Specific features of the reactions of quinazoline and its 4-hydroxy and 4-chloro substituted derivatives with C-nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2009.03.199

Reactions of quinazoline 1 with indole, pyrogallol and 1-phenyl-3-methylpyrazol-5-one in the presence of acid led to C-4 adducts 2, 3 and 5. Adduct 4 is formed by heating 1 with 1,3-dimethylbarbituric acid without acid catalysis. 1-Phenyl-3-methylpyrazol-

Full text of DOI:10.1016/j.tetlet.2009.03.199

Tetrahedron Letters 50 (2009) 2899–2903
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Tetrahedron Letters
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Specific features of the reactions of quinazoline and its 4-hydroxy and
4-chloro substituted derivatives with C-nucleophiles
c
a
Yuri A. Azev a,b, , Sergey V. Shorshnev , Boris V. Golomolzin
*
a Ural Scientific Research Institute of the Technology of Medical Preparations, 620219 Ekaterinburg, Russian Federation
b Department of Chemistry, Ural State Technical University, 620002 Ekaterinburg, Russian Federation
c Chembridge Corporation, 119435 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Reactions of quinazoline 1 with indole, pyrogallol and 1-phenyl-3-methylpyrazol-5-one in the presence
of acid led to C-4 adducts 2, 3 and 5. Adduct 4 is formed by heating 1 with 1,3-dimethylbarbituric acid
without acid catalysis. 1-Phenyl-3-methylpyrazol-5-one reacts with 1 without acid catalysis to form
dipyrazolylmethane 6. 4-Chloroquinazoline 8 reacts with 1-phenyl-3-methylpyrazol-5-one to form
4-(1-phenyl-3-methyl-5-oxopyrazol-4-yl) quinazoline 9 and dipyrazolylmethane 6. Heating 8 with
2-methylindole leads to the formation of 4-(2-methylindol-3-yl) quinazoline 10 and tris(2-methylin-
dol-3-yl)methane 11.
Received 24 October 2008
Revised 21 January 2009
Accepted 27 March 2009
Available online 2 April 2009
Keywords:
Quinazoline
Nucleophiles
Transformations
Ó 2009 Elsevier Ltd. All rights reserved.
The quinazoline moiety is an important part of many natural
alkaloids.1 Compounds with diverse biological activities (hypo-
tonic, antiallergenic, antibacterial and anthelminthic) have been
found among quinazoline derivatives.2 The search for antagonists
of folic and isofolic acids as cellular mitosis inhibitors has received
significant attention recently.3,4 Antitumour2 and radioprotec-
tive5,6 quinazoline derivatives have also been synthesized.
In acidic medium, unsubstituted quinazoline was found to form
a covalent hydrate at the N3@C4 bond.7 Similarly, 3-methylquinaz-
olinium iodide undergoes addition of alkyl- and arylamines and in-
doles to form 4-substituted-3,4-dihydroquinazolines.8
ture. We also isolated adduct 4 in crystalline state after heating
the starting components in n-butanol for a short time.
Heating quinazoline 1 with 1-phenyl-3-methylpyrazol-5-one in
boiling n-butanol in the presence of trifluoroacetic acid for 2 h
produced 4-(1-phenyl-3-methyl-3-oxopyrazol-4-yl)-3,4-dihydro-
quinazoline trifluoroacetate 5. At the same time, the known 4,
4-methylidene-bis(1-phenyl-3-methylpyrazol-5-one) 69 was ob-
tained by heating quinazoline 1 for 10 h with a threefold excess
of 1-phenyl-3-methylpyrazol-5-one in boiling n-butanol without
acidic catalysis. After cooling the reaction mixture, product 6 was
filtered off and recrystallized from n-butanol (35% yield).
Dipyrazolylmethane 6 may be formed via nucleophilic attack of
1-phenyl-3-methylpyrazol-5-one at the C-2 atom of 1 followed by
pyrimidine ring-opening and attack of a second pyrazolone fol-
lowed by elimination (Scheme 2).
In this work, we found that unsubstituted quinazoline 1, on
heating with indole in boiling butanol for 2 h in the presence of tri-
fluoroacetic acid, afforded the stable salt 4-(indol-3-yl)-3,4-dihy-
droquinazoline
2 (Scheme 1). 4-(2,3,4-Trihydroxyphenyl)-3,4-
dihydroquinazoline 3 was obtained on heating quinazoline with
pyrogallol in boiling ethanol for 2 h in the presence of hydrochloric
acid. Products 2 and 3 precipitated after the reaction mixture had
been cooled and were isolated in pure state by filtration.
We observed quantitative formation of 4-(1,2,3,4,-tetrahydro-
6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)-3,4-dihydro-
quinazoline 4 when recording the 1H NMR spectrum of a solution
of the reaction of an equimolar mixture of quinazoline 1 and 1,3-
dimethylbarbituric acid in dimethyl sulfoxide at room tempera-
4-Chloroquinazoline 8 (Scheme 3) reacts with a threefold molar
excess of 1-phenyl-3-methylpyrazol-5-one in dimethylsulfoxide in
the presence of triethylamine to form the substitution product,
namely, 4-(1-phenyl-3-methyl-5-oxopyrazol-4-yl)-quinazoline 9
(45% yield) along with dipyrazolylmethane 6 (6% yield).
Product 9 was isolated by recrystallization of the precipitate ob-
tained from the cooled reaction mixture from ethanol. Treatment
of the mother liquor from the recrystallization of 9 with water gave
dipyrazolylmethane 6. The formation of product 6 indicates that, in
this case, competitive nucleophilic attack at the C-2 atom of qui-
nazoline occurs along with nucleophilic substitution of the
halogen.
The halogen substitution product 4-(2-methylindol-3-yl)-qui-
nazoline 10, and the known tris(2-methylindol-3-yl)-methane
* Corresponding author.
E-mail address: azural@yandex.ru (Y.A. Azev).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.199

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Y. A. Azev et al. / Tetrahedron Letters 50 (2009) 2899–2903
OH
OH
H
N
H
N
N
-
Cl-
CF3COO
N
H
OH
+
+
N
N
HCl, EtOH, 78°C, 2 h
N
CF3COOH,
n-BuOH,117 °C, 2 h
H
H
1
H
H
CH3
O
N
HO
OH
H3C
N
H
N
CH3
OH
3 (45%)
O
N
2
(55%)
OH
O
N
CH3
n
-BuOH,
N
O
N
117°C,10 h
CF3COOH,
n
-BuOH,
n
-BuOH,
117°C, 2 h
117°C, 0.5h
H
N
H
-
+
H
CH3
CF3COO
N
N
H3C
CH3
H
N
N
O
H
N
N
N
N
NH
O
OH
CH3
N
N
O
HO
H3C
O
5 (40%)
4 (70%)
6 (35%)
Scheme 1.
CH3
CH3
NH2
N
N
NH2
N
N
O
O
N
N
H
H
H
CH3
N
H
N
CH3
H3C
N
CH3
1
6
N
O
N
N
O
N
N
N
N
O
HO
Scheme 2.
1110 were obtained by heating 4-chloroquinazoline 8 with a three-
fold molar excess of 2-methylindole in boiling ethanol for 1 h.
Tris(indolylmethane) 11 was filtered off from the cooled reaction
mixture (10% yield). The mother liquor was dried and 10 was iso-
lated from the solid residue by thin layer chromatography on silica
(Rf = 0, chloroform).
The formation of tris(indolylmethane) 11 results from nucleo-
philic attack of indole on the C-2 atom of 4-chloroquinazoline 8 fol-
lowed by further transformation via Scheme 4.
The high reactivity of 4-chloroquinazoline towards C-nucleo-
philes is due, most likely, to the autocatalytic effect of the hydro-
gen chloride evolved upon substitution.
Heating of product 9 in boiling n-butanol in the presence of
water also affords dipyrazolylmethane 6 in 14% yield. Product 6
was isolated by filtration after cooling the reaction mixture. The
formation of dipyrazolylmethane 6 is preceded, most likely, by
nucleophilic substitution of the pyrazole residue for the hydroxy
group.
Initially formed pyrazolone attacks 4-hydroxyquinazoline at the
C-2 atom. Next, the heterocycle is cleaved, and a second attack of
pyrazolone occurs, leading eventually to product 6 (Scheme 5).
The validity of this assumption is confirmed by the formation of
dipyrazolylmethane 6 (9% yield) on heating an authentic sample of
4-hydroxyquinoline 7 with 1-phenyl-3-methylpyrazol-5-one in
boiling n-butanol for 15 h.
Characteristic properties for adducts 2-5 are signals for the H-4
proton in the range 6.0–6.5 ppm.11 Note that in the 2D-NOESY
spectrum of compounds 4, detection of the cross-peak connecting
the proton nucleus at C-4 (heterocyclic fragment) with the proton
at C-5 (aromatic cycle) that unequivocally confirms the structures
of these C-4 adducts (Fig. 1).
The electron impact mass spectrum of adduct 2 exhibited an in-
tense peak due the molecular ion at m/z 247. At the same time,
only molecular ions of the starting components and products of
their decomposition were detected in the EI spectra of adducts 3,
4 and 5.

Y. A. Azev et al. / Tetrahedron Letters 50 (2009) 2899–2903
2901
CH3
N
N
O
NH
CH3
H3C
N
CH3
N
N
N
H3C
HN
N
N
O
n-BuOH,
117 °C, 15 h
(9%)
HO
OH
NH
H3C
7
6
11 (10%)
(6%)
H
N
H3C
N
N
CH3
N
NH
N
H
N
H
O
N
N
NH
O
Cl
CH3
H
N
8
H3C
Cl
N
H
Cl
(Et)3N,
EtOH,
78 °C, 1 h
DMSO,
N
N
20 °C, 24 h
N
N
N
CH3
O
NH
H3C
N
H
9 (45%)
10 (25%)
Scheme 3.
H3C
N
H
H
N
N
H3C
NH2
N
H
N
H
N
8
CH3
H
N
CH3
Cl
Cl
H3C
NH2
N
NH
CH3
N
H
11
+
N
NH
Cl
H3C
CH3 H3C
Cl -
H
HN
Scheme 4.
It is noteworthy that these unusual transformations result from
nucleophilic attack on the C-2 atom of quinazoline without exter-
nal activation (catalysis). The described transformations open
opportunities for the synthesis of new, potentially biologically ac-
tive products and have fundamental value in quinazoline
chemistry.

2902
Y. A. Azev et al. / Tetrahedron Letters 50 (2009) 2899–2903
H3C
N
CH3
N
N
CH3
H2O
N
N
N
N
N
O
O
+
N
HO
n
-BuOH,
117 °C, 15 h
N
CH3
O
OH
NH
N
6 (14%)
9
Scheme 5.
Figure 1. 2D-NOESY NMR spectrum of compound 4.
11. Compound 2: mp 215–218 °C; 1H NMR (400 MHz, DMSO-d6): d 6.35 (s, 1H, H-
4), 6.85–7.15 (m, 4H, CHarom), 7.15–7.45 (m, 4H, CHarom), 8.43 (s, 1H, H-2),
11.28 (s, 1H, NHindole). MS: m/z 247 (M+). Anal. Calcd for C18H14F3N3O2: C, 59.8;
H, 3.9; N, 11.6. Found: C, 60.2; H, 4.0; N, 11.3.Compound 3: mp 227–228 °C; 1H
NMR (400 MHz, DMSO-d6): d 6.08 (s, 1H, H-4), 6.32 (d, 1H, J = 8.4 Hz, CHarom),
6.48 (d, 1H, J = 8.4 Hz, CHarom), 6.90–7.00 (m, 1H, CHarom), 7.00–7.20 (m, 2H,
CHarom), 7.22–7.30 (m, 1H, CHarom), 8.39 (s, 1H, H-2), 8.62 (s, 1H, OH), 8.90 (s,
1H, OH), 9.32 (s, 1H, OH), 10.65 (br s, 1H, NH), 12.15 (br s, 1H, NH). Anal. Calcd
for C14H13ClN2O3: C, 57.4; H, 4.5; N, 9.6. Found: C, 57.0; H, 4.4; N, 9.4.Compound
4: mp>250 °C; 1H NMR (400 MHz, DMSO-d6): d 3.11 (s, 6H, 2 Â NCH3), 6.04 (s,
1H, H-4), 6.89 (dd, 1H, J = 7.8 Hz, J = 0.9 Hz, H-8), 6.93 (d, 1H, J = 7.5 Hz, H-5),
7.04 (ddd, 1H, J = 7.6, J = 7.5 Hz, J = 1.1 Hz, H-6), 7.13 (ddd, 1H, J = 7.8 Hz,
J = 7.6 Hz, J = 1.2 Hz, H-7), 8.17 (d, 1H, J = 4.5 Hz, H-2), 9.96 (d, 1H, J = 4.5,
N(1)H), 11.48 (br s, 1H, OH). Anal. Calcd for C14H14N4O3ÁH2O: C, 55.3; H, 5.3; N,
18.4. Found: C, 55.6; H, 5.6; N, 18.2.Compound 5: mp 128–130 °C; 1H NMR
(400 MHz, DMSO-d6): d 2.02 (s, 3H, CH3), 6.11 (s, 1H, H-4), 7.00–7.80 (m, 9H,
CHarom), 8.38 (s, 1H, H-2), 10.50 (br s, 1H, NH), 13.20 (br s, 1H, NH). Anal. Calcd
for C20H17 F3N4O3: C, 57.4; H, 4.1; N, 13.4. Found: C, 57.8; H, 4.4; N,
13.7.Compound 9: mp 98-99 °C; 1H NMR (400 MHz, DMSO-d6): d 2.33 (s, 3H,
CH3), 6.27 (s, 1H, H-4), 7.20–8.27 (m, 9H, CHarom), 8.73 (s, 1H, H-2). MS: m/z
References and notes
1. Johne, S.; Groeger, D. Pharmazie 1970, 25, 22–44.
2. Johne, S. Pharmazie 1981, 36, 583–596.
3. Hynes, J. B.; Ashton, W. T. J. Med. Chem. 1975, 18, 263–265.
4. Elslageu, E. T.; Jacob, P.; Johnson, J.; Werbel, L. M. J. Heterocyc1. Chem. 1980, 17,
129–136.
5. Tregubenko, I. P.; Golomolzin, B. V.; Postovsky, I. Ya.; Filjakova, V. I.; Tarahtii, E.
A. In Organic Synthesis and Biological Activity, Sverdlovsk, 1978, 3; Chem. Abstr.
1979, 91, 91589.
6. Golomolzin, B. V.; Tregubenko, I. P.; Tarahtii, E. A.; Rasina, L. N.; Tikhonova, O.
N. In Organic Synthesis and Biological Activity, Sverdlovsk, 1978, 14; Chem. Abstr.
1980, 92, 146713.
7. Albert, A. Angew. Chem. 1967, 79, 913–952.
8. Pilicheva, T. L.; Chupakhin, O. N.; Postovsky, I. Ya. Khim. Heterotsikl. Soedin.
1975, 561–565.
9. Azev, Yu. A.; Neunhoeffer, H.; Fouo, S.; Lindner, H.; Shorshnev, S. V. Mendeleev
Commun. 1995, 229–231.
10. Azev, Yu. A.; Duelks, T.; Lork, E.; Gabel, D. Mendeleev Commun. 2005, 193–196.

Y. A. Azev et al. / Tetrahedron Letters 50 (2009) 2899–2903
2903
302 (M+). Anal. Calcd for C18H14N4O: C, 71.5; H, 4.7; N, 18.5. Found: C, 71.2; H,
4.4; N, 18.2.Compound 10: mp 225–227 °C; 1H NMR (400 MHz, DMSO-d6): d
2.61 (s, 3H, CH3), 6.60–8.10 (m, 8H, CHarom), 9.20 (s, 1H, H-2), 11.54 (s, 1H, NH).
MS: m/z 259 (M+). Anal. Calcd for C17H13N3: C, 78.7; H, 5.1; N, 16.2. Found: C,
78.5; H, 4.8; N, 16.0.