First synthesis and further functionalization of 7-chloro-imidazo[2,1-b][1,3]thiazin-5-ones

Article abstract of DOI:10.1016/j.tetlet.2008.02.014

A convenient four-step preparation route to novel 7-chloro-imidazo[2,1-b][1,3]thiazin-5-ones is presented, starting from methyl phenylglyoxylate. A unique feature of this synthesis is a heterocyclization strategy, in which a halogen atom is introduced alr

Full text of DOI:10.1016/j.tetlet.2008.02.014

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2286–2288
First synthesis and further functionalization
of 7-chloro-imidazo[2,1-b][1,3]thiazin-5-ones
Clemens Lamberth *, Florian Querniard
Syngenta Crop Protection AG, Research Department, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland
Received 3 January 2008; revised 1 February 2008; accepted 4 February 2008
Available online 8 February 2008
Abstract
A convenient four-step preparation route to novel 7-chloro-imidazo[2,1-b][1,3]thiazin-5-ones is presented, starting from methyl
phenylglyoxylate. A unique feature of this synthesis is a heterocyclization strategy, in which a halogen atom is introduced already during
the ring closure. 7-Chloro-6-phenyl-imidazothiazinones with a broad range of various substituents in the phenyl and imidazole moieties
are obtainable by this method, as well as different chlorinated triazolothiazinones. The chloro function can be easily replaced in
nucleophilic substitution reactions by amino, alkoxy and arylthio groups as well as by a fluoro atom.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Heterocycle; Heterocyclization; Imidazole; Thiazine; Imidazothiazine
Although a few syntheses of imidazo[2,1-b][1,3]thiazin-
5-ones have been described already,1 so far there is no
example for a derivative with a halogen substituent in posi-
tion 7. Because of the known antibacterial2 and fungicidal3
activity of imidazo[2,1-b]thiazinones and the proven posi-
tive influence of halogen substituents on the efficacy of bio-
logical active compounds,4 we decided to prepare a series
of 7-chlorinated imidazo[2,1-b][1,3]thiazin-5-ones.
dichloro-2-phenylacryloyl chloride (3a)9 seemed to be an
appropriate intermediate for such compounds (Scheme
1). It could be easily prepared by Corey–Fuchs type dichlo-
rovinylation of methyl phenylglyoxylate (1a),10 subsequent
ester saponification and acid chloride formation. This com-
pound was directly transformed into the formerly unknown
imidazo[2,1-b][1,3]thiazin-5-one 4a by condensation with
2-mercaptoimidazole (Scheme 1).11 Hereby, one of the
Usually in thiazine chemistry, the introduction of a
chloro substituent into the ortho position of the ring sulfur
is performed either by radical5 or by ionic6 halogenation of
an unsubstituted ring carbon atom or by nucleophilic dis-
placement of a hydroxy group.7 In all the cases, the thia-
zine ring is formed before the halogen atom is
introduced. Only one example can be found in the litera-
ture, in which ring closure to thiazinones and chlorination
have been achieved in one step using different 3,3-dichloro-
acryloyl chlorides as key intermediates.8 With regard to an
efficient and atom-economic synthesis, we planned to
apply a similar approach to the synthesis of 7-chloro-
imidazo[2,1-b][1,3]thiazin-5-ones. In this connection, 3,3-
1. NaOH
2. SOCl2
CCl4,
PPh3
O
O
83%
75%
O
O
O
Cl
Cl
1a
2a
N
O
O
N
H
SH
N
Cl
72%
N
S
Cl
Cl
Cl
4a
3a
*
Scheme 1. Four-step synthesis of 7-chloro-6-phenyl-imidazo[2,1-b]-
[1,3]thiazin-5-one (4a).
Corresponding author. Tel.: +41 61 323 2373; fax: +41 61 323 8726.
E-mail address: clemens.lamberth@syngenta.com (C. Lamberth).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.014

C. Lamberth, F. Querniard / Tetrahedron Letters 49 (2008) 2286–2288
2287
Table 1
Table 2
Synthesis of 7-chloro-6-aryl-imidazo[2,1-b][1,3]thiazin-5-ones with differ-
Synthesis of 7-chloro-6-phenyl-imidazo[2,1-b][1,3]thiazin-5-ones with dif-
ent substituents in the phenyl ring
ferent substituents in the imidazole ring
N
R2
R1
N
O
O
O
O
S
N
SH
R
R
N
SH
H
Cl
N
R2
R1
H
Cl
N
N
S
Cl
Cl
Cl
Cl
Cl
N
Cl
4a-i
3a-i
3a
4a, k-m
Entry
R
Yield (%)
72
Mp (°C)
Entry
R1
R2
Yield (%)
Mp (°C)
a
116–117
a
k
l
H
Me
Ph
H
Me
Ph
72
74
63
70
116–117
182–183
Oil
m
CH@CH–CH@CH
197–198
b
c
69
75
101–104
165–166
Cl
Cl
ring. The yields were generally between 50% and 75%,
the lowest yields were usually obtained in those reactions
of 3,3-dichloro-2-arylacryloyl chlorides with ortho-substit-
uents in the phenyl moiety.
Also the synthesis of various 7-chloro-6-phenyl-
imidazo[2,1-b][1,3]thiazin-5-ones with different substituents
in the imidazole ring was possible (Table 2). The applica-
tion of 2-mercaptobenzimidazole as the reaction partner
of 3,3-dichloro-2-phenylacryloyl chloride (3a)9 led to
the unique tricyclic chloro- and phenyl-substituted 1-thia-
4a,9-diazafluorenone 4m.
Cl
Cl
d
e
56
68
181–182
118–119
Cl
Cl
CH3
f
53
167–168
When 3-mercapto-1,2,4-triazole was used instead of 2-
mercaptoimidazole, triazolothiazinones were obtained in
the heterocyclization reaction (Scheme 2). In the conver-
sion with 3,3-dichloro-2-phenylacryloyl chloride (3a),9 the
two different isomers 5 and 6 were formed in equal
amounts, depending on which triazole ring nitrogen
reacted in the cyclization.
Cl
OCH3
CN
g
h
73
64
152–155
184–187
F
F
The 7-chloro-6-aryl-imidazo[2,1-b]thiazin-5-ones 4a–m
are absolutely stable at room temperature for a very long
time, but could be easily transformed into novel com-
pounds due to the leaving group character of its chloro
function. Some possible derivatizations are the exchange
against a fluoro atom to afford 8 or the nucleophilic substi-
tution with amines, alkoxides or thiolates, delivering 7, 9
and 10 (Scheme 3).
i
57
117–120
F
vinylic chlorine atoms in 3a is substituted during the ring
closure, the other remains in the molecule.
By the application of this heterocyclization method, sev-
eral imidazo[2,1-b][1,3]thiazin-5-ones with a broad variety
of different substituents in the phenyl ring were synthesized
(Table 1). The heterocyclization is possible in the presence
of electron-donating as well as electron-withdrawing sub-
stituents in ortho-, meta- or para-positions of the phenyl
In conclusion, we have developed a concise and efficient
route to 7-chloro-6-aryl-imidazo[2,1-b][1,3]thiazin-5-ones.
Their chloro atom can be easily replaced through various
nucleophilic substitutions. Also 5-chloro-6-aryl-triazolo-
[5,1-b]thiazin-7-ones and 7-chloro-6-aryl-triazolo[3,4-b]-
thiazin-5-ones can be obtained by this method.
HN
N
O
O
O
N
SH
N
N
N
Cl
+
N
68%
N
S
Cl
N
S
Cl
Cl
Cl
3a
5
6
Scheme 2. Synthesis of 5-chloro-6-phenyl-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-one (5) and 7-chloro-6-phenyl-[1,2,4]triazolo[3,4-b][1,3]thiazin-5-one (6).

2288
C. Lamberth, F. Querniard / Tetrahedron Letters 49 (2008) 2286–2288
O
N
N
S
N
O
7
O
NH 82%
O
N
O
O
KF
NaOMe
95%
N
N
74%
N
S
Cl
N
S
O
N
S
F
8
9
4a
NaSPh 79%
O
N
N
S
S
10
Scheme 3. Further transformations of 7-chloro-6-phenyl-imidazo[2,1-b][1,3]thiazin-5-one (4a).
Chem. 1995, 38, 4393; (b) Schroth, W.; Dill, G.; Nguyen, T. K. D.;
Nguyen, T. M. K.; Phan, T. B.; Waskiewicz, H.-J.; Hildebrandt, A. Z.
Chem. 1974, 14, 52.
References and notes
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Phosphorus Sulfur Silicon 1992, 68, 297; (b) Glennon, R. A.; Tejani,
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11. Representative procedure: N,N-Diisopropylethylamine (Hunig’s base,
¨
1.6 g, 12.5 mmol) was added to a solution of 2-mercaptoimidazole
(1.1 g, 11 mmol) in 20 ml of dichloromethane at room temperature.
Subsequently, a solution of 3,3-dichloro-2-phenylacryloyl chloride8
(3a, 2.4 g, 11 mmol) in 5 ml of dichloromethane was added dropwise
while maintaining the temperature at 15–20 °C. The resulting mixture
was stirred for 16 h at room temperature, taken up in water and
extracted with dichloromethane. The combined organic phases were
washed with brine, dried over magnesium sulfate and evaporated. The
residue was purified either by crystallization from diethyl ether or by
chromatography on a silica gel, using ethyl acetate–heptane 1:3 as
eluent to deliver 7-chloro-6-phenyl-imidazo[2,1-b][1,3]thiazin-5-one
(4a, 2.1 g, 7.9 mmol, 72%). Mp: 116–117 °C. 1H NMR (ppm, CDCl3):
d 7.34 (d, 2H), 7.43 (s, 1H), 7.48–7.55 (m, 3H), 7.99 (s, 1H). 13C NMR
(ppm, CDCl3): d 114.8, 115.3, 117.9, 118.6, 120.1, 124.5, 126.4, 127.2,
132.0, 139.7, 141.4, 157.5. HRMS (m/z): calcd for (C12H7ClN2-
OS+H)+: 263.7227; found: 263.7231.
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