Efficient regioselective synthesis of triheterocyclic compounds: Imidazo[2,1-b]benzothiazoles, pyrimido[2,1-b]benzothiazolones and pyrimido[2,1-b]benzothiazoles

Article abstract of DOI:10.1039/b111639h

The preparation and characterisation of triheterocyclic compounds, via annulation reactions, are described. Amidines 1 reacted with substituted bromomethyl compounds, acid chlorides, and acrylic dienophiles to afford the corresponding imidazo[2,1-b]benzot

Full text of DOI:10.1039/b111639h

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Efficient regioselective synthesis of triheterocyclic compounds:
imidazo[2,1-b]benzothiazoles, pyrimido[2,1-b]benzothiazolones and
pyrimido[2,1-b]benzothiazoles
1
Cyrille Landreau,a David Deniaud,*a Michel Evain,b Alain Reliqueta and Jean-Claude Meslina
a Laboratoire de Synthèse Organique, Faculté des Sciences et des Techniques,
UMR C.N.R.S. 6513, BP 92208, 2, rue de la Houssinière, F44322 Nantes Cedex 03, France
b Institut des Matériaux Jean Rouxel, Laboratoire de Chimie des Solides,
Faculté des Sciences et des Techniques, 2, rue de la Houssinière, BP 32 229,
F-44322 Nantes Cedex 03, France
Received (in Cambridge, UK) 21st December 2001, Accepted 5th February 2002
First published as an Advance Article on the web 22nd February 2002
The preparation and characterisation of triheterocyclic compounds, via annulation reactions, are described.
Amidines 1 reacted with substituted bromomethyl compounds, acid chlorides, and acrylic dienophiles to afford
the corresponding imidazo[2,1-b]benzothiazoles 2 and pyrimido[2,1-b]benzothiazoles 3 or 4.
Introduction
In recent years, polyheterocycles have received increasing atten-
tion due to their potential biological properties, and consider-
able efforts have been undertaken to exploit synthetic routes to
these compounds. In particular, imidazo[2,1-b]benzothiazoles
were tested in vivo for anti-inflammatory and analgesic activ-
ities together with low ulcerogenic properties.1,2 Substituted
compounds have been shown to be fungicidal agents,3 while
tetrahydro derivatives were tested in cancer chemotherapy.4
Imidazo- and pyrimido[2,1-b]benzothiazoles were evaluated for
their affinity at the central benzodiazepine receptor.5 Trapani
and co-workers have explored the widespread activities of these
compounds displaying anxiolytic, anticonvulsant, muscle
relaxant and sedative properties.6–8 Moreover, pyrimidobenzo-
thiazolone derivatives have been shown to be useful for the
prophylactic treatment of the allergic disease state.9,10 There-
fore, it would be important to search for new, versatile and
Scheme 2 Reagents and conditions: (i) α-halogeno ketones, base; (ii)
acid chlorides, base; (iii) acrylic dienophiles.
regioselective methods to synthesise such polyheterocyclic ring
systems.
In the course of our studies directed towards the synthesis of
heterocyclic compounds based on the use of neutral or cationic
1,3-diazadienes,11–13 we have recently developed annulation
protocols for the preparation of fused thiazines or thiazoles
with pyrimidines or imidazoles (Scheme 1).
Results and discussion
Our first target compounds were NЈ-(benzothiazol-2-yl)-N,N-
dimethylamidines 1a and 1b containing a diazadiene chain. The
preparation of these compounds was accomplished according
to a procedure developed in the literature by the condensation
of N,N-dimethylformamide dimethyl acetal (R = H, 1a) or
N,N-dimethylacetamide dimethyl acetal (R = CH3, 1b) with 2-
aminobenzothiazole in boiling dichloromethane.16 With the
aim of investigating the reactivity of these amidines 1a,b we
have first realised their alkylation using α-bromo ketones or
ethyl bromoacetate (Scheme 3).
Alkylation of the heterocyclic nitrogen atom provided the
N-alkyl amidinium bromides 5. These salts were stable enough
to be isolated and were dehydrohalogenated using an ethanolic
solution of potassium hydroxide giving rise to imidazo[2,1-b]-
benzothiazoles 2a–e. In this reaction, it was postulated that
under the basic medium an enolate anion is formed which is
involved in an intramolecular cyclisation with the iminium
group, followed by loss of dimethylamine. As expected, the ring
closure of compounds 5 occurred in higher yields when the
bromomethyl reagent was substituted with a stronger electron-
withdrawing group. Thus, by this method we obtained five
imidazobenzothiazoles 2a–e, as presented in Table 1.
Scheme 1
In this context, we have reported a new and efficient
method for the synthesis of 2,3-dihydroimidazo[2,1-b]thiazole
and 2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivatives from
amidines of 2-amino-∆2-thiazoline.14 In the same manner,
7H-imidazo[2,1-b][1,3]thiazines and 2H,6H-pyrimido[2,1-b]-
[1,3]thiazines were easily obtained.15 In order to increase the
scope of this strategy to more conjugated polyheterocycles, we
focused our research by the use of the same procedure to
develop a regioselective synthesis of imidazo[2,1-b]benzo-
thiazoles 2a–e, pyrimido[2,1-b]benzothiazolones 3a–f or pyr-
imido[2,1-b]benzothiazoles 4a–c by reaction of amidines 1a,b
derived from an aromatic amine with α-bromo ketones, acid
chlorides or acrylic dienophiles, respectively (Scheme 2).
DOI: 10.1039/b111639h
J. Chem. Soc., Perkin Trans. 1, 2002, 741–745
This journal is © The Royal Society of Chemistry 2002
741

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Table 1 Yields of amidinium bromides 5 and imidazo[2,1-b]benzo-
thiazoles 2
Table 2 Yields of 4H-pyrimido[2,1-b]benzothiazol-4-ones 3a–f
R
RЈ
Product
Yield (%)
R
RЈ
Product
Yield (%)
Product
Yield (%)
H
H
CH3
H
H
COOCH3
COOC2H5
COOC2H5
C6H5
H
H
3a8,20
3b8,10,20
3c
28
35
44
35
51
87
H
H
H
H
C2H5O
5a
5b
5c
5d
5e
92
96
90
85
78
2a17
2b
36
84
72
77
68
p-BrC6H4
p-ClC6H4
p-CH3C6H4
p-ClC6H4
2c
3d
2d
3e10
3f
CH3
2e
CH3
Table 3 Yields of 4H-pyrimido[2,1-b]benzothiazoles 4a–c
R
RЈ
Product
Yield (%)
H
H
CH3
CHO
COCH3
COCH3
4a
4b
4c
43
52
48
ation. The most successful conditions found were to perform
the reaction at room temperature in dichloromethane, yielding
compounds 3a–d in 30–50% yield. When 1,3-diazadienes 1a,b
were exposed to ketene, produced by cracking of acetone,19
[4 ϩ 2] cycloaddition reactions took place, furnishing pyr-
imidobenzothiazolones 3e,f in good yield after loss of dimeth-
1
ylamine (Scheme 4, Table 2). The H NMR deshielding effect
Scheme 4 Reagents and conditions: (i) CH2Cl2, rt, 2 h; (ii) CH2Cl2, rt,
6 h; then 0 ЊC, Et3N, 16 h.
observed for the 6-methine group signal is attributed to the
proximity of the 4-carbonyl function.
According to the latter results, NЈ-(benzothiazol-2-yl)-N,N-
dimethylamidines 1a,b behaved like heterodienes in the pres-
ence of acrylic dienophiles (Scheme 5, Table 3). These [4 ϩ 2]
Scheme 3 Reagents and conditions: (i) RЈCOCH2Br, THF, 66 ЊC, 20 h;
(ii) KOH, EtOH, 78 ЊC, 18 h.
The structure of compounds 2 was confirmed by a single-
crystal X-ray analysis of 2a (Fig. 1).18 The X-ray structure
shows a fused triheterocycle with an almost planar shape obey-
ing the necessary aromatic form.
Scheme 5 Reagents and conditions: (i) CHCl3, 3 days, rt for 4a or reflux
for 4b,c.
cycloaddition reactions occurred in a regiocontrolled manner
and the intermediary cycloadducts underwent spontaneous
deamination, affording 4H-pyrimido[2,1-b]benzothiazoles 4a–c
in modest yields.
In summary, alkylation of 1,3-diazadienes 1 by arylacyl
bromides occurred smoothly, and subsequent annulation reac-
tions proceeded in good yields, affording imidazo[2,1-b]-
benzothiazoles 2 while acylation using acid chlorides gave rise to
4H-pyrimido[2,1-b]benzothiazol-4-ones 3 in lower yields. It is
noteworthy that aromaticity of benzothiazole precursors did
not prevent the course of the [4 ϩ 2] cycloaddition reactions
and only moderate decrease of yields was observed in com-
parison with less conjugated heterocyclic starting materials
such as amidines derived from 2-amino-∆2-thiazoline or 2-
amino-1,3-thiazine. The latter reaction is an easy method for
the preparation of new 3-functionalised 4H-pyrimido[2,1-b]-
benzothiazoles. These represent a class of compounds that could
be used as precursors for the synthesis of new derivatives with
usefulbiologicalactivity.Furtherworkdealingwiththeconstruc-
tion of other related heterocycles is currently under investigation.
Fig. 1 ORTEP representation of compound 2a with crystallographic
numbering scheme.
By a similar synthetic strategy, when amidines 1a,b reacted
with acid chlorides the 4H-pyrimido[2,1-b]benzothiazol-4-ones
3a–d were formed (Scheme 4). The heterocyclic nitrogen atom
was affected by acylation but intermediary salts could not be
isolated. Subsequent treatment using triethylamine afforded
cycloadducts leading to the desired compounds after deamin-
742
J. Chem. Soc., Perkin Trans. 1, 2002, 741–745

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Amidinium bromide 5b. Yield 96%; white crystals; mp 207 ЊC;
Experimental
1H NMR (DMSO-d6) δ 3.09, 3.35 (2s, 6H, N(CH3)2), 6.20 (s,
2H, NCH2), 7.46–8.19 (m, 8H, CHar), 8.74 (s, 1H, NCH ); MS,
m/z (%) 403/401 (35/35), 357 (69), 185/183 (96/100); IR (KBr)
νmax/cmϪ1 1693 (s), 1653 (s), 1517 (s), 1473 (m), 1416 (m), 1402
(m), 1130 (m), 981 (m).
All reagents were purchased from Acros Organics and Aldrich.
All chemicals were reagent grade and used without further
purification, and all solvents were freshly distilled before use.
The CNRS Analysis Laboratory (Vernaison) performed the
elemental analyses. Column chromatography was conducted
over silica gel 60 (40–63 µm), available from E. Merck. Thin-
layer chromatography was performed on 0.5 mm × 20 cm ×
20 cm E. Merck silica gel plates (60 F-254). Melting points,
measured using a Reichert microscope were uncorrected. The
Amidinium bromide 5c. Yield 90%; white crystals; mp 209 ЊC;
1H NMR (DMSO-d6) δ 3.09, 3.35 (2s, 6H, N(CH3)2), 6.21 (s,
2H, NCH2), 7.47–8.19 (m, 8H, CHar), 8.73 (s, 1H, NCH ); 13
C
NMR (DMSO-d6) δ 36.4, 42.1 (N(CH3)2), 52.2 (NCH2), 114.2,
123.9, 125.9, 128.2, 129.2 (2), 130.4 (2) (8CHar), 123.0, 132.8,
138.2, 139.5 (4Car), 161.2 (NCH), 172.3 (SCN), 190.5 (CO);
MS, m/z (%) 359/357 (14/36), 312 (74), 201 (61), 139 (100); IR
(KBr) νmax/cmϪ1 1695 (m), 1666 (m), 1521 (s), 1415 (m), 1401
(m), 1229 (w), 1133 (w), 767 (w).
1
13C and H NMR spectra were recorded at room temperature
using a Bruker AC200, operating at 50 and 200 MHz, respect-
ively. Chemical shifts (δ) are given in ppm downfield from
tetramethylsilane as internal standard. Mass spectra were
determined with a Hewlett-Packard 5989 spectrometer. The IR
spectra were obtained using a Bruker Vector 22 spectrometer.
Amidinium bromide 5d. Yield 85%; white crystals; mp 215 ЊC;
1H NMR (DMSO-d6) δ 2.43 (s, 3H, CH3), 3.07, 3.35 (2s, 6H,
N(CH3)2), 6.18 (s, 2H, NCH2), 7.42–8.19 (m, 8H, CHar), 8.75
(s, 1H, NCH ); 13C NMR (DMSO-d6) δ 21.3 (CH3), 36.4, 42.0
(N(CH3)2), 52.2 (NCH2), 114.2, 124.0, 125.8, 128.2, 128.5 (2),
129.5 (2) (8CHar), 123.0, 131.6, 138.3, 145.2 (4Car), 161.1
(NCH), 172.2 (SCN), 190.7 (CO); MS, m/z (%) 337 (35), 292
(82), 201 (35), 119 (100), 91 (69); IR (KBr) νmax/cmϪ1 1688 (m),
1648 (m), 1521 (s), 1418 (w), 1403 (w), 1233 (w), 1183 (w).
Amidines 1: general procedure
A
suspension of 2-aminobenzothiazole (10 mmol) and
N,N-dimethylformamide dimethyl acetal (11 mmol, for 1a) or
N,N-dimethylacetamide dimethyl acetal (13 mmol, for 1b) in
dichloromethane (10 mL) was refluxed for 16 h. After removal
of the solvent, the residue was chromatographed using as eluent
dichloromethane–ethyl acetate (5 : 1). Compounds 1 were
crystallised from diethyl ether.
NЈ-(Benzothiazol-2-yl)-N,N-dimethylformamidine 1a16. Yield
83%; white crystals; mp 99 ЊC (Found: C, 58.63; H, 5.37;
N, 20.60. C10H11N3S requires C, 58.51; H, 5.40; N, 20.47%);
1H NMR (CDCl3) δ 3.12 and 3.13 (2s, 6H, N(CH3)2), 7.13–7.70
(m, 4H, CHar), 8.37 (s, 1H, NCH ); 13C NMR (CDCl3) δ 35.1
and 40.9 (2C, N(CH3)2), 120.6, 121.2, 122.8 and 125.7 (4CHar),
133.3, 152.1 (2Car), 156.5 (NCH), 173.6 (SCN); MS, m/z (%)
205 (100, Mϩ), 190 (43), 189 (48), 163 (35), 135 (45); IR (KBr)
νmax/cmϪ1 1619 (s), 1490 (s), 1439 (w), 1405 (m), 1339 (m), 1097
(m), 757 (m).
Amidinium bromide 5e. Yield 78%; white crystals; mp 170 ЊC;
1H NMR (DMSO-d6) δ 2.57 (s, 3H, CH3), 3.09, 3.29 (2s, 6H,
N(CH3)2), 6.10 (s, 2H, NCH2), 7.42–8.19 (m, 8H, CHar); MS,
m/z (%) 328/326 (35/100), 291 (35), 215 (32), 146 (29), 111 (66);
IR (KBr) νmax/cmϪ1 1699 (m), 1549 (s), 1430 (w), 1408 (m), 1227
(m), 1000 (w), 833 (m), 755 (w).
Imidazo[2,1-b][benzothiazoles 2; general procedure
A solution of an amidinium bromide 5 (1.5 mmol) and potas-
sium hydroxide (3 mmol) in ethanol (20 mL) was refluxed for
18 h. After cooling to room temperature, the reaction mixture
was diluted with dichloromethane (100 mL) and washed
with water (100 mL). The aqueous phase was extracted with
dichloromethane (3 × 70 mL). The combined organic layers
were washed with water (3 × 70 mL), dried (MgSO4) and con-
centrated under reduced pressure. The resulting residue was
purified by chromatography using dichloromethane-ethyl acet-
ate (9 : 1) as eluent to furnish the corresponding compound 2
which were crystallised from diethyl ether.
NЈ-(Benzothiazol-2-yl)-N,N-dimethylacetamidine 1b. Yield
82%; white crystals; mp 86 ЊC (Found: C, 60.37; H, 5.89;
N, 19.01. C11H13N3S requires C, 60.25; H, 5.97; N, 19.16%);
1H NMR (CDCl3) δ 2.30 (s, 3H, CH3), 3.12 (s, 6H, N(CH3)2),
7.12–7.74 (m, 4H, CHar); 13C NMR (CDCl3) δ 16.4 (CCH3),
38.3 (2C, N(CH3)2), 120.6, 120.9, 122.6 and 125.4 (4CHar),
134.5, 152.5 (2Car), 161.7 (CCH3), 172.4 (SCN); MS, m/z (%)
219 (100, Mϩ), 178 (24), 175 (24), 163 (30), 135 (40); IR (KBr)
νmax/cmϪ1 1578 (s), 1539 (m), 1397 (s), 1158 (m), 953 (m),
774 (m).
3-(Ethoxycarbonyl)imidazo[2,1-b]benzothiazole 2a.17 Yield
36%; white crystals; mp 138 ЊC (Found: C, 58.57; H, 4.15;
N, 11.49. C12H10N2O2S requires C, 58.52; H, 4.09; N, 11.37%);
1H NMR (CDCl3) δ 1.43 (t, 3H, J 7.2 Hz, CH2CH3), 4.42 (q,
2H, J 7.2 Hz, OCH2), 7.34–7.73 (m, 3H, CHar), 8.05 (s, 1H,
NCH ), 9.06–9.11 (m, 1H, CHar); 13C NMR (CDCl3) δ 14.5
(CH2CH3), 61.0 (OCH3), 117.9, 123.7, 125.5, 126.5 (4CHar),
130.1, 133.3, 138.1 (2Car, CCO), 143.5 (NCH), 153.3 (SCN),
159.9 (CO); MS, m/z (%) 246 (100, Mϩ), 218 (41), 201 (79), 174
(73), 146 (39); IR (KBr) νmax/cmϪ1 1717 (s), 1472 (s), 1387 (m),
1313 (m), 1160 (m), 1128 (m), 753 (w).
N-Alkyl amidinium bromides 5; general procedure
To a solution of an amidine 1 (2 mmol) in tetrahydrofuran
(10 mL) was added ethyl bromoacetate (2.2 mmol, for 5a) or an
α-bromo ketone (2.2 mmol, p-bromophenacyl bromide for 5b,
p-chlorophenacyl bromide for 5c and 5e, p-methylphenacyl
bromide for 5d). The reaction mixture was refluxed for 20 h and
cooled to room temperature. The solvent was evaporated off
and the residue was crystallised from diethyl ether. 13C spectra
of compounds 5b,e could not be recorded due to their low
solubilities.
3-( p-Bromobenzoyl)imidazo[2,1-b]benzothiazole 2b. Yield
84%; white crystals; mp 231 ЊC (Found: C, 53.94; H, 2.46;
N, 7.74. C16H9BrN2OS requires C, 53.80; H, 2.54; N, 7.84%);
1H NMR (CDCl3) δ 7.40–7.84 (m, 7H, CHar), 7.83 (s, 1H,
NCH ), 8.90–8.96 (m, 1H, CHar); 13C NMR (CDCl3) δ 118.4,
123.9, 126.0, 126.8, 130.9 (2), 132.1 (2) (8CHar), 127.7, 129.7,
130.4, 133.7, 137.5 (4Car, CCO), 147.2 (NCH), 155.8 (SCN),
182.3 (CO); MS, m/z (%) 358/356 (100/99, Mϩ), 277 (14), 201
(97), 157/155 (20/18), 146 (37); IR (KBr) νmax/cmϪ1 1636 (s),
1466 (s), 1417 (m), 1363 (m), 1192 (w), 896 (m), 752 (s).
Amidinium bromide 5a. Yield 92%; white crystals; mp 109 ЊC;
1H NMR (DMSO-d6) δ 1.22 (t, 3H, J 7.2 Hz, CH2CH3), 3.26,
3.42 (2s, 6H, N(CH3)2), 4.21 (q, 2H, J 7.2 Hz, OCH2), 5.38 (s,
2H, NCH2), 7.47–8.18 (m, 4H, CHar), 8.77 (s, 1H, NCH ); 13
C
NMR (DMSO-d6) δ 14.0 (CH2CH3), 36.6, 42.2 (N(CH3)2), 46.8
(NCH2), 61.7 (OCH2), 114.0, 122.9, 124.0, 125.9, 128.2, 137.8
(2Car, 4CHar), 161.2 (NCH), 166.4 (CO), 172.3 (SCN); MS,
m/z (%) 291 (43), 219 (58), 174 (100); IR (KBr) νmax/cmϪ1 1739
(s), 1653 (s), 1470 (m), 1409 (m), 1224 (m), 1142 (m), 765 (m).
J. Chem. Soc., Perkin Trans. 1, 2002, 741–745
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3-( p-Chlorobenzoyl)imidazo[2,1-b]benzothiazole 2c. Yield
72%; white crystals; mp 227 ЊC (Found: C, 61.36; H, 2.94;
N, 9.07. C16H9ClN2OS requires C, 61.44; H, 2.90; N, 8.96%);
1H NMR (CDCl3) δ 7.40–7.92 (m, 7H, CHar), 7.83 (s, 1H,
NCH ), 8.89–8.95 (m, 1H, CHar); 13C NMR (CDCl3) δ 118.2,
123.7, 125.8, 126.6, 128.9 (2), 130.7 (2) (8CHar), 129.6, 130.2,
133.5, 136.9, 139.0 (4Car, CCO), 147.1 (NCH), 155.4 (SCN),
182.1 (CO); MS, m/z (%) 314/312 (38/100, Mϩ), 277 (9), 201
(73), 173 (13), 146 (31); IR (KBr) νmax/cmϪ1 1638 (s), 1466 (s),
1417 (m), 1366 (m), 1190 (w), 897 (m), 752 (s).
(s), 1688 (s), 1487 (s), 1356 (m), 1254 (m), 1126 (m), 791 (w),
768 (w).
3-Ethoxycarbonyl-2-methyl-4H-pyrimido[2,1-b]benzothiazol-
4-one 3c. Yield 44%; white crystals; mp 134 ЊC (Found: C,
58.45; H, 4.29; N, 9.61. C14H12N2O3S requires C, 58.32; H, 4.19;
N, 9.72%); 1H NMR (CDCl3) δ 1.42 (t, 3H, J 7.2 Hz, CH2CH3),
2.50 (s, 3H, CH3), 4.45 (q, 2H, J 7.2 Hz, OCH2), 7.47–7.73 (m,
3H, CHar), 9.05–9.11 (m, 1H, CHar); 13C NMR (CDCl3) δ 14.3
(CH2CH3), 22.9 (CCH3), 61.8 (OCH2), 113.7 (CCO), 120.2,
122.0, 127.5, 127.6 (4CHar), 124.1, 136.0 (2Car), 158.3 (SCN),
162.5, 162.7, 165.7 (CCH3, 2CO); MS, m/z (%) 288 (78, Mϩ),
243 (100), 242 (57), 216 (79), 175 (53), 134 (28); IR (KBr)
νmax/cmϪ1 1725 (s), 1669 (s), 1507 (s), 1230 (m), 1161 (m), 1039
(w), 776 (w).
3-( p-Toluoyl)imidazo[2,1-b]benzothiazole 2d. Yield 77%;
white crystals; mp 168 ЊC (Found: C, 69.64; H, 4.20; N, 9.76.
1
C17H12N2OS requires C, 69.84; H, 4.14; N, 9.58%); H NMR
(CDCl3) δ 2.48 (s, 3H, CH3), 7.26–7.89 (m, 7H, CHar), 7.84 (s,
1H, NCH ), 8.89–8.94 (m, 1H, CHar); 13C NMR (CDCl3) δ 21.7
(CH3), 118.3, 123.7, 125.7, 126.5, 129.3 (2), 129.6 (2) (8CHar),
130.0, 130.3, 133.6, 135.9, 143.5 (4Car, CCO), 146.7 (NCH),
154.9 (SCN), 183.3 (CO); MS, m/z (%) 292 (100, Mϩ), 146 (38),
119 (30), 91 (60); IR (KBr) νmax/cmϪ1 1634 (s), 1467 (s), 1417
(m), 1369 (m), 1176 (w), 899 (m), 746 (s).
3-Phenyl-4H-pyrimido[2,1-b]benzothiazol-4-one 3d. Yield
35%; white crystals; mp 174 ЊC (Found: C, 69.17; H, 3.73; N,
1
10.19. C16H10N2OS requires C, 69.05; H, 3.62; N, 10.06%); H
NMR (CDCl3) δ 7.42–7.72 (m, 8H, CHar), 8.12 (s, 1H, NCH ),
9.13–9.19 (m, 1H, CHar); 13C NMR (CDCl3) δ 120.5, 122.0,
127.1, 127.4, 128.2, 128.6 (2), 128.9 (2) (9CHar), 121.9, 124.8,
133.3, 136.4 (4Car), 149.9 (SCN), 160.5, 160.9 (NCH, CO);
MS, m/z (%) 278 (100, Mϩ), 250 (52), 116 (23), 89 (17); IR (KBr)
νmax/cmϪ1 1675 (s), 1507 (s), 1455 (m), 1356 (m), 1248 (m), 996
(w), 780 (m), 692 (m).
3-p-Chlorobenzoyl-2-methylimidazo[2,1-b]benzothiazole 2e.
Yield 68%; white crystals; mp 165 ЊC (Found: C, 62.37; H, 3.49;
N, 8.68. C17H11ClN2OS requires C, 62.48; H, 3.39; N, 8.57%);
1H NMR (CDCl3) δ 2.15 (s, 3H, CH3), 7.33–7.86 (m, 7H,
CHar), 8.25–8.31 (m, 1H, CHar); 13C NMR (CDCl3) δ 17.1
(CCH3), 117.4, 124.2, 125.7, 126.8, 129.6 (2), 131.3 (2)
(8CHar), 126.7, 130.4, 134.0, 138.1, 139.9 (4Car, CCO), 153.8,
154.3 (SCN, CCH3), 185.3 (CO); MS, m/z (%) 328/326 (35/100,
Mϩ), 291 (36), 290 (35), 215 (26), 187 (14), 146 (16); IR (KBr)
νmax/cmϪ1 1626 (s), 1476 (s), 1367 (m), 1133 (s), 1089 (w), 935 (s),
748 (s).
Method B
Ketene (CAUTION), produced by cracking of acetone,19 was
bubbled into a solution of an amidine 1 (4 mmol) in dichloro-
methane (150 mL) until complete consumption of the starting
material, as monitored by TLC (approximately 1 h). After
evaporation of the mixture, the residue was dissolved in a small
amount of dichloromethane and subjected to flash chrom-
atography [dichloromethane–ethyl acetate (9 : 1 for 3e and 1 : 1
for 3f )]. Compounds 3e,f were crystallised from diethyl ether.
4H-Pyrimido[2,1-b][benzothiazol-4-ones 3; general procedure.
Method A
A solution of an amidine 1 (2 mmol) and an acid chloride
(2.4 mmol) [methyl (chloroformyl)acetate for 3a, ethyl (chloro-
formyl)acetate for 3b,c or phenylacetyl chloride for 3d] in
dichloromethane (10 mL) was stirred for 4 h at room temper-
ature. After cooling of the mixture to 0 ЊC, triethylamine
(4.8 mmol) was added and stirring was continued for 16 h at
room temperature. The solvent was evaporated off and the
residue was purified by chromatography over silica, using as
eluent dichloromethane–ethyl acetate (9 : 1). Compounds 3a–d
were crystallised from diethyl ether.
4H-Pyrimido[2,1-b]benzothiazol-4-one 3e.10 Yield 51%; white
crystals; mp 173 ЊC (Found: C, 59.52; H, 3.13; N, 13.71.
C10H6N2OS requires C, 59.39; H, 2.99; N, 13.85%); H NMR
(CDCl3) δ 6.42 (d, 1H, J 6.5 Hz, CHCO), 7.46–7.73 (m, 3H,
CHar), 7.95 (d, 1H, J 6.5 Hz, NCH ), 9.08–9.13 (m, 1H, CHar);
13C NMR (CDCl3) δ 109.4 (CHCO), 120.2, 121.7, 126.9, 127.2
(4CHar), 124.2, 136.0 (2Car), 151.8 (NCH), 161.0 (CO), 162.3
(SCN); MS, m/z (%) 202 (100, Mϩ), 174 (70), 146 (10), 134 (10);
IR (KBr) νmax/cmϪ1 1681 (s), 1490 (s), 1450 (m), 1246 (m), 993
(w), 814 (w), 760 (w).
1
3-Methoxycarbonyl-4H-pyrimido[2,1-b]benzothiazol-4-one
3a.8,20 Yield 28%; white crystals; mp 192 ЊC (Found: C, 55.25;
H, 3.17; N, 10.89. C12H8N2O3S requires C, 55.38; H, 3.10; N,
10.76%); 1H NMR (CDCl3) δ 3.95 (s, 3H, OCH3), 7.51–7.77 (m,
3H, CHar), 8.72 (s, 1H, NCH ), 9.08–9.14 (m, 1H, CHar); 13C
NMR (CDCl3) δ 52.3 (OCH3), 110.4 (CCO), 120.6, 121.9,
127.5, 127.6 (4CHar), 124.4, 136.1 (2Car), 157.4 (SCN), 157.5
(NCH), 164.4, 166.3 (2CO); MS, m/z (%) 260 (57, Mϩ), 229
(100), 202 (16), 201 (13), 161 (35), 134 (19); IR (KBr) νmax/cmϪ1
1739 (s), 1669 (m), 1489 (s), 1304 (m), 1262 (w), 1125 (m), 796
(w), 755 (w).
2-Methyl-4H-pyrimido[2,1-b]benzothiazol-4-one 3f. Yield
87%; white crystals; mp 205 ЊC (Found: C, 61.22; H, 3.84;
N, 12.74. C11H8N2OS requires C, 61.09; H, 3.73; N, 12.95%);
1H NMR (CDCl3) δ 2.39 (s, 3H, CH3), 6.26 (s, 1H, CHCO),
7.26–7.71 (m, 3H, CHar), 9.05–9.10 (m, 1H, CHar); 13C NMR
(CDCl3) δ 23.8 (CCH3), 107.2 (CHCO), 120.0, 121.7, 126.9,
127.0 (4CHar), 124.1, 136.0 (2Car), 161.1, 161.4, 162.9 (CO,
SCN, CCH3); MS, m/z (%) 216 (100, Mϩ), 188 (64), 187 (56),
149 (13); IR (KBr) νmax/cmϪ1 1675 (s), 1505 (s), 1396 (m), 1240
(m), 1163 (w), 980 (w), 768 (w).
3-Ethoxycarbonyl-4H-pyrimido[2,1-b]benzothiazol-4-one
3b.8,10,20 Yield 35%; white crystals; mp 142 ЊC (Found: C, 56.79;
H, 3.55; N, 10.24. C13H10N2O3S requires C, 56.93; H, 3.67; N,
4H-Pyrimido[2,1-b]benzothiazoles 4; general procedure
A mixture of an amidine 1 (4 mmol) and a dienophile [acrolein
(10 mmol) in chloroform (10 mL) for 4a or methyl vinyl ketone
(5 mL) for 4b,c] was stirred for 20 h at room temperature (4a) or
at reflux (4b,c) for 3 days. The resulting solution was concen-
trated under reduced pressure and the residue was purified by
chromatography over silica, using dichloromethane–ethyl
acetate (1 : 1 for 4a and 7 : 3 for 4b,c). Compounds 4 were
crystallised from diethyl ether.
1
10.21%); H NMR (CDCl3) δ 1.42 (t, 3H, J 7.0 Hz, CH2CH3),
4.43 (q, 2H, J 7.0 Hz, OCH2), 7.54–7.78 (m, 3H, CHar), 8.75 (s,
1H, NCH ), 9.17–9.23 (m, 1H, CHar); 13C NMR (CDCl3) δ 14.4
(CH2CH3), 61.3 (OCH2), 110.9 (CCO), 120.7, 122.0, 127.6,
127.7 (4CHar), 124.5, 136.2 (2Car), 157.4 (SCN), 157.6
(NCH), 163.9, 166.3 (2CO); MS, m/z (%) 274 (68, Mϩ), 229
(100), 202 (97), 161 (45), 134 (26); IR (KBr) νmax/cmϪ1 1717
744
J. Chem. Soc., Perkin Trans. 1, 2002, 741–745

View Article Online
3-Formyl-4H-pyrimido[2,1-b]benzothiazole 4a. Yield 43%;
yellow crystals; mp 185 ЊC (Found: C, 61.28; H, 3.94; N, 12.79.
C11H8N2OS requires C, 61.09; H, 3.73; N, 12.95%); H NMR
(CDCl3) δ 4.86 (s, 2H, CH2), 7.14–7.61 (m, 4H, CHar), 7.38 (s,
1H, NCH ), 9.46 (s, 1H, CHO); 13C NMR (CDCl3) δ 43.0
(CH2), 111.2, 122.3, 125.0, 127.6 (4 CHar), 113.5 (CCO), 123.8,
135.1 (2Car), 154.9 (NCH), 167.9 (SCN), 188.7 (CHO); MS,
m/z (%) 216 (100, Mϩ), 215 (86), 187 (43), 160 (11), 134 (19);
IR (KBr) νmax/cmϪ1 1638 (s), 1490 (s), 1476 (s), 1363 (m), 1264
(m), 1166 (m), 749 (m).
References and notes
1
1 F. Palagiano, L. Arenare, P. De Caprariis, G. Grandolini, V.
Ambrogi, L. Perioli, W. Filippelli, G. Falcone and F. Rossi, Farmaco,
1996, 51, 483.
2 P. J. Roy, K. Landry, Y. Leblanc, C. Li and N. Tsou, Heterocycles,
1997, 45, 2239.
3 Y. Tanabe, A. Kawai, Y. Yoshida, M. Ogura and H. Okumura,
Heterocycles, 1997, 45, 1579.
4 S. Tasaka, H. Tanabe, Y. Sasaki, T. Machida, M. Iino, A. Kiue,
S. Naito and M. Kuwano, J. Heterocycl. Chem., 1997, 34, 1763.
5 S. P. Gupta and A. Paleti, Bioorg. Med. Chem., 1998, 6, 2213.
6 G. Trapani, M. Franco, A. Latrofa, A. Carotti, G. Genchi, M. Serra,
G. Biggio and G. Liso, Eur. J. Med. Chem., 1996, 31, 575.
7 G. Trapani, A. Carotti, M. Franco, A. Latrofa, G. Genchi and
G. Liso, Eur. J. Med. Chem., 1993, 28, 13.
8 G. Trapani, M. Franco, A. Latrofa, G. Genchi and G. Liso, Eur. J.
Med. Chem., 1992, 27, 39.
9 J. J. Wade, C. B. Toso, C. J. Matson and V. L. Stelzer, J. Med. Chem.,
1983, 26, 608.
3-Acetyl-4H-pyrimido[2,1-b]benzothiazole 4b. Yield 52%;
yellow crystals; mp 222 ЊC (Found: C, 62.68; H, 4.47; N, 12.24.
1
C12H10N2OS requires C, 62.59; H, 4.38; N, 12.16%); H NMR
(CDCl3) δ 2.36 (s, 3H, COCH3), 4.81 (s, 2H, CH2), 7.13–7.53
(m, 4H, CHar), 7.57 (s, 1H, NCH ); 13C NMR (CDCl3) δ 24.5
(COCH3), 43.6 (CH2), 110.8, 122.0, 124.4, 127.2 (4CHar),
123.7, 139.2 (2Car), 111.9 (CCO), 147.5 (NCH), 166.3 (SCN),
195.1 (CO); MS, m/z (%) 230 (94, Mϩ), 229 (100), 215 (86), 187
(43), 160 (11), 134 (19); IR (KBr) νmax/cmϪ1 1628 (m), 1612 (m),
1506 (s), 1365 (m), 1283 (m), 1168 (m), 735 (m).
10 J. J. Wade, R. F. Hegel and C. B. Toso, J. Org. Chem., 1979, 44, 1811.
11 C. Friot, A. Reliquet, F. Reliquet and J. C. Meslin, Phosphorus,
Sulfur Silicon Relat. Elem., 2000, 156, 135.
12 C. Friot, A. Reliquet, F. Reliquet and J. C. Meslin, Synthesis, 2000,
695.
13 C. Landreau, D. Deniaud, A. Reliquet, F. Reliquet and J. C. Meslin,
J. Heterocycl. Chem., 2001, 38, 93.
14 C. Landreau, D. Deniaud, A. Reliquet and J. C. Meslin, Synthesis,
2001, 2015.
15 C. Landreau, D. Deniaud, A. Reliquet and J. C. Meslin, Synthesis,
2002, in press.
3-Acetyl-2-methyl-4H-pyrimido[2,1-b]benzothiazole 4c. Yield
48%; yellow crystals; mp 197 ЊC (Found: C, 63.80; H, 4.85;
N, 11.35. C13H12N2OS requires C, 63.91; H, 4.95; N, 11.47%);
1H NMR (CDCl3) δ 2.41, 2.47 (2s, 6H, COCH3, CH3), 4.75
(s, 2H, CH2), 7.11–7.54 (m, 4H, CHar); 13C NMR (CDCl3)
δ 25.0 (COCH3), 31.6 (CCH3), 44.6 (CH2), 108.5 (CCO),
110.9, 122.0, 124.2, 127.1 (4CHar), 123.6, 139.1 (2Car), 155.5
(CCH3), 164.3 (SCN), 195.6 (CO); MS, m/z (%) 244 (100, Mϩ),
243 (78), 229 (69), 201 (34), 175 (22), 134 (24); IR (KBr)
νmax/cmϪ1 1616 (m), 1512 (s), 1363 (m), 1272 (m), 1209 (m),
955 (w), 750 (m).
16 R. Richter and H. Ulrich, Chem. Ber., 1970, 103, 3525.
17 R. H. Prager and Y. Singh, Tetrahedron, 1993, 49, 8147.
18 Crystal data for 2a: white crystal (0.10 × 0.10 × 0.40 mm) from
diethyl ether, C12H10N2O2S,
M = 246.30, monoclinic, a =
14.4765(18), b = 11.1064(9), c = 14.5268(18) Å, β = 150.686(15)Њ,
V = 1143.5(2) Å3, Z = 4, space group P21/c, µ = 0.273 mmϪ1, 13 223
reflections measured, 3337 independent reflections, Rint = 0.0494,
R(F 2) = 0.0487, Rw(F 2) = 0.0681 for observed data. CCDC reference
number 177912. See http://www.rsc.org/suppdata/p1/b1/b111639h/
for crystallographic files in .cif or other electronic format.
19 A. I. Vogel, A Text-book of Practical Organic Chemistry, Longman,
London, 1959, p. 372.
Acknowledgements
The authors are grateful to the French Ministry of Education
and the CNRS for financial support.
20 R. J. Alaimo, J. Heterocycl. Chem., 1973, 10, 769.
J. Chem. Soc., Perkin Trans. 1, 2002, 741–745
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