Synthesis of novel thiazolo[2,3-b]quinazolines by cyclization reaction of octahydroquinazoline-2-thiones with α-bromoketones

Article abstract of DOI:10.1515/HC.2011.041

Novel thiazolo[2,3-b]quinazolines were prepared by the cyclization reaction between octahydroquinazoline-2-thiones with α-bromoketones, which provides a readily accessible multifunctionalized quinazoline template for diversity-oriented synthesis. 2011 · Copyright by Walter de Gruyter.

Full text of DOI:10.1515/HC.2011.041

Heterocycl. Commun., Vol. 17(5-6), pp. 181–185, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.041
Synthesis of novel thiazolo[2,3-b]quinazolines by cyclization
reaction of octahydroquinazoline-2-thiones with
α-bromoketones
Zheng-Jun Quan1,2,*, Ying Wei1,2 and
thiazolo[3,2-a]pyrimidine derivatives and the existing meth-
odologies require prolonged reaction times and strict reaction
conditions (Balkan et al., 1992).
Xi-Cun Wang1,2,
*
1 Key Laboratory of Eco-Environment-Related Polymer
Materials, Ministry of Education, China, Gansu 730070,
China
2 Gansu Key Laboratory of Polymer Materials, College of
Chemistry and Chemical Engineering, Northwest Normal
University, Anning East Road 967#, Lanzhou, Gansu
730070, China
Recently, we reported the synthesis of thiazolo[3,2-a]
pyrimidines 1 (Figure 1) by the reaction of 2-thioxo-DHPMs
with α-bromoacetone in aqueous media (Quan et al., 2008).
More recently, these compounds were synthesized by the
one-pot reaction between 2-thioxo-DHPMs, ketone, bromine
and Et3N (Singh et al., 2011). The structure between thiazolo
[3,2-a]pyrimidines 1 and 5H-thiazolo[2,3-b]quinazolin-6-
(7H)-ones 2 is similar (Figure 1), so we speculated that
compound 2 could also be synthesized by the reaction of
2-thioxoquinazolin-6(7H)-one with α-bromoacetone. In
the context of our interest in the synthesis of functionalized
Biginelli compounds (Wang et al., 2006; Quan et al., 2011),
we describe a general and comprehensive strategy for the
preparation of 5H-thiazolo[2,3-b]quinazolines 2 by the direct
cyclization reactions of octahydroquinazoline-2-thiones 3
with α-bromoketones 4 (Scheme 1).
*Corresponding authors
e-mail: quanzhengjun@hotmail.com; wangxicun@nwnu.edu.cn
Abstract
Novel thiazolo[2,3-b]quinazolines were prepared by the cycl-
ization reaction between octahydroquinazoline-2-thiones
with α- bromoketones, which provides a readily accessible
multifunctionalized quinazoline template for diversity-ori-
ented synthesis.
Results and discussion
Keywords: cyclization reaction; octahydroquinazoline-2-
thiones; synthesis; thiazolo[2,3-b]quinazolines.
The reaction of octahydroquinazoline-2-thione 3 (R2=H) with
α-bromoacetone 4 (R1=CH3) was initially attempted using an
aqueous medium but it failed to produce desired product 2
(R1=CH3, R2=H). The reaction was, however, successful when
it was carried out in tetrahydrofuran (THF) under reflux. It
was also found that the one-pot reaction of 2-thioxoquinazo-
lines, acetone and bromine in refluxing THF under base-free
conditions proceeded smoothly to give the 5H-thiazolo[2,3-b]
quinazoline products.
Using optimized conditions, the scope and versatility of this
reaction was explored by conducting the reactions with vari-
ous reactants, as depicted in Scheme 1. Specifically, various
α-bromoketones 4 were allowed to react with 11 substituted
4-aryl-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazo-
line-2-thiones 3.
The structures of 5H-thiazolo[2,3-b]quinazolin-6(7H)-
ones 2a–w produced by these reactions are given in Scheme 1.
Overall, the reaction proceeded smoothly and the products
were isolated and purified by crystallization in high yields
(73–87%). This method was further simplified by reacting
methyl ketones with bromine and using the α-bromoketones
thus generated in situ for the subsequent cyclization
reaction.
Introduction
3,4-Dihydropyrimidinone (DHPM) was first reported in 1893
(Biginelli, 1893). It has gained great therapeutic significance
as a calcium-channel modulator in the treatment of cardiovas-
cular diseases, such as hypertension, cardiac arrhythmias or
angina (Janis et al., 1987). In recent years, interest has focused
on Biginelli-like reactions in which open-chain β-dicarbonyl
compounds have been extended to cyclic β-diketones,
β-ketolactones, β-diamides, cyclic β-diesters and α-keto acids
under a variety of conditions. The heterocycles thus obtained
exhibit antiviral, antitumor, and antihypertensive activities,
and neuropeptide Y (NPY) antagonism (Mokrosz et al., 1989;
Byk et al., 2000; Abelman et al., 2003; Yarim et al., 2003;
Prajapati et al., 2011). Among the synthetic products of the
Biginelli reaction, the octahydroquinazolin-5-one derivatives
are interesting compounds because of their potent antibacte-
rial (Kidwai et al., 2005, 2010) and calcium antagonist activ-
ity (Sarac et al., 1998, 2001; Sabitha et al., 2003).
Otherinterestingderivativesarethiazolo[3,2-a]pyrimidines
1 (Figure 1) due to their calcium channel-blocking activity
(Kappe, 2003). Few methods are known for the preparation of
In addition to high yields, this method benefits from having
a short reaction time and the procedure is straightforward.
Brought to you by | Brown University Rockefeller Library
Authenticated | 128.148.252.35
Download Date | 7/26/13 8:44 PM

182 Z.-J. Quan et al.
32.5 (CH2), 49.8 (CH2), 56.9 (CH), 108.7 (CH), 108.8 (CH), 127.0
(CH), 128.9 (CH), 128.9 (C), 138.7 (C), 139.7 (C), 146.5 (C), 161.2
(C), 193.3 (C); MS: m/z 324 (M+). Anal. Calcd for C19H20N2OS: C,
70.34; H, 6.21; N, 8.63. Found: C, 70.25; H, 6.13; N, 8.69.
R3
O
R2
O
R4
R1
R6
N
N
R5
S
S
N
2
3,8,8-Trimethyl-5-(4-chlorophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2b) White solid; yield
82%; mp 278–279°C; IR: 3111, 3062, 1650, 1599, 1521, 1411
R7
N
1
R1=methyl or aryl, R2=methyl, chloro, nitro
1
cm-1; H NMR (DMSO-d6): δ 0.87 (3H, s), 1.06 (3H, s), 2.12–2.30
(2H, m), 2.17 (3H, s), 2.48–2.59 (2H, m), 6.51 (1H, s), 7.18 (1H, s),
7.38 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz); 13C NMR (DMSO-
d6): δ 12.9 (CH3), 26.4 (CH3), 28.1 (C), 32.5 (CH2), 49.7 (CH2), 56.3
(CH), 108.3 (CH), 109.0 (CH), 126.3 (CH), 128.9 (C), 129.1 (C),
133.4 (C), 138.3 (C), 138.5 (C), 161.1 (C), 193.2 (C); MS: m/z 358
(M+). Anal. Calcd for C19H19ClN2OS: C, 63.59; H, 5.34; N, 7.81.
Found: C, 63.49; H, 5.39; N, 7.90.
Figure 1 Thiazolo[3,2-a]pyrimidines 1 and thiazolo[2,3-b]qui-
nazolines 2.
Experimental section
Commercially-available reagents were used without further purifi-
cation. Solvents were treated prior to use according to the standard
methods. Melting points were determined on an XT-4 electrother-
mal micromelting point apparatus and are uncorrected. Infrared (IR)
spectra were recorded using KBr pellets on a Digilab Merlin Fourier
transform infrared (FT-IR) spectrophotometer. Nuclear magnetic res-
onance (NMR) spectra were recorded at 400 MHz (1H) and 100 MHz
(13C) on a Varian Mercury plus-400 instrument. Electron-impact mass
spectra were obtained on a Bruker Daltonics APEXII 47e Fourier
transform ion cyclotron resonance spectrometer. Elemental analyses
were performed on a Carlo-Erba 1106 elemental analysis instrument.
The octahydroquinazoline-2-thiones were readily prepared accord-
ing to the procedure described by Hassani et al. (2006).
3,8,8-Trimethyl-5-(4-nitrophenyl)-8,9-dihydro-5H-thiazolo
[2,3-b]quinazolin-6(7H)-one (2c) White solid; yield 79%; mp
279–281°C; IR: 3095, 3058, 1648, 1608, 1527, 1412 cm-1; 1H
NMR (DMSO-d6): δ 0.86 (3H, s), 1.07 (3H, s), 2.13–2.31 (2H, m),
2.16 (3H, s), 2.51–2.62 (2H, m), 6.69 (1H, s), 7.21 (1H, s), 7.67
(2H, d, J=8.4 Hz), 8.23 (2H, d, J=8 Hz); 13C NMR (DMSO-d6): δ
12.9 (CH3), 26.6 (CH3), 28.1 (C), 32.6 (CH2), 49.7 (CH2), 56.4 (CH),
107.7 (CH), 109.0 (CH), 124.2 (CH), 128.7 (C), 128.9 (C), 138.3
(C), 146.1 (C), 147.5 (C), 161.8 (C), 193.3 (C); MS: m/z 369 (M+).
Anal. Calcd for C19H19N3O3S: C, 61.77; H, 5.18; N, 11.37. Found:
C, 61.69; H, 5.28; N, 11.30.
3,8,8-Trimethyl-5-(4-methoxyphenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2d) White solid; yield
86%; mp 294–296°C; IR: 3107, 3064, 1668, 1597, 1523, 1416 cm-1;
1H NMR (DMSO-d6): δ 0.89 (3H, s), 1.07 (3H, s), 2.12–2.30 (2H,
m), 2.20 (3H, s), 2.51–2.61 (2H, m), 3.73 (3H, s), 6.42 (1H, s), 6.92
(2H, d, J=8 Hz), 7.18 (1H, s), 7.27 (2H, d, J=8.4 Hz); 13C NMR
(DMSO-d6): δ 12.9 (CH3), 26.5 (CH3), 28.3 (C), 32.5 (CH2), 49.8
(CH2), 55.2 (CH3), 56.5 (CH), 108.7 (CH), 108.9 (CH), 114.2 (CH),
128.5 (C), 132.0 (C), 138.6 (C), 159.4 (C), 161.0 (C), 176.3 (C),
193.3 (C); MS: m/z 354 (M+). Anal. Calcd for C20H22N2O2S: C,
67.77; H, 6.26; N, 7.90. Found: C, 67.68; H, 6.34; N, 7.99.
General synthesis of 5H-thiazolo[2,3-b]quinazolin-
6(7H)-ones 2a–w
Bromine (1 mmol) was added to a stirred sample of a methyl ketone
(1 mmol). After the color of the mixture had faded, a solution of
4-aryl-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazoline-2-
thione 3 (1 mmol) in THF (5 ml) was added and the mixture was
stirred at 65°C for 4 h. Upon completion of the reaction as monitored
by TLC, the mixture was cooled to room temperature. The precipi-
tate was collected, dried and crystallized from ethanol to give pure
product 2.
3,8,8-Trimethyl-5-(3-nitrophenyl)-8,9-dihydro-5H-thiazolo
[2,3-b]quinazolin-6(7H)-one (2e) White solid; yield 81%;
3,8,8-Trimethyl-5-phenyl-8,9-dihydro-5H-thiazolo[2,3-b]
quinazolin-6(7H)-one (2a) White solid; yield 87%; mp 293–
295°C; IR: 3107, 3060, 1648, 1596, 1522, 1410 cm-1; 1H NMR
(DMSO-d6): δ 0.86 (3H, s), 1.06 (3H, s), 2.12–2.30 (2H, m), 2.18
(3H, s), 2.48–2.58 (2H, m), 6.48 (1H, s), 7.16 (1H, s), 7.32–7.40
(5H, m); 13C NMR (DMSO-d6): δ 12.9 (CH3), 26.4 (CH3), 28.2 (C),
1
mp 281–282°C; IR: 3112, 3040, 1647, 1605, 1520, 1445 cm-1; H
NMR (DMSO-d6): δ 0.86 (3H, s), 1.07 (3H, s), 2.12–2.30 (2H, m),
2.15 (3H, s), 2.51–2.62 (2H, m), 6.67 (1H, s), 7.20 (1H, s), 7.57
(1H, t, J=8.4 Hz), 7.74 (1H, d, J=8 Hz), 8.09–8.22 (2H, m); 13C NMR
(DMSO-d6): δ 12.9 (CH3), 26.6 (CH3), 28.2 (C), 32.6 (CH2), 49.7
(CH2), 56.5 (CH), 107.7 (CH), 109.0 (CH), 121.9 (CH), 124.2 (CH),
128.8(C), 128.9(CH), 131.8(C), 138.3(C), 146.1(C), 147.5(C), 161.8
(C), 193.3 (C); MS: m/z 369 (M+). Anal. Calcd for C19H19N3O3S: C,
61.77; H, 5.18; N, 11.37. Found: C, 61.66; H, 5.26; N, 11.31.
R2
R2
O
O
R1
O
-HBr
NH
N
+
Br
3,8,8-Trimethyl-5-(2-methoxyphenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2f) White solid; yield
83%; mp 298–299°C; IR: 3169, 3049, 1646, 1601, 1514, 1440 cm-1;
1H NMR (DMSO-d6): δ 0.86 (3H, s), 1.07 (3H, s), 2.12–2.31 (2H,
m), 2.21 (3H, s), 2.51–2.60 (2H, m), 3.73 (3H, s), 6.40 (1H, s), 6.95
(1H, s), 6.97–7.54 (4H, m); 13C NMR (DMSO-d6): δ 12.9 (CH3),
26.5 (CH3), 28.3 (C), 32.5 (CH2), 49.8 (CH), 55.2 (CH2), 56.6 (CH3),
108.6 (CH), 108.9 (CH), 114.2 (CH), 116.3 (C), 128.5 (CH), 130.0
(CH), 131.9 (C), 138.5 (C), 159.4 (C), 161.0 (C), 176.3 (C), 193.3
R1
THF, 65°C
S
N
H
3
S
N
4
2
R1=Me, Ph, 4-Cl-Ph, 4-Me-Ph; R2=H, 4-Cl, 2-Cl, 4-NO2, 3-NO2,
4-MeO, 2-MeO, 4-Br, 3-Br, 4-Me, 4-OH.
Scheme
1
Synthesis of 5H-thiazolo[2,3-b]quinazolin-6(7H)-
ones (2).
Brought to you by | Brown University Rockefeller Library
Authenticated | 128.148.252.35
Download Date | 7/26/13 8:44 PM

Novel thiazolo[2,3-b]quinazolines 183
(C); MS: m/z 354 (M+). Anal. Calcd for C20H22N2O2S: C, 67.77; H,
6.26; N, 7.90. Found: C, 67.67; H, 6.32; N, 7.97.
8,8-Dimethyl-3,5-diphenyl-8,9-dihydro-5H-thiazolo[2,3-b]qui-
nazolin-6(7H)-one (2l) White solid; yield 82%; mp 287–289°C;
IR: 3117, 3057, 1654, 1587, 1519, 1450 cm-1; 1H NMR (DMSO-d6):
δ 0.91 (3H, s), 1.10 (3H, s), 2.13–2.29 (2H, m), 2.63 (2H, s), 6.33
(1H, s), 6.64 (2H, d, J=8 Hz), 7.10 (2H, t, J=8 Hz), 7.17 (1H, t, J=8
Hz), 7.25 (2H, d, J=8 Hz), 7.47 (2H, t, J=8 Hz), 7.48 (1H, s), 7.58
(1H, t, J=8 Hz); 13C NMR (DMSO-d6): δ 26.7 (CH3), 28.2 (C), 32.6
(CH2), 49.8 (CH2), 57.5 (CH), 108.9 (CH), 111.5 (CH), 126.5 (CH),
127.3 (CH), 128.4 (CH), 128.6 (CH), 128.7 (CH), 129.7 (C), 130.5
(C), 139.1 (C), 140.7 (C), 146.3 (C), 161.2 (C), 193.4 (C); MS: m/z
386 (M+). Anal. Calcd for C24H22N2OS: C, 74.58; H, 5.74; N, 7.25.
Found: C, 74.67; H, 5.84; N, 7.33.
3,8,8-Trimethyl-5-(4-bromophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2g) White solid; yield
77%; mp 284–286°C; IR: 3114, 3054, 1650, 1599, 1519, 1408 cm-1;
1H NMR (DMSO-d6): δ 0.85 (3H, s), 1.06 (3H, s), 2.12–2.31 (2H,
m), 2.18 (3H, s), 2.48–2.59 (2H, m), 6.49 (1H, s), 7.19 (1H, s), 7.38
(2H, d, J=8 Hz), 7.52 (2H, d, J=8 Hz); 13C NMR (DMSO-d6): δ
13.0 (CH3), 26.6 (CH3), 28.1 (C), 32.6 (CH2), 49.7 (CH2), 56.4 (CH),
108.1 (CH), 109.3 (C), 121.8 (CH), 126.1 (C), 130.0 (CH), 131.8
(C), 138.3 (C), 142.1 (C), 161.5 (C), 193.3 (C); MS: m/z 402 (M+).
Anal. Calcd for C19H19BrN2OS: C, 56.58; H, 4.75; N, 6.95. Found:
C, 56.51; H, 4.85; N, 7.04.
8,8-Dimethyl-3-phenyl-5-(4-chlorophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2m) White solid; yield
74%; mp 304–306°C; IR: 3105, 3061, 1653, 1572, 1524, 1446 cm-1;
1H NMR (DMSO-d6): δ 0.90 (3H, s), 1.09 (3H, s), 2.12–2.27 (2H,
m), 2.59 (2H, s), 6.32 (1H, s), 6.66 (2H, d, J=8 Hz), 7.17 (2H, d, J=8
Hz), 7.27 (2H, d, J=8 Hz), 7.46 (1H, s), 7.49 (2H, t, J=8 Hz), 7.58
(1H, t, J=8 Hz); 13C NMR (DMSO-d6): δ 26.7 (CH3), 28.0 (C), 32.5
(CH2), 49.7 (CH2), 56.9 (CH), 108.5 (CH), 111.1 (CH), 127.3 (CH),
128.3 (CH), 128.5 (CH), 128.7 (CH), 129.6 (C), 130.5 (C), 133.1
(C), 138.0 (C), 140.5 (C), 146.3 (C), 161.4 (C), 193.4 (C); MS: m/z
420 (M+). Anal. Calcd for C24H21ClN2OS: C, 68.48; H, 5.03; N, 6.65.
Found: C, 68.41; H, 5.09; N, 6.55.
3,8,8-Trimethyl-5-(4-methylphenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2h) White solid; yield
85%; mp 311–313°C; IR: 3119, 3065, 1652, 1601, 1527, 1416 cm-1;
1H NMR (DMSO-d6): δ 0.86 (3H, s), 1.07 (3H, s), 2.12–2.30 (2H,
m), 2.20 (6H, s), 2.48–2.59 (2H, m), 6.45 (1H, s), 6.88 (2H, d, J=8
Hz), 7.21 (1H, s), 7.25 (2H, d, J=8 Hz); 13C NMR (DMSO-d6): δ
12.9 (CH3), 26.5 (CH3), 28.3 (CH3), 32.5 (C), 49.8 (CH2), 55.1
(CH2), 56.6 (CH), 108.6 (CH), 108.9 (CH), 114.2 (CH), 128.5 (C),
131.9 (C), 138.5 (C), 159.4 (C), 161.0 (C), 176.2 (C), 193.4 (C); MS:
m/z 338 (M+). Anal. Calcd for C20H22N2OS: C, 70.97; H, 6.55; N,
8.28. Found: C, 70.87; H, 6.46; N, 8.36.
8,8-Dimethyl-3-phenyl-5-(2-methoxyphenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2n) White solid; yield
80%; mp 272–274°C; IR: 3116, 3059, 1658, 1583, 1518, 1452
3,8,8-Trimethyl-5-(2-chlorophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2i) White solid; yield
84%; mp 301–302°C; IR: 3105, 3058, 1648, 1593, 1522, 1409 cm-1;
1H NMR (DMSO-d6): δ 0.91 (3H, s), 1.07 (3H, s), 2.10–2.29 (2H,
m), 2.12 (3H, s), 2.50–2.64 (2H, m), 6.78 (1H, s), 7.16 (1H, s), 7.37–
7.69 (4H, m); 13C NMR (DMSO-d6): δ 13.3 (CH3), 26.4 (CH3), 28.3
(C), 32.4 (CH2), 49.8 (CH), 56.8 (CH2), 107.1 (CH), 108.3 (CH),
109.3 (CH), 121.8 (CH), 127.6 (CH), 130.4 (C), 130.9 (C), 132.0
(C), 138.9 (C), 146.5 (C), 161.8 (C), 193.2 (C); MS: m/z 358 (M+).
Anal. Calcd for C19H19ClN2OS: C, 63.59; H, 5.34; N, 7.81. Found:
C, 63.48; H, 5.39; N, 7.90.
1
cm-1; H NMR (CDCl3): δ 0.92 (3H, s), 1.13 (3H, s), 2.13–2.29
(2H, m), 2.73–2.84 (2H, m), 3.76 (3H, s), 6.33 (1H, d, J=8 Hz),
6.35 (1H, s), 6.49 (1H, t, J=8 Hz), 6.76 (1H, d, J=8 Hz), 7.01 (2H,
d, J=8 Hz), 7.13 (1H, d, J=8 Hz), 7.15 (1H, s), 7.36 (2H, t, J=8 Hz),
7.50 (1H, t, J=8 Hz); 13C NMR (CDCl3): δ 26.7 (CH3), 28.0 (C),
32.5 (CH2), 49.7 (CH), 51.4 (CH2), 56.9 (CH3), 108.5 (CH), 109.6
(CH), 111.1 (CH), 127.3 (C), 128.3 (CH), 128.5 (CH), 128.7 (CH),
129.6 (CH), 130.5 (CH), 131.2 (C), 133.1 (C), 138.0 (C), 140.5 (C),
146.3 (C), 161.4 (C), 193.4 (C); MS: m/z 416 (M+). Anal. Calcd
for C25H24N2O2S: C, 72.09; H, 5.81; N, 6.73. Found: C, 72.18; H,
5.89; N, 6.63.
3,8,8-Trimethyl-5-(3-bromophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2j) White solid; yield
79%; mp 287–288°C; IR: 3106, 3055, 1647, 1591, 1524, 1418
8,8-Dimethyl-3-phenyl-5-(4-methylphenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2o) White solid; yield
77%; mp 270–271°C; IR: 3115, 3055, 1653, 1583, 1519, 1450 cm-1;
1H NMR (DMSO-d6): δ 0.91 (3H, s), 1.10 (3H, s), 2.13–2.29 (2H,
m), 2.34 (3H, s), 2.57 (2H, s), 6.25 (1H, s), 6.54 (2H, d, J=8 Hz), 6.64
(2H, d, J=8 Hz), 7.27 (2H, d, J=8 Hz), 7.42 (1H, s), 7.51 (2H, t, J=8
Hz), 7.59 (1H, t, J=8 Hz); 13C NMR (DMSO-d6): δ 26.7 (CH3), 28.2
(CH3), 32.6 (C), 45.3 (CH2), 49.8 (CH2), 56.9 (CH), 109.1 (CH),
111.2 (CH), 113.7 (CH), 127.5 (CH), 128.0 (CH), 128.7 (CH), 129.6
(C), 130.5 (C), 131.3 (C), 140.7 (C), 146.1 (C), 159.2 (C), 161.1
(C), 193.5 (C); MS: m/z 400 (M+). Anal. Calcd for C25H24N2OS: C,
74.97; H, 6.04; N, 6.99. Found: C, 74.88; H, 6.13; N, 6.87.
1
cm-1; H NMR (DMSO-d6): δ 0.88 (3H, s), 1.06 (3H, s), 2.15–2.30
(2H, m), 2.18 (3H, s), 2.56 (2H, s), 6.52 (1H, s), 7.20 (1H, s), 7.30–
7.37 (2H, m), 7.55 (1H, d, J=7.6 Hz), 7.63 (1H, s); 13C NMR (DMSO-
d6): δ 13.0 (CH3), 26.5 (CH3), 28.1 (C), 32.6 (CH2), 49.8 (CH2), 56.4
(CH), 108.1 (CH), 108.9 (C), 121.8 (CH), 124.1 (CH), 126.1 (C),
130.0 (CH), 131.3 (CH), 131.8 (C), 138.3 (C), 142.1 (C), 161.5 (C),
193.3 (C); MS: m/z 402 (M+). Anal. Calcd for C19H19BrN2OS: C,
56.58; H, 4.75; N, 6.95. Found: C, 56.50; H, 4.84; N, 7.04.
3,8,8-Trimethyl-5-(4-hydroxyphenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2k) White solid; yield
80%; mp 310–311°C; IR: 3124, 3068, 1650, 1599, 1527, 1422 cm-1;
1H NMR (DMSO-d6): δ 0.89 (3H, s), 1.07 (3H, s), 2.12–2.30 (2H,
m), 2.22 (3H, s), 2.51–2.63 (2H, m), 6.35 (1H, s), 6.74 (2H, d, J=8.4
Hz), 7.15 (2H, d, J=8.4 Hz), 7.20 (1H, s), 9.70 (1H, s); 13C NMR
(DMSO-d6): δ 12.9 (CH3), 26.5 (CH3), 28.3 (C), 32.5 (CH2), 49.8
(CH2), 56.6 (CH), 108.9 (CH), 109.2 (CH), 115.6 (CH), 128.5 (C),
130.3 (C), 138.6 (C), 145.6 (C), 157.8 (C), 160.6 (C), 193.3 (C); MS:
m/z 340 (M+). Anal. Calcd for C19H20N2O2S: C, 67.03; H, 5.92; N,
8.23. Found: C, 67.10; H, 5.83; N, 8.30.
8,8-Dimethyl-3-phenyl-5-(4-bromophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2p) White solid; yield
75%; mp 282–284°C; IR: 3117, 3056, 1653, 1589, 1523, 1450 cm-1;
1H NMR (DMSO-d6): δ 0.90 (3H, s), 1.09 (3H, s), 2.12–2.27 (2H,
m), 2.59 (2H, s), 6.31 (1H, s), 6.60 (2H, d, J=8 Hz), 7.28 (2H, d, J=8
Hz, 2H), 7.30 (2H, d, J=8 Hz), 7.47 (1H, s), 7.49 (2H, t, J=8 Hz),
7.58 (1H, t, J=8 Hz); 13C NMR (DMSO-d6): δ 26.7 (CH3), 28.0 (C),
32.5 (CH2), 49.6 (CH2), 56.9 (CH), 108.5 (CH), 111.1 (C), 127.2
Brought to you by | Brown University Rockefeller Library
Authenticated | 128.148.252.35
Download Date | 7/26/13 8:44 PM

184 Z.-J. Quan et al.
(CH), 128.3 (CH), 128.5 (CH), 128.7 (CH), 129.6 (C), 130.4 (CH),
133.1 (C), 138.0 (C), 140.5 (C), 146.3 (C), 161.4 (C), 193.4 (C); MS:
m/z 464 (M+). Anal. Calcd for C24H21BrN2OS: C, 61.94; H, 4.55; N,
6.02. Found: C, 61.86; H, 4.49; N, 6.11.
m), 2.55 (2H, s), 6.27 (1H, s), 6.53 (1H, s), 6.82 (1H, d, J=8 Hz), 7.12
(1H, t, J=8 Hz), 7.25 (2H, d, J=8 Hz), 7.37 (1H, d, J=8 Hz), 7.43 (1H,
s), 7.50 (2H, t, J=8 Hz), 7.60 (1H, t, J=8 Hz); 13C NMR (DMSO-d6)
δ 26.7 (CH3), 28.0 (C), 32.5 (CH2), 49.6 (CH2), 56.9 (CH), 108.5
(CH), 109.2 (C), 111.1 (CH), 127.2 (CH), 128.3 (CH), 128.4 (CH),
128.7 (CH), 129.6 (C), 130.4 (CH), 131.3 (CH), 133.1 (C), 138.0
(C), 140.5 (C), 146.3 (C), 161.4 (C), 193.4 (C); MS: m/z 464 (M+).
Anal. Calcd for C24H21BrN2OS: C, 61.94; H, 4.55; N, 6.02. Found:
C, 61.86; H, 4.49; N, 6.11.
8,8-Dimethyl-3-phenyl-5-(4-methoxyphenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2q) White solid; yield
81%; mp 276–277°C; IR: 3119, 3056, 1658, 1589, 1515, 1453 cm-1;
1H NMR (DMSO-d6): δ 0.92 (3H, s), 1.10 (3H, s), 2.11–2.28 (2H,
m), 2.59 (2H, s), 3.64 (3H, s), 6.26 (1H, s), 6.53 (2H, d, J=8 Hz, 2H),
6.64 (2H, d, J=8 Hz), 7.28 (2H, d, J=8 Hz), 7.43 (1H, s), 7.51 (2H, t,
J=8 Hz), 7.59 (1H, t, J=8 Hz); 13C NMR (DMSO-d6) δ 26.7 (CH3),
28.2 (C), 32.6 (CH2), 45.3 (CH2), 49.8 (CH3), 57.0 (CH), 109.1 (CH),
111.2 (CH), 113.7 (CH), 127.4 (CH), 128.0 (CH), 128.7 (CH), 129.6
(C), 130.5 (C), 131.3 (C), 140.7 (C), 146.1 (C), 159.2 (C), 161.0
(C), 193.4 (C); MS: m/z 416 (M+). Anal. Calcd for C25H24N2O2S: C,
72.09; H, 5.81; N, 6.73. Found: C, 72.16; H, 5.90; N, 6.67.
8,8-Dimethyl-3-(4-methylphenyl)-5-phenyl-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2v) White solid; yield
74%; mp 230–232°C; IR: 3113, 3052, 1658, 1584, 1519, 1453 cm-1;
1H NMR (CDCl3): δ 0.94 (3H, s), 1.14 (3H, s), 2.19–2.32 (2H, m),
2.44 (3H, s), 2.83 (2H, s), 6.34 (1H, s), 6.73 (2H, d, J=8 Hz), 6.93
(2H, d, J=8 Hz), 7.07 (1H, d, J=8 Hz), 7.14 (2H, t, J=8 Hz), 7.22
(2H, d, J=8 Hz), 7.27 (1H, s); 13C NMR (CDCl3): δ 26.9 (CH3), 29.1
(CH3), 33.0 (C), 39.0 (CH2), 50.5 (CH2), 58.0 (CH), 109.5 (CH),
111.4 (CH), 123.5 (CH), 126.4 (CH), 128.9 (CH), 129.3 (CH), 129.6
(C), 129.7 (C), 138.4 (C), 141.5 (C), 141.6 (C), 146.2 (C), 160.7
(C), 194.1 (C); MS: m/z 400 (M+). Anal. Calcd for C25H24N2OS: C,
74.97; H, 6.04; N, 6.99. Found: C, 74.87; H, 6.12; N, 6.88.
8,8-Dimethyl-3-phenyl-5-(2-chlorophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2r) White solid; yield
76%; mp 275–276°C; IR: 3120, 3054, 1657, 1589, 1518, 1454 cm-1;
1H NMR (CDCl3): δ 0.99 (3H, s), 1.14 (3H, s), 2.16–2.30 (2H, m),
2.82 (2H, s), 6.55 (1H, s), 6.64 (1H, d, J=8 Hz), 6.82 (1H, t, J=8 Hz),
7.01 (2H, d, J=8 Hz), 7.09 (1H, t, J=8 Hz), 7.14 (1H, s), 7.18 (1H,
d, J=8 Hz), 7.31 (2H, t, J=8 Hz), 7.47 (1H, t, J=8 Hz); 13C NMR
(CDCl3): δ 27.1 (CH3), 28.9 (C), 32.7 (CH2), 50.6 (CH), 59.1 (CH2),
107.2 (CH), 112.2 (CH), 126.3 (CH), 126.9 (CH), 128.9 (CH), 129.5
(CH), 130.1 (CH), 130.4 (CH), 130.7 (C), 132.5 (C), 133.2 (C), 134.3
(C), 141.2 (C), 146.7 (C), 161.4 (C), 194.0 (C); MS: m/z 420 (M+).
Anal. Calcd for C24H21ClN2OS: C, 68.48; H, 5.03; N, 6.65. Found:
C, 68.37; H, 5.12; N, 6.56.
8,8-Dimethyl-3-(4-chlorophenyl)-5-phenyl-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2w) White solid; yield
73%; mp 268–270°C; IR: 3102, 3060, 1654, 1576, 1522, 1446 cm-1;
1H NMR (CDCl3): δ 0.94 (3H, s), 1.15 (3H, s), 2.18–2.35 (2H, m),
2.77 (2H, s), 6.30 (1H, s), 6.75 (2H, d, J=8 Hz), 6.92 (1H, d, J=8 Hz),
7.00 (1H, t, J=8 Hz), 7.05 (1H, d, J=8 Hz), 7.15 (2H, t, J=8 Hz), 7.36
(2H, d, J=8 Hz), 7.48 (1H, s); 13C NMR (CDCl3): δ 29.0 (CH3), 32.9
(C), 38.9 (CH2), 50.3 (CH2), 58.2 (CH), 109.5 (CH), 113.0 (CH),
125.0 (CH), 126.4 (CH), 127.9 (CH), 128.9 (CH), 129.1 (C), 129.2
(C), 131.1 (C), 135.4 (C), 137.2 (C), 145.1 (C), 160.4 (C), 194.0
(C); MS: m/z 420 (M+). Anal. Calcd for C24H21ClN2OS: C, 68.48; H,
5.03; N, 6.65. Found: C, 68.40; H, 5.08; N, 6.57.
8,8-Dimethyl-3-phenyl-5-(4-nitrophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2s) White solid; yield
73%; mp 281–283°C; IR: 3108, 3051, 1656, 1588, 1516, 1448 cm-1;
1H NMR (DMSO-d6): δ 0.88 (3H, s), 1.08 (3H, s), 2.10–2.26 (2H,
m), 2.56 (2H, s), 6.42 (1H, s), 6.95 (2H, d, J=8 Hz), 7.22 (2H, d, J=8
Hz), 7.41 (1H, s), 7.44 (2H, t, J=8 Hz), 7.55 (1H, t, J=8 Hz), 7.95
(2H, d, J=8 Hz); 13C NMR (DMSO-d6): δ 26.8 (CH3), 28.2 (C), 32.5
(CH2), 49.8 (CH2), 56.9 (CH), 107.8 (CH), 109.3 (CH), 123.4 (CH),
127.4 (CH), 128.1 (CH), 128.7 (CH), 129.6 (C), 130.5 (C), 139.1
(C), 140.4 (C), 146.2 (C), 147.0 (C), 161.4 (C), 193.4 (C); MS: m/z
431 (M+). Anal. Calcd for C24H21N3O3S: C, 66.80; H, 4.91; N, 9.74.
Found: C, 66.88; H, 4.83; N, 9.65.
Conclusion
In summary, a method for the synthesis of 5H-thiazolo[2,3-b]
quinazolin-6(7H)-ones from the cyclization of octahydroqui-
nazoline-2-thiones, α-H-ketones, and bromine is described.
In addition to high yields, this method benefits from having
a short reaction time and it is base-free, and the procedure is
straightforward.
8,8-Dimethyl-3-phenyl-5-(3-nitrophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2t) White solid; yield
75%; mp 293–294°C; IR: 3119, 3058, 1650, 1581, 1520, 1445 cm-1;
1H NMR (DMSO-d6): δ 0.91 (3H, s), 1.09 (3H, s), 2.10–2.26 (2H,
m), 2.58 (2H, s), 6.41 (1H, s), 7.19 (1H, s), 7.22 (2H, d, J=8 Hz), 7.31
(1H, d, J=8 Hz), 7.40 (1H, d, J=8 Hz), 7.43 (1H, s), 7.46 (2H, t, J=8
Hz), 7.53 (1H, t, J=8 Hz), 8.02 (1H, d, J=8 Hz); 13C NMR (DMSO-
d6): δ 26.8 (CH3), 28.2 (C), 32.6 (CH2), 49.7 (CH2), 57.1 (CH), 107.8
(CH), 109.8 (CH), 121.7 (CH), 123.3 (CH), 127.6 (CH), 128.6 (CH),
129.6 (CH), 130.3 (C), 130.4 (CH), 133.4 (C), 138.1 (C), 140.4 (C),
141.5 (C), 146.9 (C), 161.4 (C), 193.5 (C); MS: m/z 431 (M+). Anal.
Calcd for C24H21N3O3S: C, 66.80; H, 4.91; N, 9.74. Found: C, 66.91;
H, 4.83; N, 9.63.
Acknowledgments
We are thankful for financial support from the National Nature
Science Foundation of China (No. 20902073 and 21062017), the
Natural Science Foundation of Gansu Province (No. 096RJZA116),
and the Scientific and Technological Innovation Engineering pro-
gram of Northwest Normal University (nwnu-kjcxgc-03-64, nwnu-
lkqn-10-15).
References
8,8-Dimethyl-3-phenyl-5-(3-bromophenyl)-8,9-dihydro-5H-
thiazolo[2,3-b]quinazolin-6(7H)-one (2u) White solid; yield
79%; mp 278–279°C; IR: 3115, 3056, 1655, 1589, 1517, 1450 cm-1;
1H NMR (DMSO-d6): δ 0.92 (3H, s), 1.09 (3H, s), 2.12–2.28 (2H,
Abelman, M. M.; Smith, S. C.; James, D. R. Cyclic ketones and sub-
stituted α-keto acids as alternative substrates for novel Biginelli-
like scaffold synthesis. Tetrahed. Lett. 2003, 44, 4559–4562.
Brought to you by | Brown University Rockefeller Library
Authenticated | 128.148.252.35
Download Date | 7/26/13 8:44 PM

Novel thiazolo[2,3-b]quinazolines 185
Balkan, A.; Uma, S.; Ertan, M.; Wiegrebe, W. Thiazolo[3,2-a]pyrim-
idine derivatives as calcium antagonists. Pharmazie. 1992, 47,
687–688.
Biginelli, P. Aldehyde-urea derivatives of aceto- and oxaloacetic
acids. Gazz. Chim. Ital. 1893, 23, 360–413.
Byk, G.; Gettlieb, H. E.; Herscovici. J.; Mirkin, F. New regioselec-
tive multicomponent reaction: one pot synthesis of spiro hetero-
bicyclic aliphatic rings. J. Comb. Chem. 2000, 2, 732–735.
Hassani, Z.; Islami, M. R.; Kalantari, M. An efficient one-pot syn-
thesis of octahydroquinazolinone derivatives using catalytic
amount of H2SO4 in water. Bioorg. Med. Chem. Lett. 2006, 16,
4479–4482.
reactions of 3,4-dihydropyrimidine-thiones with α-bromoacetone
in aqueous media. Heteroatom Chem. 2008, 19, 149–153.
Quan, Z.-J.; Ren, R.-G.; Jia, X.-D.; Da, Y.-X.; Zhang, Z.; Wang,
X.-C. N-Alkoxymethylation of heterocyclic compounds with
diethyl phosphite via cleavage of P-O bond. Tetrahedron. 2011,
67, 2462–2467.
Sabitha, G.; Reddy, G. S. K. K; Reddy, K. B.; Yadav, J. S.
Vanadium(III) chloride catalyzed Biginelli condensation: solu-
tion phase library generation of dihydropyrimidin-(2H)-ones.
Tetrehedron Lett. 2003, 44, 6497–6499.
Sarac, S.; Yarim, M.; Ertan, M.; Boydag, S.; Erol, K. Synthesis,
chemical and pharmacological properties of some 4-aryl-1,2,3,4,
5,6,7,8-octahydroquinazoline-2,5-diones. Pharmazie. 1998, 53,
91–94.
Janis, R. A.; Silver, P. J.; Triggle, D. J. Drug action and cellular cal-
cium regulation. Adv. Drug Res. 1987, 16, 309–591.
Kappe, C. O. The generation of dihydropyrimidine libraries utilizing
Biginelli multicomponent chemistry. QSAR Comb. Sci. 2003, 22,
630–645.
Kidwai, M.; Saxena, S.; Khalilur Rahman Khan, M.; Thukral, S. S.
Synthesis of 4-aryl-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydroqui-
nazoline-2-one/thione-5-one derivatives and evaluation as anti-
bacterials. Eur. J. Med. Chem. 2005, 40, 816–819.
Kidwai, M.; Bhatnagar, D.; Kumar, R.; Luthra, P. M. Synthesis of 2-oxo/
thioxooctahydroquinazolin-5-one derivatives and their evaluation
as anticancer agents. Chem. Pharm. Bull. 2010, 58, 1320–1323.
Mokrosz, J. L.; Paluchowska, M. H.; Szneler, E.; Drozdz, B. The
effect of aryl substituents in some spiro[2-oxo-4,6-bis(aryl)
hexahydropyrimidine-5,5′-barbituric acids. Arch. Chem
(Weinheim, Germany). 1989, 322, 231–235.
Prajapati, D.; Bhuyan, D.; Gohain, M.; Hu, W. H. Green chemistry
approaches to the regioselective synthesis of spiro heterobicyclic
rings using iodine as a new and efficient catalyst under solvent-
free conditions. Mol Divers. 2011, 15, 257–261.
Sarac, S.; Yarim, M.; Ertan, M.; Kilic, F. S.; Erol, K. 4-Aryl-6,6-
dimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones: syn-
thesis, chromatographic resolution and pharmacological activity.
Pharmazie. 2001, 56, 298–302.
Singh, S.; Schober, A.; Gebinoga, M.; Groß, G. A. Convenient
method for synthesis of thiazolo[3,2-a]pyrimidine derivatives in
a one-pot procedure. Tetrahed. Lett. 2011, 52, 3814–3817.
Wang, X.-C.; Quan, Z.-J.; Wang, J.-K.; Zhang, Z.; Wang, M.-G. A
practical and green approach toward synthesis of N3-substituted
dihydropyrimidinones: using Aza-Michael addition reaction
catalyzed by KF/Al2O3. Bioorg. Med. Chem. Lett. 2006, 16,
4592–4595.
Yarim, M.; Sarac, S.; Kilic, F. S.; Erol, K. Synthesis and in vitro cal-
cium antagonist activity of 4-aryl-7,7-dimethyl/1,7,7-trimethyl-
1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-dione derivatives. Il
Farmaco. 2003, 58, 17–24.
Quan, Z.-J.; Zhang, Z.; Wang, J.-K.; Wang, X.-C.; Liu, Y.-J.; Ji,
P.-Y. Efficient synthesis of 5H-thiazolo[3,2-a]pyrimidines from
Received August 9, 2011; accepted October 23, 2011
Brought to you by | Brown University Rockefeller Library
Authenticated | 128.148.252.35
Download Date | 7/26/13 8:44 PM