Synthesis of 6-substituted imidazo[2,1-b][1,3]thiazoles and 2-substituted imidazo[2,1-b][1,3]benzothiazoles via pd/cu-mediated sonogashira coupling

Article abstract of DOI:10.1055/s-0029-1217980

The reaction of iodobenzenes with 2-amino-3-(2-proipynyl)-1,3- thiazolium bromide and 2-imino-3-(2-propynyl)-1,3-benzothiazole, catalyzed by Pd/Cu, leads to the formation of 6-substituted imidazo[2,1-b][1,3]thiazoles and 2-substituted imidazo[2,1-b][1,3]b

Full text of DOI:10.1055/s-0029-1217980

LETTER
2601
Synthesis of 6-Substituted Imidazo[2,1-b][1,3]thiazoles and 2-Substituted
Imidazo[2,1-b][1,3]benzothiazoles via Pd/Cu-Mediated Sonogashira Coupling
S
ynthesis of 6-S
a
ubstituted
g
Imidazo[2,1-
h
b
][1,3]thiazo
i
les A. Kamali,a Davood Habibi,b Mahmoud Nasrollahzadeh*b
a
Laboratory of Organic Chemistry, Moshashimi Company, Kardikola Industrial Region, Babol 47571-54879, Iran
Department of Organic Chemistry, Faculty of Chemistry, Bu Ali Sina University, Hamedan 6517838683, Iran
Fax +98(811)8257407; E-mail: mahmoudnasr81@gmail.com
b
Received 26 June 2009
Although several procedures have been developed for the
synthesis of imidazo[2,1-b][1,3]thiazoles,12 no examples
involving arylation of a thiazolium alkyne by Pd/Cu-cata-
lyzed (Sonogashira coupling) reactions have been report-
ed in the literature.
Abstract: The reaction of iodobenzenes with 2-amino-3-(2-pro-
pynyl)-1,3-thiazolium bromide and 2-imino-3-(2-propynyl)-1,3-
benzothiazole, catalyzed by Pd/Cu, leads to the formation of 6-sub-
stituted imidazo[2,1-b][1,3]thiazoles and 2-substituted imida-
zo[2,1-b][1,3]benzothiazoles, respectively.
In continuation of our recent studies,13 we were interested
in developing a synthetic route to 6-substituted imida-
zo[2,1-b][1,3]thiazoles 5a–f and 2-substituted imida-
zo[2,1-b][1,3]benzothiazoles 6a,b using Pd2(dba)3,
copper iodide, and sodium lauryl sulfate in water and
DMF (Scheme 1 and Table 1).
Key words: Sonogashira coupling, aryl iodide, imidazothiazole,
Pd-catalyzed, sodium lauryl sulfate
Compounds containing the imidazo[2,1-b][1,3]thiazole
skeleton have been used as anthelmintic agents, antihy-
pertensives, anti-inflammatories, immunosuppressive
agents, fungicides, herbicides, antitumor agents, and car-
diotonic agents.1 Considering the potent bioactivities of
compounds possessing an imidazothiazole core, the de-
velopment of a new strategy to synthesize 6-substituted
imidazo[2,1-b]thiazoles and 2-substituted imidazo[2,1-
b]benzothiazoles efficiently attracted our attention.
S
S
NH2
Br–
N
N+
N
Pd2(dba)3 (5 mol%)
CuI (10 mol%)
CH2Ar
N
5a–f
2
ArI
4a–f
+
Cs2CO3, surfactant
H2O–DMF
S
N
N
The Sonogashira reaction, palladium- and copper-cocata-
lyzed coupling of terminal alkynes with aryl and vinyl ha-
lides, is a widely used C–C bond-forming reaction.2,3 It
provides an efficient route to aryl alkynes, which are in-
teresting intermediates for the preparation of a variety of
target compounds with applications ranging from natural
products4 and pharmaceuticals5 to molecular organic ma-
terials.6 Due to the utility of the products, the development
of new catalyst systems has received considerable atten-
tion.
NH
CH2Ar
S
6a,b
3
Scheme 1
In this letter, we report that treatment of 2-aminothiazole
(1) with propargyl bromide in refluxing acetonitrile af-
fords 2-amino-3-(2-propynyl)-1,3-thiazolium bromide (2)
1
in good yield (Scheme 2). The H NMR spectrum of 2
showed a CH proton signal at d = 3.73 ppm, CH2 protons
at d = 5.03 ppm, and a single resonance for the NH2 group
at d = 9.78 ppm; this signal was removed on deuteration.
The reaction is generally carried out in organic solvents
such as benzene, toluene, THF, DMF, and dioxane. It
requires a base, which is usually an amine such as tri-
ethylamine, diethylamine, and diisopropylethylamine.
The most widely used catalysts are Pd(PPh3)2Cl2 and
Pd(PPh3)4 in conjunction with copper(I) iodide.7
CH
C
N
Br–
NH2
N
NH2
MeCN
+
BrH2C
C CH
To extend the Sonogashira reaction for fine-chemical ap-
plications, numerous studies have been reported in the lit-
erature over the last 15 years including the use of a phase-
transfer agent,8 reaction in ionic liquids,9 copper-free ver-
sions,10 and the use of promoters such as Zn, Mg, Sn, and
R4NI.11
S
reflux, 1 h
S
1
Scheme 2
When compound 2 was reacted with aryl iodides 4a–f and
cesium carbonate in the presence of Pd2(dba)3, copper
iodide, and sodium lauryl sulfate at 60 °C, 6-substituted
imidazo[2,1-b][1,3]thiazoles 5a–f were obtained in mod-
erate to high yields (Scheme 1). The reactions were car-
ried out under an argon atmosphere, DMF, water, and
cesium carbonate were degassed prior to use.
SYNLETT 2009, No. 16, pp 2601–2604
x
x
.x
x
.2
0
0
9
Advanced online publication: 14.09.2009
DOI: 10.1055/s-0029-1217980; Art ID: D16909ST
© Georg Thieme Verlag Stuttgart · New York

2602
T. A. Kamali et al.
LETTER
Recently, the synthesis of 2-substituted imidazo[2,1- In conclusion, we have developed a successful palladium-
b][1,3]benzothiazoles has been reported by Bakherad and catalyzed reaction for the synthesis of 6-substituted imi-
co-workers using (PPh3)2PdCl2 and CuI.14 Now we report dazo[2,1-b][1,3]thiazoles and 2-substituted imidazo[2,1-
an efficient method for the preparation of 2-substituted b][1,3]benzothiazoles in the presence of sodium lauryl
imidazo[2,1-b][1,3]benzothiazole derivatives 6a,b using sulfate as the surfactant and cesium carbonate as the base.
Pd2(dba)3, copper iodide, and sodium lauryl sulfate.
As shown in Table 1, the presence of electron-withdraw-
ing groups such as NO2 and Cl on the aryl iodide is essen-
tial for successful reaction. When iodobenzene or p-
iodoanisole was used as the aryl iodide, the Sonogashira
coupling was not achieved. In addition, when the 2-ami-
no-3-(2-propynyl)-1,3-thiazolium bromide (2) was used,
the reaction was complete in less time than when the 2-
All reagents were purchased from Merck and Aldrich and used
without further purification. H NMR spectra were recorded on
1
Bruker Avance DRX 500 MHz instruments, using TMS as internal
standard. IR spectra were recorded on a Shimadzu 470 spectropho-
tometer. The elemental analysis was performed using Heraeus
CHN-O-Rapid analyzer. Melting points were taken in open capil-
lary tubes with a Büchi 510 melting point apparatus and were un-
corrected. TLC was performed on Merck-precoated silica gel 60-
imino-3-(2-propynyl)-1,3-benzothiazole (3) was used F254 plates. Mass spectra were recorded on an Agilent technologies
5973 network mass selective detector (MSD) operating at an ioniza-
(compare entries 1, 3, 5–8 with entries 2, 4). The products
were characterized by 1H NMR, 13C NMR, IR, mass spec-
tion potential of 70 eV.
troscopy, and elemental analysis (CHN).
Table 1 Melting Points and Yields of 6-Substituted Imidazo[2,1-b][1,3]thiazoles 5a–f and 2-Substituted Imidazo[2,1-b][1,3]benzothiazoles
6a,b
Entry
Substrate
Ar
Product
Time (h)
Yield (%)a
mp (lit. mp)
S
NH2
Br–
1
5a
11
78
224–225
N+
NO2
NO2
2
3
4
5
6a
5b
6b
5c
14
11
14
11
72
89
83
80
282–283 (281–28211)
N
S
NH
S
NH2
Br–
229–230
N+
NO2
289–291 (289–29011)
N
S
NO2
NH
S
H3C
NH2
Br–
254–255
N+
NO2
NO2
Cl
S
Cl
NH2
Br–
6
7
8
5d
5e
5f
11
11
11
80
90
80
209–210
231–232
243–244
N+
S
O2N
NH2
Br–
N+
S
NO2
Cl
NH2
Br–
N+
a Yields refer to the pure isolated products.
Synlett 2009, No. 16, 2601–2604 © Thieme Stuttgart · New York

LETTER
Synthesis of 6-Substituted Imidazo[2,1-b][1,3]thiazoles
2603
Preparation of 2-Amino-3-(2-propynyl)-1,3-thiazolium Bro-
mide (2)
6-(2-Chloro-4-nitrobenzyl)imidazo[2,1-b][1,3]thiazole (5d,
Table 1, Entry 7)
A mixture of 2-aminothiazole (1, 2 g, 20 mmol) and propargyl bro-
mide (2 mL, 24 mmol) in MeCN (10 mL) was heated under reflux
for 1 h. The precipitate formed was filtered off and recrystallized
from MeCN to afford the title compound; yield 95%; mp 159–
160 °C. 1H NMR (500 MHz, DMSO-d6): d = 3.73 (t, J = 2.4 Hz, 1
H, CH), 5.03 (d, J = 2.3 Hz, 2 H, CH2), 7.07 (d, J = 4.5 Hz, 1 H, CH
of thiazole), 7.50 (d, J = 4.5 Hz, 1 H, CH of thiazole), 9.78 (s, 2 H,
NH2). IR (KBr): 3300, 3250, 2150 cm–1. MS (EI): m/z (%) = 220
(22) [M+(81Br)], 218 (22) [M+(79Br)], 139 (100), 112 (18), 99 (20),
80 (22), 58 (26), 45 (27). Anal. Calcd (%) for C6H7BrN2S: C, 32.89;
H, 3.22; N, 12.79, S, 14.63. Found: C, 32.65; H, 3.03; N, 12.55, S,
14.47.
1H NMR (500 MHz, DMSO-d6): d = 4.28 (s, 2 H, CH2), 7.24–8.28
(m, 5 H, thiazole, ArH), 8.32 (s, 1 H, CH of imidazole). 13C NMR
(125 MHz, DMSO-d6): d = 34.9, 109.5, 123.2, 123.8, 128.3, 130.6,
131.2, 131.9, 132.2, 133.9, 151.1, 155.1. IR (KBr): 1525, 1340 cm–
1. MS (EI): m/z (%) = 295 (10) [M+(37Cl)], 293 (28) [M+(35Cl)], 247
(100), 212 (42), 156 (37), 137 (22). Anal. Calcd (%) for
C12H8ClN3O2S: C, 49.07; H, 2.75; N, 14.31; S, 10.92. Found: C,
49.29; H, 2.87; N, 14.20; S, 11.02.
6-(4-Chloro-2-nitrobenzyl)imidazo[2,1-b][1,3]thiazole (5e,
Table 1, Entry 9)
1H NMR (500 MHz, DMSO-d6): d = 4.34 (s, 2 H, CH2), 7.26–7.93
(m, 5 H, thiazole, ArH), 8.08 (s, 1 H, CH of imidazole). 13C NMR
(125 MHz, DMSO-d6): d = 35.5, 110.3, 123.6, 129.2, 130.1, 130.9,
131.5, 132.0, 132.7, 134.3, 148.9, 155.5. IR (KBr): 1520, 1340 cm–
1. MS (EI): m/z (%) = 295 (7) [M+(37Cl)], 293 (18) [M+(35Cl)], 276
(100), 248 (75), 213 (50), 153 (42), 127 (40), 111 (38). Anal. Calcd
(%) for C12H8ClN3O2S: C, 49.07; H, 2.75; N, 14.31; S, 10.92.
Found: C, 48.88; H, 2.62; N, 14.47; S, 10.77.
General Procedure for the Preparation of 6-Substituted Imida-
zo[2,1-b][1,3]thiazoles and 2-Substituted Imidazo[2,1-b][1,3]-
benzothiazoles
A mixture of aryl iodide 4a–f (1 mmol), Pd2(dba)3 (5 mol%), CuI
(10 mol%), sodium lauryl sulfate (10 mol%), and Cs2CO3 (3 mmol)
was stirred in DMF (1 mL) and H2O (4 mL) at 60 °C for 35 min un-
der an argon atmosphere. 2-Amino-3-(2-propynyl)-1,3-thiazolium
bromide (2, 1 mmol) or 2-imino-3-(2-propynyl)-1,3-benzothiazole
(3, 1 mmol) was then added, and the mixture was stirred at 60 °C for
11 h and 14 h, respectively. After completion of the reaction, the re-
sulting solution was concentrated in vacuo, and the crude product
was subjected to silica gel column chromatography using CHCl3–
MeOH (95:5) as eluent to afford the pure product (Table 1). All the
products 6a,b are known compounds, and the spectroscopic data
and melting points were identical to those reported in the litera-
ture.14 The spectroscopic data of six representative 6-substituted
imidazo[2,1-b][1,3]thiazoles are given below.
6-(4-Chloro-3-nitrobenzyl)imidazo[2,1-b][1,3]thiazole (5f,
Table 1, Entry 11)
1H NMR (500 MHz, DMSO-d6): d = 4.13 (s, 2 H, CH2), 7.25–7.95
(m, 5 H, thiazole, ArH), 8.02 (s, 1 H, CH of imidazole). 13C NMR
(125 MHz, DMSO-d6): d = 34.9, 109.9, 127.0, 129.1, 129.9, 130.6,
131.1, 134.9, 135.6, 136.0, 148.8, 154.5. IR (KBr): 1530, 1350 cm–
1. MS (EI): m/z (%) = 295 (13) [M+(37Cl)], 293 (40) [M+(35Cl)], 248
(100), 214 (35), 156 (42), 138 (15). Anal. Calcd (%) for
C12H8ClN3O2S: C, 49.07; H, 2.75; N, 14.31; S, 10.92. Found: C,
49.23; H, 2.90; N, 14.45; S, 10.81.
6-(2-Nitrobenzyl)imidazo[2,1-b][1,3]thiazole (5a, Table 1, Entry
1)
Acknowledgment
1H NMR (500 MHz, DMSO-d6): d = 4.25 (s, 2 H, CH2), 6.95–7.96
(m, 6 H, thiazole, ArH), 8.63 (s, 1 H, CH of imidazole). 13C NMR
(125 MHz, DMSO-d6): d = 35.3, 110.5, 122.5, 124.1, 128.9, 129.8,
130.4, 131.3, 131.9, 134.2, 147.7, 154.6. IR (KBr): 1520, 1340
cm–1. MS (EI): m/z (%) = 259 (45) [M+], 213 (100), 137 (20), 123
(8). Anal. Calcd (%) for C12H9N3O2S: C, 55.59; H, 3.50; N, 16.21;
S, 12.37. Found: C, 55.32; H, 3.36; N, 16.40; S, 12.21.
We are grateful to Bu Ali Sina University and the Moshashimi
Company for the partial support of this research.
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LETTER
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Synlett 2009, No. 16, 2601–2604 © Thieme Stuttgart · New York