Pd-catalyzed heterocyclization during sonogashira coupling: Synthesis of 3-aryl-substituted imidazo[2,1-b]thiazoles

Article abstract of DOI:10.1080/10426507.2010.514683

The reaction of 4,5-diphenyl-2-propargylmercaptoimidazole with various aryl iodides catalyzed by Pd-Cu in the presence of triethylamine as base in dimethyl formamide (DMF) leads to the formation of 3-aryl-substituted imidazo[2,1-b]thiazoles.

Full text of DOI:10.1080/10426507.2010.514683

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Phosphorus, Sulfur, and Silicon and the
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Pd-Catalyzed Heterocyclization During
Sonogashira Coupling: Synthesis of 3-
Aryl-substituted Imidazo[2,1-b]thiazoles
Mohammad Bakherad a , Ali Keivanloo a , Hossein Nasr-Isfahani a &
Mersad Raeissi a
a School of Chemistry, Shahrood University of Technology, Shahrood,
Iran
Version of record first published: 04 Aug 2011.
To cite this article: Mohammad Bakherad, Ali Keivanloo, Hossein Nasr-Isfahani & Mersad Raeissi
(2011): Pd-Catalyzed Heterocyclization During Sonogashira Coupling: Synthesis of 3-Aryl-substituted
Imidazo[2,1-b]thiazoles, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:7, 1422-1427
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Phosphorus, Sulfur, and Silicon, 186:1422–1427, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.514683
Pd-CATALYZED HETEROCYCLIZATION DURING
SONOGASHIRA COUPLING: SYNTHESIS OF
3-ARYL-SUBSTITUTED IMIDAZO[2,1-b]THIAZOLES
Mohammad Bakherad, Ali Keivanloo, Hossein Nasr-Isfahani,
and Mersad Raeissi
School of Chemistry, Shahrood University of Technology, Shahrood, Iran
Abstract The reaction of 4,5-diphenyl-2-propargylmercaptoimidazole with various aryl io-
dides catalyzed by Pd-Cu in the presence of triethylamine as base in dimethyl formamide
(DMF) leads to the formation of 3-aryl-substituted imidazo[2,1-b]thiazoles.
Keywords Aryl iodide; imidazothiazole; Pd catalyst; Sonogashira reaction
INTRODUCTION
Sonogashira coupling reaction of terminal alkynes with aryl halides catalyzed over
a Pd(0)/Cu(I) system is a powerful tool in organic synthesis because the reaction directly
provides unique organic compounds having the C(sp2) C(sp) bond.1–6 It provides an efficient
route to aryl alkynes, which are interesting intermediates for the preparation of a variety of
target compounds with applications ranging from natural products7 and pharmaceuticals8
to molecular organic materials.9 Due to the utility of the products, the development of new
catalytic systems has received considerable attention.
The imidazo[2,1-b]thiazole derivatives have been shown to possess antibacterial, anti-
fungal, anthelmintic, antiviral, antiprotozoal, anti-inflammatory, anticonvulsant, anxiolytic,
hypnotic, gastrointestinal, anti-ulcer, and immunomodulatory activities.10–14 Compounds
containing the imidazo[2,1-b][1,3]thiazole skeleton have been used as anthelmintic agents,
antihypertensives, anti-inflammatories, immunosuppressive agents, fungicides, herbicides,
antitumor agents, and cardiotonic agents.15 Considering the potent bioactivities of com-
pounds possessing an imidazothiazole core, the development of a new strategy to synthesize
3-aryl-substituted imidazo[2,1-b]thiazoles efficiently attracted our attention.
In continuation of our recent studies16 on the synthesis of fused heterocycles and
the Pd-catalyzed reaction of acetylenes leading to heterocyclic compounds of biological
significance, we became interested in developing a synthetic route to 3-aryl-substituted
imidazo[2,1-b]thiazoles.
Received 22 June 2010; accepted 8 August 2010.
We gratefully acknowledge the financial support from the Research Council of Shahrood University of
Technology.
Address correspondence to Mohammad Bakherad, Faculty of Chemistry, Shahrood University of Technol-
ogy, Daneshgah Ave., Shahrood, 3619995161, Iran. E-mail: m.bakherad@yahoo.com
1422

Pd-CATALYZED HETEROCYCLIZATION
1423
RESULTS AND DISCUSSION
In this article, we report that treatment of 4,5-diphenyl-1,3-dihydro imidazole-
2-thione 117 with propargyl bromide in refluxing ethanol affords 4,5-diphenyl-2-
1
propargylmercaptoimidazole 2 in a good yield. The H-NMR spectrum of 2 shows a CH
proton at 3.25 ppm, CH2 protons at 3.98 ppm, and a single resonance for the NH group at
12.82 ppm, which was removed on deuteration.
For preliminary optimization of the reaction conditions, we studied the reaction of
compound 2 with p-iodonitrobenzene as the model reaction, and the effects of the base,
◦
solvent, and catalyst at 70 C were examined (Table 1). First, several bases and solvents
were screened for the reaction in the presence of a catalytic amount of the PdCl2(PPh3)2. It
was found that among the solvents used (dimethyl formamide [DMF], dimethyl acetamid
[DMAC], and N-methyl pyrrolidone [NMP]), DMF was the best choice (entry 1). Among
the organic and inorganic bases tested (Et3N, diisopropylethylamine [DIEA], morpholine,
pyrrolidine, K2CO3, KOH, and Cs2CO3), Et3N proved to be the most efficient (entry 1).
Increasing the amount of palladium catalyst shortened the reaction time but did not increase
the yield of compound 4a (entry 18). A low palladium concentration prolonged the reaction
time and gave a decreased yield (entry 19). Thus, the optimum conditions required 5.0 mol%
of the PdCl2(PPh3)2, 10 mol% of CuI, Et3N as the base, and DMF as the solvent at 70 ◦C
(entry 1).
Using the optimized reaction conditions, when compound 2 was treated in DMF with
aryl iodides 3a–f and triethylamine in the presence of bis(triphenylphosphine)palladium
chloride and copper iodide at 70 ◦C, 3-aryl-substituted imidazo[2,1-b]thiazoles 4a–f were
Table 1 Reaction of Compound 2 with p-Iodonitrobenzene in the Presence of Several Bases and Solventsa
Entry
Solvent
Base
Cat. (mol%)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
NMP
Et3N
DIEAc
Pyrrolidine
Morpholine
K2CO3
Cs2CO3
KOH
Et3N
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
7.0
3.0
12
14
12
15
12
12
16
15
16
15
13
12
14
15
12
14
16
10
15
85
53
57
80
80
78
75
54
43
45
70
73
44
48
68
82
65
85
78
DIEA
NMP
NMP
Pyrrolidine
Morpholine
Et3N
DMAC
DMAC
DMAC
DMAC
Morpholine
Pyrrolidine
DMF
DIEA
Pyrrolidine
Morpholine
Morpholine
Pyrrolidine
Et3N
DMF
Et3N
aReaction conditions: compound 2 (1.2 mmol), p-iodonitrobenzene (1.0 mmol), base (2.0 mmol), CuI
(10 mol%), solvent (5 mL) at 70 ◦C.
bIsolated yield.
cDiisopropylethylamine.

1424
M. BAKHERAD ET AL.
Pd (PPh3)2Cl2
a
ArI
3a-f
Pd (0)
(I)
ArPdI
(II)
H
N
Ph
Ph
Ph
Ph
Ph
Ph
N
N
BrH2C C CH
EtOH
b
S
S
S
N
H
N
H
N
H
CuI
CCu
1
2
(III)
Ph
Ph
Ph
Ph
N
N
N
Ph
Ph
Ph
d
N
N
c
S
S
S
S
N
H
N
H
N
H
C
Ph
C
Pd(0)
ArH2C
CPdAr
CAr
CHAr
4a-f
(VI)
(V)
(IV)
Scheme 1 Proposed mechanism for the formation of 3-aryl-substituted imidazo[2,1-b]thiazoles 4a–f at 70 ◦C:
(a) reduction of Pd(II) to Pd(0) with alkyne and Et3N; (b) CuI, Et3N; (c) isomerization to an allene with CuI,
Et3N; (d) nucleophilic attack on the allene (VI) to generate the product 4a–f.
obtained in good to high yields (Scheme 1, Table 2). The reactions had to be carried out
under an argon atmosphere, and the mixture of DMF and triethylamine had to be degassed
prior to use. [PdCl2(PPh3)2] and triethylamine were found to be the catalyst and base of
choice, respectively. However, cuprous iodide was found to be an essential cocatalyst.
Reactions carried out with either copper (I) iodide or palladium (II) chloride as catalyst
alone led to very poor yields of products.
Mechanistically, the formation of 3-aryl-substituted imidazo[2,1-b]thiazoles involves
the following steps (as shown in Scheme 1): (a) formation of ArPdI (II) through oxidative
addition of Pd(0) (I) to ArI; (b) transmetallation of ArPdI with the Cu salt of (III), generating
the alkynyl palladium species (IV); (c) extrusion of Pd(0) to yield the alkynes (V); and
(d) isomerization to the allenic intermediates16b,18 (VI), which then cyclize to products 4a–f.
CONCLUSION
In conclusion, we have developed a successful palladium-catalyzed reaction for
the synthesis of 3-aryl-substituted imidazo[2,1-b]thiazoles from readily available start-
ing materials. To our knowledge, this is the first reported general procedure for the
palladium–copper–catalyzed synthesis of 3-aryl-substituted imidazo[2,1-b]thiazoles.
EXPERIMENTAL
Synthesis of 4,5-Diphenyl-2-propargylmercaptoimidazole 2
A mixture of 4,5-diphenyl-1,3-dihydro-imidazole-2-thione 1 (2.52 g, 10 mmol) and
propargyl bromide (1 mL, 12 mmol) in EtOH (10 mL) was heated under reflux for 3 h. The

Pd-CATALYZED HETEROCYCLIZATION
1425
Table 2 Yields of 3-Aryl-Substituted Imidazo[2,1-b]thiazoles 4a-fa
Entry
1
Ar
Product
m.p. (◦C)
129–131
Yield (%)
85
4a
2
3
4b
4c
142–144
146–148
78
90
4
4d
138–140
92
5
6
4e
4f
136–138
133–135
80
78
aReaction conditions: 2 (1.2 mmol), 3a–f (1.0 mmol), Et3N (2 mmol), [PdCl2(PPh3)2] (0.05 mmol), CuI
(0.1 mmol), DMF (5 mL) at 70 ◦C for 12 h.
precipitate formed was filtered off and recrystallized from EtOH/H2O to afford the title
compound. Yield, 45%; M.P. 162–164 ◦C; 1H NMR (500 MHz, DMSO-d6 δ ppm): 3.25 (t,
J = 2.6 Hz, 1H, CH), 3.98 (d, J = 2.4 Hz, 2H, CH2), 7.26–7.45 (m, 10H, Ph), 12.84 (broad,
1H, NH); 13C NMR δ (125 MHz, DMSO-d6): 22.0 (CH2), 75.0 (CH, alkyne), 80.5 (CH,
alkyne), 120.9 (CH, phenyl), 127.7 (CH, phenyl), 127.9 (CH, phenyl), 128.7 (CH, phenyl),
128.9 (CH, phenyl), 132.9 (CH, imidazole), 138.7 (CH, imidazole); IR, υ (KBr disc): 3300,
2150 cm−1; Anal. Calcd. for C18H14N2S: C, 74.45; H, 4.86; N, 9.65; S, 11.04%. Found: C,
74.68; H, 4.72; N, 9.82; S, 11.18%.
Synthesis of 3-Aryl-Substituted Imidazo[2,1-b]thiazoles 4a–f
A mixture of the aryl iodide 3a–f (1.0 mmol), [PdCl2(PPh3)2] (0.05 mmol), CuI (0.1
mmol), and triethylamine (2 mmol) was stirred in DMF (5 mL) at room temperature under
an argon atmosphere. 4,5-Diphenyl-2-propargylmercaptoimidazole 2 (1.2 mmol, 0.3 g)
◦
was then added, and the mixture was stirred at 70 C for 12 h. After completion of the
reaction, the resulting solution was concentrated and the crude product was subjected to
silica gel column chromatography using CHCl3–CH3OH (95:5) as the eluent to afford the
pure product (Table 2).

1426
M. BAKHERAD ET AL.
5,6-Diphenyl-3-(4-nitrobenzyl)imidazo[2,1-b]thiazole 4a
1H NMR (500 MHz, DMSO-d6 δ ppm): 4.25 (s, 2H, CH2), 6.90 (s, 1H, CH of thiazol),
7.15–7.55 (m, 9H, ArH), 7.70–8.10 (m, 5H, ArH); 13C NMR δ (125 MHz, DMSO-d6): 31.5,
111.0, 123.0, 124.9, 125.1, 127.9, 128.8, 129.3, 130.7, 131.4, 132.2, 132.8, 133.1, 133.5,
134.2, 146.9, 149.7; IR, υ (KBr disc): 1520, 1345 cm−1. Anal. Calcd. for C24H17N3O2S:
C, 70.06; H, 4.16; N, 10.21; S, 7.79%. Found: C, 70.24; H, 4.30; N, 10.38; S, 7.57%.
5,6-Diphenyl-3-(3-nitrobenzyl)imidazo[2,1-b]thiazole 4b
1H NMR (500 MHz, DMSO-d6 δ ppm): 4.23 (s, 2H, CH2), 6.69 (s, 1H, CH of thiazol),
7.10–7.45 (m, 10H, ArH), 7.60–7.90 (m, 4H, ArH); 13C NMR δ (125 MHz, DMSO-d6):
31.6, 110.7, 122.4, 125.4, 125.7, 128.0, 128.3, 128.9, 129.6, 130.3, 130.8, 131.2, 131.7,
132.5, 133.0, 133.4, 133.9, 148.0, 150.1; IR, υ (KBr disc): 1525, 1340 cm−1; Anal. Calcd.
for C24H17N3O2S: C, 70.06; H, 4.16; N, 10.21; S, 7.79%. Found: C, 70.29; H, 4.28; N,
10.05; S, 7.90%.
5,6-Diphenyl-3-(4-acetobenzyl)imidazo[2,1-b]thiazole 4c
1H NMR (500 MHz, DMSO-d6 δ ppm): 2.52 (s, 3H, CH3), 3.80 (s, 2H, CH2), 6.76
(s, 1H, CH of thiazol), 6.80–7.15 (m, 5H, ArH), 7.30–7.76 (m, 9H, ArH); 13C NMR δ
(125 MHz, DMSO-d6): 27.1, 33.8, 110.8, 124.1, 126.9, 127.1, 128.5, 128.7, 128.9, 129.5,
130.0, 132.1, 132.2, 134.8, 135.6, 142.0, 142.8, 149.1, 197.9; IR, υ (KBr disc): 1690 cm−1
;
Anal. Calcd. for C26H20N2OS: C, 76.44; H, 4.93; N, 6.86; S, 7.85%. Found: C, 76.65; H,
5.07; N, 6.65; S, 7.70%.
5,6-Diphenyl-3-(2-methyl-4-nitrobenzyl)imidazo[2,1-b]thiazole 4d
1H NMR (500 MHz, DMSO-d6 δ ppm): 2.35 (s, 3H, CH3), 4.20 (s, 2H, CH2), 6.82
(s, 1H, CH of thiazol), 6.95–7.50 (m, 8H, ArH), 7.65–7.87 (m, 5H, ArH); 13C NMR δ
(125 MHz, DMSO-d6): 19.0, 31.6, 111.3, 121.5, 124.6, 126.7, 127.1, 127.5, 128.5, 128.6,
129.1, 129.2, 129.5, 129.8, 130.4, 131.9, 131.9, 132.0, 132.5, 134.7, 138.5, 143.5, 146.6;
IR, υ (KBr disc): 1525, 1340 cm−1; Anal. Calcd. for C25H19N3O2S: C, 70.57; H, 4.50; N,
9.88; S, 7.54%. Found: C, 70.80; H, 4.64; N, 9.62; S, 7.71%.
5,6-Diphenyl-3-(4-chloro-3-nitrobenzyl)imidazo[2,1-b]thiazole 4e
1H NMR (500 MHz, DMSO-d6 δ ppm): 3.86 (s, 2H, CH2), 6.97 (s, 1H, CH of thiazol),
7.05–7.26 (m, 5H, ArH), 7.32–7.54 (m, 8H, ArH);13C NMR δ (125 MHz, DMSO-d6): 31.8,
110.6, 125.6, 126.9, 128.1, 128.2, 128.8, 128.9, 129.4, 130.5, 130.8, 131.5, 131.8, 132.8,
133.4, 133.8, 134.0, 147.9, 149.4; IR, υ (KBr disc): 1520, 1335 cm−1; Anal. Calcd. for
C24H16ClN3O2S: C, 64.64; H, 3.62; N, 9.42; S, 7.19%. Found: C, 64.42; H, 3.76; N, 9.62;
S, 7.36%.
5,6-Diphenyl-3-(4-chloro-2-nitrobenzyl)imidazo[2,1-b]thiazole 4f
1H NMR (500 MHz, DMSO-d6 δ ppm): 4.10 (s, 2H, CH2), 6.50 (s, 1H, CH of
thiazol), 6.80–7.25 (m, 8H, ArH), 7.30–7.45 (m, 4H, ArH), 7.92 (s, 1H, ArH); 13C NMR δ

Pd-CATALYZED HETEROCYCLIZATION
1427
(125 MHz, DMSO-d6): 31.7, 110.5, 124.9, 125.8, 127.9, 128.2, 128.4, 128.8, 129.3, 129.8,
130.4, 130.7, 131.5, 132.2, 132.9, 133.9, 134.1, 147.6, 149.6; IR, υ (KBr disc): 1545, 1350
cm−1; Anal. Calcd. for C24H16ClN3O2S: C, 64.64; H, 3.62; N, 9.42; S, 7.19%. Found: C,
64.48; H, 3.48; N, 9.23; S, 7.02%.
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