonium salts. Dimroth type rearrangement was
observed during the reaction of the arylhydrazonals with malononitrile or ethyl cyanoacetate leading to
the formation of arylazonicotinic acid derivatives. The reaction of arylhydrazonals with malononitrile and
aldehydes in the presence of DABCO afforded 4-styryl-1,2-dihydropyridine-3-carbonitrile whose structure
was established by X-ray crystallography. Pyrazolyl-enaminone was accomplished and used as a scaffold
to synthesize bioactive fused heterocyclic compounds such as 1,2,4-triazolo[1,5-a]pyrimidine 28, benzo
[4,5]imidazo[1,2-a]pyrimidine 30 and pyrazole[1,5-a]pyrimidine derivatives 32.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
electrophilic [1,17–19] and nucleophilic [20,21] reagents
has been explored. We also report on the utility of the
commercially available, inexpensive acetylacetaldehyde
dimethyl acetal 7 as precursor to poly-substituted
heteroaromatics of potential biological activity (Fig. 1).
Functionally substituted 2-arylhydrazonals are versa-
tile reagents, and their chemistry has recently received
considerable interest [1–8]. In previous work from
Elnagdi’s laboratories [1,9–15] the 2-arylhydrazonals
were prepared through condensation of methylketones 1
with dimethylformamide dimethylacetal (DMFDMA) 2
followed by coupling reaction of the formed enamines
with aromatic diazonium salts. Although, this process is
the most extensively utilized route for the preparation
of 2-arylhydrazonals, it is energy consuming, quite ex-
pensive, multistage and environmentally non-friendly
process. Trials to prepare the arylhydrazonal 4 through
the reaction of arylhydrazones 5 with formaldehyde in
ethanol gives compound 6 as side product[16]. In our
RESULTS AND DISCUSSIONS
Coupling of acetylacetaldehyde dimethyl acetal 7 in aque-
ous media with aromatic diazonium salts afforded 4a in ex-
cellent yield with good purity. The reaction of 4a with ethyl
cyanoacetate in the presence of an excess amount of ammo-
nium acetate and a few drops of acetic acid afforded ethyl
2-amino-6-methyl-5-arylazonicotinate 12a. The pathway of
this reaction may involve initial condensation of 4a with ethyl
cyanoacetate to yield the hydrazono-enone 8 that then
cyclized to generate the pyran-imine 10. In the presence of
a high concentration of ammonium acetate, pyran-imine 10
undergoes a Dimroth type rearrangement to yield 11 that then
cyclized via elimination of water to yield 12a (Scheme 1).
contribution 2-arylhydrazonals
4 were prepared in
excellent yields with good purity through the direct cou-
pling of acetoacetaldehyde dimethylacetale 7 in aqueous
media with aromatic diazonium salts (cf. Fig. 1). The re-
activity of 2-arylhydrazonals of type 4 toward both
© 2016 Wiley Periodicals, Inc.

H. M. E. Hassaneen and I. A. Abdelhamid
Vol 000
Figure 1. The synthetic strategies of 2-arylhydrazonals.
Similarly, reaction of 4a with malononitrile in the presence of
an excess amount of ammonium acetate and a few drops of
acetic acid afforded 12b (Scheme 1). Formation of 12a,b is
believed to follow the well-established previously published
route [22]. The structures of products 12a,b were confirmed
based on their spectral and elemental analyses (see Experi-
mental). Furthermore, the condensation of arylhydrazonal
4a with DMFDMA afforded the hydrazonal-enaminone 13.
Trials to affect further cyclization of 13 into 14 or 15 did
not succeed (Scheme 1).
Scheme 2. Multicomponent synthesis of pyridine-2-one.
A novel multicomponent synthesis of pyridine 21a–c
could be achieved via heating a mixture of 7, malononitrile
and aromatic aldehyde in the presence of DABCO. It is be-
lieved that acetoacetaldehyde dimethylacetale 7 initially
Scheme 1. Synthesis of arylazonicotinic acid derivatives.
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Acetylacetaldehyde Dimethyl Acetal as Versatile Precursors
19 underwent Dimroth rearrangement to yield 20 that then
condensed subsequently with aromatic aldehydes to afford
(E)-2-oxo-4-styryl-1,2-dihydropyridine-3-carbonitrile. The
structure of 21a was established via x-ray crystallography
(CCDC 983759) (Scheme 2 and Fig. 2).
Condensation of compound 7 with DMFDMA in
refluxing xylene afforded enaminone 22 that then reacted
with phenylhydrazine to give 4-acetylprazole 23. Further
condensation of 23 with DMFDMA in xylene leads to
the formation of 3-[(E)-3-N,N-dimethylamino)acryloyl]-1-
phenyl-1H-pyrazole 24. It is noteworthy to mention that
compound 24 has not been reported hitherto. The structure
of the enaminone 24 was confirmed by its elemental anal-
ysis and spectral data. For example, the 1H NMR spectrum
displayed two singlet at δ = 2.83 and 3.09ppm characteris-
tic for the ―N(CH3)2 group, two doublets at δ= 5.63 and
7.86 ppm with coupling constant J = 12Hz, assignable to
the two olefinic protons (Scheme 3).
Figure 2. X-ray crystal structure of compound 21a. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
condensed with malononitrile to yield non-isolable product
16 that hydrolyzes into 17 followed by isomerization and
cyclization to generate the pyran-2-imine 19. Compound
Scheme 3. Synthesis of 4-acetyl pyrazole.
Scheme 4. Reactivity of enaminone of 4-acetylpyrazole.
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H. M. E. Hassaneen and I. A. Abdelhamid
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The pyrazolyl enaminone 24 can be used as scaffold for
synthesis of a diversity of other heterocycles (Scheme 4).
Thus treatment of enaminone 24 with hydroxylamine
hydrochloride or hydrazine hydrate in refluxing ethanol re-
sulted in formation of 3-(1H-pyrazol-4-yl)isoxazole 25 and
3,4′-bipyrazole derivatives 26, respectively (Scheme 4).
The reactivity of enaminone 24 toward some heterocyclic
amines was also examined. Thus, reaction of 24 with
3-amino-1,2,4-triazole 27 in acetic acid under reflux
afforded the respective 1,2,4-triazolo[1,5-a]pyrimidine
derivative 28. Similar reaction of 24 with 2-amino-
benzimidazole 29 and 5-amino-3-phenyl-pyrazole 31 un-
der the same reaction conditions yielded the respective
benzimidazo[1,2-a]pyrimidine and pyrazole[1,5-a] pyrimi-
dine derivatives 30 and 32. The reaction of heterocyclic
amines with enaminone proceeded first via Michael-type
addition of exocyclic amino group of each amine used to
the activated double bond of 24 with concurrent elimina-
tion of dimethyl amine and dehydrative cyclization
crystal X-ray Diffractometers. All reactions were
monitored by using TLC with 1:1 ethyl acetate-petroleum
ether as eluent and run the starting materials were
completely consumed.
Synthesis of (E)-2-(2-(4-chlorophenyl)hydrazono)-3-oxobutanal
4a.
A cold solution of aromatic diazonium salt
(10 mmol) was prepared by adding a solution of sodium
nitrite (10 mmol) to cold solution of 4-chloroaniline
hydrochloride (10 mmol) with stirring. The resulting
solution of diazonium salt was added to cold solution
of 7 (1.32 g, 10 mmol), containing sodium acetate
(0.5 g). The reaction mixture was stirred at rt for
30 min; the solid product formed was washed with
water and crystallized from ethanol.
Yellow crystals, (88%), mp 137–139°C. 1H NMR
(400 MHz, CDCl3): δ 2.50 (s, 3H, CH3), 7.41–7.44 (m,
4H, Ar―H), 10.11 (s, 1H, CHO), 14.62 (br., 1H, NH,
D2O exchangeable). 13C NMR (100MHz, CDCl3): 24.6,
117.5, 125.6, 129.8, 131.8, 139.6, 189.9, 197.0. MS, m/z
(%) = 226 (M +2, 12), 225 (M + 1, 13), 224 (M+, 45),
181 (10), 127 (100), 111 (30), 75 (10); Anal. Calcd for
C10H9ClN2O2 (224.64): C, 53.47; H, 4.04; N, 12.47.
Found: C, 53.36; H, 3.93; N, 12.33%.
1
[15,23,24]. The H NMR spectrum of each product 28,
30, and 32 revealed two doublets signals in the regions at
δ= 7.89–8.06 and 8.48–8.62ppm assignable to the two
vicinal protons of pyrimidine ring residue [25].
General synthetic procedure, exemplified by ethyl
2-amino-6-methyl-5-p-chlorophenyl-azonicotinate 12a,b.
A reaction mixture of 2-arylhydrazonal 4a (2.24g,
10mmol), active methylenenitrile derivatives (ethyl
cyanoacetate or malononitrile) (10mmol), and ammonium
acetate (3g) in acetic acid (10mL) was stirred at reflux
for 30min. The mixture was cooled to r.t. and then
poured into ice-water. The crude product was collected
by filtration and crystallized from ethanol.
CONCLUSION
In conclusion, we have developed a simple and efficient
method for the synthesis of 2-arylhydrazonals and
acetylpyrazole utilizing acetoacetaldehyde dimethylacetale
as starting material. The synthetic utility of these
compounds as building blocks for novel arylazonicotinic
acid as well as other functionally substituted heterocycles
has also been investigated. These new classes of com-
pounds are interesting both in their own right as unusual
molecules and for their potential pharmacological and bio-
logical activities.
Ethyl
(E)-2-amino-5-((4-chlorophenyl)diazenyl)-6-
methylnicotinate 12a. Brown solid (80%), mp 202–204°C.
IR (KBr): 3345, 3310 (NH2); 1700 (CO). 1H NMR
(400 MHz, DMSO-d6): δ 1.24 (t, 3H, J=7.2Hz, CH3),
2.51 (s, 3H, CH3), 4.29 (q, 2H, J=7.2Hz, CH2), 7.32 (br.,
2H, NH2, D2O exchangeable) 7.41 (d, 2H, J=8.2Hz,
Ar―H), 7.77 (d, 2H, J=8.2Hz, Ar―H), 8.20 (s, 1H,
Pyridine-H). 13C NMR (100MHz, DMSO-d6): δ 14.4,
24.96, 62.3, 115.6, 128.2, 129.3, 130.1, 133.9, 140.2,
141.8, 156.5, 162.9, 194.6. MS, m/z (%) =320 (M + 2, 8),
319 (M+1, 36), 318 (M+, 97), 277 (25), 248 (100), 207
(15), 111 (72), 75 (18); Anal. Calcd for C15H15ClN4O2
(318.76): C, 56.52; H, 4.74; N, 17.58. Found: C, 56.39; H,
4.59; N, 17.39%.
EXPERIMENTAL
General. Melting points are reported uncorrected and
were determined with a Sanyo (Gallaenkamp) instrument.
Infrared spectra were recorded using KBr pellets and a
Jasco FT-IR 6300 instrument, and absorption bands are
reported in cmꢀ1 1H- and 13C NMR spectra were
.
determined by using a Bruker DPX instrument at 400MHz
for 1H NMR and 100MHz for 13C NMR and either CDCl3
or DMSO-d6 solutions with TMS as internal standards.
Chemical shifts are reported in δ (ppm). Mass spectra
and accurate mass were measured using a GCMS DFS
Thermo spectrometer with the EI (70 EV) mode. X-ray
crystallographic structure determinations were performed
by using Rigaku Rapid II and Bruker X8 Prospector single
2-Amino-5-((4-chlorophenyl)diazenyl)-6-methylnicotinonitrile
12b. Brown solid (84%), mp 195–197°C. IR (KBr):
3342, 3275 (NH2); 2201 (CN). 1H NMR (400 MHz,
DMSO-d6): δ 2.51 (s, 3H, CH3), 7.51 (br., 2H, NH2,
D2O exchangeable) 7.61 (d, 2H, J = 8.2 Hz, Ar―H),
7.79 (d, 2H, J = 8.2 Hz, Ar―H), 8.65 (s, 1H, Pyridine-
H). 13C NMR (100 MHz, DMSO-d6): δ 25.1, 114.0,
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Acetylacetaldehyde Dimethyl Acetal as Versatile Precursors
127.9, 128.4, 129.5, 134.3, 136.6, 139.7, 141.7, 156.8.
MS, m/z (%) = 273 (M + 2, 8), 272 (M + 1, 33), 271 (M
+, 100), 230 (10), 225 (100), 196 (8), 111 (45), 75
(15); Anal. Calcd for C13H10ClN5 (271.71): C, 57.47;
H, 3.71; N, 25.78 Found: C, 57.39; H, 3.65; N, 25.71%.
(M+1, 16), 256 (M+, 55), 220 (20), 196 (100), 178 (20), 166
(10), 117 (5), 77 (10), 66 (15); Anal. Calcd. for C14H9ClN2O
(256.69): C, 65.51; H, 3.53; N, 10.91. Found: C, 65.47; H,
3.49; N, 10.88%.
B:(E)-4-(4-methoxystyryl)-2-oxo-1,2-dihydropyridine-3-
Synthesis of 2-(2-(4-chlorophenyl)hydrazono)-5-(dimethylamino)-
3-oxopent-4-enal 13. A reaction mixture of hydrazonal 4a
(2.24g, 10mmol) and DMFDMA (2.64, 20mmol) in
toluene (5mL) was heated under reflux for 8h. The solid
product that formed was collected and crystallized from
ethanol. The reaction gave dark yellow crystal, yield
(70%); mp 173–175°C. IR (KBr): 3322 (NH); 1660, 1698
carbonitrile 21c.
17c. Yellow crystals, (78%); mp.
289–290°C. IR (KBr): 3226 (NH); 2219 (CN); 1670
1
(CO). H NMR (400 MHz, DMSO-d6): δ= 3.53 (s, 3H,
CH3O) 4.52 (br., 1H, NH, D2O exchangeable) 5.15 (d,
1H, J = 4 Hz, pyridine-H), 7.23 (d, 1H, J = 16 Hz, CH¼),
7.47–7.75 (m, 4H, Ph―H), 7.62 (d, 1H, J = 16 Hz,
CH¼), 8.88 (d, 1H, J = 4 Hz, pyridine-H). 13C NMR
(100 MHz, DMSO-d6): δ= 53.2, 105.3, 112.5, 114.3,
115.2, 123.2, 127.8, 130.8, 135.0, 142.3, 158.2, 159.4,
162.3, MS, m/z (%) = 252 (M+, 62), 221 (45), 196 (100),
178 (22), 166 (11), 117 (8), 77 (15), 66 (18); Anal.
Calcd. for C15H12N2O2 (252.27): C, 71.42; H, 4.79; N,
11.10. Found: C, 71.36; H, 4.76; N, 11.08%.
1
(2CO). H NMR (400MHz, DMSO-d6): δ 2.64 (s, 3H,
CH3), 3.03 (s, 3H, CH3), 6.26 (d, 1H, J=12Hz, CH),
7.07–7.65 (m, 4H, Ar―H), 7.73 (d, 1H, J=12Hz, CH),
8.89 (s, 1H, CHO), 10.32 (br., 1H, NH, D2O
exchangeable). 13C NMR (100MHz, DMSO-d6): δ 30.1,
36.2, 113.3, 118.7, 121.2, 125.8, 129.0, 129.7, 154.4,
162.8, 196.2. MS, m/z (%)=279 (M+, 10), 237 (35), 182
(80), 140 (100), 127 (93), 111 (55), 75 (25); Anal. Calcd
for C13H14ClN3O2 (279.72): C, 55.82; H, 5.04; N, 15.02.
Found: C, 55.65; H, 4.89; N, 14.86%.
Synthesis of 1-(1-phenyl-1H-pyrazol-4-yl)ethan-1-one
23.
A mixture of 4,4-dimethoxybutan-2-one 7
(1.32 g, 10 mmol) and DMFDMA (1.19 g, 10 mmol) in
xylene (25 mL) was reflux for 3 h, cooled and then
poured into ice-water. The formed yellowish oil was
extracted by dichloromethane then refluxed with
phenylhydrazine (1.08 g, 10 mmol) in ethanol (25 mL) for
3 h, cooled, and then poured into ice-water. The formed
product was collected by filtration and recrystallized
from EtOH to give faint yellow crystals, (78%); mp.
Synthesis of 2-oxo-4-styryl-1,2-dihydropyridine-3-carbonitrile
derivatives 21a–c. A mixture of 4,4-dimethoxybutan-2-one
7 (1.32g, 10 mmol), aromatic aldehydes (10mmol), and
malononitrile (0.66 g, 10 mmol) in EtOH (25 mL) in the
presence of DABCO (20%) was stirred at reflux for 3–4h,
cooled, and then poured into ice-water. The formed solid
was collected by filtration and recrystallized from proper
solvents.
1
125–126°C. IR (KBr): 1689 (CO). H NMR (400 MHz,
DMSO-d6): δ= 2.49 (s, 3H, CH3), 7.37–7.92 (m, 5H,
Ph―H), 8.17 (s, 1H, pyrazole-H), 9.18 (s, 1H, pyrazole-
H). 13C NMR (100 MHz, DMSO-d6): δ= 28.4, 119.5,
125.8, 127.8, 130.1, 131.5, 139.4, 141.6, 192.2, MS, m/z
(%) = 186 (M+, 45), 171 (100), 116 (20), 77 (25); Anal.
Calcd. for C11H10N2O (186.21): C, 70.95; H, 5.41; N,
15.04. Found: C, 71.04; H, 5.33; N, 15.18%.
(E)-2-oxo-4-styryl-1,2-dihydropyridine-3-carbonitrile
21a. Faint yellow crystals, (78%); mp. 299–300°C. IR
(KBr): 3221 (NH); 2221 (CN); 1675 (CO). 1H NMR
(400 MHz, DMSO-d6): δ = 4.49 (br., 1H, NH, D2O
exchangeable) 5.15 (d, 1H, J = 4 Hz, pyridine-H), 7.23
(d, 1H, J = 16 Hz, CH¼), 7.47–7.75 (m, 5H, Ph―H),
7.62 (d, 1H, J = 16 Hz, CH¼), 8.96 (d, 1H, J = 4 Hz,
pyridine-H). 13C NMR (100 MHz, DMSO-d6): δ= 105.7,
112.5, 114.3, 123.2, 127.8, 128.2, 129.2, 130.8, 135.0,
142.3, 157.4, 160.2, MS, m/z (%) = 222 (M+, 60), 196
(100), 178 (20), 166 (10), 117 (5), 77 (10), 66 (15);
Anal. Calcd. for C14H10N2O (222.24): C, 75.66; H,
4.54; N, 12.60. Found: C, 75.53; H, 4.49; N, 12.54%.
Synthesis of (E)-3-(dimethylamino)-1-(1-phenyl-1H-pyrazol-
4-yl)prop-2-en-1-one 24. A mixture of 4-acetyl-1-phenyl-
1H-pyrazole 23 (0.93g, 5mmol) and DMFDMA (3mL)
was refluxed for 6h in xylene (30mL). The solid that
precipitated was collected and crystallized from EtOH to
yield yellow crystals, (78%); mp. 142–144°C. IR (KBr):
1
1659 (CO). H NMR (400MHz, DMSO-d6): δ=2.83 (s,
3H, CH3), 3.09 (s, 3H, CH3), 5.63 (d, 1H, J=16Hz,
―CH¼) 7.38–7.96 (m, 5H, Ph―H), 7.86 (d, 1H,
J=16Hz, ¼CH―) 8.17 (s, 1H, pyrazole-H), 8.98 (s, 1H,
pyrazole-H). MS, m/z (%)=241 (M+, 38), 186 (19), 185
(25), 170 (100), 116 (20), 75 (35); Anal. Calcd. for
C14H15N3O (241.29): C, 69.69; H, 6.27; N, 17.41. Found:
C, 69.65; H, 6.19; N, 17.36%.
(E)-4-(4-chlorostyryl)-2-oxo-4-styryl-1,2-dihydropyridine-
3-carbonitrile 21b. Yellow crystals, (78%); mp. 310–312°C.
1
IR (KBr): 3223 (NH); 2220 (CN); 1675 (CO). H NMR
(400MHz, DMSO-d6): δ=4.49 (br., 1H, NH, D2O
exchangeable) 5.35 (d, 1H, J=4 Hz, pyridine-H), 7.23 (d, 1H,
J=16Hz, CH¼), 7.43 (d, 2H, J=8.4Hz, Ar―H) 7.72 (d,
2H, J=8.4Hz, Ar―H), 7.62 (d, 1H, J=16Hz, CH¼), 8.90
(d, 1H, J= 4Hz, pyridine-H). 13C NMR (100MHz, DMSO-
d6): δ=105.7, 112.5, 114.3, 123.2, 127.8, 128.2, 129.2, 130.8,
135.0, 142.3, 157.4, 160.2, MS, m/z (%)=258 (M +2, 6), 257
Synthesis of 3-(1-phenyl-1H-pyrazol-4-yl)isoxazole 25. To
a solution of 24 (1.2g, 5mmol) in absolute ethanol was
added hydroxylamine hydrochloride (0.35g, 5mmol) and
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H. M. E. Hassaneen and I. A. Abdelhamid
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anhydrous potassium carbonate (0.5g, 5mmol). The
reaction mixture was refluxed for 6h. The precipitate
formed upon cooling was filtered off and crystallized from
ethanol to yield yellow crystals, (80%); mp. 150–152°C.
1H NMR (400MHz, DMSO-d6): δ =6.79 (d, 1H,
J=10Hz, isoxazole-H), 7.18 (d, 1H, J=10Hz, isoxazole-
H), 7.38–7.92 (m, 5H, Ph―H), 8.12 (s, 1H, pyrazole-H),
8.68 (s, 1H, pyrazole-H). MS, m/z (%)=211 (M+, 55),
167 (100), 166 (53), 115 (22), 70 (30); Anal. Calcd. for
C12H9N3O (211.22): C, 68.24; H, 4.29; N, 19.89. Found:
C, 68.19; H, 4.23; N, 19.81%.
2-Phenyl-7-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]
pyrimidine 32. Yellow crystals, (78%), mp. 195–197°C.
1H NMR (400MHz, DMSO-d6): δ=7.38–7.87 (m, 10H,
Ar―H), 7.92 (d, 1H, J=6Hz, pyrimidine-H), 8.12 (s, 1H,
pyrazole-H), 8.33 (s, 1H, pyrazole-H), 8.62 (d, 1H,
J=6Hz, pyrimidine-H), 8.96 (s, 1H, triazole-H), MS, m/z
(%)=338 (M+1, 30), 337 (M+, 54), 262 (100), 170 (60),
165 (53), 111 (31), 75 (55), 70 (50); Anal. Calcd. for
C21H15N5 (337.38): C, 74.76; H, 4.48; N, 20.76. Found:
C, 74.69; H, 4.43; N, 20.71%.
Synthesis of 1′-phenyl-1′H,2H-3,4′-bipyrazole 26. To a
solution of 24 (1.2 g, 5mmol) in absolute ethanol was
added hydrazine hydrate (5 mL, 10 mmol). The reaction
mixture was refluxed for 5h. The precipitate formed upon
cooling was filtered off and crystallized from ethanol to
give pale yellow crystals, (80%), mp. 185–187°C. IR
(KBr): 3295 (NH). 1H NMR (400 MHz, DMSO-d6):
δ= 6.93 (d, 1H, J = 10 Hz, pyrazole-H), 7.23–7.82 (m,
5H, Ph―H), 7.88 (d, 1H, J =10 Hz, pyrazole-H), 8.13 (s,
1H, pyrazole-H), 8.58 (s, 1H, pyrazole-H), 10.24 (s, 1H,
NH, D2O exchangeable), MS, m/z (%) = 211 (M + 1, 14),
210 (M+, 100), 170 (75), 166 (53), 115 (31), 75 (55), 70
(50); Anal. Calcd. for C12H10N4 (210.23): C, 68.56; H,
4.79; N, 26.65. Found: C, 68.51; H, 4.71; N, 26.59%.
Acknowledgments. The authors express deep sense of gratitude
to the Prof. M. H. Elnagdi for his keen interest and constant
encouragement.
REFERENCES AND NOTES
[1] Makhseed, S.; Hassaneen, H. M. E.; Elnagdi, M. H. Zeitschrift
Für Naturforsch B 2007, 62, 529.
[2] Hassaneen, H. M.; Elwan, N. M.; Hassaneen, H. M. Synth
Commun 2006, 32, 3047.
[3] Elwan, N. M.; Hassaneen, H. M.; Hassaneen, H. M. Heteroat
Chem 2002, 13, 585.
[4] Hassaneen, H. M.; Abdallah, T. A.; Abdelhadi, H. A.;
Hassaneen, H. M. E.; Pagni, R. M. Heteroat Chem 2003, 14, 491.
[5] Hassaneen, H. M. E.; Hassaneen, H. M.; Elnagdi, M. H.
Zeitschrift Für Naturforsch B 2004, 59, 1132.
General method for synthesis of compounds 28, 30, and
[6] Abdelhamid, I. A.; Nasra, M. A.; Elnagdi, M. H. Synlett 2009
3237.
[7] Al-awadi, N. A.; Ibrahim, M. R.; Abdelhamid, I. A.; Elnagdi, M. H.
Tetrahydron 2008, 64, 8202.
32.
To a solution of 24 (1.2 g, 5 mmol) in acetic
acid (25 mL) was added the appropriate heterocyclic
amine (27, 29, and 31) (5 mmol). The reaction mixture
was refluxed for 5 h then cooled. The solid that
formed was collected and crystallized from proper
solvents.
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Elnagdi, M. H. Heterocycles 2007, 71, 2627.
7-(1-Phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidine
1
28. Yellow crystals, (76%), mp. 173–175°C. H NMR
(400MHz, DMSO-d6): δ =7.23–7.92 (m, 5H, Ph―H),
8.06 (d, 1H, J=6Hz, pyrimidine-H), 8.17 (s, 1H, pyrazole-
H), 8.38 (s, 1H, pyrazole-H), 8.59 (d, 1H, J=6Hz,
pyrimidine-H), 8.76 (s, 1H, triazole-H), MS, m/z (%)=263
(M+1, 19), 262 (M+, 32), 216 (100), 170 (60), 165 (53),
111 (31), 75 (55), 70 (50); Anal. Calcd. for C14H10N6
(262.27): C, 64.11; H, 3.84; N, 32.04. Found: C, 64.05; H,
4.06; N, 32.12%.
4-(1-Phenyl-1H-pyrazol-4-yl)benzo[4,5]imidazo[1,2-a]
pyrimidine 30.
Pale yellow crystals, (73%), mp.
165–167°C. 1H NMR (400MHz, DMSO-d6): δ =7.33–
7.86 (m, 9H, Ar―H), 7.89 (d, 1H, J=6Hz, pyrimidine-
H), 8.17 (s, 1H, pyrazole-H), 8.36 (s, 1H, pyrazole-H),
8.48 (d, 1H, J=6Hz, pyrimidine-H), 8.91 (s, 1H,
triazole-H), MS, m/z (%)=312 (M+1, 19), 311 (M+,
32), 236 (11), 195 (100), 170 (55), 165 (50), 111 (31),
75 (55), 70 (50); Anal. Calcd. for C19H13N5 (311.34):
C, 73.30; H, 4.21; N, 22.49. Found: C, 73.26; H, 4.19;
N, 22.47%.
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Gaber, H. M. J Heterocycl Chem 2005, 42, 1185.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet