Regioselective synthesis of N(3)- and O-acylmethyl derivatives of 2-methylthio-4(3H)-quinazolinone

Article abstract of DOI:10.1002/jhet.5570450250

(Chemical Equation Presented) Reaction of 2-methylthio-4(3H)-quinazolinone with chloroacetone, ω-bromoacetophenone or ethyl bromoacetate in different solvents (methanol, acetonitrile, dimethylformamide and toluene) using sodium methoxide or potassium carb

Full text of DOI:10.1002/jhet.5570450250

Mar-Apr 2008
607
Regioselective Synthesis of N(3)- and O-acylmethyl Derivatives
of 2-Methylthio-4(3H)-quinazolinone
Milda M. Burbuliene, Rita Mazeikaite and Povilas Vainilavicius
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24,
LT-03225, Vilnius, Lithuania. E-mail: milda.burbuliene@chf.vu.lt
Received July 12, 2007
R
O
N
O
N
O
N
O
S
R
N
N
NH
or
O
S
S
R = CH3, C6H5, OC2H5
Reaction of 2-methylthio-4(3H)-quinazolinone with chloroacetone, ω-bromoacetophenone or ethyl
bromoacetate in different solvents (methanol, acetonitrile, dimethylformamide and toluene) using sodium
methoxide or potassium carbonate as a base were studied. Regioselective N(3)-alkylation took place in
toluene using potassium carbonate, whereas in dimethylformamide O-acylmethyl derivatives were
obtained. However chloroacetone reacted with 2-methylthio-4(3H)-quinazolinone under various conditions
to give a mixture of N(3)/O-isomers.
J. Heterocyclic Chem., 45, 607 (2008).
substitution in the dual reactivity of 4(3H)-quinazolinone
anion is determined by the influence of each of these
factors. The effect of 2-substituent of the quinazoline ring,
on the ratio of N-/O-alkyl products formation was studied
by different authors [10,24,26].
INTRODUCTION
4(3H)-Quinazolinones are of considerable interest due
their wide range of useful biological activities. 4(3H)-
Quinazolinone is a constituent of alkaloids [1-3]. The
quinazolinone skeleton is considered to be a privileged
structure and has been utilized as a druglike scafold in
medicinal chemistry [4]. N(3)-Substituted 4(3H)-quinazo-
linones show antimalarial [5-9], anti-inflammatory and
antitumor [10] activities. A derivative of (N(1)-quina-
zolinyl)acetic acid Zanerestat is a remedy of diabetic
complications [11]. Substituted N(3)-propyl 4(3H)-quina-
zolinone Proquinazid is a representative of a new class
of antifungal agents, which show high activity on
powdery mildew of cereal, grapes and other crops [12].
Some O-substituted derivatives of 4(3H)-quinazoline
exhibit antifungal or insecticidal activity [13]. In
consideration of diverse biological properties of N/O-
substituted 4(3H)-quinazolinones it is important to
develop convenient and efficient methods for synthesis
of this type of compounds.
RESULTS AND DISCUSSION
Previously we have found that alkylation of 2-methyl-
thio-4(3H)-quinazolinone with methyl bromoacetate in a
methanol - sodium methoxide solution resulted in N(3)-
substituted ester formation [28].
As a continuation of our ongoing studies, herein we
report the results of the reaction of 2-methylthio-4(3H)-
quinazolinone 1 with chloroacetone, ω-bromoaceto-
phenone and ethyl bromoacetate, that involves regio-
selective alkylation of the ambident anion. Convenient
methods for the synthesis of O-acylmethyl substituted
quinazolines (2b,c) and N(3)-acylmethyl derivatives of
4(3H)-quinazolinone (3a-c) are presented (Scheme 1).
Compounds 3b and 3c are known from the literature
though they were prepared in
a different way.
N-Substituted 4(3H)-quinazolinones usually are
obtained during the quinazolinone ring formation
procedure. Anthranilic acid or derivatives, carboxylic
acids and amines are used for cyclocondensation reactions
to form various 2,3-disubstituted 4(3H)-quinazolinones.
[14-23]. Another way to N/O-substituted quinazolines is
alkylation of ambident 4(3H)-quinazolinone anion
[10,11,24-28]. However, dual reactivity of ambident
anions frequently leads to the formation of mixtures of
isomers. The direction of alkylation is dependent on the
alkylating agent, substrate, reaction solvent and other
reaction conditions [29]. Naturally, the ratio of N/O-
Compound 3b was obtained by Sinha [17] from 3-(2-
oxo-2-phenylethyl)-2-thioxo-2,3-dihydro-4(1H)-quina-
zolinone alkylation with iodomethane [17]. The
synthetic route to ester 3c also utilized cycloconden-
sation reaction of anthranilic acid ester with the
appropriate amine [19].
Reactions of ambident 4(3H)-quinazolinone anion 1
with halo acylmethyl derivatives were carried out in
different solvents - methanol, acetonitrile, dimethyl-
formamide and toluene. As a base in these reactions
sodium methoxide or potassium carbonate was used.

608
M. M. Burbuliene, R. Mazeikaite and P. Vainilavicius
Vol 45
Scheme 1
2 hours, while reaction with ω-bromoacetophenone
proceeded for 24 hours. Unexpectedly, chloroacetone
reacted with 1 in dimethylformamide to give a mixture of
2a/3a with marked predominance of N(3)-acetylmethyl
derivative 3a (entry 5). Unfortunately we did not succeed
to find out conditions for the regioselective synthesis of
O-acetylmethyl derivative 2a. The compound 2a was
isolated from the mixture of isomers by column
chromatography.
It is evident that in an aprotic nonpolar solvent (toluene)
in the presence of potassium carbonate regioselective N(3)-
substitution proceeded independently of the electrophile
used (entries 4, 6, 8). The yields of compounds 3a-c are
about 70%.
O
N
O
M
S
N
NH
Solvent, base
N
S
1
X-CH2CO-R
R
O
O
N
O
S
R
N
N
+
O
S
N
2a-c
3a-c
X = Br, Cl
M = K, Na
The structure of compounds was identified by ir, 1H and
13C nmr data. In the ir spectra of 3a-c strong absorption
bands of the substituent acyl group are observed in the
region of 1698-1728 cm-1 along with the quinazolinone
C4=O group absorption at 1673-1684 cm-1, which is
characteristic of 2-alkylthio-N(3)-substituted 4(3H)-
quinazolinones [30]. The ir spectra of O-acylmethyl
derivatives 2a-c showed strong peaks at 1698-1750 cm-1,
indicating acyl group absorption.
R = CH3 (a), C6H5 (b), OC2H5 (c)
Reactions in dimethylformamide were carried out at
room temperature. At higher temperatures formation of
the mixtures of N/O-derivatives was observed. Reactions
in other solvents were performed at reflux. The optimal
reaction time for compounds 2a,b, and 3a-c is 14-18
hours.
The current results showed that regioselectivity to form
N(3)- or O-derivatives mainly depends on the solvent and
the nature of the electrophile used. Reaction conditions
and the ratio of isomers are depicted in Table 1.
The nmr spectra are not informative enough to indicate
whether N- or O-derivative was formed, however
comparison of the data shows that CH2 peaks in O-
substituted derivatives 2 are shifted downfield compared
to the corresponding peaks of N(3)-substituted 3. For
example, the OCH2 peak of 2a is at 5.13 and 70.7 ppm in
Table 1
Reaction conditions and the ratio of isomers
1
the H and 13C nmr, respectively, whereas NCH2 peak of
Entry
R
Solvent
Base
Time Temp.
*Ratio
of 2/3
-
1/6
1/1
3a is at 5.00 and 52.9 ppm, respectively. It was observed
that solubility in organic solvents (methanol, 2-propanol,
chloroform, hexane, benzene) is high and similar for both
N(3)- and O-isomers and consequently they could not be
separated by crystallization. Melting points of 3a-c are
higher than those of 2a-c by 20 to 40°C.
(h)
14
18
18
18
18
14
16
16
2
(°C)
1
2
3
4
5
6
7
8
9
CH3
CH3
CH3
CH3OH
CH3CN
CH3CN
C6H5CH3
DMF
C6H5CH3
DMF
C6H5CH3
DMF
NaOCH3
NaOCH3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
reflux
reflux
reflux
reflux
room t. 1/4
reflux 0/1
room t. 1/0
reflux 0/1
room t. 1/0
CH3
CH3
C6H5
C6H5
OC2H5
OC2H5
0/1
EXPERIMENTAL
Melting points were determined in open capillaries and are
uncorrected. The ir spectra were recorded on a Spectrum BX
FT-IR (Perkin-Elmer, Sweden) as potassium bromide pellets.
Nuclear magnetic resonance (nmr) spectra were recorded on a
* Ratio of compounds 2/3 was estimated by the data of 1H nmr.
1
The ratio of isomers was estimated from the data of H
nmr of the crude product. Surprisingly, chloroacetone did
not react with 1 in sodium methoxide-methanol solution,
while in acetonitrile a mixture of N(3)/O-isomer was
formed with the predominance of N(3)-substituted
derivative 3a in ratio 6:1 (entry 2). In acetonitrile in the
presence of potassium carbonate as a base, the content
both of 2a and 3a in the mixture is equal (entry 3). Using
dimethylformamide as a solvent, the direction and time of
the reaction was determined by the electrophile. Reaction
of 1 with ω-bromoacetophenone or ethyl bromacetate
gave O-acylmethyl derivatives 2b,c (entries 7, 9). It
should be noted that formation of 2c was complete within
1
Unity Varian INOVA spectrometer at 300 MHz for H and 75
MHz for 13C using CDCl3 as a solvent. Chemical shifts (δ) are
reported in ppm relative to TMS. The reactions and purity of
compounds was controlled by tlc on Alugram Sil G/UV254
plates. Elemental analyses were performed at the
Microanalytical Laboratory of the Department. All solvents
were dried and distilled before use.
2-Methylthio-4(3H)-quinazolinone (1) was prepared as
reported in [28].
1-(2-Methylthio-4-quinazolinyloxy)acetone (2a). A mixture
of quinazolinone 1 (0.83 g, 4.3 mmol), potassium carbonate 0.42
g, 3 mmol) and acetonitrile (20 ml) was stirred for 10 min. at
reflux and then a solution of chloroacetone (0.463 g, 0.42 ml, 5

Mar-Apr 2008
Regioselective Synthesis of N(3)- and O-acylmethyl Derivatives
609
mmol) in acetonitrile (2 ml) was slowly added dropwise. The
reaction mixture was refluxed for 18 hours and filtered of. The
solvent was evaporated and the crude material was purified by
column chromatography using silica gel Kieselgel 60 (0.063-0.2
mm) with eluent chloroform-ethyl acetate (25:1); Rf = 0.78 (2a),
Rf = 0.58 (3a). Compound 2a, yield 0.19 g (18%), mp 99-100
was stirred at reflux for 14 hours and filtered. Toluene was
evaporated under reduced pressure. The remainder was
crystallized from ethanol to give 0.93 g (70%) of 3b as a white
solid, mp 176-178 C°: ir 1673, 1698 (C=O) cm-1; 1H nmr
(CDCl3): δ 2.69 (s, 3H, SCH3), 5.68 (s, 2H, NCH2), 7.40-7.46
(m, 1H, Ar-H), 7.55-7.78 (m, 5H, Ar-H), 8.07-8.11 (m, 2H, Ar-
H), 8.24-8.27 (m, 1H, Ar-H) ppm; 13C nmr: δ 15.4, 50.0, 119.3,
126.1, 126.6, 127.4, 128.4, 129.2, 134.3, 134.8, 135.0, 147.9,
162.0, 191.3 ppm. Anal. Calcd for C17H14N2O2S (310.37): C,
65.79; H, 4.55; N, 9.03. Found: C, 65.60; H, 4.75; N, 8.77.
Ethyl (2-Methylthio-4-oxo-3-quinazolinyl)acetate (3c). A
mixture of quinazolinone 1 (0.83 g, 4.3 mmol), potassium
carbonate 0.42 g, 3 mmol) and toluene (20 ml) was stirred for 5
min. at reflux and then a solution of ethyl bromoacetate (0.835
g, 0.55 ml, 5 mmol) in toluene (2 ml) was slowly added
dropwise. The reaction mixture was refluxed for 16 hours and
filtered. The solvent was removed in vacuum. The remainder
was stirred with 1% sodium hydroxide solution (ca 20 ml) at
room temperature for 0.5 hour, then the pH was adjusted to 7 by
dropwise addition of acetic acid. The precipitate was collected
by filtration and crystallized from ethanol to give colorless
crystals of 3c, yield 0.86 g (72%), mp 108-109 °C (ref. [19] mp
107-109 °C): (ir 1685, 1728 (C=O) cm-1; 1H nmr (CDCl3): δ 1.33
(t, J = 7.2 Hz, 3H, CH3), 2.71 (s, 3H, SCH3), 4.29 (q, J = 7.2 Hz,
2H, CH2), 4.95 (s, 2H, OCH2), 7.42-7.45, 7.60-7.63, 7.72-7.75,
8.23-8.26 (4m, 4x1H, quinazoline) ppm; 13C nmr: δ 14.4, 15.5,
45.1, 62.3, 119.2, 126.1, 126.5, 134.9, 147.8, 153.5, 161.8, 167.3
ppm. Anal. Calcd for C13H14N2O2S (278.33): C, 56.10; H, 5.07;
N, 10.06. Found: C, 56.14; H, 4.99; N, 10.14.
1
°C: ir 1744 (C=O) cm-1; H nmr (CDCl3): δ 2.30 (s, 3H, CH3),
2.63 (s, 3H, SCH3), 5.13 (s, 2H, OCH2), 7.44-7.50 (m, 1H,
quinazoline), 7.79-7.80 (m, 2H, quinazoline), 8.14-8.17 (m, 1H,
quinazoline) ppm; 13C nmr: δ 14.4, 26.7, 70.7, 113.9, 123.9,
125.9, 126.6, 134.5, 152.3, 165.0, 167.2, 202.7 ppm. Anal. Calcd
for C12H12N2O2S (248.30): C, 58.05; H, 4.87; N, 11.28. Found:
C, 58.24; H, 5.01; N, 11.23.
2-(2-Methylthio-4-quinazolinyloxy)-1-phenylethanone (2b).
A mixture of quinazolinone 1 (0.83 g, 4.3 mmol), potassium
carbonate 0.42 g, 3 mmol) and dimethylformamide (15 ml) was
stirred for 10 min. at room temperature and then ω-
bromoacetophenone (0.995 g, 5 mmol) was added portion wise
over an hour. The reaction mixture was stirred at room
temperature for 16 hours and filtered of. Water was added to the
filtrate. The precipitate formed was collected by filtration and
recrystallized from 2-propanol to give 2b as a white solid, 0.91 g
1
(68%), mp 133-135 C°: ir 1698 (C=O) cm-1; H nmr (CDCl3): δ
2.54 (s, 3H, SCH3), 5.86 (s, 2H, OCH2), 7.50-7.59 (m, 3H, Ar-
H), 7.65-7.68 (m, 1H, Ar-H), 7.80-7.82 (m, 2H, Ar-H), 8.03-
8.06 (m, 2H, Ar-H), 8.24-8.26 (m, 1H, Ar-H) ppm; 13C nmr: δ
14.4, 68.4, 114.1, 124.2, 125.9, 126.5, 128.1, 129.2, 134.2,
134.4, 134.8, 152.4, 165.2, 167.2, 192.8 ppm. Anal. Calcd for
C17H14N2O2S (310.37): C, 65.79; H, 4.55; N, 9.03. Found: C,
66.04; H, 4.63; N, 8.89.
Ethyl (2-Methylthio-4-quinazolinyloxy))acetate (2c).
Compound 2c was prepared analogously 2b using ethyl bromo
acetate (5 mmol, 0.835 g, 0.57 ml). The reaction mixture was
stirred at room temperature for 2 hours and isolated as above
to give 2c as a white solid, 0.96 g (80%), mp 75-76 °C: ir 1750
REFERENCES
[1] Michael, J. P. Natural Prod. Reports 2007, 24, 223.
[2] Mashe, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787.
[3] Sinha, S.; Srivastava, M. Progress. Drug Res. 1994, 43, 143.
[4] Horton, D. A.; Boume, G. T.; Smythe, M. C. Chem. Rev.,
2003, 103, 893.
1
(C=O) cm-1; H nmr (CDCl3): δ 1.33 (t, J = 7.2 Hz, 3H, CH3),
2.64 (s, 3H, SCH3), 4.30 (q, J = 7.2 Hz, 2H, CH2), 5.12 (s, 2H,
OCH2), 7.46-7.48 (m, 1H, quinazoline), 7.80-7.82 (m, 2H,
quinazoline), 8.16-8.19 (m, 1H, quinazoline) ppm; 13C nmr: δ
14.4, 14.5, 61.7, 63.5, 113.9, 124.1, 125.9, 126.5, 134.4, 152.4,
165.1, 167.1, 168.2 ppm. Anal. Calcd for C13H14N2O2S
(278.33): C, 56.10; H, 5.07; N, 10.06. Found: C, 56.07; H,
4.95; N, 10.34.
[5] Baker, B. R.; Querry, M. V.; Kadish, A. F.; Williams, J. H. J.
Org. Chem. 1952, 17, 35.
[6] Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2001, 3, 953.
[7] Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-
S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833.
2-Methylthio-3-(2-oxopropyl)-4(3H)-quinazolinone (3a). A
mixture of quinazolinone 1 (0.83 g, 4.3 mmol), potassium
carbonate 0.42 g, 3 mmol) and toluene (20 ml) was stirred for 5
min. at reflux and then a solution of chloroacetone (0.463 g, 0.42
ml, 5 mmol) in toluene (2 ml) was slowly added dropwise. The
reaction mixture was refluxed for 18 hours. The solid was
collected by filtration and recrystallized from 2-propanol to give
3a, yield 0.79 g (74%), mp 132-133 °C: ir 1685, 1728 (C=O)
[8] Takaya, Y.; Tasaka, H.; Chiba, T.; Uwai, K.; Tanitsu, H.-S.;
Kim, Y.; Wataya, Y.; Miura, M.; Takeshita, M.; Oshima, Y. J. Med.
Chem. 1999, 42, 3163.
[9] Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.
Tetrahedron Lett. 1999, 40, 2175.
[10] Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.;
Carson, D. A.; Cottan, H. B. J. Med. Chem. 1999, 42, 3860.
[11] Goto; S.; Tsuboi, H.; Kanoda, M.; Mukai, K.; Kagara, K.
Org. Procc. Res.& Develop. 2003, 7, 700.
1
cm-1; H nmr (CDCl3): δ 2.33 (s, 3H, CH3), 2.69 (s, 3H, SCH3),
5.00 (s, 2H, NCH2), 7.39-7.45, 7.60-7.64, 7.71-7.75, 8.21-8.24
(4m, 4x1H, quinazoline) ppm; 13C nmr: δ 15.4, 27.5, 52.9,
119.2, 126.1, 126.6, 127.4, 134.9, 147.9, 156.5, 161.7, 200.2
ppm. Anal. Calcd for C12H12N2O2S (248.30): C, 58.23; H, 4.83;
N, 11.29. Found: C, 58.05; H, 4.87; N, 11.28.
[12] Walter, H.; Zeun, R. Chimia 2003, 57, 692.
[13] Lamberth, C. Heterocycles 2006, 68, 561.
[14] Lempert, K.; Doleschall, G. Acta Chim. Acad. Sci. Hung.,
1963, 37, 457; Chem. Abstr. 1963, 59, 12809e.
[15] Kienzle, F.; Kaiser, A.; Minder, R. E. Helv. Chim. Acta 1983,
66, 148.
2-Methylthio-3-(2-oxo-2-phenylethyl)-4(3H)-quinazolinone
(3b). A mixture of quinazolinone 1 (0.83 g, 4.3 mmol),
potassium carbonate 0.42 g, 3 mmol) and toluene (20 ml) was
stirred for 5 min. at reflux and then ω-bromoacetophenone
(0.995 g, 5 mmol) was added portion wise. The reaction mixture
[16] Chan, Ch. H.; Shish, F. J.; Liu, K., Ch.; Chern, J. W.
Heterocycles 1987, 26, 3193.
[17] Sinha, S. K. P.; Kumar, P. Indian J. Chem. Sec. B. 1989, 28B
(3), 274; Chem. Abstr. 1989, 111, 174058a.

610
M. M. Burbuliene, R. Mazeikaite and P. Vainilavicius
Vol 45
[18] Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492.
[19] Sauter, F.; Froehlich, J.; Blasl, K.; Gewald, K. Heterocycles
1995, 40, 851.
367 944, 1990; Chem. Abstr., 1991, 114, 62107w.
[25] Hori, M.; Ohtaka, H. Chem. Pharm. Bull. 1993, 41, 1114;
Chem. Abstr. 1994, 120, 217509d.
[20] Wippich, P.; Gutschow, M.; Leistner, S. Synthesis 2000, 5,
[21] Gutchow, M.; Powers, J. C. J. Heterocycl. Chem. 2001, 38,
[22] Apfel, Ch.; Banner, D. W.; Bur, D.; Dietz, M.;
[26] Kovalenko, S. I.; Siniak, R. S.; Mazur, I. A.; Belenichev, I.
F.; Stebliuk, P. N. Farm. Zh. (Kiev) 1992, 5-6, 38 (Russ.); Chem. Abstr.
1993, 119, 8762w.
[27] Chen, G. S.; Kalchar, S.; Kuo, Ch.-W.; Chang, Ch.-S.;
Usifoh, C. O.; Chern, J.-W. J. Org. Chem. 2003, 68, 2502.
[28] Burbuliene, M. M.; Bobrovas, O.; Vainilavicius, P. J.
Heterocycl. Chem. 2006, 43, 43.
714.
419.
Hubschwerlen, Ch.; Locher, H.; Marlin, F.; Masciardi, R.; Pirson, W.;
Stadler, H. J. Med. Chem. 2001, 44, 1847.
[23] Liu, J.-F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C.
M.; McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241.
[24] Fisnerova, L.; Brunova, B.; Maturova, E.; Grimova, J. EP
[29] Shevalev, S. A. Russ. Chem. Rev. 1970, 39, 844.
[30] Orysyk, V. V.; Zborovskij, Yu. L.; Staninets, V. I.; Dobosh,
A. A.; Khripak, S. M. Chem. Heterocycl. Comp. 2003, 39, 640.