Synthesis of 6,7,8,9-Tetrahydropyrazolo[1,5-a]quinazolines containing a 5-phenylamine fragment

Full text of DOI:10.1134/S1070428013080307

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 8, pp. 1250−1252. © Pleiades Publishing, Ltd., 2013.
Original English Text © A.A. Petrov, A.N. Kasatochkin, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 8, pp. 1262−1264.
SHORT
COMMUNICATIONS
Synthesis of 6,7,8,9-Tetrahydropyrazolo[1,5-a]quinazolines
Containing a 5-Phenylamine Fragment
A. A. Petrov and A. N. Kasatochkin
St. Petersburg State University, St. Petersburg, 198504 Russia
e-mail: aap47@hotmail.ru
Received February 13, 2013
DOI: 10.1134/S1070428013080307
3(5)-Aminoazoles are key reagents in the synthesis of
nitrogen bi-and polycyclic compounds possessing a wide
range of biological activity [1–5].At the multicomponent
heterocyclization of 3(5)-aminopyrazoles the reaction
may proceed by several alternative routes and lead to
the formation of isomeric products owing to the presence
of two nonequivalent nucleophilic sites (NH2 and NH).
the cyclohexanone to the polarized C=N bond giving an
aminoketone that either first undergoes cyclization into
octahydropyrazolo[1,5-a]quinazolin-9а-ol with subse-
quent dehydration and dehydrogenation, or suffers the
dehydrogenation affording enaminoketone followed by
the cyclization and water elimination. The intermediate
3,5-diphenyl-4,6,7,8,9,9а-hexahydro-pyrazolo[1,5-a]
quinazoline was detected at monitoring the reaction by
1Н NMR spectroscopy and mass spectrometry ([M +
Н]+ 328.1817) and was isolated as an impurity when
the reaction was carried out less than 5 h. The similar
bicyclic 4,7-dihydropyrazolo[1,5-a]pyrimidines form in
reactions of aminopyrazoles with chalcones and benzyli-
deneacetones [6, 7].
Three-component reaction of 3(5)-amino-4-
phenylpyrazole (I) with aromatic aldehydes IIIа–IIIc and
cyclohexanone in acetic acid within 5 h led to the formation
of 5-aryl-3-phenyl-6,7,8,9-tetra-hydropyrazolo[1,5-a]
quinazolines IVа–IVc in 75–80% yields. The reaction
proceeds regioselectively (see the scheme).
The most probable sequence of the reactions between
the reagents in the three-component process may be
presumed: In the first stage the aminopyrazole reacts
with the aldehyde forming the Schiff base which adds
In compound IVc the chlorine atom is activated by
the adjacent nitro group and it is capable of an easy nu-
cleophilic substitution (SNAr). In order to functionalize
Scheme.
O
NO2
Heterocyclic amine
NO2
NH2
+
+
ArCHO
N
NR2
N
Ar
N
NH
N N
N N
IIIа_IIIc
I
II
Ar =
Cl
IVа_IVc
VIа_VIc
(c).
O
III, IV, Ar = H (a), 4-Cl (b), 4-Cl-3-NO2 (c); VI, NR2 =
(b),
(a),
N
N
N
1250

SYNTHESIS OF 6,7,8,9-TETRAHYDROPYRAZOLO[1,5-a]QUINAZOLINES
1251
the pyrimidine ring in the position 5 of the aromatic ring
we introduced cyclic secondary amines.
trum, δ, ppm: 1.88 m (2Н, 7-СН2), 2.10 m (2Н, 8-СН2),
2.79 t.t (2Н, 6-СН2, J 6.5, J 1.5 Hz), 3.29 t.t (2Н, 9-СН2,
J 6.5, J 1.5 Hz), 7.27 t (1Н, Нp, 3-Ph, J 7.4 Hz), 7.45 t
(2Н, Нm, 3-Ph, J 7.8 Hz), 7.71 d (1Н, 5-Ar, J 8.2 Hz),
7.88 d.d (1Н, 5-Ar, J 8.2, J 1.9 Hz), 8.09 d (2Н, Нo, 3-Ph,
J 7.8 Hz), 8.22 s (1Н, 5-Ar, J 1.9 Hz), 8.47 с (1Н, С2Н).
13С NMR spectrum, δ, ppm: 21.89, 22.39, 24.74, 26.54
(С6–9), 110.96 (С3), 115.03 (С5а), 126.05 (CH, 3-Ph),
126.09, 126.18 (CHp, 3-Ph, CHo, 5-Ar), 127.54 (Cp,
5-Ar), 128.71 (CH, 3-Ph), 131.78 (CHm, 5-Ar), 132.03
(Ci, 3-Ph), 133.66 (CHo, 5-Ar), 138.78 (Ci, 5-Ar), 141.92
(С2), 142.91 (С3а), 145.40 (С9а), 147.54 (Cm, 5-Ar),
154.48 (С5). Found [M + H]+ 405.1096. С22Н18ClN4O2.
Calculated 405.1113.
At boiling compound IVc in toluene with 3-fold
excess of heterocyclic amines Vа–Vc (pyrrolidine,
piperidine, morpholine) over 5 h we obtained substi-
tuted tetrahydropyrazolo-[1,5-a]quinazolines, containing
pharmacophore pyrazole, pyrimidine fragments and a
phenyl ring substituted with hydrophilic cyclic amines.
The composition and structure of compounds IVа–IVc,
VIа–VIc were established by 1Н and 13С NMR spectra
and high resolution mass spectra.
Compounds IVa–IVc. General procedure. Amixture
of 1 mmol of aminopyrazole, 1.1 mmol of cyclohexanone,
and 1 mmol of aromatic aldehyde was boiled in 3 ml of
acetic acid for 5 h. The solvent was removed at a reduced
pressure, the residue was washed with water, filtered off,
dried, and.
Compounds VIа–VIc. General procedure. 1 mmol
of compound IVc and 3 mmol of amine Vа–Vc were
boiled in 5 ml of toluene for 5 h. The solvent was removed
at a reduced pressure, the residue was recrystallized from
butanol.
3,5-Diphenyl-6,7,8,9-tetrahydropyrazolo[1,5-a]
quinazoline (IVa). Yield 78%, yellow crystals, mp 176–
177°C (butanol). 1Н NMR spectrum, δ, ppm: 1.83 m (2Н,
7-СН2), 2.07 m (2Н, 8-СН2), 2.78 t.t (2Н, 6-СН2, J 6.5,
1.5 Hz), 3.27 t.t (2Н, 9-СН2, J 6.5, 1.5 Hz), 7.24 t (1Н,
Нp, 3-Ph, J 7.4 Hz), 7.44 t (2Н, Нm, 3-Ph, J 7.8 Hz), 7.50
m (2H, Ho, 5-Ph), 7.70 m (3Н, Нm,p, 5-Ph), 8.16 d (2Н,
Нo, 3-Ph, J 7.8 Hz), 8.45 s (1Н, Н2). 13С NMR spectrum,
δ, ppm: 21.13, 22.54, 24.71, 26.74 (С6–9), 110.32 (С3),
115.44 (С5а), 125.52 (Сp, 3-Ph), 126.06, 128.11, 128.58,
129.00 (СНarom), 128.81 (Сp, 5-Ph), 132.57 (Сi, 3-Ph),
139.05 (Сi, 5-Ph), 141.43 (С2), 143.25 (С3а), 144.39
(С9а), 158.68 (С5). Found [M + H]+ 326.1657. С22Н20N3.
Calculated 326.1652.
5-[3-Nitro-4-(pyrrolidin-1-yl)phenyl]-3-phenyl-
6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline (VIа).
Yield 88%, light brown crystals, mp 214–216єС.
1Н NMR spectrum, δ, ppm: 1.87 m (2Н, 7-СН2), 2.06 m
(6Н, 8-СН2 + 4Нpyrrolidine), 2.88 t.t (2Н, 6-СН2, J 6.5,
J 1.5 Hz), 3.29 t.t (2Н, 9-СН2, J 6.5, J 1.5 Hz), 3.33 m
(4Нpyrrolidine), 7.05 d ( 1Н, Нm, 5-Ph, J 8.9 Hz), 7.25 t
(1Н, Нp, 3-Ph, J 7.5 Hz), 7.44 t (2Н, Hm, 3-Ph, J 7.8 Hz),
7.88 d.d (1Н, Нo, 5-Ph, J 8.9, J 2.0 Hz), 8.12 d (2Н, Нo,
3-Ph, J 7.8 Hz), 8.17 d (1Н, Нo, 5-Ph, J 2.0 Hz), 8.47 s
(1Н, С2Н). 13С NMR spectrum, δ, ppm: 21.15, 22.72,
24.87, 27.07 (С6–9), 25.74, 50.58 (4CH2 pyrrolidine), 110.25
(С3), 115.48 (С5а), 115.80 (CHm, 5-Ph), 125.82 (Сp, 3-Ph),
126.08 (СН, 3-Ph), 127.66 (СНo, 5-Ph), 128.68 (СН,
3-Ph), 132.62 (Сi, 3-Ph), 133.93 (СНo, 5-Ph), 136.21 (С,
5-Ph), 141.60 (С2, 5-Ph), 142.94, 143.26 (Cm, 5-Ph, С3а),
144.68 (С9а), 156.28 (С5). Found [M + H]+ 440.2069.
С26Н26N5O2. Calculated [M + H] 440.2082.
3-Phenyl-5-(4-chlorophenyl)-6,7,8,9-tetrahydro-
pyrazolo[1,5-a]quinazoline (IVb). Yield 80%, yellow
crystals, mp 195–196°C (butanol). 1Н NMR spectrum, δ,
ppm: 1.81 m (2Н, 7-СН2), 2.04 m (2Н, 8-СН2), 2.72 t.t
(2Н, 6-СН2, J 6.5, J 1.5 Hz), 3.24 t.t (2Н, 9-СН2, J 6.5,
J 1.5 Hz), 7.23 t (1Н, Нp, 3-Ph, J 7.5 Hz), 7.42 t (2Н, Нm,
3-Ph, J 7.6 Hz), 7.47 d (2H, Hm, 5-Ar, J 8.0 Hz), 7.61 d
(2Н, Нo, 5-Ar, J 8.0 Hz), 8.12 d (2Н, Нo, 3-Ph, J 7.6 Hz),
8.44 s (1Н, Н2). 13С NMR spectrum, δ, ppm: 21.02, 22.46,
24.68, 26.68 (С6–9), 110.35 (С3), 115.44 (С5а), 125.80 (Сp,
3-Ph), 125.96, 128.33, 128.56, 130.40 (СНarom), 132.38
(Сi, 3-Ph), 134.99 (Сp, 5-Ar), 137.35 (Сi, 5-Ar), 141.49
(С2), 143.08 (С3а), 144.59 (С9а), 157.27 (С5). Found [M
+ H]+ 360.1260. С22Н19ClN3. Calculated 360.1263.
5-[3-Nitro-4-(piperidine-1-yl)phenyl]-3-phenyl-
6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline
(VIb). Yield 82%, light brown crystals, mp 197–
1
199єС. Н NMR spectrum, δ, ppm: 1.67 m (2Н,
СН2 piperidine), 1.78 m (4Н, СН2 piperidine), 1.86 m (2Н,
7-СН2), 2.09 m (2Н, 8-СН2 ), 2.85 t.t (2Н, 6-СН2,
J 6.5, 1.5 Hz), 3.16 m (4Нpiperidine), 3.29 t.t (2Н, 9-СН2,
J 6.5, 1.5 Hz), 7.24 t (1Н, Нp, 3-Ph, J 7.5 Hz), 7.27 m
(1Н, Нm, 5-Ar), 7.45 t (2Н, Нm, 3-Ph, J 7.8 Hz), 7.87
d.d (1Н, Нo, 5-Ar, J 8.7, 2.0 Hz), 8.12 d (2Н, Нo, 3-Ph,
J 7.8 Hz), 8.16 d (1Н, Нo, 5-Ar, J 2.0 Hz), 8.44 s (1Н,
5-(3-Nitro-4-chlorophenyl)-3-phenyl-6,7,8,9-
tetrahydropyrazolo[1,5-a]quinazoline (IVc). Yield
75%, light brown crystals, mp 216–217єС. 1Н NMR spec-
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PETROV, KASATOCHKIN
1252
С2Н). 13С NMR spectrum, δ, ppm: 21.03, 22.57, 24.77,
26.85 (С6–9), 23.94, 25.79, 50.47 (5 CH2 piperidine), 110.38
(С3), 115.39 (С5а), 120.21 (CHo, 5-Ar), 125.88 (Сp,
3-Ph), 126.02, 128.67 (СН, 3-Ph), 127.24 (CHo, 5-Ar),
130.24 (Сi, 5-Ar), 132.42 (Сi, 3-Ph), 134.27 (CHo, 5-Ar),
140.55 (Cp, 5-Ar), 141.62 (С2), 143.12 (С3а), 144.79
(С9а), 147.06 (Cm, 5-Ar), 155.94 (С5). Found [M + H]+
454.2240. С27Н28N5O2. Calculated 454.2238.
trometer Bruker DPX-300 (300.13 and 75.47 MHz) in
CDCl3 at 22°С. Chemical shifts were measured from
the signals of residual protons of the deuterated solvent
CDCl3 (7.28, 77.00 ppm). Elemental composition was
determined with the help of the high resolution mas spec-
trometry on an instrument Bruker Daltonics microTOF
at the positive electrospray ionization. The synthesis of
3(5)-amino-4-phenyl-1Н-pyrazole was described in [8].
5-[4-(Morpholine-1-yl)-3-nitrophenyl]-3-phenyl-
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6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline (VIc).
1
Yield 85%, yellow crystals, mp 172–173єС. Н NMR
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8-СН2), 2.84 t.t (2Н, 6-СН2, J 6.5, J 1.5 Hz), 3.19 m
(4Нmorpholine), 3.28 t.t (2Н, 9-СН2, J 6.5, 1.5 Hz), 3.91 m
(4Нmorpholine), 7.27 m ( 2Н, Нp, 3-Ph , Нm, 5-Ar), 7.45 t
(2Н, Нm, 3-Ph, J 7.8 Hz), 7.90 d.d (1Н, Нo, 5-Ar, J 8.7,
2.0 Hz), 8.11 d (2Н, Нo, 3-Ph, J 7.8 Hz), 8.19 d (1Н, Нo,
5-Ar, J 2.0 Hz), 8.45 s (1Н, С2Н). 13С NMR spectrum,
δ, ppm: 20.95, 22.50, 24.73, 27.20 (С6–9), 51.66, 66.66
(4CH2 morpholine), 110.50 (С3), 115.28 (С5а), 120.22 (CHm,
5-Ar), 125.94 (Сp, 3-Ph), 126.00, 128.66 (СН, 3-Ph),
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1Н and 13С NMR spectra were registered on a spec-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013