Synthesis of tetrahydro-2(1H)quinazolinones, cyclopenta[d]-2(1H) pyrimidinones, and their thioxo analogs from 2-trifluoroacetyl-1- methoxycycloalkenes

Article abstract of DOI:10.1080/00397910500278818

A series of six (8)-alkyl-4-trifluoromethyl-5,6,7,8-tetrahydro-2(1 H)quinazolinones, 4-trifluoromethyl-cyclopenta[d]-2(1 H)pyrimidinones, and their thioxo analogs from the reaction of five β-alkoxyvinyl trifluoromethyl ketones, derived from alkylated cyclohexanones and cyclopentanone with urea and thiourea, is reported. The reactions were carried out in a single step in propan-2-ol as solvent and boron trifluoride diethyl etherate as catalyst in 18-65% yield. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500278818

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Synthesis of
Tetrahydro‐2(1H)quinazolinones,
Cyclopenta[d]‐2(1H)pyrimidinones,
and Their Thioxo Analogs from
2‐Trifluoroacetyl‐1‐methoxycycloal
Helio G. Bonacorso a , Michelle B. Costa a , Itamar S.
Lopes a , Marlí R. Oliveira a , Roberta L. Drekener a
, Marcos A. P. Martins a , Nilo Zanatta a & Alex F. C.
Flores a
a Núcleo de Química de Heterociclos—NUQUIMHE,
Departamento de Química, Universidade Federal de
Santa Maria, Santa Maria, Brazil
Published online: 21 Aug 2006.
To cite this article: Helio G. Bonacorso , Michelle B. Costa , Itamar S. Lopes ,
Marlí R. Oliveira , Roberta L. Drekener , Marcos A. P. Martins , Nilo Zanatta
& Alex F. C. Flores (2005): Synthesis of Tetrahydro‐2(1H)quinazolinones,
Cyclopenta[d]‐2(1H)pyrimidinones, and Their Thioxo Analogs from
2‐Trifluoroacetyl‐1‐methoxycycloalkenes, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:23, 3055-3064
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Synthetic Communicationsw, 35: 3055–3064, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500278818
Synthesis of Tetrahydro-
2(1H)quinazolinones, Cyclopenta[d]-
2(1H)pyrimidinones, and Their Thioxo
Analogs from 2-Trifluoroacetyl-
1-methoxycycloalkenes
Helio G. Bonacorso, Michelle B. Costa, Itamar S. Lopes,
´
Marlı R. Oliveira, Roberta L. Drekener,
Marcos A. P. Martins, Nilo Zanatta, and Alex F. C. Flores
´
´
Nucleo de Quımica de Heterociclos—NUQUIMHE, Departamento de
´
Quımica, Universidade Federal de Santa Maria, Santa Maria, Brazil
Abstract: A series of six (8)-alkyl-4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H)quinazo-
linones, 4-trifluoromethyl-cyclopenta[d]-2(1H)pyrimidinones, and their thioxo analogs
from the reaction of five b-alkoxyvinyl trifluoromethyl ketones, derived from alkylated
cyclohexanones and cyclopentanone with urea and thiourea, is reported. The reactions
were carried out in a single step in propan-2-ol as solvent and boron trifluoride diethyl
etherate as catalyst in 18–65% yield.
Keywords: Quinazolines, quinazolinones, pyrimidines, pyrimidinones, cycloalkenes
Quinazolines are of great interest for combinatorial library synthesis because
of their wide spectrum of biological activities including CNS depressant,[1]
analgesic,[2] antibacterial,[3] and anti-HIV[4] activity. Recently, Corbett
et al.[4] reported that 4-alkenyl and 4-alkynyl-3,4-dihydro-4-trifluoromethyl-
2(1H)quinazolinones were potent nonnucleoside reverse transcriptase inhibitors
Received in the USA June 30, 2005
Address correspondence to Helio G. Bonacorso, Nucleo de Quımica de Heteroci-
´
´
´
clos—NUQUIMHE, Departamento de Quımica, Universidade Federal de Santa
Maria, 97105-900 Santa Maria, RS, Brazil. E-mail: heliogb@base.ufsm.br
3055

3056
H. G. Bonacorso et al.
(NNRTIs) of human immunodeficiency virus type 1 (HIV-1). Some of these
derivatives exhibited low nanomolar potency toward wild-type RF virus and
various single and many multiple amino-acid-substituted HIV-1 mutant
viruses. In the same year, 4-polyfluoroalkyl-5,6-oligomethylenepyrimidines
have been obtained from the reaction of 2-polyfluoroacyl cycloalkanones
derived from cyclopentanone and cyclohexanone with guanidine, urea,
thiourea, methylisothiourea, benzamidine, guanylthiourea, dicyanodiamine,
and trifluoroacetylurea by Lewis acid catalysis. A decrease in the yield with
an increasing in length of the polyfluoroalkyl substituent in the cycloalkanone
was observed for reagents with lower nucleophilicity (urea, thiourea, and dicya-
nodiamide).[5] In 2002, Yarim et al. described how 4-(3-chlorophenyl)- and
4-(3-bromophenyl)-1,7,7-trimethyl-1,2,3,4,5,6,7,8,-octahydroquinazoline-2,5-
dione were synthesized by condensing N-methylurea with 5,5-dimethyl-l,3-
cyclohexanedione and appropriate aromatic aldehydes according to the
Biginelli reaction. These compounds exhibited a calcium antagonist activity
on isolated rat ileum and were the most active derivatives compared with
nicardipine, used as a reference drug.[6]
Since 1991, studies about the regiochemistry of the cyclocondensa-
tion reactions of b-alkoxyvinyl trihalomethyl ketones with urea,[7–9]
N-methylurea,[10] 2-methyl-2-thiopseudourea sulfate,[11] guanidine hydro-
chloride,[12] acetamidine and benzamidine hydrochloride,[13] and N-methyl
thiourea[14] have been developed in our research group. However, the employ-
ment of b-alkoxyvinyl trihalomethyl ketones with a Lewis acid as catalyst to
generate a substituted six- or five-membered carbocycle fused at positions 5
and 6 of the pyrimidine ring resulting in tetramethylene-2(1H)pyrimidinones
(tetrahydroquinazolinones), cyclopenta[d]-2(1H)pyrimidin-ones, or their
thioxo analogs has not yet been reported.
Despite extensive studies devoted to the synthesis of acyclic b-alkoxyvinyl
trihalomethyl ketones and their cyclocondensation reactions involving a
variety of nitrogen dinucleophiles, the synthesis and reactions of cyclic
b-alkoxyvinyl trihalomethyl ketones has been much less developed. Thus,
considering the importance of 2(1H)quinazolinones, we now report the
synthesis of novel 4(6)-alkyl-2-trifluoroacetyl-l-methoxycyclohexen (and
cyclopenten) and the application of these new functionalized cycloalken to
synthesize 5,6,7,8-tetrahydro-2(1H)quinazolinones, cyclopenta[d]-2(1H)-
pyrimidinones, and their thioxo analogs.
The b-methoxyvinyl trifluoromethyl ketones 2a and 2e derived from cyclo-
hexanone (1a) and cyclopentanone (1e) were prepared previously.[15] I herein,
we reported the synthesis of new b-methoxyvinyl trifluoromethyl ketones 2b–d
derived from alkyl-substituted cyclohexanones (1b–d). Reaction of the respect-
ive 1,1-dimethylcyclohexanone acetals with trifluoroacetic anhydride by a
procedure similar to the one described in the literature[15] furnished new hetero-
cycle precursors in high purity and in good yield (Scheme 1).
The cyclization reactions of 2a–e with urea were carried out in propan-2-
ol in the presence of a catalytic amount of boron trifluoride diethyl etherate.

Synthesis of Quinazolinones and Thioxo Analogs
3057
Scheme 1.
The mixtures were stirred for 20 h at reflux to afford 4-trifluoromethyl-5,6,7,8-
tetrahydro-2(1H)quinazolinones (3a–d) and 4-trifluoromethyl-cyclopenta[d]-
2(1H)pyrimidinone (3e), respectively. Similarly, cyclization of vinylketones
2a–e with thiourea gave 4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H)thio-
quinazolinones (4a–d) and 4-trifluoromethyl-cyclopenta[d]-2(1H)thiopyrimi-
dinone (4e), in moderate to good yield. All cyclization reactions were
monitored by TLC.
Previously, our research group[7–14] synthesized trihalomethyl-2(1H)-
pyrimidinones using a mixture of methanol and concentrated hydrochloric
acid. We found that the use of boron trifluoride diethyl etherate as
catalyst, instead of using the conventional procedure, gave more satisfactory
results.[7] Herein, we demonstrated that the reaction of b-methoxyvinyl tri-
fluoromethyl ketone 2d with urea gave a higher yield (50% of 3d) when
catalyzed by boron trifluoride diethyl etherate than the reaction carried
out in methanol–hydrochloric acid (,20% of 3d). Compounds 3a, 4a,
and 4e have been previously synthesized by Sevenard et al., who reacted
2-trifluoroacetylcyclohexanone with urea and thiourea or 2-trifluoroacetyl-
cyclopentanone with thiourea in 64%, 34%, and 16% yields, respectively.[5]
These improved yields were obtained only when the reactions were
carried out in propan-2-ol in the presence of boron trifluoride diethyl
etherate. These reactions, when conducted in our laboratory without
boron trifluoride diethyl etherate, rendered ,30% yield with urea for 3a
and ,10% yield with thiourea for 4a and 4e.
In the present work we have synthesized the same three products (3a, 4a,
and 4e) reported by Sevenard[5] but now using cyclic b-methoxyvinyl trifluor-
omethyl ketones 2a and 2e instead of 1,3-diketones. In this case, we obtained

3058
H. G. Bonacorso et al.
very similar yields of 65%, 35%, and 20%, respectively. However, we
observed a decrease in yield (Table 1) when the enones 2 bear an alkyl
substituent on positions 4 (R1 ¼ Me and t-Bu) and 6 (R ¼ Me). Because of
the reaction conditions and the reagents adopted in this work, it seems that
the thermodynamic stability of products 3 and 4 governs its formation, but
one can observe that when a methyl group is attached to the carbon 6
(e.g., 2b), a reasonable steric interference should be considered in the
quinazolinone synthesis pathway.
As expected, a minor steric interference is observable for substituents
attached to carbon-4 at the cyclohexenes 2c–d. In comparation to the
synthesis of quinazolinones 3a–d, a decrease of the yields for the synthesis
of thioquinazolinones 4a–d was observed. However, in this case, the substi-
tuent effect of the alkyl groups attached to carbon 6 (2b) and carbon 4 (2c–d)
does not decrease the yield. After 1 h at reflux we observed that all cyclizations
involving thiourea showed a dark yellow color and had an unpleasant sulfide-
like smell. Thus, the lower yield obtained for these cyclizations may probably
be due to the decomposition of the thiourea.
In conclusion, the present methodology allows us to obtain a series of
trifluoromethylated 5,6,7,8-tetrahydro-2(1H)quinazolinones, cyclopenta[d]-
2(1H)pyrimidinones, and their thioxo analogs from b-alkoxyvinyl trifluoro-
methyl ketones, derived from substituted cyclohexanones and cyclopentanone,
Table 1. Yields for the synthesis of 4-trifluoromethyl-5,6,7,8-
tetrahydro 2(1H)quinazolinones and 4-trifluoromethyl-cyclopenta[d]-
2(1H)pyrimidinone, and their thioxo analogs (3a–e, 4a–e)
No.
R
R1
Z
Yield (%)
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
H
H
O
O
O
O
O
S
65
31
40
50
35
35
20
18
25
20
Me
H
H
Me
t-Bu
—
H
—
H
H
Me
H
H
S
Me
t-Bu
—
S
H
S
—
S

Synthesis of Quinazolinones and Thioxo Analogs
3059
in a single step and in moderate to good yield. In addition we observed that the
cyclization yield depends on two factors. The reaction yield is very sensitive to
first the nucleophile employed [i.e., urea (31–65%) and thiourea (18–35%)],
and second the inclusion of alkyl substituents at positions 4 and 6 of the
vinyl ketones.
EXPERIMENTAL
Unless otherwise indicated all common reagents and solvents were used as
obtained from commercial suppliers without further purification. All
melting points were determined on a Reichert Thermovar apparatus and are
1
uncorrected. H and 13C NMR spectra were acquired on a Bruker DPX 400
spectrometer (1H at 400.13 MHz and 13C at 100.62 MHz) with 5-mm
sample tubes, at 298 K, at digital resolution +0.01 ppm, in CDCl3 (2a–e)
or in DMSO-d6 (3, 4a–e), and using TMS as internal reference. Mass
spectra were registered in a Hewlett-Packard Company 6890 GC connected
to a HP 5973 Mass Selective Detector and interfaced by a Pentium PC. The
GC was equipped with a split–splitless injector, autosampler, and cross-
linked HP-5 capillary column (30m, 0.32 mm of internal diameter), and
helium was used as the carrier gas. The CHN elemental analyses were
performed on a Perkin Elmer 2400 CHN elemental analyzer (USP University,
Sa˜o Paulo, Brazil).
Synthesis of 2-Trifluoroacetyl-1-methoxycycloalkenes
Trifluoroacetic anhydride (60 mmol) was added dropwise to a stirred solution
of dimethoxy acetals derived from cycloalkanones (30 mmol) and pyridine
(60 mmol, 4.8 g) in chloroform (30 mL) kept at 08C (ice bath). The mixture
was stirred for 16 h at 458C. The mixture was quenched and extracted with
0.1 M hydrochloric acid solution (3 ꢀ 15 mL) and then with water
(1 ꢀ 15 mL). The organic layer was dried with magnesium sulfate and
filtered. The filtrate was evaporated and the products were obtained in high
purity by distillation under reduced pressure.
Data
2-Trifluoroacetyl-1-methoxycyclohexene (2a). Yellow oil; yield 68%; bp
43–458C/2.8 mbar. Lit.[15]: yield 65%; bp 106–109/10mbar. 1H NMR
(CDCl3) d ¼ 3.7 (s, 3H, OCH3); 2.45–2.42 (m, 2H, CH2); 2.33–2.30 (m, 2H,
CH2); 1.80–1.74 (m, 2H, CH2); 1.65–1.59 (m, 2H, CH2). 13C NMR (CDCl3)
2
1
d ¼ 181.4 (C55O, JCF ¼ 35.3); 170.1 (C-1); 116.8 (CF3, JCF ¼ 288.9);
110.4 (C-2); 54.8 (OCH3); 25.9 (CH2); 24.1 (CH2); 22 (CH2); 21.6 (CH2).

3060
H. G. Bonacorso et al.
MS [m/z (%)] for C9H11F3O2 (208.18): 208 (Mþ, 42), 139 (100), 79 (66),
69 (31).
6-Methyl-2-trifluoroacetyl-1-methoxycyclohexene (2b). Yellow oil; yield
60%; bp 79–818C/3.5 mbar. 1H NMR (CDCl3) d ¼ 3.7 (s, 3H, OCH3);
2.77 (m, 1H, CH2); 2.52–2.44 (m, 1H, CH2); 2.20–2.05 (m, 1H, CH2);
1.72–1.59 (m, 4H, CH2); 1.2 (d, 3H, JHH ¼ 7.1, CH3). 13C NMR (CDCl3)
2
1
d ¼ 182.9 (C55O, JCF ¼ 36.7); 172.7 (C-1); 116.6 (CF3, JCF ¼ 288.9);
112.1 (C-2); 55.4 (OCH3); 29.7 (CH2); 28.9 (CH2); 24.4 (CH2); 18.2 (CH2);
17.6 (CH3). MS [m/z (%)] for C10H13F3O2 (222.20): 222 (Mþ, 24), 153
(100), 93 (33), 69 (15).
4-Methyl-2-trifluoroacetyl-1-methoxycyclohexene (2c). Yellow oil; yield
60%; bp 89–928C/3.4 mbar. 1H NMR (CDCl3) d ¼ 3.7 (s, 3H, OCH3);
2.53–2.40 (m, 3H, CH2); 1.89–1.77 (m, 2H, CH2); 1.67–1.61 (m, 1H,
CH2); 1.45–1.30 (m, 1H, CH2); 1.0 (d, 3H, JHH ¼ 6.6, CH3). 13C NMR
2
(CDCl3) d ¼ 181.3 (C55O, JCF ¼ 35.3); 169.9 (C-1); 116.8 (CF3,
1JCF ¼ 289.6); 109.8 (C-2); 54.9 (OCH3); 32.2 (CH2); 29.9 (CH2); 27.9
(CH2); 25.8 (CH2); 20.7 (CH3). MS [m/z (%)] for C10H13F3O2 (222.20):
222 (Mþ, 8), 153 (100), 69 (9).
4-(1,1-Dimethyethyl)-2-trifluoroacetyl-1-methoxycyclohexene (2d). Yellow
1
oil; yield 60%; bp 84–868C/1.5 mbar. H NMR (CDCl3) d ¼ 3.7 (s, 3H,
OCH3); 2.68–2.47 (m, 2H, CH2); 2.41–2.35 (m, 1H, CH2); 1.98–1.86
(m, 2H, CH2); 1.33–1.21 (m, 2H, CH2); 0.9 (s, 9H, 3CH3). 13C NMR
2
(CDCl3) d ¼ 181.6 (C55O, JCF ¼ 35.3); 170.1 (C-1); 116.8 (CF3,
1JCF ¼ 289.6); 110.3 (C-2); 54.9 (OCH3); 43.5 (CH2); 32.1 (CH2); 27.3, 27.1
(t-Bu); 25.5 (CH2); 23.3 (CH2). MS [m/z (%)] for C13H19F3O2 (264.28): 264
(Mþ, 21), 249 (66), 111 (50), 57 (100).
2-Trifluoroacetyl-1-methoxycyclopentene (2e). Yellow oil; yield 65%; bp
49–508C/3.2 mbar. Lit.[15]: yield 70%; bp 97–998C/10 mbar. 1H NMR
(CDCl3) d ¼ 3.9 (s, 3H, OCH3); 2.80–2.76 (m, 2H, CH2); 2.70–2.66
(m, 2H, CH2); 1.99–1.91 (m, 2H, CH2). 13C NMR (CDCl3) d ¼ 177.4
2
1
(C-1); 175.4 (C55O, JCF ¼ 36.03); 116.5 (CF3, JCF ¼ 290.3); 107.9 (C-2);
58.4 (OCH3); 31.6 (CH2); 28.2 (CH2); 19.1 (CH2). MS [m/z (%)] for
C8H9F3O2 (194.15): 194 (Mþ, 17), 125 (100), 95 (7), 67 (22).
Synthesis of 4-Trifluoromethyl-5,6,7,8-tetrahydro-
2(1H)quinazolinones, 4-Trifluoromethyl-cyclopenta[d]-
2(1H)pyrimidinone, and their thioxo analogs (3a–e, 4a–e)
Ketone 2 (5 mmol) and boron trifluoride diethyl etherate (sol. 45% in MeOH)
(10 drops) were added to a stirred solution of urea or thiourea (7 mmol) in

Synthesis of Quinazolinones and Thioxo Analogs
3061
propan-2-ol (10 mL) kept at room temperature (20–258C). The mixture was
stirred for 20 h at 858C for compounds 3a–d and 4a–d and at 658C for 3e
and 4e. After cooling (,108C), the crystalline solids were filtered off,
washed with water to remove the residual urea or thiourea, and recrystallized
from ethanol.
Data
4-Trifluoromethyl-5,6,7,8-tetrahydro-2(1H)quinazolinone (3a). Yellow
1
solid; yield 65%; mp 208–2108C. Lit.[5]: yield 64%; mp 206–2078C. H
NMR (DMSO-d6) d ¼ 12.6 (s, 1H, NH); 2.7 (m, 2H, CH2); 2.5 (m, 2H,
CH2); 1.7 (m, 4H, CH2). 13C NMR (DMSO-d6) d ¼ 162.9 (C550); 158.6
2
1
(C-4, J ¼ 31.8); 155.9 (C-8a); 120.6 (CF3, J ¼ 279); 109.4 (C-4a); 27.6
(CH2); 21.4 (CH2); 21.2 (CH2); 20 (CH2). MS [m/z (%)] for C9H9F3N2O
(218.18) ¼ 218 (Mþ, 100), 149 (27), 69 (30).
8-Methyl-4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H)quinazolinone (3b).
1
Yellow solid; yield 31%; mp 187–1898C. H NMR (DMSO-d6) d ¼ 12.5
(s, 1H, H-1), 2.92–2.84 (m, 1H, CH), 2.62–2.60 (m, 2H, CH2), 1.87–1.85
(m, 2H, CH2), 1.73–1.66 (m, 2H, CH2), 1.3 (d, 3H, H-9). 13C NMR
2
(DMSO-d6) d ¼ 168.1 (C550); 157.6 (C-4, JCF ¼ 52.3); 150.9 (C-8a);
1
120.6 (CF3, JCF ¼ 278.3); 110.7 (C-4a); 37.2 (C-8); 27.9 (CH2); 22.1
(CH2); 20.2 (CH3); 18.2 (CH2). MS [m/z (%)] for C10H11F3N2O
(232.21) ¼ 232 (Mþ, 49), 217 (100), 163 (3), 69 (8). Anal. calcd. for
C10H11F3N2O (232.21) ¼ C, 51.73; H, 7.77; N, 12.06%. Found: C, 51.82;
H, 4.47; N, 11.92%.
6-Methyl-4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H)quinazolinone (3c).
1
Yellow solid; yield 40%; mp 212–2148C. H NMR (DMSO-d6) d ¼ 12.5
(s, 1H, H-1), 2.74–2.70 (m, 3H, CH2), 2.18–2.05 (m, 1H, CH2), 1.80
(m, 2H, CH2), 1.42–1.32 (m, 1H, CH), 1.0 (d, 3H, CH3). 13C NMR
2
(DMSO-d6) d ¼ 162.5 (C55O), 158.2 (C-4, JCF ¼ 31.8), 155.7 (C-8a),
1
120.4 (CF3, JCF ¼ 279.04), 108.9 (C-4a), 29.5 (CH2), 27.8 (CH2), 27.4
(C-6), 20.9 (CH3). MS [m/z (%)] for C10H11F3N2O (232.21) ¼ 232
(Mþ, 100), 217 (87), 163 (16), 69 (22). Anal. calcd. for C10H11F3N2O
(232.21) ¼ C, 51.73; H, 7.77; N, 12.06%. Found: C, 51.96; H, 4.67;
N, 12.15%.5
6-(1,1-Dimethylethyl)-4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H) quinazo-
1
linone (3d). Yellow solid; yield 50%; mp 229–2318C. H NMR (DMSO-d6)
d ¼ 12.5 (s, 1H, H-1), 2.79–2.75 (m, 1H, CH), 2.67–2.63 (m, 2H, CH2),
2.24–2.17 (m, 1H, CH2), 1.95–1.93 (m, 1H, CH2), 1.38–1.29 (m, 2H, CH2),
0.9 (s, 9H, 3CH3). 13C NMR (DMSO-d6) d ¼ 168.5 (C55O), 164.3 (C-4,

3062
H. G. Bonacorso et al.
1
2JCF ¼ 33.2), 161.7 (C-8a), 126.4 (CF3, JCF ¼ 278.3), 115.4 (C-4a), 48.6
(C-6), 37.9 (CH2), 34.6 (Cquat), 32.7 (3CH3), 28.8 (CH2), 27.3 (CH2). MS
[m/z (%)] for C13H17F3N2O (274.29) ¼ 274 (Mþ, 5), 218 (76), 69 (3), 56
(100). Anal. calcd. for C13H17F3N2O (274.29) ¼ C, 56.93; H, 6.25; N,
10.21%. Found: C, 56.64; H, 6.00; N, 10.31%.
4-Trifluoromethyl-cyclopenta[d]-2(1H)pyrimidinone (3e). Brown solid;
1
yield 35%; mp 183–1858C. H NMR (DMSO-d6) d ¼ 12.6 (s, 1H, NH),
2.93–2.86 (m, 4H, CH2), 2.13–2.05 (m, 2H, CH2). 13C NMR (DMSO-d6)
2
d ¼ 176.8 (C55O), 160.4 (C-8a), 152.7 (C-4, JCF ¼ 31.1), 120.6 (CF3,
1JCF ¼ 276.2), 118.2 (C-4a), 32.2 (CH2), 27.04 (CH2), 21.9 (CH2). MS
[m/z (%)] for C8H7F3N2O (204.15) ¼ 204 (Mþ, 83), 107 (100), 135 (55).
Anal. calcd. for C8H7F3N2O (204.15) ¼ C, 47.07; H, 3.46; N, 13.72%.
Found: C, 47.66; H, 4.07; N, 14.58%. (highly hygroscopic compound).
4-Trifluoromethyl-5,6,7,8-tetrahydro-2(1H)thioquinazolinone (4a). Yellow
1
solid; yield 35%; mp 130–1328C. Lit.[5]: yield 34%; mp 1238C. H NMR
(DMSO-d6) d ¼ 14.2 (s, 1H, H-1), 2.8 (m, 2H, CH2), 2.6 (m, 2H, CH2),
1.73–1.72 (m, 4H, CH2). 13C NMR (DMSO-d6) d ¼ 171.9 (C-2), 164.3
2
1
(C-8a), 151.8 (C-4, JCF ¼ 40.97), 125.7 (C-4a), 120.9 (CF3, JCF ¼ 275.5),
32.3 (CH2), 22.9 (CH2), 20.7 (CH2), 18.5 (CH2). MS [m/z (%)] for
C9H9F3N2S (234.24) ¼ 234 (Mþ, 100), 165 (22), 69 (1).
8-Methyl-4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H)thioquinazolinone (4b).
1
Yellow solid; yield 20%; mp 176–1788C. H NMR (DMSO-d6) d ¼ 2.93–
2.89 (m, 2H, CH2), 2.88–2.84 (m, 2H, CH2), 2.01–1.97 (m, 2H, CH2),
1.87–1.85 (m, 2H, CH2), 1.75–1.73 (m, 2H, CH2), 1.54–1.48 (m, 2H,
CH2), 1.40–1.34 (m, 1H, CH), 1.27–1.25 (m, 1H, CH), 1.12 (d, 3H, CH3),
1.02 (d, 3H, CH3). 13C NMR (DMSO-d6) d ¼ 174.9 (C55O), 164.2 (C-8a),
2
1
151.8 (C-4, JCF ¼ 33.2), 124.9 (C-4a), 120.8 (CF3, JCF ¼ 276.9), 35.7
(C-8), 28.8 (CH2), 23.2 (CH2), 19.2 (CH3), 18.9 (CH2). MS [m/z (%)] for
C10H11F13N2S (248.27) ¼ 248 (Mþ, 79), 233 (100), 179 (17), 69 (9). Anal.
calcd. for C10H11F13N2S (248.27) ¼ C, 48.38; H, 4.47; N, 11.28%. Found:
C, 48.63; H, 4.25; N, 11.29%.
6-Methyl-4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H)thioquinazolinone (4c).
1
Yellow solid; yield 18%; mp 167–1698C. H NMR (DMSO-d6) d ¼ 14.3
(s, 1H, H-1), 2.79–2.64 (m, 3H, CH2), 2.19–2.05 (m, 1H, CH2), 1.78
(m, 2H, CH2), 1.45–1.31 (m, 1H, CH), 1.0 (d, 3H, CH3, JHH ¼ 6.0). 13C
NMR (DMSO-d6) d ¼ 171.5 (C55O), 164.3 (C-8a), 153.8 (C-4,
2JCF ¼ 33.2), 120.3, (CF3JCF ¼ 278.3), 114.9 (C-4a), 29.6 (CH2), 27.4
(CH2), 26.9 (CH2), 26.7 (C-6), 20.8 (CH3). MS [m/z (%)] for
C10H11F13N2S (248.27) ¼ 248 (Mþ, 100), 233 (44), 179 (12), 149 (31).
Anal. calcd. for C10H11F13N2S (248.27) ¼ C, 48.38; H, 4.47; N, 11.28%.
Found: C, 48.66; H, 4.28; N, 11.20%.

Synthesis of Quinazolinones and Thioxo Analogs
3063
6-(1,1-Dimethylethyl)-4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H)thioqui-
nazolinone (4d). Yellow solid; yield 25%; mp 126–1288C. 1H NMR (DMSO-
d6) d ¼ 14.2 (s, 1H, H-1), 2.99–2.90 (m, 2H, CH2), 2.54 (m, 1H, CH),
2.06–2.05 (m, 1H, CH2), 1.54–1.38 (m, 2H, CH2), 0.9 (s, 9H, 3CH3). 13C
NMR (DMSO-d6) d ¼ 171.6 (C55O), 163.6 (C-8a), 152.2 (C-4,
1
2JCF ¼ 33.2), 126.4 (C-4a), 121.0 (CF3, JCF ¼ 277.6), 42.5 (C-6), 32.9
(CH2), 31.9 (Cquat), 26.6 (3CH3), 24.4 (CH2), 22.1 (CH2). MS [m/z(%)] for
C13H17F3N2S (290.35) ¼ 290 (Mþ, 49), 234 (61), 69 (3), 56 (100). Anal.
calcd. for C13H17F3N2S (290.35) ¼ C, 53.78; H, 5.90; N, 9.65%. Found: C,
54.14; H, 5.99; N, 10.02%.
4-Trifluoromethyl-cyclopenta[d]-2(1H)thiopyrimidinone (4e). Brown
1
solid; yield 20%; mp 138–1408C. Lit.[5]: yield 16%; mp 130–1318C H
NMR (DMSO-d6) d ¼ 3.07–2.98 (m, 4H, CH2), 2.15–2.11 (m, 2H, CH2).
2
13C NMR (DMSO-d6) d ¼ 181.5 (C-2), 166.3 (C-7a), 148.5 (C-4, J ¼ 36),
1
129.9 (C-4a), 120.6 (CF3, J ¼ 275.5), 33.4 (CH2), 27.4 (CH2), 21.6 (CH2).
MS [m/z (%)] for C8H7F3N2S (220.21) ¼ 220 (Mþ, 100), 201 (8), 151
(46), 69 (17).
ACKNOWLEDGMENTS
´
The authors are thankful to Conselho Nacional de Desenvolvimento Cientıfico
e Tecnologico (CNPq) for financial support. Fellowships from Coordenac¸a˜o
´
´
de Aperfeic¸oamento de Pessoal de Nıvel Superior (CAPES) (to M. R.
Oliveira and M. B. Costa) and Fundac¸a˜o de Apoio a Ciencia e Tecnologia
`
ˆ
(FATEC) (to R. L. Drekener) are also acknowledged.
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