Peculiarities of transformations of unsubstituted quinazoline with C-nucleophiles

Full text of DOI:10.1007/s10593-009-0235-5

Chemistry of Heterocyclic Compounds, Vol. 45, No. 1, 2009
PECULIARITIES OF TRANSFORMATIONS
OF UNSUBSTITUTED QUINAZOLINE WITH
C-NUCLEOPHILES
1
2
Yu. A. Azev * and S. V. Shorshnev
Keywords: 1,3-dimethylbarbituric acid, 3-methyl-1-phenyl-5-pyrazolone, quinazoline.
In acidic media, quinazoline forms a covalent hydrate with water at the N(3)=C(4) bond [1].
Analogously, 3-methylquinazolinium iodide adds alkylamines, arylamines, and indoles to give 4-substituted
3
,4-dihydroquinazolines [2].
We have found that unsubstituted quinazoline 1 reacts with 1,3-dimethylbarbituric acid upon heating in
butanol to give C(4)-substituted adduct 2.
Me
O
N
Me
N
N
O
N
N
O
N
OH
1
Me
N
Me
N
Me
N
NH
H
O
O
H
N
N
O
O
H
N
N
Me
Me
O
2
3
1
The quantitative formation of adduct 2 was indicated from an examination of the H NMR spectrum of a
solution of an equimolar mixture of the starting components in DMSO-d at room temperature. The signal for
6
1
3
H-4 at 6.0 ppm is diagnostic for adduct 2. The H NMR signal for sp -hybridized C-4 in dihydroquinazoline 2 is
found at 48.3 ppm. The discovery of cross peaks in the 2D-NOESY correlation spectrum between quinazoline
protons H-4 (in the heterocyclic fragment) and H-5 (6.93 ppm, in the aromatic ring) unequivocally confirms the
C-4 adduct structure for dihydroquinazoline 2.
Heating quinazoline 1 in butanol with 3-methyl-1-phenyl-5-pyrazolone gave 4,4'-methylidenebis-
(
3-methyl-1-phenyl-5-pyrazolone) 3, which we described in our earlier work [3].
_
*
______
To whom correspondence should be addressed, e-mail: azural@dialup.utk.ru, azural@yandex.ru.
1
Urals State Technological University, Yekaterinburg 620002, Russia.
ChemBridge Corporation, Moscow, 119435 Russia; e-mail: shorshnev@chembridge.ru.
2
_
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 135-136, January, 2009. Original
article submitted June 25, 2008.
009-3122/09/4501-0115©2009 Springer Science+Business Media, Inc.
0
115

The formation of bispyrazolone 3 probably proceeds through nucleophilic attack at C-2 with subsequent
opening of the pyrimidine ring, a second attack by 3-methyl-1-phenyl-5-pyrazolone, and elimination of the
quinazoline C-2 atom.
The unusually facile addition of dimethylbarbituric acid is likely a consequence of protonation of the
quinazoline system by the nucleophile itself. This is the first observation of a neutral pyrazolone molecule
attacking unsubstituted quinazoline at C-2.
1
31
The H NMR, C NMR, and 2D-NOESY spectra were taken on a Bruker DRX-400 spectrometer at 400
and 100 MHz, respectively, in DMSO-d with the signal of the residual protons of the deuterated solvent as the
6
standard (δ 2.50 ppm). The sample of quinazoline was acquired from Acros Organics.
4
-(1,2,3,4-Tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxa-5-pyrimidinyl)-3,4-dihydroquinazoline
(
2). A mixture of quinazoline 1 (0.039 g, 0.3 mmol) and 1,3-dimethylbarbituric acid (0.047 g, 0.3 mmol) in
butanol (2 ml) was heated at reflux for 2-3 min. The precipitate was filtered off, washed with 1 ml butanol, and
1
dried to give compound 2, yield 0.55 g (64%); mp >250°C. H NMR spectrum, δ, ppm (J, Hz): 3.11 (6H, s,
2
NCH ); 6.04 (1H, s, H-4); 6.89 (1H, dd, J = 7.8, J = 0.9, H-8); 6.93 (1H, d, J = 7.5, H-5); 7.04 (1H, ddd,
3 1 2
J = 7.6, J = 7.5, J = 1.1, H-6); 7.13 (1H, ddd, J = 7.8, J = 7.6, J = 1.2, H-7); 8.17 (1H, d, J = 4.5, H-2); 9.96
1
2
3
1
2
3
1
3
(
1H, d, J = 4.5, N H); 11.48 (1H, br. s, OH). C NMR spectrum, δ, ppm: 26.7, 48.3, 91.7, 115.2, 125.0, 126.0,
(3)
1
26.5, 127.2, 131.1, 147.3, 152.8, 161.7. Found, %: C 58.5; H 5.0; N 9.4. C H N O . Calculated, %: C 58.7;
14 14 4 3
H 4.9; N 19.6.
Reaction of Quinazoline 1 with 3-Methyl-1-phenyl-5-pyrazolone. A mixture of quinazoline 1
(
0.039 g, 0.3 mmol) and 3-methyl-1-phenyl-5-pyrazolone (0.157 g, 0.9 mmol) in butanol (3 ml) was heated at
reflux for 8 h. The reaction mixture was cooled. Filtration gave 3 in 35% yield. Product 3 was identical to a
sample of 4,4'-methylidenebis(3-methyl-1-phenyl-5-pyrazolone) obtained according to our previous procedure
[3].
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2
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(
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1
16