Synthesis of some novel pyrazolo[1,5-a]quinazolines and their fused derivatives

Article abstract of DOI:10.1080/00397911.2016.1257722

New pyrazolo[1,5-a]quinazoline-3-carbonitriles 4a,b were obtained via cyclocondensation of 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile (1) with enaminones of 1,3-cyclohexanedione derivatives 2a,b in refluxing glacial acetic acid. Condensation of compounds 4a,b with various aromatic aldehydes furnished the corresponding arylidene derivatives 6a–j. On the other hand, condensation of 4a,b with o-hydroxybenzaldehydes yielded the polyheterocyclic compounds 10a–h. Coupling of compounds 4a,b with aryldiazonium chlorides led to formation of 2-arylhydrazono derivatives 12a–h. Also, reaction of compounds 4a,b with phenyl isothiocyanate, followed by addition of ethyl chloroacetate and chloroacetonitrile, afforded the polyheterocyclic compounds based on pyrazolo[1,5-a]quinazoline core. The reaction of compounds 4a,b with phenyl isothiocyanate and elemental sulfur gave the thiazole-2-thione derivatives 25a,b. The reaction of enamines of compounds 4a,b with each of hydrazine hydrate and guanidine hydrochloride afforded pyrazolo[4″,3″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-8-ones 30a,b and pyrimido[5″,4″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-9(10H)-ones 33a,b, respectively. The structures of all the newly synthesized compounds were elucidated by elemental analyses and spectral data. The plausible mechanisms have been postulated to account for their formation.

Full text of DOI:10.1080/00397911.2016.1257722

Synthesis of Some Novel Pyrazolo[1,5-a]quinazolines and Their Fused Derivatives
Eman Ali Ragab1, Nadia Hanafy Metwally1, Mona Said Mohamed1
1Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Corresponding author Mona Said Mohamed E-mail: nhmmohamed@yahoo.com
Abstract
New pyrazolo[1,5-a]quinazoline-3-carbonitriles 4a,b were obtained via
cyclocondensation of 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile (1) with
enaminones of 1,3-cyclohexanedione derivatives 2a,b in refluxing glacial acetic acid.
The condensation of compounds 4a,b with various aromatic aldehydes furnished the
corresponding arylidene derivatives 6a-j. On the other hand, condensation of 4a,b with o-
hydroxybenzaldehydes yielded the polyheterocyclic compounds 10a-h. Coupling of
compounds 4a,b with aryldiazonium chlorides led to formation of 2-arylhydrazono
derivatives 12a-h. Also, reaction of compounds 4a,b with phenyl isothiocyanate,
followed by addition of ethyl chloroacetate and chloroacetonitrile afforded the
polyheterocyclic compounds based on pyrazolo[1,5-a]quinazoline core. The reaction of
compounds 4a,b with phenyl isothiocyanate and elemental sulfur gave the thiazole-2-
thione derivatives 25a,b. The reaction of enamines of compounds 4a,b with each of
hydrazine hydrate and guanidine hydrochloride afforded
pyrazolo[4'',3'':5',6']pyrido[4',3':3,4]pyrazolo[1,5-a]quinazolin-8-ones 30a,b and
pyrimido[5'',4'':5',6']pyrido[4',3':3,4]pyrazolo[1,5-a]quinazolin-9(10H)-ones 33a,b,
respectively. The structure of all the newly synthesized compounds was elucidated by
elemental analyses and spectral data. The plausible mechanisms have been postulated to
account for their formation.
1

Graphical Abstract
KEYWORDS: 2-(Cyanomethyl)-6-oxo-pyrazolo[1,5-a]quinazolines; pyrazolo-
[4'',3'':5',6']pyrido[4',3':3,4]pyrazolo[1,5-a]quinazolinones;pyrimido[5'',4'':5',6']-
pyrido[4',3':3,4]pyrazolo[1,5-a]quinazolinones
INTRODUCTION
Pyrazolo[1,5-a]quinazoline derivatives have a broad spectrum of biological activity such
as anticancer,[1–3] anti-inflammatory[4] and antimicrobial[5]. Also, they are effective as
antisecretory agents[6] and as poly(ADP-ribose) polymerase-1(PARP-1) inhibitors[7].
Therefore, based on the previous reports and in continuation of our interest in the
synthesis of new bioactive heterocyclic compounds,[8–17] we report herein the preparation
of some new polyheterocyclic compounds containing pyrazolo[1,5-a]quinazoline moiety
starting with the unreported hitherto 2-(cyanomethyl)-6-oxo-pyrazolo[1,5-a]quinazoline-
3-carbonitriles 4a,b as key intermediates for our objectives.
2

RESULTS AND DISCUSSION
Chemistry
The reaction of 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile (1) with enaminone
of 1,3-cyclohexanedione derivatives 2a,b in refluxing glacial acetic acid, afforded the
colored products 4a,b (Scheme 1). The structure of the isolated products was determined
by their elemental analyses and spectral data (IR, 1H NMR, 13C NMR and MS). The IR
spectrum of the isolated product 4b showed absorption bands at νmax 2227 and 1687 cm-1
corresponding to CN and CO groups, respectively. The 1H NMR spectrum of compound
4b revealed a singlet signal at δ = 4.47 ppm assigned to the methylene protons (CH2CN)
and a singlet signal at δ = 9.02 ppm attributable to the pyrimidine proton. Also, 13C NMR
spectrum of 4b showed characteristic three signals at δ = 17.3, 154.5 and 194.3 ppm
assigned for methylene (CH2CN), pyrimidine and carbonyl (CO) carbons, respectively.
Also, elemental analysis with mass spectrum of 4b showed a correct molecular ion peak
at m/z = 279 (M+). Consistent with the formula C15H13N5O. Thus, the reaction between
aminopyrazole 1 and enaminone 2b proceeded through an initial Michael addition of the
exocyclic amino group in the aminopyrazole 1 to the α,β-unsaturated moiety in the
enaminone 2b yielded the corresponding acyclic non-isolable intermediates which
undergo dehydrative cyclization and aromatization to give the final product 4b rather
than the isomeric structure 3b (Scheme 1).
Condensation of compounds 4a,b with various aromatic aldehydes 5a-e in absolute
ethanol in the presence of few drops of piperidine afforded the corresponding arylidene
3

derivatives of pyrazolo[1,5-a]quinazolines 6a-j (Scheme 2). The IR spectrum of the
isolated product 6b taken as a typical example of the prepared series showed absorption
bands at νmax 2226 and 1688 cm-1 corresponding to CN and CO groups, respectively. The
1H NMR spectrum of 6b revealed the presence of a singlet signal at δ = 3.88 ppm
assigned to the methoxy protons, in addition to a singlet signal at δ = 8.34 ppm
attributable to vinylic proton and a singlet signal at δ = 9.11 ppm assigned for pyrimidine
proton. Also, the elemental analyses are in agreement with the structure 6b (Scheme 2).
On the other hand, refluxing compounds 4a,b with o-hydroxybenzaldehydes 7a,b in dry
ethanol containing few drops of piperidine produced, in each case, yellowish orange solid
of melting point above 300oC (Scheme 3). The IR spectrum of compound 9a showed
absorption bands at νmax 3372, 2228 and 1683 cm-1 corresponding to NH, CN and CO
groups, respectively. The 1H NMR spectrum of 9a revealed the presence of a D2O-
exchangeable signal at δ = 9.13 ppm assigned to the NH proton. The elemental analyses
are in agreement with the structures 9a-d (Scheme 3). Refluxing the latter compounds in
sodium ethoxide solution afforded products 10a-d. The structure of the isolated products
10a-d was inferred from correct analytical and spectral data. As typical example, the IR
spectrum of 10a showed disappearance of an absorption band corresponding to nitrile
group near νmax ~2200 cm-1 and instead revealed an absorption band at νmax 3371 cm-1 due
to the NH group. The1H NMR spectrum of 10a revealed a D2O-exchangeable signal at δ
= 9.17 ppm attributable to NH proton.
4

Subsequently, we extended our study in synthesizing new azodye derivatives. Thus,
compounds 4a,b were coupled with the diazotized aromatic amines 11a-d in N,N-
dimethylformamide (DMF) in the presence of anhydrous sodium acetate at 0-5oC leading
to yellow colored compounds 12a-h (Scheme 4). The IR spectrum of the isolated
compound 12a which was taken as a typical example of the prepared series, showed
absorption bands at νmax3238, 2224 and 1687 cm-1 corresponding to the NH, CN and CO
groups, respectively. The 1H NMR spectrum of the isolated product 12a revealed a
singlet signal at δ = 8.99 ppm due to the pyrimidine proton, in addition, a D2O-
exchangeable signal appeared at δ = 12.12 ppm assigned to the NH proton, beside the
other expected signals for aryl protons. 13C NMR spectrum of 12a showed characteristic
signals at δ = 155.6 and 194.0 ppm assigned for pyrimidine and carbonyl carbons,
respectively. The mass spectrum of 12a showed correct molecular ion peak at m/z = 285
(M+). However, our attempts to cyclize these hydrazone derivatives 12a-h to give
iminopyridazino[4`,5`:3,4]pyrazolo[1,5-a]quinazoline derivatives 13a-h failed under
all the different conditions reported for such cyclization[18,19] (Scheme 4).
The electronic absorption spectra of the products 12a-h in DMF revealed, in each case,
two absorption bands in the regions λmax 413-390 and 314-303 nm. This absorption
pattern seems to indicate that the studied compounds 12a-h exist predominantly in
solution as hydrazone form A. The reason is that such an absorption pattern is similar to
that of typical hydrazones[20,21]. 1H NMR spectra provide additional evidence that they
have the hydrazone form A rather than the azo-forms B. For instance, the 1H NMR spec-
tra of compounds 12 in DMSO-d6 exhibit, in each case, one singlet signal near 12.0 ppm
5

due to the =NNH-proton and this is substantiated by the literature data which indicate that
the chemical shift (δ) of hydrazone NH resonance is usually observed near 13.0 ppm[22,23]
(see Table 1).
The reaction of 4a,b with phenyl isothiocyanate in N,N-dimethylformamide (DMF) in the
presence of potassium hydroxide, followed by addition of ethyl chloroacetate 15 at room
temperature, afforded in each case a single product (17a or 17b, as evidenced by TLC)
(Scheme 6). The IR spectrum of 17a showed absorption bands at νmax 3453, 3065, 2225,
1710 and 1691 cm-1 due to the NH2, NH, CN and two CO groups, respectively. The 1H
NMR spectrum of compound 17a revealed a triplet signal at δ = 1.12 ppm with J = 6.9
Hz assigned to the methyl (CH3) protons and a quartet signal at δ = 4.13 ppm with J = 6.9
Hz assigned to methylene (CH2) protons of ester group. In addition, two D2O
exchangeable signals at δ = 6.92 and 10.21 ppm attributable to NH2 and NH protons,
beside the other expected signals for pyrimidine and aromatic protons. Elemental
analyses together with the spectral data are in agreement with structure 17. Refluxing
compounds 17a,b in sodium ethoxide solution afforded compounds 18a,b (Scheme 5).
The IR spectrum of 18b showed absorption bands at νmax 3435, 3073, 1712 and 1693 cm-
1 due to the NH2, NH and two CO groups, respectively. The 1H NMR spectrum of
compound 18b revealed signals at δ = 1.17 and 4.14 ppm with J = 6.9 ppm assigned to
the methyl (CH3) and methylene (CH2) protons for ester group, respectively, in addition
to, two D2O exchangeable signals at δ = 6.89 and 10.12 ppm assigned to NH2 and NH
protons, beside the other expected signals. Also, elemental analyses are in agreement
with structure 18b. The formation of compounds 18a,b assumed to proceed through
6

formation of thiophene derivatives 17 via non-isolable intermediate 16, followed by
addition of amino function to cyano group to generate
thieno[3'',4'':5',6']pyrido[4',3':3,4]pyrazolo[1,5-a]quinazoline deri-vatives 18a,b (Scheme
5).
In the same manner, the reaction of the non-isolable potassium salt of pyrazolo[1,5-
a]quinazoline derivative 14 with chloroacetonitrile 19 in DMF at room temperature,
afforded a single product identified as thiophene derivatives 21a,b via non-isolable
intermediate S-alkyl derivative 20 (Scheme 6). Refluxing compounds 21a,b in a solution
of sodium ethoxide afforded products identified as
thieno[3'',4'':5',6']pyrido[4',3':3,4]pyrazolo[1,5-a]quinazoline derivatives 22a,b (Scheme
6).
The reaction of compounds 4a,b with phenyl isothiocyanate and elemental sulfur in DMF
in the presence of triethylamine as catalyst, gave isolated products 25a,b (Scheme 7).
The IR spectrum of product 25b showed absorption bands at νmax 3293, 2203 and 1682
cm-1 due to the NH2, CN and CO groups, respectively. The 1H NMR spectrum of
compound 25b revealed a multiplet signal at δ = 7.29-7.95 ppm assigned to the NH2 and
aromatic protons. Mass spectrum showed correct molecular ion peak at m/z 446 (M+).
Furthermore, elemental analyses are in agreement with the proposed structure 25b.
However, trials to cyclize the compounds 25a,b into 5-amino-3-phenyl-2-
thioxothiazolo[5'',4'':5',6']pyrido-[4',3':3,4]pyrazolo[1,5-a]quinazolin-8(9H)-one
derivatives 26a,b failed under reflux in a solution of sodium ethoxide (Scheme 7).
7

Enamines are interesting class of organic compounds; the special value of these
compounds is due to their utility as valuable intermediate for the synthesis of several
interesting compounds[24-29]. Based on this, we prepared the enamine derivatives of
compounds 4a,b. Thus, the reaction of compounds 4a,b with dimethylformamide-
dimethylacetal (DMF-DMA) in dry dioxane afforded the corresponding enamine deriva-
tives 27a,b (Scheme 8). The IR spectrum of the isolated product 27b showed absorption
bands at νmax 2217, 2192 and 1692 cm-1 corresponding to the two CN and CO groups,
respectively. The 1H NMR spectrum of 27b revealed the presence of two singlet signals
at δ = 3.28 and 3.33 ppm, corresponding to the methyl protons [-N(Me)2] and a singlet
signal at δ = 7.89 ppm attributable to the olefinic proton. The 13C NMR spectrum of the
isolated product 27b showed three characteristic signals at δ = 153.4, 156.6 and 194.2
ppm assigned to pyrimidine, olefinic [=CHN(Me)2] and carbonyl carbons, respectively.
Treatment of the enamine derivatives 27a,b with hydrazine hydrate in DMF in the
presence of few a drops of piperidine afforded brown solid products 30a,b (Scheme 8).
The IR spectrum of compound 30b showed absorption bands at vmax 3287, 3071 and 1692
cm-1 due to the NH2, NH and CO groups, respectively. Its 1H NMR spectrum revealed
two D2O exchangeable singlet signals at δ = 7.63 and 13.13 ppm attributable to the NH2
and NH protons, beside the other expected signals assigned to aromatic and pyrimidine
protons. Elemental analyses and mass spectra are in consistent with structure 30a,b (see
Exp.).
8

The reaction of enamines 27a,b with guanidine hydrochloride in DMF in the presence of
anhydrous sodium acetate furnished the fused pyrimidine derivatives 33a,b (Scheme 9).
EXPERIMENTAL
Materials And Methods
Melting points were determined on an Electrothermal (9100) apparatus and are
uncorrected. The IR spectra were recorded as KBr pellets on a Perkin Elmer 1430
spectrophotometer. 1H NMR and 13C NMR spectra were recorded in deuterated
dimethylsulfoxide at 300 and 75 MHz, respectively, on a Varian Gemini NMR
spectrometer using tetramethylsilane as internal reference and the results are expected as
δ value. Mass spectra were taken on a Shimadzu GCMS-QP 1000 Ex mass spectrometer
at 70 eV. UV spectra and elemental analyses were carried out at the Microanalyses
Center of Cairo University, Giza, Egypt.
Synthesis Of 2-(Cyanomethyl)-6-Oxo-6,7,8,9-Tetrahydropyrazolo[1,5-
A]Quinazoline-3-Carbonitriles (4a,B).
A mixture of 5-amino-2-cyanomethyl-1H-pyrazole-4-carbonitrile 1 (0.01 mol) and 2-
(dimethylaminomethylene)-1,3-cyclohexanedione derivatives 2a,b (0.01 mol) in glacial
acetic acid (10 ml) was heated under reflux for 6 h, then allowed to cool. The solid was
collected by filtration and recrystallized from an ethanol-dioxane mixture to give
compounds 4a,b.
9

2-(Cyanomethyl)-6-Oxo-6,7,8,9-Tetrahydropyrazolo[1,5-A]Quinazoline-3-
Carbonitrile (4a).
Brown crystals, yield 60%, m.p = 205°C, vmax / cm-1 (KBr) 2225 (2CN), 1691 (CO); 1H
NMR (DMSO) δ = 2.24-2.28 (m, 2H, CH2), 2.68 (t, 2H, J = 6.6 Hz, CH2), 3.43 (t, 2H, J
= 6 Hz, CH2), 4.65 (s, 2H, CH2), 9.09 (s, 1H, pyrimidine-H); 13C NMR (DMSO) δ = 17.3,
19.7, 23.7, 36.6, 82.4, 111.8, 115.9, 116.8, 151.1, 151.4, 152.8, 156.4, 194.4; Anal. Calcd
for C13H9N5O: C, 62.15; H, 3.61; N, 27.87. Found: C, 62.32; H, 3.42; N, 27.62 %.
Synthesis Of Compounds 6a-J
General Procedure
A solution of the appropriate compound 4a,b (0.01 mol) in ethanol (20 ml) containing a
few drops of piperidine was added to the appropriate aldehyde 5a-e (0.01 mol). The
mixture was heated under reflux for 5 h and the reaction mixture was followed by TLC.
The solid product that precipitated by cooling was filtered off and recrystallized from
N,N-dimethylformamide to give the respective products 6a-j. The physical constants and
spectral data are shown below:
2-(1-Cyano-2-Phenylvinyl)-6-Oxo-6,7,8,9-Tetrahydropyrazolo[1,5-A]Quinazoline-3-
Carbonitrile (6a).
Reddish brown crystals, yield 65%, m.p = 240°C, vmax / cm-1 (KBr) 2225 (2CN), 1691
(CO); 1H NMR (DMSO) δ = 2.22-2.26 (m, 2H, CH2), 2.61 (t, 2H, J = 6.3 Hz, CH2), 3.39
(t, 2H, J = 6 Hz, CH2), 7.49-7.65 (m, 5H,Ar ), 8.51 (s, 1H, CH ), 9.09 (s, 1H, pyrimidine-
10

H ); Anal. Calcd for C20H13N5O: C, 70.79; H, 3.86; N, 20.64. Found: C, 70.59; H, 3.68;
N, 20.92 %.
Synthesis Of Compounds 9a-D
General Procedure:
To a solution of each of 4a,b (0.01 mol) was added the appropriate o-
hydroxybenzaldehydes 7a,b (0.01 mol) in absolute ethanol (20 ml) containing few drops
of piperidine under reflux for 3 h. The solid product so formed was collected by filtration,
washed with ethanol and recrystallized from an ethanol-dioxane mixture to give the
respective products 9a-d.
2-(2-Imino-2H-Chromen-3-Yl)-6-Oxo-6,7,8,9-Tetrahydropyrazolo[1,5-
A]Quinazoline-3-Carbonitrile (9a).
Brownish yellow crystals, yield 94%, m.p >300oC, νmax /cm-1 (KBr) 3372 (NH), 2228
(CN), 1683 (CO); 1H NMR (DMSO) δ = 2.23-2.26 (m, 2H, CH2), 2.46 (t, 2H, J = 6.6 Hz,
CH2), 3.14 (t, 2H, J = 6 Hz, CH2), 6.52-7.44 (m, 4H, Ar), 7.97 (s, 1H, CH), 8.96 (s, 1H,
pyrimidine-H), 9.13 (s, 1H, NH); Anal. Calcd for C20H13N5O2: C, 67.60; H, 3.69; N,
19.71. Found: C, 67.43; H, 3.51; N, 19.45 %.
CONCLUSION
In conclusion, we have described an efficient synthesis of some novel pyrazolo[1,5-
a]quinazolin-6-ones and their fused derivatives via the reaction of readily accessible
starting material, 2-cyanomethylpyrazolo[1,5-a]quinazolinones with various aromatic
11

aldehydes furnished the corresponding arylidene derivatives. Also, formation of
polyheterocyclic compounds based on pyrazolo[1,5-a]quinazoline core. Also, the
reaction of enamines of 2-cyanomethylpyrazolo[1,5-a]quinazolinones with each of
hydrazine hydrate and guanidine hydrochloride afforded
pyrazolo[4'',3'':5',6']pyrido[4',3':3,4]pyrazolo[1,5-a]8-ones and pyrimido[5'',4'':5',6']-
pyrido[4',3':3,4]pyrazolo[1,5-a]quinazolin-9(10H)-ones.
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15

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16

Table 1. Electronic absorption spectral data of compounds 12a-h in N,N-
dimethylformamide (DMF)
Compound No. λmax(nm) DMF Compound No. λmax(nm) DMF
390, 313
392, 310
413, 303
398, 313
394, 312
400, 307
400, 314
395, 308
12a
12b
12c
12d
12e
12f
12g
12h
17

Scheme 1. Synthetic route to 2-cyanomethyl-6-oxo-pyrazolo[1.5-a]quinazolines 4a,b
18

Scheme 2. Synthetic route to 2-(1-cyano-2-arylvinyl)-6-oxo-pyrazolo[1,5-a]-
quinazolines 6a-j
19

Scheme 3. Synthetic pathway to 2-(2-imino-2H-chromen-3-yl)-6-oxo-pyrazolo-[1,5-
a]quinazolines 9a-d and fused pyrazolo[1,5-a]quinazolines 10a-d
20

Scheme 4. Synthetic route to 2-arylhydrazono-6-oxo-pyrazolo[1,5-a]quinazolines 12a-h
21

Scheme 5. Synthetic pathway to pyrazolo[1,5-a]quinazolines 17 and polyfused
heterocyclic compounds 18
22

Scheme 6. Synthetic pathway to pyrazolo[1,5-a]quinazolines 21 and polyfused
heterocyclic compounds 22
23

Scheme 7. Synthetic pathway to 2-(4-amino-3-phenyl-2-thioxo-thiazol-5-yl)-6-oxo-
pyrazolo[1,5-a]quinazoline-3-carbonitriles 25
24

Scheme 8. Synthetic pathway to 2-[1-cyano-2-(dimethylamino)vinyl[-6-oxopyrazolo-
[1,5-a]quinazolines 27a,b and 5-amino pyrazolo[4'',3'':5',6']pyrido-
[4',3':3,4]pyrazolo[1,5-a]quinazolin-8-ones 30a,b
25

Scheme 9. Synthetic pathway to 3,6-diamino-11,12-dihydropyrimido[5'',4'':5',6']-
pyrido4',3':3,4]pyrazolo[1,5-a]quinazolin-9(10H)-ones 33a,b
26