A new approach to fluorinated 4(3H)-quinazolinones

Article abstract of DOI:10.1016/j.jfluchem.2007.03.005

A new approach for the synthesis of fluorinated 1H-quinazolin-4-ones and 4-substituted quinazolines has been developed. 6-Fluoro-1H-quinazolin-4-ones were obtained by intramolecular cyclization of fluorine-containing S-ethyl N-benzoylisothioureas. Nucleop

Full text of DOI:10.1016/j.jfluchem.2007.03.005

Journal of Fluorine Chemistry 128 (2007) 748–754
www.elsevier.com/locate/fluor
A new approach to fluorinated 4(3H)-quinazolinones
Anastacia A. Layeva a, Emilia V. Nosova a, Galina N. Lipunova a,
Tatyana V. Trashakhova a, Valerii N. Charushin b,
*
a Ural State Technical University, 19 Mira Str., 620002 Ekaterinburg, Russian Federation
b I. Ya. Postovskiy Institute of Organic Synthesis, Ural Division of the Russian Academy of Sciences, 22 S. Kovalevskoy Str.,
620219 Ekaterinburg, Russian Federation
Received 29 January 2007; received in revised form 7 March 2007; accepted 7 March 2007
Available online 12 March 2007
Dedicated to 100-anniversary of Prof. I. L. Knunyants.
Abstract
A new approach for the synthesis of fluorinated 1H-quinazolin-4-ones and 4-substituted quinazolines has been developed. 6-Fluoro-1H-
quinazolin-4-ones were obtained by intramolecular cyclization of fluorine-containing S-ethyl N-benzoylisothioureas. Nucleophilic substitution
reactions at positions 2 and 7, as well as alkylation at 1-position of quinazolinones were investigated. In addition, the synthesis of fluorine-
containing 4-aminoquinazolines was carried out.
# 2007 Published by Elsevier B.V.
Keywords: Fluorine-containing quinazolinones; Intramolecular cyclization; Nucleophilic substitution; S-Ethyl N-benzoylisothioureas
1. Introduction
To our knowledge, the synthesis of 1H-quinazolin-4-ones
from fluorinated benzoyl chlorides has not so far been
described, although, 2-halogenobenzoyl chlorides can be used
for preparation of [a]-annelated quinazolinones [5]. We wish to
report here a new approach to the 1H-quinazolin-4-ones based
on the reaction of ortho-halogen substituted benzoyl chlorides
with S-ethyl isothiourea, as N,N0-dinucleophile.
4(3H)-Quinazolinones belong to a well known class of
heterocyclic compounds exhibiting antihypertensive, antidia-
betic, anti-inflammatory, anticonvulsant and antibacterial
properties [1]. On the other hand, it has been established that
incorporation of one or several fluorine atoms into organic
molecules enhances their biological potency, bioavailability
and metabolic stability [2].
2. Results and discussion
The synthesis of the quinazolinone system has been
extensively studied and described in the literature [3]. There
are three general approaches to 1H-quinazolin-4-ones deriving
from different starting materials, such as anthranilic acid,
anthranilonitrile or aniline derivatives [4]. The most straight-
forward procedure was developed by Niementowski in 1895
and improved later by Grimmel et al. in 1946. They found that
4(3H)-quinazolinones could be obtained from N-acetylanthra-
nilic acid and anilines in toluene or xylene with phosphorus
oxychloride as condensing agent [4].
In order to obtain fluorinated quinazolinones bearing
fluorine atoms we have studied interaction of tetrafluoroben-
zoyl, 2,5-difluoro-4-chlorobenzoyl, 2-chloro-4,5-difluoroben-
zoyl and 2-chloro-4-fluorobenzoyl chlorides (1a–d) with
S-ethyl isothioureum iodide 2 (Scheme 1). Benzoyl chlorides
(1a–d) were reacted with S-ethyl isothioureum iodide (2) in
methylene chloride at room temperature in the presence of
triethyl amine to give S-ethyl N-aroylisothioureas (3a–d) in
good yields (71–82%), as evidenced by their 1H NMR spectra.
In case of tetrafluorobenzoyl chloride diaroyl derivative (4a)
was found to be formed when the reaction mixture was slightly
heated. Use of S-benzyl derivative (2b) instead of S-ethyl
isothiourea in the reaction with tetrafluorobenzoyl chloride
* Corresponding author. Tel.: +7 343 349 3227; fax: +7 343 374 1189.
E-mail address: charushin@ios.uran.ru (V.N. Charushin).
0022-1139/$ – see front matter # 2007 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2007.03.005

A.A. Layeva et al. / Journal of Fluorine Chemistry 128 (2007) 748–754
749
Scheme 1. 1, 3: X = Y = Z = W = F (a); X = W = F, Z = Cl, Y = H (b); X = Cl, W = Z = F, Y = H (c); X = Cl, Z = F, W = Y = H (d); 2, 4: R = Et (a), CH2Ph (b). 6:
Z = Y = F (a), Z = Cl, Y = H (b).
gave diaroyl compound (4b) even at room temperature. For this
reason S-ethyl isothiourea was chosen for further studies.
When compounds (3a–d) were kept on reflux in toluene for
5 h in the presence of NEt3 only 1H-quinazolin-4-one (6a) was
obtained in 15% yield. Heating of (3a) in DMF with pyrrolidine
as a base for 5 h failed to give a cyclization product, instead of
it the displacement of fluorine atom and the SEt-group by
pyrrolidine proved to take place under these conditions
(Scheme 1). The structure of compound (5) was established
displacement of one F atom and the formation of the cyclic
system. Indeed, the double doublet assigned to F(6) has been
1
observed in case of compound (6b) in H NMR; also the 19F
NMR spectrum of (6b) reveals the signal of one fluorine atom in
the form of dd (J = 8.9, 6.7 Hz). In addition, the peaks with m/z
260 [M]+ (100%) for (6a) and m/z 258 [M]+ (87%) for (6b) in
their mass spectra are in full agreement with the suggested
structures. The feature of mass spectra of both compounds is the
presence of highly intensive peaks of [M ꢀ EtS ꢀ CN]+ (m/z
173 (98%) and 171 (100%) for (6a) and (6b), respectively).
In order to perform some structural modifications of
quinazolinone (6a) we have studied nucleophilic substitution
of atom F(7) and SEt-group at position 2, alkylation at position
1, as well as chlorination and the ability to introduce an amine
moiety at position 4 (Scheme 2).
1
by H NMR. Isothiourea derivatives bearing fluorine atoms at
ortho-position (3a, b) undergo intramolecular cyclization
on reflux in DMF for 5 h to give 1H-quinazolin-4-ones (6a,
b) in high yields. Attempts to cause intramolecular displace-
ment of chlorine atom at 2-position of (3c, d) under a variety of
conditions (heating in DMF, diphenyl ether, hexadecane,
bis(octyl)phthalate, acetic anhydride or in DMF, 1,4-dioxane,
toluene in the presence of bases, e.g. potassium carbonate,
potassium fluoride, potassium tert-butoxide, sodium hydride)
have failed.
When compound (6a) was refluxed in anhydrous DMF with
pyrrolidine for 2 h substitution of fluorine atom at 7-position by
pyrrolidine moiety occurred, as evidenced by the presence of
signals of pyrrolidine protons and the signal of H(5) as double
doublet in 1H NMR spectrum. In contrast, the displacement of
SEt-group of 7-chloro derivative (6b) by pyrrolidine takes place
under similar conditions, 1H NMR and mass spectroscopy data
being in agreement with the structure (9).
1
The structure of quinazolinones (6a, b) was proved by H,
19F NMR data. The 1H NMR spectrum of (6a) reveals a
characteristic signal of H(5) (ddd, J = 10.0, 8.0, 2.4 Hz), a
broadened singlet of NH-group and appropriate signals of the
SEt-group. The 19F NMR spectrum of (6a) displays signals of
three fluorine atoms in the form of ddd, thus indicating the
It was found that quinazolinone (6a) was reacted with
morpholine to give a mixture of 7-morpholino derivative (7b)
Scheme 2. 6: Z = Y = F (a), Z = Cl, Y = H (b); 7: NR1R2 = pyrrolidin-1-yl (a), morpholin-4-yl (b), 3-(morpholin-4-yl)-1-propylamine (c), 3-methylpipyridin-1-yl (d).

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A.A. Layeva et al. / Journal of Fluorine Chemistry 128 (2007) 748–754
Scheme 3.
and 2,7-bis(morpholino) derivative (8), and it became possible
to separate the compounds from each other using treatment
of the mixture with hot ethanol. In the reaction of (6a) with
3-(4-morpholino)-1-propanamine and 3-methylpiperidine only
fluorine atom at 7-position was replaced with nucleophiles to
afford (7c) and (7d), respectively.
The ethylthio group at position 2 of (6a) was smoothly
replaced by the hydrazino moiety to give compound (10) upon
heating under reflux with hydrazine hydrate for 1 h. Compound
(10) can be used for preparation of quinazolinones bearing a
heterocyclic substituent at 2-position. For example, the reaction
of (10) with acetylacetone takes place in refluxing acetonitrile
in the presence of acetic acid, thus leading to 2-pyrazolylqui-
nazolinone (11).
compound (13) was formed, as evidenced by the presence of
two CH2-signals together with the absence of SEt-signals in the
1H NMR spectrum. The formation of (13) probably proceeds
via N-alkylation of (6a) with 2-bromoethanol followed
by intramolecular nucleophilic substitution of SEt-group.
The reaction of (6a) with 2-bromoethyl methyl ether gave
quinazolin-4-one (14).
Since 4-anilinoquinazolines are known as inhibitors of
neurominidasa of smallpox virus [6], it was of interest to
convert quinazolinone (6a) into fluorinated 4-anilinoquinazo-
lines (15a–c) (Scheme 4). Compound (6a) was treated with
phosphorus oxychloride and the chloro compound A was
reacted with aniline in CH3CN to give (15a). Quinazolines
(15b, c), (16), (17) were prepared similarly. This procedure
proved to be effective for incorporation of C-nucleophile in
positions 4 of quinazolin-4-one (6a) to afford 4-(N-methy-
lindole-3-yl)-quinazoline (18). Interestingly, the reaction of
N-Alkylation of (6a) with ethyl iodide in the presence of
NaOH gave (12) (Scheme 3). When quinazolin-4-one (6a)
was reacted with 2-bromoethanol under similar conditions
Scheme 4. 15: Ar = Ph (a); 3,4-F2C6H3 (b); 2-ClC6H4 (c).

A.A. Layeva et al. / Journal of Fluorine Chemistry 128 (2007) 748–754
751
compound Awith N-methylindole proceeds without any base or
any catalyst.
The structure of quinazolines (15)–(18) was established on
8.9 Hz, H-60 or H-30), 9.5 (2H, br s, NH). Anal. Calcd for
C10H9ClF2N2OS, C 43.10; H 3.25; N 10.05. Found: C 43.11; H
3.22; N 10.07.
1
the basis of H NMR and mass spectrum data.
In summary, a new approach for the synthesis of fluorinated
1H-quinazolin-4-ones and 4-substituted quinazolines has been
developed. Also, it has been shown that the presence of three
fluorine atoms in quinazoline-4-ones enhances the reactivity of
positions 2 and 4 toward N,C,O-nucleophilic reagents.
3.2.4. 2-Ethyl-1-(4-fluoro-2-chlorobenzoyl)isothiourea (3d)
A white solid; mp 88–90 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.32 (3H, t, CH3), 3.06 (2H, q, SCH2), 7.09 (1H,
ddd, J = 10.9, 8.5, 2.5 Hz, H-60), 7.20 (1H, dd, J = 9.0, 2.5 Hz,
H-30), 7.92 (1H, dd, J = 9.0, 7.0 Hz, H-50), 9.4 (2H, br s, NH).
Anal. Calcd for C10H10ClFN2OS, C 46.07; H 3.87; N 10.74.
Found: C 46.10; H 3.84; N 10.77.
3. Experimental
3.1. General
3.3. 2,3,5-Trifluoro-N-(iminopyrrolidin-1-ylmethyl)-4-
(pyrrolidin-1-yl)benzamide (5)
1H NMR spectra were recorded on Bruker WM-250 and
Bruker DRX-400 spectrometers operating at 250.14 and
400.13 MHz, respectively. 19F NMR spectra were recorded
on Bruker DRX-500 spectrometer operating at 376.45 MHz.
All spectral data are reported in ppm in the d scale relative to
internal TMS (1H NMR) or hexafluorobenzene (19F NMR),
respectively. Mass spectra were recorded on a Varian MAT
311A spectrometer (accelerating voltage 3 kV, cathode emis-
sion current 300 mA, energy of ionizing electrons 70 eV, direct
inlet probe).
A white solid; mp 83–85 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.90 (8H, m, 2(CH2)2), 3.57 (8H, m, 2N(CH2)2),
7.38 (1H, ddd, J = 15.7, 6.7, 2.5 Hz, H-60).
3.4. Typical procedure for the synthesis of 2-ethylthio-6-
fluoro-7-Z-8-Y-1H-quinazolin-4-ones (6a, b)
Compound 3a (0.6 g, 2.1 mmol) in 10 mL of anhydrous
DMF was refluxed for 4 h. The reaction mixture was then
evaporated and the residue was recrystallized from ethanol to
give 0.42 g (76%) of 6a.
3.2. Typical procedure for the synthesis of 2-ethyl-1-(2-X-
3-Y-4-Z-5-W-benzoyl)isothioureas (3a–d)
3.4.1. 2-Ethylthio-6,7,8-trifluoro-1H-quinazolin-4-one (6a)
A white solid; mp 207–209 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.36 (3H, t, CH3), 3.18 (2H, q, SCH2), 7.64 (1H,
ddd, J = 10.0, 8.0, 2.4 Hz, H-5), 12.6 (1H, br s, NH). 19F NMR
([2H6]DMSO, 376.45 MHz): dF 10.84 (1F, ddd, J = 19.3, 22.4,
8.1 Hz, F-7), 15.94 (1F, ddd, J = 19.3, 4.0, 2.3 Hz, F-8), 25.6
(1F, ddd, J = 22.4, 10.0, 4.0 Hz, F-6). MS, m/z: 260 [M]+ (100),
173 [M ꢀ EtS ꢀ CN]+ (98), 174 [M ꢀ 86]+ (58), 144
[M ꢀ 116]+ (58). Anal. Calcd for C10H7F3N2OS, C 46.15; H
2.71; N 10.76. Found: C 46.18; H 2.68; N 10.70.
A solution of tetrafluorobenzoyl chloride (1a) (0.92 g,
4.3 mmol) in 1 mL of toluene was added to a suspension of S-
ethylisothiourea hydroiodide (1 g, 4.3 mmol) in 15 mL of
CH2Cl2 to which 1.2 mL (8.6 mmol) of NEt3 had been added.
After a day at room temperature the mixture was evaporated.
The residue was washed with water and recrystallized from
ethanol to give 0.85 g (71%) of (3a).
3.2.1. 2-Ethyl-1-(2,3,4,5-tetrafluorobenzoyl)isothiourea
(3a)
A white solid; mp 70–72 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.35 (3H, t, CH3), 3.11 (2H, q, SCH2), 7.72 (1H,
m, C6HF4), 9.5 (2H, br s, NH). Anal. Calcd for C10H8F4N2OS,
C 42.86; H 2.86; N 10.00. Found: C 42.89; H 2.83; N 10.09.
3.4.2. 2-Ethylthio-6-fluoro-7-chloro-1H-quinazolin-4-one
(6b)
A white solid; mp 210–212 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.39 (3H, t, CH3), 3.17 (2H, q, SCH2), 7.61 (1H, d,
J = 6.7 Hz, H-8), 7.78 (1H, d, J = 8.9 Hz, H-5), 12.5 (1H, br s,
NH). 19F NMR ([2H6]DMSO, 376.45 MHz): dF 43.66 (1F, dd,
J = 8.9, 6.7 Hz). MS, m/z: 258 [M]+ (87), 171 [M ꢀ EtS ꢀ CN]+
(100), 142 [M ꢀ 116]+ (97), 225 [M ꢀ 33]+ (81), 172 [M ꢀ 86]+
(60). Anal. Calcd for C10H8ClFN2OS, C 46.43; H 3.12; N 10.83.
Found: C 46.40; H 3.10; N 10.81.
3.2.2. 2-Ethyl-1-(2,5-difluoro-4-chlorobenzoyl)isothiourea
(3b)
A white solid; mp 115–117 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.33 (3H, t, CH3), 3.05 (2H, q, SCH2), 7.35 (1H,
dd, J = 9.7, 6.1 Hz, H-60 or H-30), 7.80 (1H, dd, J = 9.3, 6.4 Hz,
H-30 or H-60), 9.4 (2H, br s, NH). Anal. Calcd for
C10H9ClF2N2OS, C 43.10; H 3.25; N 10.0. Found: C 43.15;
H 3.24; N 10.07.
3.5. Typical procedure for the synthesis of 2-ethylthio-6,8-
difluoro-7-(alkylimino)-1H-quinazolin-4-ones (7a, c, d) and
7-chloro-6-fluoro-2-(pyrrolidin-1-yl)-1H-quinazolin-4-one
(9)
3.2.3. 2-Ethyl-1-(4,5-difluoro-2-chlorobenzoyl)isothiourea
(3c)
A white solid; mp 90–92 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.36 (3H, t, CH3), 3.10 (2H, q, SCH2), 7.45 (1H,
dd, J = 9.8, 6.9 Hz, H-30 or H-60), 7.83 (1H, dd, J = 10.9,
Pyrrolidine (0.7 mL, 8.5 mmol) was added to a solution of
(6a) (0.6 g, 2.3 mmol) in 4 mL of anhydrous DMF. The reaction
mixture was refluxed for 2 h. After the mixture was cooled the

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A.A. Layeva et al. / Journal of Fluorine Chemistry 128 (2007) 748–754
precipitate formed was collected by filtration and recrystallized
from DMSO to give 0.5 g (70%) of (7a).
3.6.1. 2-Ethylthio-6,8-difluoro-7-(morpholin-4-yl)-1H-
quinazolin-4-one (7b)
A white solid; mp 190–192 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.41 (3H, t, CH3), 3.00 (4H, m, N(CH2)2), 3.24
(2H, q, SCH2), 3.30 (2H, m, OCH2), 3.74 (2H, m, OCH2), 7.41
(1H, dd, J = 12.8, 2.0 Hz, H-5), 12.10 (1H, br s, NH). MS, m/z:
327 [M]+ (15), 285 [M ꢀ 42]+ (100). Anal. Calcd for
C14H15F2N3O2S, C 51.37; H 4.62; N 12.84. Found: C 51.35;
H 4.60; N 12.89.
3.5.1. 2-Ethylthio-6,8-difluoro-7-(pyrrolidin-1-yl)-1H-
quinazolin-4-one (7a)
A white solid; mp 246–248 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.38 (3H, t, CH3), 1.92 (4H, m, (CH2)2), 3.19 (2H,
q, SCH2), 3.65 (4H, m, N(CH2)2), 7.32 (1H, dd, J = 13.8,
2.0 Hz, H-5), 12.19 (1H, br s, NH). 19F NMR ([2H6]DMSO,
376.45 MHz): dF 23.27 (1F, d, J = 13.1 Hz), 39.63 (1F, m). MS,
m/z: 311 [M]+ (100), 310 [M ꢀ H]+ (48), 278 [M ꢀ 33]+ (31),
282 [M ꢀ Et]+ (26). Anal. Calcd for C14H15F2N3OS, C 54.01;
H 4.86; N 13.50. Found: C 54.05; H 4.80; N 13.53.
3.6.2. 2,7-Bis(morpholino)-6,8-difluoro-1H-quinazolin-4-
one (8)
A white solid; mp 285–287 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 3.13 (8H, m, 2N(CH2)2), 3.64 (8H, m, 2O(CH2)2),
7.25 (1H, m, H(5)), 11.11 (1H, s, NH). MS, m/z: 352 [M]+ (9),
310 [M ꢀ 42]+ (100). Anal. Calcd for C16H18F2N4O3, C 54.49;
H 5.11; N 15.89. Found: C 54.35; H 5.60; N 15.89.
3.5.2. 2-Ethylthio-6,8-difluoro-7-(3-(morpholie-4-yl)-1-
propylamine)-1H-quinazolin-4-one (7c)
A white solid; mp 214–216 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.43 (3H, t, CH3), 1.77 (2H, m, CH2), 2.40 (2H, m,
CH2), 2.54 (2H, m, CH2), 3.21 (2H, q, SCH2), 3.47 (4H, m,
N(CH2)2), 3.61 (4H, m, O(CH2)2), 7.35 (1H, dd, J = 11.8,
1.5 Hz, H-5), 12.19 (1H, br s, NH). 19F NMR ([2H6]DMSO,
376.45 MHz): dF 16.58 (1F, d, J = 12.8 Hz), 32.96 (1F, m). MS,
m/z: 384 [M]+ (7), 100 [M ꢀ 284]+ (100). Anal. Calcd for
C17H22F2N4O2S, C 53.11; H 5.77; N 14.57. Found: C 53.15; H
5.70; N 14.53.
3.7. The procedure for the synthesis of 2-hydrazino-6,8-
difluoro-7-(pyrrolidin-1-yl)-1H-quinazolin-4-one (10)
Compound (7b) (0.56 g, 1.8 mmol) in 5 mL of hydrazine
hydrate was heated under reflux during 1 h. After the mixture
was cooled the precipitate formed was collected by filtration
and recrystallized from DMSO to give 0.45 g (88%) of (10), mp
329–331 8C. 1H NMR ([2H6]DMSO, 250 MHz): d 1.94 (4H, m,
(CH2)2), 3.64 (4H, m, N(CH2)2), 7.26 (1H, dd, J = 12.9, 1.2 Hz,
H-5). MS, m/z: 281 [M]+ (100), 280 [M ꢀ H]+ (54). Anal. Calcd
for C12H13F2N5O, C 51.24; H 4.66; N 24.90. Found: C 51.25; H
4.60; N 24.53.
3.5.3. 2-Ethylthio-6,8-difluoro-7-(3-methylpipyridin-1-yl)-
1H-quinazolin-4-one (7d)
A white solid; mp 150–152 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 0.92 (3H, d, CH3, J = 6.3 Hz), 1.12 (1H, m, CH),
1.41 (3H, t, CH3), 1.73 (2H, m, CH2), 1.78 (2H, m, CH2), 2.81
(2H, m, CH2), 3.20 (2H, q, SCH2), 3.33 (2H, m, CH2), 7.38 (1H,
dd, J = 11.5, 1.6 Hz, H-5), 12.15 (1H, br s, NH). MS, m/z: 339
[M]+ (100), 284 [M ꢀ 55]+ (60), 338 [M ꢀ H]+ (58). Anal.
Calcd for C16H19F2N3OS, C 56.62; H 5.64; N 12.38. Found: C
56.65; H 5.60; N 12.53.
3.8. The procedure for the synthesis of 2-(3,5-
dimethylpyrazol-1-yl)-6,8-difluoro-7-(pyrrolidin-1-yl)-1H-
quinazolin-4-one (11)
Acetylacetone (0.37 mL, 3.6 mmol) was added to a solution
of quinazolinone (10) (0.5 g, 1.8 mmol) in 10 mL of anhydrous
acetonitrile to which 0.35 mL of acetic acid had been added. The
reaction mixturewas refluxed for 2. After the mixturewas cooled
the precipitate formed was collected by filtration and recrys-
tallized from ethanol to give 0.50 g (81%) of (11), mp 225–
227 8C. 1H NMR ([2H6]DMSO, 250 MHz): d 1.92 (3H, s, CH3),
1.99 (3H, s, CH3), 2.27 (4H, m, (CH2)2), 2.71 (4H, m, N(CH2)2),
6.18 (1H, s, CH), 7.43 (1H, dd, J = 13.5, 1.8 Hz, H-5), 11.22 (1H,
br s, NH). MS, m/z: 345 [M]+ (100), 344 [M ꢀ H]+ (69), 346
[M + H]+ (20). Anal. CalcdforC17H17F2N5O, C 59.13;H 4.93;N
20.29. Found: C 59.15; H 4.89; N 20.23.
3.5.4. 7-Chloro-6-fluoro-2-(pyrrolidin-1-yl)-1H-
quinazolin-4-one (9)
A white solid; mp 308–310 8C. 1H NMR ([2H6]DMSO,
250 MHz): d 1.92 (4H, m, (CH2)2), 3.50 (4H, m, N(CH2)2), 7.29
(1H, d, J = 5.5 Hz, H-8), 7.62 (1H, d, J = 8.4 Hz, H-5), 11.2
(1H, br s, NH). MS, m/z: 267 [M]+ (64), 238 [M ꢀ Et]+ (100).
Anal. Calcd for C12H11ClFN3O, C 53.88; H 4.15; N 15.71.
Found: C 53.85; H 4.10; N 15.53.
3.6. The procedure for the synthesis of 2-ethylthio-6,8-
difluoro-7-(morpholin-4-yl)-1H-quinazolin-4-one (7b) and
2,7-bis(morpholino)-6,8-difluoro-1H-quinazolin-4-one (8)
3.9. Typical procedure for the synthesis of 1-ethyl-2-
ethylthio-6,7,8-trifluoro-1H-quinazolin-4-one (12)
Morpholine (0.86 mL, 9.6 mmol) was added to a solution of
(6a) (0.6 g, 2.3 mmol) in 4 mL of anhydrous DMF. The reaction
mixture was refluxed for 2 h and then evaporated. The residue
was added to 6 mL of hot ethanol. The unsolved solid which
was filtered off proved to be quinazolinone (8). It was then
recrystallized from DMSO. The material which was recrys-
tallized from ethanol proved to be quinazilinone (7b).
Ethyl iodide (0.62 mL, 7.7 mmol) was added to a solution of
quinazolinone (6a) (0.5 g, 1.9 mmol) in 5 mL of ethanol to
which 0.62 mL of 30% aqueous NaOH had been added. The
reaction mixture was refluxed for 2. After the mixture was
evaporated the residue was washed with water and recrys-
tallized from ethanol to give 0.37 g (68%) of (12).

A.A. Layeva et al. / Journal of Fluorine Chemistry 128 (2007) 748–754
753
3.9.1. 1-Ethyl-2-ethylthio-6,7,8-trifluoro-1H-quinazolin-4-
one (12)
3.10.3. 2-Ethylthio-4-(20-chloroanilino)-6,7,8-
trifluoroquinazolines (15c)
Mp 95–97 8C. H NMR ([2H6]DMSO, 250 MHz): d 1.28
(3H, t, CH3), 1.41 (3H, t, CH3), 3.29 (2H, q, SCH2), 4.07 (2H, q,
NCH2), 7.80 (1H, ddd, J = 10.3, 8.1, 2.2 Hz, H-5). MS, m/z: 288
[M]+ (39), 173 [M ꢀ 115]+ (100), 259 [M ꢀ Et]+ (81), 200
[M ꢀ 88]+ (76). Anal. Calcd for C12H11F3N2OS, C 50.00; H
3.85; N 9.72. Found: C 50.15; H 3.89; N 10.00.
Mp 158–160 8C. 1H NMR ([2H6]DMSO, 250 MHz): d 1.20
(3H, t, CH3), 2.90 (2H, q, SCH2), 7.29–7.54 (4H, m, C6H4Cl),
8.34 (1H, ddd, J = 11.4, 8.5, 1.8 Hz, H-5), 9.92 (1H, br s, NH).
MS, m/z: 369 [M]+ (100), 274 [M ꢀ 95]+ (86). Anal. Calcd for
C16H11ClF3N3S, C 51.97; H 3.00; N 11.36. Found: C 51.92; H
2.99; N 11.32.
1
3.9.2. 5,6,7-Trifluoro-8,9H-oxazolo[2,3-a]-quinazolin-4-
one (13)
3.10.4. 2-Ethylthio-4-benzylamino-6,7,8-
trifluoroquinazolines (16)
Mp 310–312 8C. 1H NMR ([2H6]DMSO, 250 MHz): d 4.31
(3H, m, CH2), 4.81 (2H, m, CH2), 7.73 (1H, ddd, J = 9.9, 7.5,
2.0 Hz, H-5). MS, m/z: 242 [M]+ (65), 200 [M ꢀ 42]+ (100).
Anal. Calcd for C10H5F3N2O2, C 49.60; H 2.08; N 11.57.
Found: C 49.61; H 2.31; N 11.53.
Mp 149–151 8C. 1H NMR ([2H6]DMSO, 250 MHz): d 1.40
(3H, t, CH3), 3.14 (2H, q, SCH2), 4.82 (2H, m, CH2), 7.22–7.39
(5H, m, Ph), 8.18 (1H, m, H-5), 8.85 (1H, s, NH). MS, m/z: 349
[M]+ (52), 91 [CH2C6H5]+ (100). Anal. Calcd for C17H14F3N3S,
C 58.45; H 4.01; N 12.03. Found: C 58.42; H 3.99; N 12.00.
3.9.3. 1-(2-Methoxyethyl)-2-ethylthio-6,7,8-trifluoro-1H-
quinazolin-4-one (14)
3.10.5. 2-Ethylthio-4-(50-tert-butylisoxazole-3-yl)-6,7,8-
trifluoroquinazolines (17)
Mp 190–192 8C. 1H NMR ([2H6]DMSO, 250 MHz): d 1.33
(3H, t, CH3), 3.07 (2H, q, SCH2), 3.20–3.35 (4H, m, (CH2)2),
3.35 (3H, s, OCH3), 7.61 (1H, ddd, J = 10.6, 8.5, 2.1 Hz, H-5).
MS, m/z: 318 [M]+ (2), 173 [M ꢀ 145]+ (100), 260 [M ꢀ 58]+
(87). Anal. Calcd for C13H13F3N2O2S, C 49.05; H 4.12; N 8.80.
Found: C 50.10; H 4.09; N 9.00.
Mp 219–221 8C. 1H NMR ([2H6]DMSO, 250 MHz): d 1.40
(3H, t, CH3), 1.41 (9H, s, (CH3)3), 3.20 (2H, q, SCH2), 6.87
(1H, s, isoxazole), 8.55 (1H, m, H-5), 10.98 (1H, s, NH). MS, m/
z: 382 [M]+ (34), 57 [C(CH3)3]+ (100). Anal. Calcd for
C17H17F3N4OS, C 53.40; H 4.48; N 14.65. Found: C 53.35; H
4.52; N 14.70.
3.10. Typical procedure for the synthesis of 2-ethylthio-4-
amino-6,7,8-trifluoroquinazolines (15a–c), (16), (17)
3.10.6. 2-Ethylthio-4-(N-methylindole-3-yl)-6,7,8-
trifluoroquinazolines (18)
1
Mp 211–213 8C. H NMR ([2H6]DMSO, 250 MHz): 1.47
Compound (6a) (0.8 g, 3.1 mmol) in 4 mL of POCl3 was
heated under reflux during 2 h. The mixture was then poured
into ice water and neutralised with NaHCO3. The aqueous
mixture was extracted with ethyl acetate. The extracts were
dried (Na2SO4) and then evaporated. The residue thus obtained
was added to a solution of aniline (0.41 mL, 6.2 mmol) in 8 mL
of anhydrous acetonitrile. The mixture was refluxed for 4 h.
After the mixture was evaporated the residue was washed with
water and recrystallized from ethanol to give (15a).
(3H, t, CH3), 3.28 (2H, q, SCH2), 3.97 (3H, s, CH3), 7.19–7.33
(2H, m, H-50, H-60), 7.50 (1H, m, H-40), 8.18 (1H, m, H-5), 8.22
(1H, s, H-20), 8.26 (1H, m, H-70). MS, m/z: 373 [M]+ (100), 287
[M ꢀ Et ꢀ SCN]+ (69), 312 [M ꢀ SEt]+ (68). Anal. Calcd for
C19H14F3N3S, C 61.12; H 3.78; N 11.25. Found: C 60.35; H
4.00; N 11.20.
Acknowledgements
This work was supported by the Russian Foundation for
Basic Research (Projects Nos. 06-03-32791 and 07-03-96074-
Ural), the Civilian Research and Development Foundation of
the United States (CDRF Grants Annex BF4M05 and EK-005-
X2[REC-005]) within the scope of the Program ‘‘Basic
Research and Higher Education’’ (BRHE 2004 Post-Doctoral
Fellowship Award, Grant Y2-C-05-01) as well as the Grant of
the Progressive Scientific Schools HSh-9178.2006.3.
3.10.1. 2-Ethylthio-4-anilino-6,7,8-trifluoroquinazolines
(15a)
1
Mp 79–81 8C. H NMR ([2H6]DMSO, 250 MHz): d 1.42
(3H, t, CH3), 3.17 (2H, q, SCH2), 7.19 (1H, m, Ph), 7.42 (2H, m,
Ph), 7.82 (2H, m, Ph), 8.47 (1H, m, H-5), 9.80 (1H, s, NH). MS,
m/z: 335 [M]+ (97), 274 [M ꢀ SEt]+ (100). Anal. Calcd for
C18H16F3N3S, C 59.50; H 4.41; N 11.57. Found: C 59.52; H
4.49; N 11.52.
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