Formation of 1-methyl[1,2,4]triazolo[4,3-a] quinazolin-5(4H)-ones by reaction of 2-hydrazinoquinazolin-4(3H)-ones with acetylacetone

Article abstract of DOI:10.1515/hc-2015-0104

Reaction of 2-hydrazinoquinazolin-4(3H)-ones with acetylacetone results in the formation of 1-methyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones instead of 2-(3,5-dimethyl-1H-pyrazol-1-yl)quinazolin-4(3H)-ones. Under similar conditions, the 7-hydrazinocarbonyl group in quinazolin-4(3H)-one moiety is transformed into a pyrazole derivative, which can be replaced by amine with the amide formation.

Full text of DOI:10.1515/hc-2015-0104

Heterocycl. Commun. 2015; aop
Svitlana Yuriyivna Danylchenko, Oleksandr Grygorovych Drushlyak*, Svitlana Sergiyivna
Kovalenko and Sergiy Mykolayovych Kovalenko
Formation of 1-methyl[1,2,4]triazolo[4,3-a]
quinazolin-5(4H)-ones by reaction of
2-hydrazinoquinazolin-4(3H)-ones with
acetylacetone
DOI 10.1515/hc-2015-0104
Results and discussion
Received May 21, 2015; accepted June 19, 2015
Our attempt to obtain pyrazole derivatives by treatment
of 2-hydrazinoquinazolin-4(3H)-ones 4, 5 with acety-
Abstract: Reaction of 2-hydrazinoquinazolin-4(3H)-
lacetone led to the formation of [1,2,4]triazolo[4,3-a]
ones with acetylacetone results in the formation of
quinazolin-5(4H)-ones 6, 7 as main products. Under
1-methyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones
similar conditions, the 7-hydrazinocarbonyl group in
instead of 2-(3,5-dimethyl-1H-pyrazol-1-yl)quinazolin-
2-hydrazino-7-hydrazinocarbonyl-4-oxo-3-phenyl-3,4-di-
4(3H)-ones. Under similar conditions, the 7-hydrazino-
hydroquinazoline (5) was converted into a pyrazole deriv-
carbonyl group in quinazolin-4(3H)-one moiety is
ative 6 (Scheme 1). In a full agreement with this result,
transformed into a pyrazole derivative, which can be
the treatment of 6 with 2-methylbutylamine gave the
replaced by amine with the amide formation.
expected amide 7.
The purity and structures of synthesized compounds
Keywords: acetylacetone; amide formation; 2-hydrazino-
1
were confirmed by LC/MS and H NMR spectroscopy
quinazolin-4(3H)-one; pyrazole; [1,2,4]triazolo[4,3-a]
data. The singlet for 1-CH3 group at 2.36 ppm is charac-
quinazolin-5(4H)-one.
teristic for [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones
6, 7. Other singlets at 2.12 and 2.55 ppm are attributed
to the respective 3-CH3 and 5-CH3 groups of the pyra-
Introduction
zole. The singlet at 6.26 ppm in the 1H NMR spectrum of 6
belongs to 4-H of the pyrazole. The signal of the NHCO
The reaction of hydrazines with β-dicarbonyl compounds proton of amides 3, 4, 7 appears as triplet at 8.55 ppm.
is the common approach to the synthesis of pyrazoles
The formation of [1,2,4]triazolo[4,3-a]quinazolin-
[1, 2]. However, in the case of heterocyclic hydrazines, 5(4H)-ones by reaction of 2-hydrazinoquinazolin-4(3H)-
such as 2-hydrazino-3-methylquinoxaline, the formation ones with acetylacetone is consistent with the suggestion
of a triazole has been reported [3, 4]. 1,4-Dimethyl-1,2,4- that heterocyclic hydrazines may react with β-diketones
triazolo[4,3-a]quinoxaline has been identified as the side via intermediate dihydro[1,2,4]triazole, such as 8 fol-
product of the reaction of 2-hydrazino-3-methylquinoxa- lowed by cleavage of the ketone residue, as shown in
line with 1-phenyl-1,3-butanedione [4].
Scheme 2 [4].
*Corresponding author: Oleksandr Grygorovych Drushlyak, The
National University of Pharmacy, Kharkiv, Pushkinska Street, 53,
Kharkiv 61002, Ukraine, e-mail: aldry18@hotmail.com
Svitlana Yuriyivna Danylchenko and Svitlana Sergiyivna Kovalenko:
The National University of Pharmacy, Kharkiv, Pushkinska Street,
53, Kharkiv 61002, Ukraine
Conclusion
Reaction of 2-hydrazinoquinazolin-4(3H)-ones with acet-
ylacetone results in the formation of triazole derivatives
instead of pyrazole.
Sergiy Mykolayovych Kovalenko: Kharkiv National University,
Svobody Sq., 4, Kharkiv 61022, Ukraine
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ꢀꢀꢀꢁ
2ꢀ
ꢀS.Y. Danylchenko et al.: 1-Methyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones
O
O
O
NaOH
i-PrOH
N
N
N
i
HN
HO
O
80°C, 3 h
N
H
S
N
H
S
N
H
S
O
O
O
2
1
3
N2H4
dioxane
Reflux
3 h
N2H4
dioxane
Reflux
3 h
O
N
O
NH2
HN
N
N
HN
NH
N
NH
O
NH2
O
NH2
5
4
100°C, 5 h
100°C, 5 h
-CH3COCH3
Acac
Acac
-CH3COCH3
O
N
N
O
N
N
N
N
i-C5H11NH2, DMF
HN
Reflux, 8 h
N
N
N
O
O
N
6
7
i CDI, dioxane, reflux 1 h; i-C5H11NH2, dioxane, reflux 2 h
Scheme 1ꢀ
O
N
O
N
O
N
Acac
N
N
N
-CH3COCH3
R
R
R
NH
N
N
N
NH2
NH
8
O
Scheme 2ꢀ
diluted with 50 mL of water and neutralized with 3 mL of 10% aque-
ous HCl. The precipitate was filtered and crystallized from a mixture
of DMF (5 mL) and isopropanol (20 mL): yield 2.56 g (86%); a creamy
solid; mpꢀ>ꢀ300°C (dec.); 1H NMR: δ 7.08 (t, J ꢀ=ꢀ 7.8 Hz, 1H), 7.33 (t, J ꢀ=ꢀ
7.8 Hz, 2H), 7.80 (dd, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 2.0 Hz, 1H), 7.88 (d, J ꢀ=ꢀ 7.8 Hz, 2H),
7.95 (d, J ꢀ=ꢀ 2.0 Hz, 1H), 8.02 (d, J ꢀ=ꢀ 7.8 Hz, 1H), 13.10 (s, 1H, NH), 13.50
(br s, 1H, OH); 13C NMR: δ 118.8, 123.8, 125.1, 126.8, 128.3, 129.2, 130.4,
139.00, 139.3, 146.2, 153.6, 167.1, 170.0. Anal. Calcd for C15H10N2O3S: C,
60.39; H, 3.38; N, 9.39. Found: C, 60.47; H, 3.36; N, 9.34.
Experimental
1H NMR-spectra were recorded in DMSO-d6 on Varian WXR-400
(400 MHz) spectrometer. 13C NMR spectra were recorded in DMSO-
d6 on a Bruker DRX-300 spectrometer (100 MHz). Elemental analysis
was performed on a Euro EA-3000 apparatus. Melting points were
measured with a Buchi B-520 melting point apparatus and were not
corrected. LC/MS spectra were recorded with a PE SCIEX API 150EX
liquid chromatograph equipped with a UV detector (λmax 215 and
254 nm) and using a Luna-C18 column, Phenomenex (100ꢀ×ꢀ4 mm). Elu-
tion started with water and ended with acetonitrile/water (95:5, v/v)
using a linear gradient at a flow rate of 0.15 mL/min and an analy-
sis cycle time of 25 min. Starting 2-hydrazinoquinazolin-4-ones 4, 5
were obtained from commercially available methyl 4-oxo-3-phenyl-
2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (1) according to a
published method [5].
N-(3-Methylbutyl)-4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahy-
droquinazoline-7-carboxamide (3)ꢀ The mixture of 4-oxo-3-phe-
nyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (2, 1.79 g,
6 mmol) and 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole (CDІ, 1.05 g,
6.5 mmol) in 30 mL of anhydrous dioxane was heated under reflux
with stirring for 1 h. Then 2-methylbutylamine (0.52 g, 6 mmol) was
added. The mixture was heated under reflux for 2 h. Afer cooling, the
mixture was diluted with water (50 mL) and allowed to stand over-
4-Oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-car- night to form a precipitate, which was filtered, washed with water,
boxylic acid (2)ꢀTo an agitated suspension of methyl 4-oxo-3-phe- and crystallized from a mixture of dimethylformamide (10 mL) and
nyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (1, 3.12 g, isopropanol (20 mL): yield 1.92 g (87%); a white solid; mp 290–292°C;
10 mmol) in 30 mL of isopropanol, 20% aqueous solution of NaOH 1H NMR: δ 0.88 (d, J ꢀ=ꢀ 7.0 Hz, 6H), 1.40 (q, J ꢀ=ꢀ 7.0 Hz, 2H), 1.52–1.72 (m,
(5 mL) was added. The solution was heated under reflux for 3 h then 1H), 3.25 (q, J ꢀ=ꢀ 7.0 Hz, 2H), 7.08 (t, J ꢀ=ꢀ 7.8 Hz, 1H), 7.33 (t, J ꢀ=ꢀ 7.8 Hz, 2H),
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ꢁꢀꢀꢀ
ꢂ3
S.Y. Danylchenko et al.: 1-Methyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-onesꢂ
+
LC/MS: m/z 399.3 [M+H ] (64%). Anal. Calcd for C22H18N6O2: C, 66.32;
7.80 (dd, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 2.0 Hz, 1H), 7.88 (d, J ꢀ=ꢀ 7.8 Hz, 2H), 7.95 (d,
J ꢀ=ꢀ 2.0 Hz, 1H), 8.02 (d, J ꢀ=ꢀ 7.8 Hz, 1H), 8.55 (t, J ꢀ=ꢀ 7.0 Hz, 1H, CONH),
13.10 (s, 1H, NH); 13C NMR: δ 22.7, 25.1, 38.4, 41.2, 118.7, 123.9, 125.0,
126.3, 128.3, 129.2, 130.3, 139.0, 139.6, 146.3, 153.6, 166.8, 169.9. Anal.
Calcd for C20H21N3O2S: C, 65.37; H, 5.76; N, 11.44. Found: C, 65.43; H,
5.74; N, 11.48.
H, 4.55; N, 21.09. Found: C, 66.39; H, 4.52; N, 21.16.
1-Methyl-N-(3-methylbutyl)-5-oxo-4-phenyl-4,5-dihydro[1,2,4]
triazolo[4,3-a]quinazoline-8-carboxamide (7): Protocol AꢁThe
suspension of 2-hydrazino-N-(3-methylbutyl)-4-oxo-3-phenyl-3,4-di-
hydroquinazoline-7-carboxamide 4 (1.83 g, 5 mmol) in acetylacetone
(20 mL) was heated at 100ºC with stirring for 5 h. Afer cooling, the
mixture was diluted with isopropanol (50 mL). The resultant precipi-
tate was filtered, washed with isopropanol (10 mL), and crystallized
from a mixture of DMF (10 mL) and isopropanol (20 mL): yield 1.29 g
(68%), a white solid; mpꢀ>ꢀ300°C; 1H NMR: δ 0.88 (d, J ꢀ=ꢀ 7.0 Hz, 6H),
1.40 (q, J ꢀ=ꢀ 7.0 Hz, 2H), 1.52–1.72 (m, 1H), 2.36 (s, 3H, CH3-1), 3.25 (q,
J ꢀ=ꢀ 7.0 Hz, 2H), 7.42–7.56 (m, 5H), 7.74 (dd, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 2.0 Hz, 1H),
8.00 (d, J ꢀ=ꢀ 2.0 Hz, 1H), 8.26 (d, J ꢀ=ꢀ 7.8 Hz, 1H), 8.55 (t, J ꢀ=ꢀ 7.0 Hz, 1H,
CONH); 13C NMR: δ 13.4, 22.7, 25.1, 38.36, 4.2, 118.6, 123.4, 125.8, 126.9,
128.3, 129.1, 130.7, 135.4, 139.0, 139.9, 144.2, 155.5, 161.6, 166.9; LC/MS:
2-Hydrazino-N-(3-methylbutyl)-4-oxo-3-phenyl-3,4-dihydro-
quinazoline-7-carboxamide (4)ꢀA mixture of dioxane (10 mL),
hydrazine hydrate (3 mL), and N-(3-methylbutyl)-4-oxo-3-phenyl-
2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (3, 1.84 g,
5 mmol) was heated under reflux with stirring for 3 h. The lower
dioxane layer was separated and diluted with water (20 mL). The
precipitate was filtered, washed with isopropanol (10 mL), and
crystallized from mixture of DMF (10 mL) and isopropanol (20 mL):
1
yield 1.29 g (68%); a white solid; mpꢀ>ꢀ300°C (dec.); H NMR: δ 0.88
(d, J ꢀ=ꢀ 7.0 Hz, 6H), 1.40 (q, J ꢀ=ꢀ 7.0 Hz, 2H), 1.52–1.72 (m, 1H), 3.25 (q,
J ꢀ=ꢀ 7.0 Hz, 2H), 5.70 (s, 2H, NHNH2-2), 7.06 (t, J ꢀ=ꢀ 7.8 Hz, 1H), 7.33 (t,
J ꢀ=ꢀ 7.8 Hz, 2H), 7.57 (dd, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 2.0 Hz, 1H), 7.75 (d, J ꢀ=ꢀ 2.0
Hz, 1H), 7.88 (d, J ꢀ=ꢀ 7.8 Hz, 2H), 7.98 (d, J ꢀ=ꢀ 7.8 Hz, 1H), 8.55 (t, J ꢀ=ꢀ
7.0 Hz, 1H, CONH), 9.33 (s, 1H, NHNH2-2); 13C NMR: δ 22.7, 25.0, 38.4,
41.2, 118.8, 123.9, 125.6, 126.8, 128.4, 129.1, 130.0, 139.1, 139.7, 146.1,
154.1, 159.2, 166.8. Anal. Calcd for C20H23N5O2 : 65.73; H, 6.34; N, 19.16.
Found: C, 65.79; H, 6.31; N, 19.21.
+
m/z 390.4 [M+H ] (62%). Anal. Calcd for C22H23N5O2: C, 67.85; H, 5.95;
N, 17.98. Found: C, 67.78; H, 5.99; N, 18.03.
Protocol BꢁA solution of 8-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-
1-methyl-4-phenyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (6, 0.80 g,
2 mmol) and 2-methylbutylamine (0.26 g, 3 mmol) in anhydrous DMF
(10 mL) was heated under reflux for 8 h. Afer cooling, the mixture
was diluted with water (30 mL) and the resultant precipitate was
filtered, washed with isopropanol (10 mL), and crystallized from a
mixture of DMF (5 mL) and isopropanol (10 mL): yield 0.64 g (84%);
a white solid; mpꢀ>ꢀ300°C (dec.). This sample was identical to the
2-Hydrazino-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carbo-
hydrazide (5)ꢀA mixture of dioxane (10 mL), hydrazine hydrate
(4 mL), and methyl 4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquina-
zoline-7-carboxylate (1, 1.56 g, 5 mmol) was heated and stirred under
reflux for 3 h. The lower dioxane layer was separated and diluted with
water (20 mL). The resultant precipitate was filtered, washed with
isopropanol (10 mL), and crystallized from a mixture of DMF (10 mL)
and isopropanol (20 mL): yield 1.21 g (78%); a white solid; mpꢀ>ꢀ300°C
1
sample obtained by protocol A both by H NMR spectrum and LC/
MS data.
1
(dec.); H NMR: δ 4.55 (br. s, 2H, CONHNH2), 5.70 (s, 2H, NHNH2-2),
References
7.08 (t, J ꢀ=ꢀ 7.8 Hz, 1H), 7.33 (t, J ꢀ=ꢀ 7.8 Hz, 2H), 7.57 (dd, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ
2.0 Hz, 1H), 7.75 (d, J ꢀ=ꢀ 2.0 Hz, 1H), 7.88 (d, J ꢀ=ꢀ 7.8 Hz, 2H), 8.00 (d, J ꢀ=ꢀ
7.8 Hz, 1H), 9.40 (s, 1H, NHNH2-2), 10.02 (s, 1H, CONHNH2); 13C NMR: [1] Elguero, J. Pyrazoles. In Comprehensive Heterocyclic Chemistry II;
δ 118.6, 123.4, 125.7, 126.9, 128.3, 129.1, 130.4, 139.1, 140.0, 144.2, 155.5,
161.7, 166.0. Anal. Calcd for C15H14N6O2: C, 58.06; H, 4.55; N, 27.08.
Found: C, 57.97; H, 4.58; N, 27.13.
Katritzky, A. R.; Rees, C. W.; Scriven, E. F., Eds. Pergamon Press:
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of 2-hydrazino-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carbohy-
drazide 5 (1.55 g, 5 mmol) in acetylacetone (20 mL) was heated at
pyrazine. II. The reaction of 3-substituted-2-hydrazinoqui-
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100ºC with stirring for 5 h. Afer cooling, the mixture was diluted with [4] Aggarwal, R.; Sumran, G.; Kumar, R.; Singh, Sh. P. Reaction of
isopropanol (50 mL). The resultant precipitate was filtered, washed
with isopropanol (10 mL), and crystallized from a mixture of DMF (10
2-hydrazino-3-methylquinoxaline with aryl-1,3-diketones: a
structural reinvestigation. ARKIVOC 2007, 15, 292–302.
mL) and isopropanol (20 mL): yield 1.47 g (74%); a creamy solid; mp [5] Danilchenko, S. Yu.; Drushlyak, O. G.; Kovalenko, S. M.
296–298°C; 1H NMR: δ 2.12 (s, 3H), 2.36 (s, 3H, CH3-1), 2.55 (s, 3H), 6.26
(s, 1H), 7.52–7.76 (m, 6H), 8.00 (d, J ꢀ=ꢀ 2.0 Hz, 1H), 8.31 (d, J ꢀ=ꢀ 7.8 Hz,
1H); 13C NMR: δ 12.6, 13.3, 14.1, 113.6, 118.8, 123.5, 125.8, 126.9, 128.3,
129.2, 130.8, 135.3, 139.0, 139.9, 141.8, 144.3, 152.3, 155.3, 161.5, 166.1;
Synthesis of substituted 2-hydrazinoquinazolin-4-ones as
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2014, 12(3), 66–73].
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