Regioselective preparation of 1-(bromomethyl)-5H-thiazolo[3,2- a]quinazolin-5-ones and analogous 5H-thieno[3,2-e]thiazolo[3,2-a]pyrimidin-5- ones from fused 2-(alkenylthio)pyrimidin-4-ones

Article abstract of DOI:10.1055/s-2000-6390

A convenient procedure for the regioselective preparation of polycyclic angular thiazolo[3,2-a]pyrimidin-5-ones is reported. 2- (Alkenylthio)quinazolin-4(3H)-ones and analogues thieno[2,3-d]pyrimidines were treated with bromine in acetic acid to obtain I-

Full text of DOI:10.1055/s-2000-6390

714
PAPER
Regioselective Preparation of 1-(Bromomethyl)-5H-thiazolo[3,2-a]quinazolin-
5-ones and Analogous 5H-Thieno[3,2-e]thiazolo[3,2-a]pyrimidin-5-ones from
Fused 2-(Alkenylthio)pyrimidin-4-ones
Petra Wippich, Michael Gütschow,* Siegfried Leistner
Institut für Pharmazie -Pharmazeutische Chemie- der Universität Leipzig, Brüderstr.34, D-04103 Leipzig, Germany
Fax +49(341)0736749; E-mail: guetscho@uni-leipzig.de
Received 8 November 1999; revised 14 January 2000
Abstract: A convenient procedure for the regioselective prepara-
tion of polycyclic angular thiazolo[3,2-a]pyrimidin-5-ones is re-
ported. 2-(Alkenylthio)quinazolin-4(3H)-ones and analogues
thieno[2,3-d]pyrimidines were treated with bromine in acetic acid
to obtain 1-(bromomethyl)-5H-thiazolo[3,2-a]quinazolin-5-ones
8a,d, and 1-(bromomethyl)-5H-thieno[3,2-e]thiazolo[3,2-a]pyrim-
idin-5-ones 8b,c,e,f, respectively. A route starting from 2-(alkeny-
lamino)benzamides, which were converted to corresponding
2-thioxoquinazolin-4-ones and subsequently treated with bromine
in acetic acid furnished angular 2-(bromomethyl)thiazolo[3,2-
a]quinazolin-5-ones 11, or 3-(bromomethyl)[1,3]thiazino[3,2-
a]quinazolin-6-one 14, respectively.
Key words: polycyclic pyrimidinones, thiazolo[3,2-a]quinazolin-
5-ones, thieno[3,2-e]thiazolo[3,2-a]pyrimidin-5-ones; bromocy-
clization, 2-(alkenylthio)pyrimidin-4-ones, heterocycles
Bicyclic
and
tricyclic
thiazolo(1,3-thiazino)-
pyrimidinones1 have been found to exhibit various biolog-
ical activities2 and are useful intermediates for the prepa-
ration
of
immunostimulating
mercaptoalkyl
pyrimidinediones,6,7 or heterocyclic substituted alkyl di-
sulfides.8 Recently, the anti-HIV-1 activity of 2,3-dihy-
dro-7H-thiazolo[3,2-a]pyrimidin-7-ones has been de-
scribed.5 In a previous paper,3 we have reported on the
regioselective cyclization of 2-allylthioquinazolinones
(and thieno[2,3-d]pyrimidinones) 1 to 2,3-dihydro-3-me-
thyl-5H-thiazolo[2,3-b]quinazolinones 2 and analogous
thienopyrimidinones 3 (Scheme 1). These linear thiazolo
compounds were obtained exclusively by an acid-cata-
lyzed reaction on treating allyl derivatives 1 with concen-
trated sulfuric acid. Linear 4-methyl-[1,3]thiazino[2,3-
b]quinazolinones 4 and analogous thienopyrimidinones 5
were prepared from the corresponding 2-trans-crotyl de-
rivatives 1. Herein, we wish to report on the cyclization of
Scheme 1
9a-c, 12 with thiophosgene, or potassium ethyl xanthoge-
nate were not successful. However, the introduction of the
C=S unit was achieved on treatment with benzoyl isothio-
cyanate to furnish 10a-c, 13 in moderate yields (Table 1).
The alkenyl derivatives 7, 10, and 13 were reacted with
bromine in acetic acid. This procedure turned out to be a
convenient access to polycyclic bromomethyl substituted
thiazolo- or 1,3-thiazinopyrimidinones. In most of the
transformations, the products were either formed without
remarkable impurities, or the main products could be iso-
lated in sufficient yields without column chromatography.
The structural assignment of the products 8, 11, 14 was
based on elemental analyses, MS, UV, and NMR data. As
expected, upon treatment with bromine, bromocyclization
occured to result in a loss of the double bond and the con-
densation of an additional bromo-, or bromoalkyl substi-
tuted ring.
2-alkenylthio
substituted
quinazolin-4-ones
and
thieno[2,3-d]pyrimidin-4-ones upon treatment with bro-
mine.
The required alkenylthio derivatives 7a-f were conve-
niently obtained on reacting the corresponding 2-thioxo
derivatives 6 with alkenyl halides (Scheme 2). Their tau-
tomeric form such as 3H-pyrimidin-4-ones was conclud-
ed from UV and NMR data.9 In addition to the starting
compounds 7, 1-alkenyl-2-thioxoquinazolin-4-ones 10a-
c and 13 were considered to be used as substrates for cy-
clization reactions with bromine. Attempts to obtain these
compounds by reacting 2-(alkenylamino)benzamides
For example, in the transformation of 7a or 7d, four pos-
sible isomeric products, with a linear or angular, as well
as five-membered or six-membered ring had to be consid-
ered. However, treatment of 7a or 7d with bromine result-
Synthesis 2000, No. 5, 714–720 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselektive Preparation of 1-(Bromomethyl)-5H-thiazolo[3,2-a]quinazolin-5-ones
715
Scheme 2
ed in the regioselective formation of the angular thiazolo field signal in the range of 115-117 ppm was attributed to
compounds 8a, 8d, respectively, whose structural elucida- C-9, whereas in linear thiazolo or 1,3-thiazinoquinazoli-
tion was achieved as follows. The UV spectra of the prod- nones 2, 4 all of the aromatic CH carbon resonances were
ucts showed three maxima at l = 231-232, 256, and l = observed at higher field.3 The angular thiazolo structures
307 nm (Table 1). Maxima were consistent (Table 2) with 8a, 8d could be confirmed by 1H nuclear Overhauser ef-
the data of the fused quinazolinones 11a-c and 14, which fect (Figure). In particular, in the case of 8a, on irradiation
are necessarily angular products. On the other hand, linear of the 9-H resonance a NOE in 1-H was observed. In the
thiazolo(or 1,3-thiazino) quinazolinones 2, 4 exhibit dif- case of 8d, irradiation of the methyl resonance resulted in
ferent UV maxima. Examples are outlined in Table 2. In NOEs in 9-H as well as 2-HA, the diastereotopic proton
particular, the absorbance between l = 275-284 nm indi- situated at the same face as the methyl group.
cates the linear type, and the absence of a maximum in this
range the angular isomer. Significant differences of the
13C NMR signals could also be used to distinguish angular
from linear regioisomers. The characteristic features of
the angular compounds are the NMR shifts of C-9a car-
bons at lower field, as well as the C-3a and C-5 signals at
higher field, compared to the linear thiazolo- or 1,3-thiaz-
inoquinazolinones 2, 4 (Table 2).10 The angular structure
of 8a and 8d could by concluded from their magnetic
shifts. 13C NMR signals of the aromatic CH carbons were
assigned on the basis of 13C/1H correlation experiments.
Thus, in angular compounds 8a,d, 11a-c, 14, the low
Figure Relevant NOE enhancements of 8a and 8d. Compound 8d
is shown as a single enantiomer
Synthesis 2000, No. 5, 714–720 ISSN 0039-7881 © Thieme Stuttgart · New York

716
P. Wippich et al.
PAPER
Table 1 Compounds 7-14 Prepared
Prod- Yield mp (°C)
IR (KBr) MS
UV (EtOH) 1H NMR (DMSO-d6/TMS)
max (nm)
(log e)
13C NMR (DMSO-d6/TMS)
d
uct
(%)
(solvent)
n
c=o (cm−1) (70 eV)
l
d, J (Hz)
m/z (%)
7d
91
168-170 1668
(EtOH)
232 (M+, 51)
230 (4.48),
275 (4.23),
315 (3.82)
1.86 (s, 3 H, CH3), 3.99 (s, 2 H, 21.10 (CH3), 36.18 (SCH2),
SCH2), 4.90 (s, 1 H, C=CH2), 114.54 (C=CH2), 119.96 (C-4a),
5.09 (s, 1 H, C=CH2), 7.37-8.11 125.52, 125.77, 125.96 (C-5, C-6,
(m, 4 Harom), 12.55 (s, 1 H, NH) C-8), 134.55 (C-7), 140.29
(C=CH2), 148.25 (C-8a), 155.12
(C-2), 161.17 (C-4)
7e
7f
89
92
230-232 1650
266 (M+, 100) 274 (3.80),
318 (4.04)
1.79 (s, 3 H, CH3), 2.31 and 2.33 12.38, 12.70 (5-CH3, 6-CH3),
(2 s, 2 × 3 H, 5-CH3 and 6-CH3), 21.12 (CH3), 36.39 (SCH2),
3.84 (s, 2 H, SCH2), 4.88 (s, 1 H, 114.65 (C=CH2), 119.87 (C-4a),
(EtOH)
C=CH2), 5.03 (s, 1 H, C=CH2),
12.54 (s, 1 H, NH)
127.39, 128.43 (C-5, C-6), 140.06
(C=CH2), 154.90, 158.30 (C-2,
C-7a), 161.67 (C-4)
214-216 1660
(EtOH)
292 (M+, 100) 274 (3.80,
320 (4.08)
1.68-1.74 (m, 4 H, CH2), 1.78 (s, 21.11 (CH3), 21.71, 22.47 (C-6,
3 H, CH3), 2.65-2.85 (m, 4 H, C-7), 24.28, 25.15 (C-5, C-8),
CH2), 3.85 (s, 2 H, SCH2), 4.88 (s, 36.42 (SCH2), 114.65 (C=CH2),
1 H, C=CH2), 5.02 (s, 1 H,
C=CH2), 12.55 (s, 1 H, NH)
119.05 (C-4a), 130.36, 130.56
(C-4b, C-8a), 140.07 (C=CH2),
154.70, 158.07 (C-2, C-9a),
162.44 (C-4)
8a
74
178-183 1706
(EtOH)
298, 296 (M+, 231 (4.11),
16), 203 (M+ - 256 (4.15),
CH2Br, 56), 80, 307 (3.60)
82 (100)
3.66 (d, 1 H, J = 12.1, CH2), 3.83 31.21, 31.61 (CH2Br, C-2), 61.92
(dd, 1 H, J = 11.3, 2.6, CH2), (C-1), 116.45 (C-9), 117.63 (C-
3.91-4.09 (m, 2 H, CH2), 5.78- 5a), 126.38 (C-7), 127.96 (C-6),
5.86 (m, 1 H, CH), 7.51-7.58 (m, 135.04 (C-8), 137.64 (C-9a),
1 H, H-7), 7.60-7.63 (m, 1 H, H- 163.82, 168.61 (C-3a, C-5)
9), 7.85-7.92 (m, 1 H, H-8),
8.08-8.11 (m, 1 H, H-6)
8b
8c
52
38
190-192 1636
332, 330 (M+, 237 (4.30),
33), 250 (M+ - 293 (4.01)
HBr, 100)
2.34 (s, 6 H, CH3), 3.50 (dd, 1 H, 12.08, 12.67 (6-CH3, 7-CH3),
(MeOH)
J = 12.0, 1.9, CH2), 3.84-4.05
30.62, 32.00 (CH2Br, C-2), 63.49
(m, 3 H, CH2), 5.24-5.32 (m, 1 H, (C-1), 119.24 (C-5a), 125.11,
CH)
130.18 (C-6, C-7), 145.84 (C-8a),
163.76, 164.30 (C-3a, C-5)
178-180 1632
(MeCN)
358, 356 (M+, 237 (4.33),
9), 276 (M+ - 296 (4.07)
HBr, 100)
1.62-1.83 (m, 4 H, CH2), 2.66- 21.57, 22.47 (C-7, C-8), 24.05,
2.88 (m, 4 H, CH2), 3.50 (dd, 1 H, 25.25 (C-6, C-9), 30.60, 32.06
J = 11.8, 1.9, CH2), 3.84-4.04
(CH2Br, C-2), 63.52 (C-1),
(m, 3 H, CH2), 5.22-5.30 (m, 1 H, 118.54 (C-5a), 128.19, 132.24
CH)
(C-5b, C-9a), 146.40 (C-10a),
163.91, 164.16 (C-3a, C-5)
8d
86
259 (dec.) 1702
(EtOH)
312, 310 (M+, 232 (4.21),
1.99 (s, 3 H, CH3), 3.56 (d, 1 H, 23.48 (CH3), 38.38, 38.79
28), 231 (M+ - 256 (4.22),
JAB = 12.2, 2-HA), 3.74 (d, 1 H, (CH2Br, C-2), 74.51 (C-1),
Br, 29), 217
(M+ - CH2Br,
100)
307 (3.65)
JAB = 12.2, 2-HB), 4.17 (d, 1 H,
116.07 (C-9), 118.29 (C-5a),
JAB = 11.8, CHHBBr), 4.62 (d, 1 126.90 (C-7), 128.52 (C-6),
H, JAB = 11.8, CHAHBr), 7.48- 135.19 (C-8), 137.66 (C-9a),
7.54 (m , 1 H, H-7), 7.73-7.80
(m, 1 H, H-8), 7.94-7.98 (m, 1 H,
H-9), 8.10-8.14 (m, 1 H, H-6)
161.96, 169.22 (C-3a, C-5)
8e
68
146-148 1644
(MeOH/
H2O)
346, 344 (M+, 236 (4.31),
19), 265 (M+ - 293 (3.97)
Br, 34), 80, 82
1.85 (s, 3 H, 1-CH3), 2.34 (s, 6 H, 11.83, 12.65 (6-CH3, 7-CH3),
6-CH3, 7-CH3), 3.55 (d, 1 H, J = 21.94 (1-CH3), 36.16, 37.32
12.1, CH2), 3.72 (d, 1 H, J = 12.1, (CH2Br, C-2), 72.49 (C-1),
CH2), 4.11 (d, 1 H, J = 12.1, CH2), 120.18 (C-5a), 124.82, 129.62
(100)
4.24 (d, 1 H, J = 12.1, CH2)
(C-6, C-7), 144.38 (C-8a),
163.57, 163.97 (C-3a, C-5)
Synthesis 2000, No. 5, 714–720 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselektive Preparation of 1-(Bromomethyl)-5H-thiazolo[3,2-a]quinazolin-5-ones
717
Table 1 (continued)
Prod- Yield mp (°C)
IR (KBr) MS
UV (EtOH) 1H NMR (DMSO-d6/TMS)
max (nm)
(log e)
13C NMR (DMSO-d6/TMS)
d
uct
(%)
(solvent)
n
c=o (cm−1) (70 eV)
l
d, J (Hz)
m/z (%)
8f
42
187-189 1638
(MeCN)
372, 370 (M+, 237 (4.26),
41), 291 (M+ - 296 (4.00)
Br, 100)
1.63-1.85 (m, 4 H, CH2), 1.84 (s, 21.59, 22.37 (C-7, C-8), 21.91
3 H, CH3), 2.64-2.84 (m, 4 H, (CH3), 23.73, 25.18 (C-6, C-9),
CH2), 3.53 (d, 1 H, J = 12.0, CH2), 35.99, 37.39 (CH2Br, C-2), 72.29
3.71 (d, 1 H, J = 12.0, CH2), 4.10 (C-1), 119.44 (C-5a), 127.65,
(d, 1 H, J = 12.1, CH2), 4.24 (d, 1 131.64 (C-5b, C-9a), 144.94 (C-
H, J = 12.1, CH2)
10a), 163.77, 164.05 (C-3a, C-5)
9a
9b
79
87
88-92
(EtOH/
H2O)
1642
1622
-
-
-
3.78-3.84 (m, 2 H, NHCH2),
5.12-5.29 (m, 2 H, CH=CH2),
5.85-6.05 (m, 1 H, CH), 6.51- (C-1), 115.58 (CH=CH2), 132.77
7.65 (m, 5Harom and CONH2), (CH=CH2), 135.89 (C-4), 149.91
7.86 (br s, 1 H, CONH2), 8.31 (t, (C-2), 171.96 (CONH2)
1 H, J = 7.3 , NH)
44.82 (NHCH2), 111.68, 114.37,
129.30 (C-3, C-5, C-6), 114.27
130
(EtOH/
H2O)
190 (M+, 50),
132 (100)
1.71 (s, 3 H, CH3), 3.69 (d, 2 H, J 20.13 (CH3), 47.93 (NHCH2),
= 5.8, NHCH2), 4.82 (s, 1 H,
C=CH2), 4.86 (s, 1 H, C=CH2),
109.99 (C=CH2), 113.82 (C-1),
111.45, 113.98, 128.98 (C-3, C-5,
6.51-7.63 (m, 4 Harom), 7.14 (s, 1 C-6), 132.39 (C-4), 142.50
H, CONH2), 7.84 (s, 1 H,
CONH2), 8.39 (t, 1 H, J = 5.8,
NH)
(C=CH2), 149.80 (C-2), 171.67
(CONH2)
9c
83
118-121 1666
(EtOH/
H2O)
190 (M+, 88),
77 (100)
-
-
-
-
1.66 (d, 3 H, J = 11.6, CH3),
3.69-3.73 (m, 2 H, NHCH2),
5.59-5.66 (m, 2 H, CH=CH),
17.77 (CH3), 44.22 (NHCH2),
111.55, 114.10, 128.91 (C-3, C-5,
C-6), 114.06 (C-1), 132.69 (C-4),
6.49-7.64 (m, 4 Harom), 7.14 (s, 1 126.62 (CH=CH), 129.18
H, CONH2), 7.81 (s, 1 H,
CONH2), 8.18 (br s, 1 H, NH)
(CH=CH), 149.90 (C-2), 171.93
(CONH2)
10a 49
10b 53
10c 47
179-180 1692
(EtOH)
218 (M+, 27),
203 (100)
5.09-5.23 (m, 2 H, CH=CH2),
50.39 (NCH2), 116.79, 124.56,
5.33-5.40 (m, 2 H, NCH2), 5.86- 127.30 (C-5, C-6, C-8), 135.46
6.00 (m, 1 H, CH=CH2), 7.37-
(C-7), 117.12 (CH=CH2), 117.94
8.07 (m, 4 Harom), 12.71 (s, 1 H, (C-4a), 131.18 (CH=CH2),
NH)
140.60 (C-8a), 158.24 (C-4),
175.84 (C-2)
181-182 1682
(EtOH)
232 (M+, 31),
217 (100)
1.80 (s, 3 H, CH3), 4.46 (s, 1 H, 19.86 (CH3), 53.20 (NCH2),
C=CH2), 4.86 (s, 1 H, C=CH2), 110.36 (C=CH2), 116.90, 124.58,
5.11-5.18 (m, 2H, NCH2), 7.33- 127.18 (C-5, C-6, C-8), 117.70
8.07 (m, 4 Harom), 12.72 (s, 1 H, (C-4a), 135.43 (C-7), 138.08
NH)
(C=CH2), 140.77 (C-8a), 158.22
(C-4), 176.13 (C-2)
199-202 1684
(EtOH)
232 (M+, 25),
203 (100)
1.63 (dd, 3 H, J = 6.9, 1.1, CH3), 17.51 (CH3), 49.69 (NCH2),
5.23-5.33 (m, 2 H, NCH2), 5.50- 116.71, 124.53, 127.32 (C-5, C-6,
5.62 (m, 1 H, CH=CHCH3),
C-8), 117.98 (C-4a), 123.87,
5.67-5.78 (m, 1 H, CH=CHCH3), 128.75 (CH=CHCH3,
7.35-8.07 (m, 4 Harom), 12.67 (s, CH=CHCH3), 135.51 (C-7),
1 H, NH)
140.62 (C-8a), 158.21 (C-4),
175.60 (C-2)
11a 62
241 (dec.) 1700
(MeOH)
298, 296 (M+, 237 (4.14),
5), 216 (M+ - 252 (4.22),
HBr, 38), 80, 82 309 (3.67)
(100)
3.98 (d, 2 H, J = 5.9, CH2Br),
35.57 (CH2Br), 45.26 (C-2),
4.70-4.80 (m, 1 H, CH), 4.80- 55.05 (C-1), 117.28 (C-9), 117.72
4.82 (m, 2 H, NCH2), 7.62-8.13 (C-5a), 127.22, 127.63 (C-6, C-
(m, 4 Harom
)
7), 135.85 (C-8), 138.40 (C-9a),
161.15, 166.63 (C-3a, C-5)
11b 69
223-226 1720
(MeOH)
312, 310 (M+, 236 (4.28),
1.82 (s, 3 H, CH3), 4.11 (d, 1 H, J 24.69 (CH3), 41.66 (CH2Br),
= 7.7, CH2Br), 4.17 (d, 1 H, J = 54.31 (C-1), 59.50 (C-2), 116.47
65), 231 (M+ - 252 (4.30),
Br, 55), 230
310 (3.77)
7.7, CH2Br), 4.54 (d, 1 H, J =
11.8, NCH2), 4.78 (d, 1H , J =
11.8, NCH2), 7.55-8.11 (m, 4
(C-9), 117.79 (C-5a), 126.24,
127.59 (C-6, C-7), 134.83 (C-8),
138.96 (C-9a), 164.06, 166.84
(C-3a, C-5)
(M+ - HBr, 62),
80, 82 (100)
Harom
)
Synthesis 2000, No. 5, 714–720 ISSN 0039-7881 © Thieme Stuttgart · New York

718
P. Wippich et al.
PAPER
Table 1 (continued)
Prod- Yield mp (°C)
IR (KBr) MS
UV (EtOH) 1H NMR (DMSO-d6/TMS)
max (nm)
(log e)
13C NMR (DMSO-d6/TMS)
d
uct
(%)
(solvent)
n
c=o (cm−1) (70 eV)
l
d, J (Hz)
m/z (%)
11c 61
290 (dec.) 1698
(EtOH)
312, 310 (M+, 237 (4.57),
7), 230 (M+ - 252 (4.34),
HBr, 23), 80, 82 309 (3.77)
(100)
1.78 (d, 3 H, J = 6.3, CH3), 4.76- 22.87 (CH3), 50.54 (C-2), 52.90
4.91 (m, 4 H, NCH2 and (CHBr), 54.50 (C-1), 117.23 (C-
NCH2CHCHBr), 7.60-8.14 (m, 4 9), 117.64 (C-5a), 127.20, 127.67
Harom
)
(C-6, C-7), 135.76 (C-8), 138.15
(C-9a), 161.44, 166.58 (C-3a, C-
5)
12
13
14
76
39
86
114-115 1622
190 (M+, 15),
132 (100)
-
2.25-2.40 (m. 2 H, NHCH2CH2), 33.01 (NHCH2CH2), 41.52
(EtOH)
3.09-3.23 (m, 2 H, NHCH2),
5.04-5.17 (m, 2 H, CH=CH2),
5.55-5.95 (m, 1 H, CH=CH2)
(NHCH2), 110.98, 113.78, 129.01
(C-3, C-5, C-6), 113.83 (C-1),
116.72 (CH=CH2), 132.56
6.49-7.61 (m, 4 Harom), 7.09 (s, 1 (CH=CH2), 135.99 (C-4), 149.66
H, CONH2), 7.77 (s, 1 H,
CONH2), 8.13 (t, 1 H, NH)
(C-2), 171.56 (CONH2)
184-185 1682
(EtOH)
232 (M+, 25),
203 (74), 120
(100)
-
2.43-2.53 (m, 2 H, NCH2CH2),
30.25 (NCH2CH2), 47.22
4.60-4.82 (m, 2 H, NCH2), 5.04- (NCH2), 116.18, 124.49, 127.44
5.20 (m, 2 H, CH=CH2), 5.86-
6.00 (m, 1 H, CH=CH2), 7.36-
(C-5, C-6, C-8), 117.32
(CH=CH2), 117.93 (C-4a),
8.20 (m, 4 Harom), 12.63 (s, 1 H, 134.23 (CH=CH2), 135.68 (C-7),
NH)
140.42 (C-8a), 158.11 (C-4),
175.35 (C-2)
205
1696
312, 310 (M+, 230 (4.34),
2.25-2.40 (m, 1 H), 2.45-2.61
(m, 2 H), 3.84-3.98 (m, 2H),
4.21-4.38 (m, 2 H), 7.46-8.06
26.57 (C-2), 35.23 (CH2Br),
41.43 (C-3), 43.31 (C-1), 114.89
(C-10), 119.59 (C-6a), 125.66,
127.22 (C-7, C-8), 133.48 (C-9),
141.67 (C-10a), 161.68, 164.88
(C-4a, C-6)
(MeOH)
28), 230 (M+ - 256 (4.48),
HBr, 100)
301 (4.09)
(m, 4 Harom
)
Table 2 Characteristic 13C NMR Chemical Shiftsa and UV Data of Angular and Linearb,c,d Thiazolo(1,3-thiazino)quinazolinones and
Thienopyrimidinones
Spectra Recorded
13C NMR
C-9a
137.6-141.7 C-9a
146.9-148.5
153.6-159.5
159.2-160.5
C-8a
144.4-146.4 C-9a, C-8a
154.1-160.0
160.1-162.6
(DMSO-d6/TMS) d
C-3a, C-5 161.2-169.2 C-10a
C-3a, C-5 163.8-164.3 C-5
C-5
UV (EtOH)
230-237,
252-256,
301-310
235-237,
236-237,
293-296
276-281,
320-331
lmax (nm)
275-284,
312-326e
a Atomic numbering refers to tricyclic thiazolo compounds.
b Data3,14 of the following compounds 2, 4 were considered; 2a: n = 1, R1 = R2 = H; 2b: n = 1, R1 = Me, R2 = H; 2c: n = 1, R1 = Et, R2 = H; 4a:
n = 2, R1 = R2 = H; 4b: n = 2, R1 = Me, R2 = H.
c Data3,19 of the following compounds 3, 5 were considered; 3a: n = 1, R1 = H, R2R2 = (CH2)4; 3b: n =1, R1 = R2 = Me; 3c: n = 1, R1 = Me, R2R2
= (CH2)4; 5a: n = 2, R1 = H, R2 = Me; 5b: n = 2, R1 = H, R2R2 = (CH2)4; 5c: n = 2, R1 = R2 = Me; 5d: n = 2, R1 = Me, R2R2 = (CH2)4.
d The complete 13C NMR data unless already published are given in the text.
e In some compounds as shoulder.
Synthesis 2000, No. 5, 714–720 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselektive Preparation of 1-(Bromomethyl)-5H-thiazolo[3,2-a]quinazolin-5-ones
719
Similar results on bromination-cyclization reactions of In summary, a convenient bromination-cyclization reac-
monocyclic 2-(allylthio)pyrimidin-4-ones have been pub- tion of various alkenyl substituted substrates was found to
lished recently by Danel et al.5 Prior to the addition of bro- result in a regioselective cyclization to bromomethyl sub-
mine, the substrates were treated with N,O- stituted 5H-thiazolo[3,2-a]quinazolin-5-ones and analo-
bis(trimethylsilyl)acetamide. After column chromato- gous 5H-thieno[3,2-e]thiazolo[3,2-a]pyrimidin-5-ones.
graphic purification, corresponding N-1 cyclized These methodologies allows one a ready access to such
3-(bromomethyl)thiazolo[3,2-a]pyrimidin-7-ones were heterocycles which may find applications as bioactive
obtained in moderate yields. In the present quinazolinone compounds as well as useful intermediates for further
series, regioselective cyclization was achieved without si- transformations.
lylation to form the tricyclic products 8a and 8d in 74%
and 86% yields, respectively. Chromatographic purifica-
Melting points were determined on a Boetius apparatus and are not
tion was not nessecary.
corrected. IR spectra were measured with a Perkin Elmer 16 PC
Regioselective cyclization to angular, 5-membered rings FTIR spectrometer. Mass spectra (70 eV) were obtained using a
Varian MAT CH6 spectrometer. UV spectra were recorded on a
was also achieved with 2-(alkenylthio)thieno[2,3-d]pyri-
midin-4-ones 7b,c,e,f as substrates. The corresponding
products 8 were obtained only in moderate yields, since
the main products had to be purified by fractional crystal-
Shimadzu UV-VIS spectrophotometer UV-160A. 1H NMR spectra
(300 MHz) and 13C NMR spectra (75 MHz) were recorded on a
Varian Gemini 300. TLC was performed on Merck aluminum
sheets, silica gel 60 F254. Satisfactory elemental analyses were ob-
lization. Again, structural elucidation of the thiophene de-
rived products was based on characteristic features to
distinguish angular from linear structures (Table 2). Com-
parison of the UV and 13C NMR data of 8b,c,e,f with
those of the linear reference compounds 3, 5 unequivocal-
ly indicated their angular structure.
tained for all new compounds: C ± 0.36, H ± 0.38, N ± 0.41.
Compounds 615-17 and 7a-c3 were synthesized as reported. 2-Meth-
allylthio derivatives 7d-f (Table 1) were prepared from the corre-
sponding 2-thioxo derivative 6 and 3-chloro-2-methylpropene
according to a reported procedure.3 Angular thiazolo(1,3-thiazino)
quinazolinones 2, 43,15,18 and thienopyrimidinones 3, 53,19 (Table 2)
were prepared as reported.
Angular anellation was structurally forced in the route to
the tricyclic compounds 11 and 14. The final bromocy-
clization was found to be selective with respect to the for-
mation of the five-membered (11) or six-membered (14)
regioisomers, which were obtained in 61-86% yields.
Some unpublished spectral data of 2-5 are given below:
2,3-Dihydro-5H-thiazolo[2,3-b]quinazolin-5-one (2a)
13C NMR (DMSO-d6): d = 26.04 (C-2), 48.32 (C-3), 118.72 (C-5a),
125.62, 125.94 (C-6, 7, 9), 134.46 (C-8), 148.54 (C-9a), 159.51
(C-10a), 160.27 (C-5).
Whereas 2-alkenylthio derivatives were found to undergo
a regioselective cyclization3 to the corresponding linear
products 2-5 upon treatment with concentrated sulfuric
2,3,6,7,8,9-Hexahydro-5H-[1]benzothieno[2,3-d]thiazolo[3,2-
a]pyrimidin-5-one (3a)
13C NMR (DMSO-d6): d = 21.70, 22.44, 24.35, 25.13 (CH2), 26.70
acid (Scheme 1), in the present transformation (Scheme 2) (C-2), 48.17 (C-3), 118.08 (C-5a), 130.34, 130.75 (C-5b, 9a),
156.39, 160.00 (C-11a, 10a), 162.62 (C-5).
angular products were formed. Likely, this difference is
attributed to protonation of the N-1 in the former case,
leading to an intramolecular alkylation of the lactam nitro-
gen. In the present conversion, intramolecular alkylation
of the more nucleophilic, non-protonated N-1 atom pro-
vided cyclization to the final products. Their structures are
in accordance with the tendency for preferential formation
of a five-membered (compared to six-membered) ring (8,
11), as well as the favoured formation of a six-membered
(compared to seven-membered) ring (14). Probably, the
ring-closure to 8, 11, 14 involves direct nucleophilic at-
tack of the N-1 or S atom at an intermediate carbocation12
or bromonium ion respectively.13 However, dibromo ad-
dition on the side chain followed by intramolecular nu-
cleophilic attack of the N-1, or S atom at the
corresponding bromosubstituted carbon might also be op-
erative.
3,4-Dihydro-2H,6H-[1,3]thiazino[2,3-b]quinazolin-6-one (4a)
13C NMR (DMSO-d6): d = 22.40 (C-3), 27.18 (C-2), 41.66 (C-4),
118.95 (C-6a), 125.23, 125.27, 126.34 (C-7, 8, 10), 134.55 (C-9),
146.95 (C-10a), 154.48 (C-11a), 160.53 (C-6).
2,3-Dimethyl-7,8-dihydro-4H,6H-thieno[2’,3’:4,5]pyrimido-
[2,1-b][1,3]thiazin-4-one (5a)
13C NMR (DMSO-d6): d = 12.49, 12.80 (2-CH3, 3-CH3), 22.43 (C-
7), 27.18 (C-8), 40.96 (C-6), 118.84 (C-3a), 127.11, 128.34 (C-2,
3), 154.14, 157.45 (C-9a, 10a), 160.34 (C-4).
3,4,7,8,9,10-Hexahydro-2H,6H-[1]benzothieno[2’,3’:4,5]pyrim-
ido[2,1-b][1,3]thiazin-6-one (5b)
13C NMR (DMSO-d6): d = 21.74, 22.45, 24.36, 25.21 (CH2), 22.39
(C-3), 27.24 (C-2), 40.90 (C-4), 117.99 (C-6a), 130.12, 130.50 (C-
6b, 10a), 154.26, 157,18 (C-12a, 11a), 160.10 (C-6).
2-(Alkenylamino)benzamides 9a-c, 12; General Procedure
A mixture of 2-aminobenzamide (13.6 g, 100 mmmol) and K2CO3
(6.9 g, 50 mmol) was suspended in H2O (80 mL). The appropriate
alkenyl halide (allyl chloride, 3-chloro-2-methylpropene, crotyl
chloride,20 or 4-bromobut-1-ene, respectively, each 100 mmol) was
Previously, Chern et al.11 have reported on the transforma-
tion of 2-(allylthio)quinazolin-4(3H)-one 7a with N-bro-
mosuccinimide in THF to the linear 3-(bromomethyl)- added and the mixture was refluxed. The reaction was monitored by
5H-thiazolo[2,3-b]quinazolin-5-one 2 (n = 1, R1 = CH2Br,
TLC. After completion, the mixture was cooled and the precipitate
R2 = H; Table 2). Following the reported procedure, we
was collected by filtration. Oily products were mixed with a small
amount of EtOH to obtain a solid. The crude product was recrystal-
have obtained a product (mp 177-179 °C, instead of the
lized as indicated (Table 1).
reported value 235-237 °C), which was identical with the
angular 8a, prepared from 7a and bromine in acetic acid.
Synthesis 2000, No. 5, 714–720 ISSN 0039-7881 © Thieme Stuttgart · New York

720
P. Wippich et al.
PAPER
(4) Shaban, M. A. E.; Taha, M. A. M.; Sharshira, E. M. Adv.
1-Alkenyl-2-thioxo-1H-quinazolin-4(3H)-ones 10a-c, 13; Gen-
eral Procedure
Heterocycl. Chem. 1991, 52, 5.
The
corresponding 2-(alkenylamino)benzamide 9a-c, 12
(5) Danel, K.; Pedersen, E. B.; Nielsen, C. J. Med. Chem. 1998,
41, 191.
(6) Leistner, S.; Gütschow, M.; Drößler, K.; Vieweg, H.; Wagner,
G.; Strohscheidt, T.; Lohmann, D.; Laban, G.; Siegling, A.;
European Patent 0454060, 1991; Chem. Abstr. 1992, 116,
83689.
(50 mmol) was dissolved in acetone (50 mL) and treated with a
freshly prepared solution of benzoyl isothiocyanate21 (19.56 g, 120
mmol) in acetone (60 mL). The mixture was stirred at r.t. for 24 h.
Aq 3 N NaOH was added to obtain pH 9. The mixture was heated
to 60 °C and the insoluble material was removed by filtration. The
filtrate was acidified with 3 N HCl to pH 2, the mixture was cooled,
the precipitate was collected by filtration and washed with H2O. The
crude product was recrystallized as indicated (Table 1).
(7) Gütschow, M.; Drößler, K.; Leistner, S. Arch. Pharm.
(Weinheim) 1995, 328, 231.
(8) Gütschow, M.; Leistner, S. Synthesis 1995, 1488.
(9) UV and 13C NMR data of alkenylthio derivatives 7 were
similar to those of the linear compounds 2-5 (Table 2),
indicating the tautomeric 3H-pyrimidin-4-one structure.
(10) Similar differences in the 13C NMR shifts have been
considered to distinguish between angular and linear
thiazolopyrimidinones, as well as
thiazolo[1,2,4]benzothiadiazine 5,5-dioxides, see Refs 5, 11.
(11) Chern, J.-W.; Tao, P.-L.; Wang, K.-C.; Gutcait, A.; Liu, S.-
W.; Yen, M.-H.; Chien, S.-L.; Rong, J.-K. J. Med. Chem.
1998, 41, 3128.
(12) Cyclization of 2-(allylthio)pyrimidin-4(3H)-ones with
bromine in CH2Cl2 was assumed to occur via electrophilic
attack of the intermediate carbocation at N-1 atom, see Ref 5.
Following this mechanism, in the present transformations a
direct attack of the stabilized secondary (formed from 7a-c,
10a) or tertiary carbocation (from 7d-f, 10b) at the N-1 or S,
respectively, would provide the thiazolo products 8, 11. The
formation of the six-membered 1,3-thiazine ring in 14 could
be explained accordingly.
(13) From the NMR data of 11c, the purified compound appears as
one of two possible diastereomers. Its predominant formation
might be explained by assuming a bromonium ion
intermediate and anti addition of the sulfur atom which gives
the racemic (2R,1’S), (2S,1’R) pair.
1,2-Dihydro-5H-thiazolo[3,2-a]quinazolin-5-ones 8a, 8d, 11a-c
and 3-(Bromomethyl)-2,3-dihydro-1H,6H-[1,3]thiazino[3,2-
a]quinazolin-6-one (14); General Procedure
The corresponding 2-(alkenylthio)quinazolin-4-one 7a,d or 1-alke-
nyl-2-thioxoquinazolin-4-one 10 a-e and 13 (10 mmol) was sus-
pended in 95% AcOH (40 mL). The mixture was cooled to 7 °C and
stirred. A solution of Br2 (1.76 g, 11 mmol) in glacial AcOH
(11 mL) was added dropwise over 30 min. The temperature of the
mixture was kept below 10 °C. Stirring was then continued and the
temperature was slowly increased to 40 °C. The precipitate was col-
lected by filtration, washed with H2O, suspended in NaHCO3 solu-
tion, and filtered off. The crude product was recrystallized as
indicated (Table 1).
1,2-Dihydro-5H-thieno[3,2-e]thiazolo[3,2-a]pyrimidin-5-ones
8b, 8e and 1,2,6,7,8,9-hexahydro-5H-[1]benzothieno[3,2-e]thia-
zolo[3,2-a]pyrimidin-5-ones 8c, 8f; General Procedure
The corresponding 2-(alkenylthio)thieno[2,3-d]pyrimidin-4-one
7b, c,e,f (10 mmol) was suspended in 95% AcOH (200 mL). At
7 °C, a solution of Br2 (2.4 g, 15 mmol) in glacial AcOH (15 mL)
was added dropwise over 30 min to the stirred mixture. The temper-
ature was allowed to reach 40 °C. The mixture was then cooled
again, and the precipitate was collected by filtration, washed with
ice-water, NaHCO3 solution, and H2O. Further product was ob-
tained by pouring the filtrate onto ice-water (200 mL) and collecting
the precipitate by filtration. This material was washed with
aq NaHCO3 solution, H2O, and dried. It was then suspended in
boiling cyclohexane (100 mL), stirred for 2 min, and filtered off.
The combined crude product was purified by fractional crystal-
lization from the indicated solvent (Table 1).
(14) Liu, K. C.; Hsu, L. Y. Arch. Pharm. (Weinheim) 1985, 318,
502.
(15) Howard, J. C.; Klein, G. J. Org. Chem. 1962, 27, 3701.
(16) Kriphak, S. M.; Dobosh, A. A.; Smolanka, I. V. Khim.
Geterotsikl. Soedin. 1973, 567; Chem. Abstr. 1973, 79, 32005.
(17) Dobosh, A. A.; Kriphak, S. M.; Smolanka, I. V. Khim.
Geterotsikl. Soedin. 1974, 486; Chem. Abstr. 1974, 81, 37529.
(18) Cherbuliez, E.; Willhalm, B.; Espejo, O.; Jaccard, S.;
Rabinowitz, J. Helv. Chim. Acta 1967, 50, 1440.
(19) Leistner, S.; Gütschow, M.; Wagner, G. Pharmazie 1989, 44,
153.
References
(1) For synthetic routes to tricyclic thiazolo(1,3-thiazino)
pyrimidinones, see Ref. 3 and references therein. For a review
on thiazolo(1,3-thiazino)quinazolines, see Ref. 4.
(2) For thiazolo[3,2-a]pyrimidinones, see Ref. 5, for thiazolo[2,3-
b]quinazolinones, see Ref. 3 and references therein.
(3) Wippich, P.; Hendreich, C.; Gütschow, M.; Leistner, S.
Synthesis 1996, 741.
(20) Crotyl chloride (Merck) containing 90% of the trans isomer
was used.
(21) Frank, R. L.; Smith, P. V. Org. Synth. 1948, 28, 89.
Article Identifier:
1437-210X,E;2000,0,05,0714,0720,ftx,en;H08999SS.pdf
Synthesis 2000, No. 5, 714–720 ISSN 0039-7881 © Thieme Stuttgart · New York