A facile access to imidazo[2,1-b]thiazole and thiazolo[3,2-a]pyrimidine derivatives

Article abstract of DOI:10.1055/s-2001-17718

A new and efficient method for the synthesis of 2,3-dihydroimidazo [2,1-b]thiazoles 3, 2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-ones 4 and 2,3-dihydro-5H-thiazolo[3,2-a]pyrimidines 5 has been developed. The reactions of N′-(4,5-dihydrothiazol-2-yl)-N,N-dimethylamidines 1 with α-halogenoketones, acid chlorides or acrylic dienophiles were performed, leading to the title products.

Full text of DOI:10.1055/s-2001-17718

PAPER
2015
A Facile Access to Imidazo[2,1-b]thiazole and Thiazolo[3,2-a]pyrimidine
Derivatives
A
C
F
acile
A
ccess
y
r
,1-
b
]
thia
z
i
ole and
l
Thiaz
l
olo[3,2
e
-
a
]pyrimidine De
L
rivatives andreau, David Deniaud,* Alain Reliquet, Jean Claude Meslin
Laboratoire de Synthèse Organique, UMR CNRS 6513, Faculté des Sciences et des Techniques, 2, Rue de la Houssinière, BP 92208,
4322 Nantes Cedex 03, France
4
Fax +33(2)51125402; E-mail: david.deniaud@chimie.univ-nantes.fr
Received 1 June 2001; revised 20 July 2001
These considerations as well as our strong background in
heterocyclic chemistry12 led us to develop an alternative
approach to build these systems. In previous papers,1
we described the versatility of cationic diazadienes as sta-
Abstract: A new and efficient method for the synthesis of 2,3-dihy-
droimidazo[2,1-b]thiazoles 3, 2,3-dihydro-5H-thiazolo[3,2-a]pyri-
midin-5-ones 4 and 2,3-dihydro-5H-thiazolo[3,2-a]pyrimidines 5
has been developed. The reactions of N -(4,5-dihydrothiazol-2-yl)-
2a,c
N,N-dimethylamidines 1 with -halogenoketones, acid chlorides or ble synthons for the preparation of various monocycles.
acrylic dienophiles were performed, leading to the title products.
As a consequence, we planned to investigate the syntheses
Keywords: bicyclic compounds, heterocycles, acylations, alkyla- of fused ring systems applying these methods to analo-
tions, Diels–Alder reactions
gous heterocyclic diazadienes.
The use of such substrates is not unprecedented since sev-
eral teams have mentioned their reaction with isothiocy-
Imidazo[2,1-b]thiazole and thiazolo[3,2-a]pyrimidine de-
rivatives are important heterocycles found in numerous
biologically active compounds. Particularly, Levamisole1
is well known as a potent immuno-modulating agent,
13
14
15
anates, diphenylketene or diketene. Furthermore,
16
Stanovnik and coworkers have widely exploited a simi-
lar synthetic sequence leading to fused imidazoles. This
path consisted of the alkylation of this type of amidines by
a bromide possessing an activated methylene group, fol-
lowed by intramolecular cyclization. These works, how-
ever, were not specifically directed to the synthesis of the
title compounds.
2
while Ritanserin finds application in several psychophar-
macological fields. Furthermore, Andreani and
3
coworkers have explored the widespread activities of
3
a
various imidazo[2,1-b]thiazoles displaying herbicidal,
3
b
3c
antiarrhythmic and antitumor properties and have
shown that some of them have an interesting potential for
the treatment of human neurodegenerative diseases. Di-
aryl derivatives of these heterocycles have also been
found to possess anti-arthritic and anti-inflammatory
The method starts with the preparation of the heterocyclic
diazadienes 1, which was carried out according to
3d
literature13 by heating a CH Cl solution of 2-amino-
2
-
2
2
thiazoline and N,N-dimethylformamide dimethyl acetal or
N,N-dimethylacetamide dimethyl acetal.
4
properties, and to be interesting intermediates for the
5
preparation of trisubstituted imidazoles. On the other As shown in Scheme 1, amidines 1 were first subjected to
hand, some thiazolo[3,2-a]pyrimidines were recently re- alkylation with -halogenoketones leading to amidinium
ported to be active against HIV-1 as annulated analogues bromides 2. Treatment with a base generated the enolate,
of HEPT, while another series of these compounds have which underwent intramolecular condensation with the
been successfully tested as anti-inflammatory agents by iminium group, followed by spontaneous elimination of
6
Tozkoparan and coworkers.7
dimethylamine to give imidazo[2,1-b]thiazoles 3 in mod-
erate to good yields (Table 1).
Several methods have been published for the construction
of these structures. Both may be obtained via the alkyla-
tion of a cyclic thiourea by an appropriate dielectrophile.
However, this route induces the formation of two regioi-
N
N
S
Br
8
N
somers in certain cases. Thiazolo[3,2-a]pyrimidines are
1
N
R
S
N
a
generally prepared by subjecting 2-aminothiazoles to cy-
+
R
9
N
O
clization with difunctionalized reagents. The most com-
R'
Br
mon preparation of imidazo[2,1-b]thiazoles remains the
O
1
0
R'
well-known Hantzch type synthesis. Consequently, de-
rivatives are synthesized by substitutions of previously
2
N
S
1
1
b
known compounds.
R
N
R'
3
O
Scheme 1 Reagents and conditions: (a) THF, 78 °C, 20 h; (b) Et N,
r.t., 24 h or KOH/EtOH, 78 °C, 18 h
Synthesis 2001, No. 13, 08 10 2001. Article Identifier:
437-210X,E;2001,0,10,2015,2020,ftx,en;Z07401SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
3
1
©

2
016
C. Landreau et al.
PAPER
Table 1 Yields of Amidinium Bromides 2 and 2,3-Dihydroimida-
zo[2,1-b]thiazoles 3 Prepared
Table 2 Yields of 2,3-Dihydro-5H-thiazolo[3,2-a]pyrimidin-5-
ones 4 Prepared
R
R
Product
Yield (%) Product Yield (%)
Product
4a19,20
4b19
R
R
Yield (%)
H
p-BrC H4
2a
–
79
–
3a
3b
3c
3d
79a
32
H
H
33
61
89
56
98
63
6
H
p-ClC H4
CH3
H
H
6
CH3
p-BrC H4
–
–
78
4c
COOCH3
COOCH3
6
H
p-CH C H
4
2d
73
40a
4d
CH3
H
3
6
a
4e19–21
Yields based on compounds 2.
COOC H
2
5
4
f21,22
H
C H
6
5
Salts 2 were found to be stable but quite hygroscopic.
When bromides 2 could not be isolated, deprotonation
was performed in situ by addition of two equivalents of
Most of these compounds were accessible by previous
methods,1
9–22
like treatment of 2-aminothiazoline with
ethoxymethylenemalonic esters. However, theses proce-
dures provided in some cases a mixture of both the 5- and
Et N; in the other case, treatment with an ethanolic solu-
3
tion of KOH was preferred. The use of other bases (e.g.,
NaH, EtONa) did not significantly increase the yield of
cyclization. Thus, we were able to prepare imidazo[2,1-
b]thiazoles bearing an electron-withdrawing group in po-
7
-oxoisomers. Our pathway excludes any regioisomeric
1
ambiguity: indeed, the H NMR deshielding effect ob-
served for the 3-methylene group signal is unambiguously
attributed to the proximity of the 5-carbonyl function.
Moreover, this regioselective route seems simpler and
more general than the one proposed by Bernáth and co-
1
7
sition 5, similarly to those obtained by Iwata et al., but
with the benefit that position 6 is not occupied by an ami-
no group and therefore may be used as a candidate for a
later substitution.
23
workers, involving the retrodiene decomposition of the
corresponding norbornene-fused derivatives.
The synthetic value of compounds 1 was then emphasized
by three further cyclization reactions. The [4+2] cycload-
dition with ketene, prepared according to Vogel18 by
We continued our investigations towards thiazolo[3,2-
a]pyrimidines by exposing dienes 1 to acrylic dienophiles
cracking of acetone, was first examined. As expected, cy-
clization took place followed by deamination of the inter-
mediary cycloadduct leading to 6-unsubstituted
thiazolo[3,2-a]pyrimidin-5-ones 4a,b (Scheme 2).
(
Scheme 4). The [4+2] cycloaddition with acrolein, meth-
yl vinyl ketone or methyl acrylate proceeded as expected,
followed once again by spontaneous deamination, afford-
ing 2,3-dihydro-5H-thiazolo[3,2-a]pyrimidines 5 in mod-
1
est to excellent yields (Table 3). Both H NMR spectra of
R
N
5b and 5e present a singlet due to the methyl group in po-
sition 7, allowing us to rule out an unlikely rearrangement
leading to the 7H-isomer. It should be noticed that this
methodology is somewhat complementary to the prece-
dent since position 5 of the furnished compounds is not
occupied by a carbonyl function.
N
S
N
S
a
+
H2C
C O
1
N
R
N
4a,b
O
Scheme 2 Reagents and conditions: (a) CH Cl , r.t., 1 h
2
2
The 6-substituted analogues 4c–f were then obtained in
good yields by condensation of 1 with acid chlorides
N
N
R
N
S
S
a
(
Scheme 3, Table 2). Acylation of 1 occurred smoothly
R'
+
R
N
and cyclization of the resulting non-isolated salt was
N
R'
achieved by addition of 2 equivalents of Et N. We assume
1
5
3
that the reaction proceeds by a classical [4+2] cycloaddi-
tion with the ketenes generated by dehydrohalogenation
of acid chlorides, since the same results were obtained
Scheme 4 Reagents and conditions: (a) CHCl , 20 h, for 5a,b; neat,
3
2
0 h, r.t. for 5c,e; or for 5d
when Et N was added first.
3
In conclusion, a reliable and regiocontrolled alternative
route to imidazo[2,1-b]thiazoles 3, 5H-imidazo[3,2-a]py-
rimidin-5-ones 4 and 5H-imidazo[3,2-a]pyrimidines 5
has been established. We believe the present methodology
to have a broad applicability to the synthesis of biological-
ly active derivatives.
R
N
N
S
N
S
Cl
a
+
R'
1
N
R
N
R'
O
4c-f
O
Scheme 3 Reagents and conditions: (a) CH Cl , r.t., 4 h then Et N,
2
2
3
All reagents were purchased either from Acros Organics or Aldrich.
The elemental analyses were performed at the C.N.R.S. Analysis
Laboratory (Vernaison). Column chromatography was conducted
CH Cl , r.t., 16 h
2
2
Synthesis 2001, No. 13, 2015–2020 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Facile Access to Imidazo[2,1-b]thiazole and Thiazolo[3,2-a]pyrimidine Derivatives
2017
Amidinium Bromides 2 and Imidazo[2,1-b]thiazoles 3; General
Procedure
Table 3 Yields of 2,3-Dihydro-5H-thiazolo[3,2-a]pyrimidines 5
Prepared
A solution of -bromoketone (2.2 mmol) (2,4 -dibromoacetophe-
none for 3a,c, 2-bromo-4 -chloroacetophenone for 3b, 2-bromo-4 -
methylacetophenone for 3d) and amidine 1 (2 mmol) in THF (10
mL) was refluxed for 20 h.
Product
R
R
Yield (%)
5
5
5
5
5
a
b
c
H
CHO
88
64
61
23
51
CH3
H
CHO
Method A
After cooling to r.t., Et N (4.4 mmol) was added. The reaction mix-
COCH3
COOCH3
COCH3
3
ture was further stirred at r.t. for 24 h, then concentrated in vacuo.
The resulting residue was purified by chromatography (CH Cl –
d
e
H
2
2
EtOAc, 9:1) to furnish compounds 4b,c, which were crystallized
CH3
from Et O.
2
Method B
The solvent was evaporated and amidinium bromides 2a, d were
on silica gel 60 (40–63 m), available from E. Merck. TLC was per-
formed on 0.5 mm 20 cm 20 cm E. Merck silica gel plates (60
F-254). Mps (uncorrected) were measured using a Reichert micro-
scope. 13C and H NMR spectra were recorded at r.t. using a Bruker
AC 200 at 50 MHz and 200 MHz, respectively. Chemical shifts ( )
are given in ppm downfield from TMS as internal standard. Mass
spectra were recorded with a Hewlett Packard 5989 spectrometer.
The IR spectra were obtained using a Bruker Vector 22 spectrome-
ter. All chemicals were reagent grade and used without further pu-
rification. THF was freshly distilled from Na/benzophenone ketyl,
while CH Cl was distilled over CaH . All reactions were carried in
precipitated with Et O, collected by filtration and dried. A solution
2
of compound 2 (1.5 mmol) and KOH (3 mmol) in EtOH (20 mL)
was refluxed for 18 h. The mixture was cooled to r.t., diluted with
CH Cl (100 mL) and washed with H O (100 mL). The aqueous
1
2
2
2
phase was extracted with CH Cl (3 50 mL). The combined organ-
2
2
ic layers were washed with H O (3 50 mL), dried (MgSO ) and
2
4
concentrated under reduced pressure. Chromatography (CH Cl –
2
2
EtOAc, 9:1), followed by precipitation with Et O, furnished com-
2
pounds 3a,d as white crystals.
Amidinium Bromide (2a)
2
2
2
a N atm.
Yield: 79%; white crystals; hygroscopic.
2
1
H NMR (DMSO-d ): = 3.01, 3.28 [2s, 6 H, N(CH ) ], 3.68 (t, 2
6
3 2
Amidines 1; General Procedure
H, J = 7.8 Hz, SCH ), 4.10 (t, 2 H, J = 7.8 Hz, NCH ), 5.38 (s, 2 H,
A suspension of 2-amino- 2-thiazoline (10 mmol) and N,N-dimeth-
2
2
NCH CO), 7.78–8.00 (m, 4 H, ArH), 8.35 (s, 1 H, NCH).
2
ylformamide dimethylacetal (11 mmol, for 1a) or N,N-dimethylac-
etamide dimethylacetal (13 mmol, for 1b) in CH Cl (10 mL) was
refluxed for 4 h. Compound 1a was obtained by filtration through
1
3
C NMR (DMSO-d ): = 28.1 (SCH ), 36.3, 41.9 [N(CH ) ], 53.7,
6
2
3 2
2
2
5
3.8 (2 NCH ), 128.3 (ArC), 130.1, 132.0 (4 ArCH), 133.2
2
(ArC), 163.0 (NCH), 176.9 (SCN), 191.3 (CO).
cotton, evaporation of the solvent and crystallization from Et O.
2
Compound 1b was obtained as an oil by chromatography (CH Cl –
EtOH, 5:1).
2
2
5
-p-Bromobenzoyl-2,3-dihydroimidazo[2,1-b]thiazole (3a)
Yield:79%; white crystals.
N -(4,5-Dihydrothiazol-2-yl)-N,N-dimethylformamidine (1a)13
Yield: 96%; white crystals.
Mp 72 °C (Lit.13 mp 70–72 °C).
Mp 216 °C.
–
1
IR (KBr): 1623, 1585, 1510, 1366, 1243, 1166, 902, 753 cm .
1H NMR (DMSO-d6): = 4.02 (t, 2 H, J = 7.6 Hz, SCH ), 4.52 (t, 2
H, J = 7.6 Hz, NCH ), 7.62 (s, 1 H, NCH), 7.74–7.76 (m, 4H, ArH).
13C NMR (DMSO-d6): = 35.1 (SCH ), 47.0 (NCH ), 126.3, 129.9,
2
–
1
IR (KBr): 1639, 1559, 1419, 1362, 1113, 1022 cm .
2
1
H NMR (CDCl3): = 3.04, 3.06 [2s, 6 H, (NCH ) ], 3.36 (t, 2 H,
3
2
2
2
J = 7.8 Hz, SCH ), 4.11 (t, 2 H, J = 7.8 Hz, NCH ), 7.91 (s, 1 H,
2
2
136.5 (NCCO, 2 ArC), 130.5, 131.8 (4 ArCH), 144.5 (NCH),
68.7 (SCN), 181.2 (CO).
CH).
1
1
3
C NMR (CDCl3): = 33.9 (SCH ), 34.4, 40.2 [(NCH ) ], 59.7
+
2
3 2
MS (EI): m/z (%) = 310/308 (M , 100/99), 229 (7), 185/183 (48/
51), 157/155 (26/28), 125 (13).
(
NCH ), 158.4 (CH), 168.2 (SCN).
2
+
MS (EI): m/z (%) = 157 (M , 55), 124 (12), 110 (95), 98 (89), 83
Anal. Calcd for C H BrN OS (309.2): C, 46.62; H, 2.93; N, 9.06.
Found: 46.48; H, 2.79; N, 9.17.
1
2
9
2
(
58), 42 (100).
N -(4,5-Dihydrothiazol-2-yl)-N,N-dimethylacetamidine (1b)
Yield: 97%; yellow oil.
5
-p-Chlorobenzoyl-2,3-dihydroimidazo[2,1-b]thiazole (3b)
Yield: 32%; white crystals.
R = 0.4 (EtOH–CH Cl , 1:1).
f
2
2
Mp 212 °C.
–
1
IR (film): 1597, 1419, 1399, 1312, 1163, 1013 cm .
IR (KBr): 1624, 1404, 1366, 1246, 1166, 904, 755 cm–1.
1H NMR (CDCl3): = 3.95 (t, 2 H, J = 7.6 Hz, SCH ), 4.62 (t, 2 H,
J = 7.6 Hz, NCH ), 7.39–7.86 (m, 4 H, ArH). 7.55 (s, 1 H, NCH).
13C NMR (CDCl3): = 35.2 (SCH ), 47.1 (NCH ), 126.3, 129.6,
1
H NMR (CDCl ): = 2.15 (s, 3 H, CH ), 3.03 [s, 6 H, (NCH ) ],
3
3
3 2
2
3
.39 (t, 2 H, J = 7.8 Hz, SCH ), 4.14 (t, 2 H, J = 7.8 Hz, NCH ).
2
2
2
1
3
C NMR (CDCl ): = 11.8 (CCH ), 31.2 (SCH ), 33.6 [(NCH ) ],
3
3
2
3 2
2
2
5
7.0 (NCH ), 156.0 (CCH ), 164.4 (SCN).
2
3
137.5 (NCCO, 2 ArC), 129.2, 130.8 (4 ArCH), 142.5 (NCH),
163.5 (SCN), 181.7 (CO).
+
MS (EI): m/z (%) = 171 (M , 43), 138 (14), 124 (100), 112 (33), 97
21).
(
+
MS (EI): m/z (%) = 266/264 (M , 41/100), 153 (18), 141/139 (33/
9
6), 125 (15), 113/111 (18/55), 97 (21).
Anal. Calcd for C H ClN OS (264.7): C, 54.44; H, 3.43; N, 10.58.
1
2
9
2
Found: 55.08; H, 3.29; N, 10.76.
Synthesis 2001, No. 13, 2015–2020 ISSN 0039-7881 © Thieme Stuttgart · New York

2
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C. Landreau et al.
PAPER
+
6
-Methyl-5-p-bromobenzoyl-2,3-dihydroimidazo[2,1-b]thiazole
MS (EI): m/z (%) = 154 (M , 100), 126 (22), 108 (8), 95 (24), 80
(3c)
(13).
Yield: 78%; yellow crystals.
Anal. Calcd for C H N OS (154.2): C, 46.74; H, 3.92; N, 18.17.
6
6
2
Mp 161 °C.
Found: 46.86; H, 3.99; N, 18.24.
–
1
IR (KBr): 1606, 1584, 1507, 1360, 1312, 1251, 941, 757 cm .
7
-Methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one (4b)19
1
H NMR (CDCl3): = 2.03 (s, 3 H, CH ), 3.88 (t, 2 H, J = 7.8 Hz,
3
Yield: 61%; white crystals.
Mp 128 °C (Lit.19 mp 127–128 °C).
IR (KBr): 1678, 1581, 1516, 1446, 1404, 1123, 865 cm–1.
SCH ), 4.50 (t, 2 H, J = 7.8 Hz, NCH ), 7.55–7.65 (m, 4 H, ArH).
1
2
2
3
C NMR (CDCl3): = 17.2 (CCH ), 35.4 (SCH ), 47.5 (NCH ),
3
2
2
1
1
26.9, 127.8, 137.8 (NCCO, 2 ArC), 130.2, 131.8 (4 ArCH),
1
53.3 (CCH ), 175.8 (SCN), 184.4 (CO).
H NMR (CDCl ): = 2.23 (s, 3 H, CH ), 3.44 (t, 2 H, J = 7.8 Hz,
3
3
3
+
SCH
2
), 4.45 (t, 2 H, J = 7.8 Hz, NCH
2
), 6.00 (s, 1 H, CH).
MS (EI): m/z (%) = 324/322 (M , 100/98), 243 (62), 185/183 (36/
3
1
3C NMR (CDCl3): = 23.5 (CCH ), 26.2 (SCH ), 48.5 (NCH ),
8), 167 (20), 157/155 (35/34), 139 (21).
3 2 2
1
07.6 (CH), 161.0 (NCO), 164.2, 164.7 (SCN, CCH3).
Anal. Calcd for C H BrN OS (323.2): C, 48.31; H, 3.43; N, 8.67.
Found: 48.43; H, 3.38; N, 8.60.
1
3
11
2
+
MS (EI): m/z (%) = 168 (M , 100), 140 (17), 122 (6), 109 (34), 94
(
7).
Amidinium Bromide (2d)
Yield: 73%; white crystals; hygroscopic.
1H NMR (DMSO-d6): = 2.39 (s, 3 H, CH ), 3.00, 3.29 [2s, 6 H,
Anal. Calcd for C H N OS (168.2): C, 49.98; H, 4.79; N, 16.65.
Found: 50.07; H, 4.87; N, 16.75.
7
8
2
3
N(CH ) ], 3.68 (t, 2 H, J = 7.8 Hz, SCH ), 4.11 (t, 2 H, J = 7.8 Hz,
Method B
3
2
2
NCH ), 5.35 (s, 2 H, NCH CO), 7.36–7.94 (m, 4 H, ArH), 8.34 (s,
A solution of amidine 1 (2 mmol) and acid chloride (2.4 mmol) (me-
thyl malonyl chloride for 4c,d, ethyl malonyl chloride for 4e, or
2
2
1
H, NCH).
1
3C NMR (DMSO-d6): = 21.2 (CH ), 28.1 (SCH ), 36.2, 41.9
phenylacetyl chloride for 4f) in CH Cl (10 mL) was stirred at r.t.
2 2
3
2
for 4 h. After cooling to 0 °C, Et N (4.8 mmol) was added and stir-
3
[
1
N(CH ) ], 53.7, 54.0 (2 NCH ), 128.2, 129.5 (4 ArCH), 131.8,
3
2
2
ring was continued at r.t. for 16 h. After removal of the solvent, the
44.8 (2 ArC), 163.0 (NCH), 176.9 (SCN), 191.3 (CO).
-p-Toluoyl-2,3-dihydroimidazo[2,1-b]thiazole (3d)
residue was chromatographed using CH Cl –EtOAc (1:1 for 4c, e,
2
2
5
:1 for 4d,f). Compounds 4c–f were crystallized from Et O.
2
5
Yield: 40%; white crystals.
6
5
-Methoxycarbonyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-
-one (4c)
Mp 180 °C.
Yield: 89%; white crystals.
IR (KBr): 1621, 1603, 1512, 1402, 1359, 1241, 1157, 902, 751
cm .
–
1
Mp 127 °C.
IR (KBr): 1735, 1496, 1119 cm–1.
1H NMR (CDCl3): = 3.53 (t, 2 H, J = 7.9 Hz, SCH ), 3.88 (s, 3 H,
1H NMR (CDCl3): = 2.44 (s, 3 H, CH ), 3.93 (t, 2 H, J = 7.6 Hz,
3
SCH ), 4.62 (t, 2 H, J = 7.6 Hz, NCH ), 7.27–7.78 (m, 4 H, ArH),
2
2
2
7
.56 (s, 1 H, NCH).
OCH ), 4.56 (t, 2 H, J = 7.9 Hz, NCH ), 8.53 (s, 1 H, CH).
3
2
1
3
C NMR (CDCl ): = 21.2 (CH ), 35.4 (SCH ), 46.8 (NCH ),
3
3
2
2
13C NMR (CDCl3):
= 27.5 (SCH ), 50.3 (NCH ), 53.1 (OCH ),
2
2
3
1
1
28.4, 128.8 (4 ArCH), 130.2, 134.8 (2 ArC), 142.8 (NCCO),
43.9 (NCH), 156.8 (SCN), 182.9 (CO).
1
13.0 (CCO), 158.2 (NCO), 160.9 (NCH), 165.1 (SCN), 171.2
(
COO).
+
MS (EI): m/z (%) = 244 (M , 100), 229 (14), 119 (66), 91 (39), 65
+
MS (EI): m/z (%) = 212 (M , 35), 181 (100), 154 (23), 113 (21).
(
19).
Anal. Calcd for C H N O S (212.2): C, 45.28; H, 3.80; N, 13.20.
Found: 45.35; H, 3.85; N, 13.31.
8
8
2
3
Anal. Calcd for C H N OS (244.3): C, 63.91; H, 4.95; N, 11.47.
Found: 63.83; H, 4.79; N, 11.35.
13
12
2
6
-Methoxycarbonyl-7-methyl-2,3-dihydro-5H-thiazolo[3,2-
Thiazolo[3,2-a]pyrimidin-5-ones 4; General Procedure
Method A
a]pyrimidin-5-one (4d)
Yield: 56%; white crystals.
Ketene (CAUTION), produced by cracking of acetone, was bub-
bled into a solution of amidine 1 (4 mmol) in CH Cl (150 mL) until
Mp 109 °C.
2
2
complete consumption of the starting material, as monitored by
TLC (approx. 1 h). After evaporation of the solvent, the residue was
dissolved in a small amount of CH Cl and subjected to flash chro-
IR (KBr): 1700, 1675, 1496, 1254, 1129 cm–1.
1
H NMR (CDCl ): = 2.36 (s, 3 H, CH ), 3.47 (t, 2 H, J = 7.9 Hz,
3
3
2
2
SCH ), 3.90 (s, 3 H, OCH ), 4.49 (t, 2 H, J = 7.9 Hz, NCH ).
matography (EtOAc–acetone, 9:1 for 4a; EtOAc–CH Cl , 5:1 for
2
3
2
2
2
4
b). Compounds 4a,b were crystallized from Et O.
13C NMR (CDCl3): = 22.8 (CCH ), 26.3 (SCH ), 49.1 (NCH ),
2
3 2 2
5
2.4 (OCH ), 113.8 (CCO), 158.0 (NCO), 165.3, 165.6, 165.9
3
2
,3-Dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one (4a)19,20
(
CCH , SCN, COO).
3
Yield: 33%; yellow crystals.
Mp 110 °C (Lit.19 mp 107–108 °C).
+
MS (EI): m/z (%) = 226 (M , 28), 195 (100), 168 (11), 127 (44), 67
46).
(
–
1
IR (KBr): 1684, 1570, 1493, 1451, 1377, 1148, 833 cm .
Anal. Calcd for C H N O S (226.2): C, 47.78; H, 4.45; N, 12.38.
9
10
2
3
1H NMR (CDCl3): = 3.46 (t, 2 H, J = 7.7 Hz, SCH ), 4.45 (t, 2 H,
Found: 47.65; H, 4.52; N, 12.46.
2
J = 7.7 Hz, NCH ), 6.15 (d, 1 H, J = 6.7 Hz, CHCO), 7.73 (d, 1 H,
J = 6.7 Hz, NCH).
2
6
-Ethoxycarbonyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-
1
9,20,21
one (4e)
Yield: 98%; white crystals.
Mp 174 °C (Lit.19 mp 174–176 °C).
1
3C NMR (CDCl3): = 26.3 (SCH ), 48.8 (NCH ), 110.4 (CHCO),
2
2
1
53.9 (NCH), 160.9 (NCO), 165.6 (SCN).
Synthesis 2001, No. 13, 2015–2020 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Facile Access to Imidazo[2,1-b]thiazole and Thiazolo[3,2-a]pyrimidine Derivatives
2019
–
1
13C NMR (CDCl3): = 19.1 (CCH ), 25.7 (SCH ), 44.4 (NCH ),
IR (KBr): 1730, 1653, 1496, 1286, 1127, 799 cm .
3
2
2
1H NMR (CDCl3): = 1.36 (t, 3 H, J = 7.2 Hz, CH CH ), 3.53 (t, 2
54.1 (NCH
CHO).
2
CH
2
), 109.1 (CCO), 162.1 (CCH ), 170.4 (SCN), 187.1
3
2
3
(
H, J = 7.9 Hz, SCH ), 4.35 (q, 2 H, J = 7.2 Hz, OCH ), 4.56 (t, 2 H,
2
2
+
J = 7.9 Hz, NCH ), 8.51 (s, 1 H, CH).
MS (EI): m/z (%) = 182 (M , 100), 181 (60), 154 (16), 126 (21).
2
1
3
C NMR (CDCl ): = 14.0 (CH CH ), 26.4 (SCH ), 49.1 (NCH ),
Anal. Calcd for C H N OS (182.2): C, 52.73; H, 5.53; N, 15.37.
3
2
3
2
2
8
10
2
6
0.8 (OCH ), 112.1 (CCO), 157.0 (NCO), 159.3 (NCH), 163.3
Found: 52.59; H, 5.44; N, 15.49.
2
(
SCN), 170.2 (COO).
+
6-Acetyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine (5c)
Yield: 61%; yellow crystals.
MS (EI): m/z (%) = 226 (M , 25), 181 (100), 154 (87), 113 (22).
Anal. Calcd for C H N O S (226.2): C, 47.78; H, 4.45; N, 12.38.
9
10
2
3
Mp 151 °C.
Found: 47.88; H, 4.53; N, 12.45.
–
1
IR (KBr): 1627, 1521, 1394, 1309, 1262, 1138 cm .
6
-Phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
1
H NMR (CDCl3): = 2.27 (s, 3 H, COCH ), 3.32 (t, 2 H, J = 7.5
2
1,22
3
(
4f)
Hz, SCH ), 3.69 (t, 2 H, J = 7.5 Hz, NCH CH ), 4.17 (s, 2 H,
NCH ), 7.37 (s, 1 H, NCH).
2
2
2
Yield: 63%; white crystals.
Mp 180 °C (Lit.22 mp 181 °C).
2
13
C NMR (CDCl ): = 24.3 (COCH ), 25.7 (SCH ), 45.0 (NCH ),
3
3
2
2
–
1
IR (KBr): 1653, 1517, 1465, 1394, 786, 696 cm .
53.8 (NCH CH ), 112.8 (CCO), 148.3 (NCH), 170.2 (SCN), 195.1
2 2
1H NMR (CDCl3): = 3.51 (t, 2 H, J = 7.7 Hz, SCH ), 4.56 (t, 2 H,
(CO).
2
+
J = 7.7 Hz, NCH ), 7.33–7.65 (m, 5 H, ArH), 7.92 (s, 1 H, NCH).
MS (EI): m/z (%) = 182 (M , 100), 181 (61), 154 (25), 139 (29).
2
1
3C NMR (CDCl3): = 26.5 (SCH ), 49.0 (NCH ), 122.5 (CCO),
Anal. Calcd for C H N OS (182.2): C, 52.73; H, 5.53; N, 15.37.
2
2
8
10
2
1
23.0, 128.2, 128.3 (5 ArCH), 132.9 (ArC), 151.4 (NCH), 159.9
Found: 52.88; H, 5.69; N, 15.29.
(
NCO), 163.8 (SCN).
+
6-Methoxycarbonyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine
MS (EI): m/z (%) = 230 (M , 100), 202 (9), 174 (6), 142 (10), 102
22), 63 (7).
(
5d)
(
Yield: 23%; yellow crystals.
Anal. Calcd for C H N OS (230.3): C, 62.59; H, 4.38; N, 12.16.
Found: 62.48; H, 4.36; N, 12.23.
12
10
2
Mp 150 °C.
–
1
IR (KBr): 1689, 1623, 1533, 1405, 1296, 1136, 1095 cm .
Thiazolo[3,2-a]pyrimidines 5: General Procedure
A mixture of amidine 1 (4 mmol) and dienophile [acrolein (10
1H NMR (CDCl3): = 3.30 (t, 2 H, J = 7.5 Hz, SCH ), 3.64 (t, 2 H,
2
J = 7.5 Hz, NCH CH ), 3.73 (s, 3 H, OCH ), 4.19 (s, 2 H, NCH ),
2
2
3
2
mmol) in CHCl (10 mL) for 5a,b; methyl acrylate (5 mL) for 5d;
3
7
.37 (s, 1 H, NCH).
methyl vinyl ketone (5 mL) for 5c,e] was stirred for 20 h at r.t. (5a–
c, e) or at reflux (5d), then evaporated under reduced pressure and
chromatographed (EtOAc–acetone, 7:3 for 5a,b; 9:1 for 5c; 5:1 for
1
3
C NMR (CDCl3): = 25.8 (SCH ), 45.4 (NCH ), 51.3 (OCH ),
2
2
3
5
3.8 (NCH CH ), 102.7 (CCO), 146.5 (NCH), 166.7 (CO), 170.0
2 2
(
SCN).
MS (EI): m/z (%) = 198 (M , 30), 197 (50), 183 (100), 167 (14), 139
11).
Anal. Calcd for C H N O S (198.2): C, 48.47; H, 5.08; N, 14.13.
5
e; CH Cl –EtOAc, 7:3 for 5d). Compounds 5 were crystallized
2 2
from Et O (except for 5e, which was isolated as an oil).
+
2
(
6
-Formyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine (5a)
8
10
2
2
Yield: 88%; yellow crystals.
Found: 48.63; H, 5.24; N, 14.30.
Mp 135 °C.
–
1
6-Acetyl-7-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine
IR (KBr): 1646, 1612, 1513, 1380, 1132, 1055 cm .
(
5e)
1H NMR (CDCl3): = 3.35 (t, 2 H, J = 7.6 Hz, SCH ), 3.73 (t, 2 H,
2
Yield: 51%; yellow oil.
J = 7.6 Hz, NCH CH ), 4.21 (s, 2 H, NCH ), 7.18 (s, 1 H, NCH),
2
2
2
R = 0.2 (acetone).
9
.33 (s, 1 H, CHO).
f
–
1
13C
IR (KBr): 1653, 1621, 1525, 1416, 1377, 1318, 1276, 1194 cm .
NMR (CDCl ):
= 25.7 (SCH2), 44.0 (NCH2), 53.8
3
(
(
NCH CH ), 114.3 (CCO), 155.9 (NCH), 171.8 (SCN), 188.5
CHO).
1
2
2
H NMR (CDCl ): = 2.29 (s, 3 H, CH ), 2.36 (s, 3 H, COCH ),
3
3
3
3
.30 (t, 2 H, J = 7.6 Hz, SCH ), 3.67 (t, 2 H, J = 7.6 Hz, NCH CH ),
2
2
2
+
4.12 (s, 2 H, NCH2).
MS (EI): m/z (%) = 168 (M , 100), 167 (52), 140 (23), 112 (37).
1
3
C NMR (CDCl3): = 24.2, 25.7, 31.1 (COCH , SCH , CCH ),
6.6 (NCH ), 53.9 (NCH CH ), 109.1 (CCO), 155.8 (CCH ), 168.4
SCN), 195.9 (CO).
MS (EI): m/z (%) = 196 (M , 44), 195 (100), 181 (27), 153 (12), 127
32).
Anal. Calcd for C H N OS (168.2): C, 49.98; H, 4.79; N, 16.65.
Found: 49.77; H, 4.82; N, 16.72.
3
2
3
7
8
2
4
2
2
2
3
(
6
-Formyl-7-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine
+
(
5b)
(
Yield: 64%; orange crystals.
Although the purity of this compound was confirmed by TLC (only
one spot was present after purification by flash chromatography),
we did not obtain the desirable result by elemental analyses.
Mp 162 °C.
–
1
IR (KBr): 1628, 1600, 1526, 1387, 1188, 1022 cm .
1H NMR (CDCl3): = 2.23 (s, 3 H, CH ), 3.32 (t, 2 H, J = 7.6 Hz,
3
SCH ), 3.74 (t, 2 H, J = 7.6 Hz, NCH CH ), 4.12 (s, 2 H, NCH ),
2
2
2
2
Acknowledgment
9
.85 (s, 1 H, CHO).
The authors are indebted to the French Ministry of Education and
CNRS for financial support. Dr Praveen Thoniyot is gratefully ack-
nowledged for fruitful discussions.
Synthesis 2001, No. 13, 2015–2020 ISSN 0039-7881 © Thieme Stuttgart · New York

2
020
C. Landreau et al.
PAPER
(9) For examples: (a) Malei, M.; Krbavi, A.; Stanovnik, B. J.
Heterocycl. Chem. 1997, 34, 49. (b) Kutyrev, A.; Kappe, T.
J. Heterocycl. Chem. 1999, 36, 237.
10) For an example: Meakins, G. D.; Musk, S. R. R.; Robertson,
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Synthesis 2001, No. 13, 2015–2020 ISSN 0039-7881 © Thieme Stuttgart · New York