Ligand-free copper-catalyzed regioselective C-2 arylation of imidazo[2,1-b]thiazoles

Article abstract of DOI:10.1021/ol2021109

An effective, regioselective C-2 arylation of imidazo[2,1-b]thiazoles catalyzed by Cu(I) has been developed. This arylation proceeded smoothly without promotion of the ligands, and various functional (22 samples) groups were well tolerated. Preliminary mechanistic studies of this arylation are also reported.

Full text of DOI:10.1021/ol2021109

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5224–5227
Ligand-Free Copper-Catalyzed
Regioselective C-2 Arylation of
Imidazo[2,1-b]thiazoles
Guoli Huang,† Hongsheng Sun,† Xiaojie Qiu,†,‡ Can Jin,† Chen Lin,† Yingzhong Shen,‡
Juli Jiang,*,† and Leyong Wang*,†
Key Laboratory of Mesoscopic Chemistry of MOE, Institute of Chemical Biology and
Drug Innovation, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China, and College of Material Science and Technology,
Nanjing University of Aeronautics and Astronautics, Nanjing 210016, China
jjl@nju.edu.cn; lywang@nju.edu.cn.
Received August 3, 2011
ABSTRACT
An effective, regioselective C-2 arylation of imidazo[2,1-b]thiazoles catalyzed by Cu(I) has been developed. This arylation proceeded smoothly
without promotion of the ligands, and various functional (22 samples) groups were well tolerated. Preliminary mechanistic studies of this arylation
are also reported.
Many natural products and biologically active com-
pounds containing imidazo[2,1-b]thiazole moieties have
been discovered and synthesized so far.1 As some typical
examples, anthelmintics tetramisole (i),2 thieno[3,2-d]
pyrimidinone (ii),3 5,6-diarylimidazo[2,1-b][1,3]thiazoles
(iii),4 C-2 aryl-substituted pilicides (iv),5 and 11C-labeled
imidazo[2,1-b]benzothiazoles (v)6 all showed effective
biological and medicinal activity (Figure 1). Milne et al.7
described the identification and characterization of a
molecule (vi) bearing imidazo[2,1-b]thiazole as an acti-
vator of SIRT1, which was structurally unrelated to,
and 1000-fold more potent, than resveratrol. And it can
bind to the SIRT1 enzymeꢀpeptide substrate complex
at an allosteric site amino terminal to the catalytic
domain and lower the Michaelis constant for acetylated
substrates.
Imidazo[2,1-b]thiazoles designed with the desired
substituents in appropriate positions were often speci-
fic (Figure 1). Current strategies for preparing imidazo-
[2,1-b]thiazole derivatives are focused on the construc-
tion of the fused ring with the desired aryl substituents
or hopeful heterocycles at oriented position in advance.8
To the best of our knowledge, there has been no re-
ported example of direct arylation of the imidazo[2,1-b]-
thiazole core.
† Nanjing University.
‡ Nanjing University of Aeronautics and Astronautics.
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r
10.1021/ol2021109
Published on Web 09/13/2011
2011 American Chemical Society

Table 1. Pd-Catalyzed Arylation of Imidazo[2,1-b]thiazolea
entry
conditions
solvent yields of 3a/3a0b (%)
1
2
3
Pd(OAc)2/K3PO4/t-BuCO2Hd DMF
5/6
Pd(PPh3)2Cl2/KOAc/H2Oe
NMP
22/13 (15)c
19/3
f
Pd(OAc)2/PPh3/K2CO3
dioxane
a Reaction was performed with 1a (0.5 mmol) and 2a (1.5 mmol) in 1
mL of solvent. b Unless specified, the yield was estimated by 1H NMR.
c Isolated yield of 3a. d See ref 10i. e See ref 16. f See ref 21.
Figure 1. Imidazo[2,1-b]thiazoles with biological and medicinal
activity.
The concept of direct arylation via CꢀH bond cleavage
has received substantial attention over the past few years.9
Expensive metal-catalyzed sp2 CꢀH bond arylations such
as palladium,10 rhodium,11 or ruthenium12 have
undergone explosive growth in the past few years. Less-
expensive copper,13 iron,14 and nickel15 compounds have
also shown to be highly active in catalytic direct arylations
in recent years and have great potential for future
development.9c,d Although metal-catalyzed arylations on
various heterocyclic systems such as indolizines,16
imidazo[1,5-a]pyrazines,17 xanthines,18 and thiazoles19 ex-
ist, no direct, regioselective arylation of the imidazo[2,1-
b]thiazole core have been developed so far.
3-Methyl-6-phenylimidazo[2,1-b]thiazole (1a) was se-
lected as a substrate to investigate the possibility of aryla-
tion. In this substrate (1a), the activity of the C2ꢀH bond
was clearly different from that of the C5ꢀH bond, deduced
from their different chemical shifts (6.39 ppm for C2ꢀH
and 7.61 ppm for C5ꢀH).20 We initially tested direct
arylation of 1a using typical Pd-catalyzed conditions opti-
mized in the literature.10i,16,21 As shown in Table 1, these
approachs were largely unsuccessful. Both 3a, C-2 arylated
product, and 3a0, C-5 arylated product, were obtained in
poor yields,22 and byproduct biphenyl was also found in
the reaction (<5% yield).
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Org. Lett., Vol. 13, No. 19, 2011
5225

Table 2. Cu-Catalyzed C-2 Arylation of Imidazo[2,1-b]thiazolea
Table 3. Scope of Cu-Catalyzed Arylation of Imidazo[2,1-b]
thiazolea
entry
[Cu]
solventb
yield of 3ac (%)
entry
Ar
R1
R2
product (% yield)b
1
2
CuI
DMF/xylene (1:1)
DMF/xylene (1:1)
DMF/xylene (1:1)
DMF/xylene (1:1)
DMF/xylene (1:1)
DMF/xylene (1:1)
DMF/xylene (1:1)
DMF/xylene (1:1)
DMF/xylene (1:1)
DMF
87
CuCl
CuBr
89
1
2
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
Ph
3a (89) (94)c
3b (91) (97)c
3c (91)
3d (87)
3e (70)
3f (87)
3
87
4-CH3C6H4
4-OCH3C6H4
4-FC6H4
Ph
4
CuCN
CuCl2
80
3
Ph
5
76
4
Ph
6
CuCl2 2H2O
51
3
5
4-CF3C6H4
3-OCH3C6H4
2-C2H5C6H4
1-naphthyl
Ph
Ph
7
Cu(OAc)2 2H2O
68d
54d
62d
81
3
6
Ph
8
Cu(OTf)2
Cu(acac)2
CuCl
7
Ph
3g (94)
3h (97)
3i (80)
9
8
Ph
10
11
12
9
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
CuCl
DMA
94 (89)d
82
10
11
12
13
14
15
16
17
18
19
20
21
22
4-CH3C6H4
4-OCH3C6H4
4-FC6H4
3j (84)
CuCl
DMA/xylene (1:1)
3k (87)
3l (72)
a The reaction was performed with 1a (0.5 mmol) and 2a (1.5 mmol)
in 1 mL of solvent at 140 °C for 18 h. b Substrate concentration = 0.5 M.
c Unless specified, the yield was estimated by 1H NMR. d Isolated
yield.
2-C2H5C6H4
3-OCH3C6H4
1-naphthyl
Ph
3m (92)
3n (81)
3o (95)
3p (98)
3q (91)
3r (92)
3s (86)
3t (74)
4-CH3C6H4
4-OCH3C6H4
2-C2H5C6H4
4-FC6H4
Ph
Ph
Copper, as the first transition metal used to promote
CꢀH bond functionalization, appeared tobeunderutilized
as a catalyst for CꢀH bond arylation.23 The successful
Cu-catalyzed arylation by Daugulis13a,b inspired us to
attempt the possible direct arylation of imidazo[2,1-b]
thiazole by Cu catalyst. The initial reaction was per-
formed with 1a and iodobenzene 2a as reactants,
t-BuOLi as a base, and DMFꢀxylene mixture as
a solvent (Table 2). To our surprise, four Cu(I) salts
showed good yields uniformly (entries 1ꢀ4). More pro-
misingly, only regioselectively C-2-arylated imidazo[2,1-b]-
thiazole product was obtained, and no side product
biphenyl was found. Unambiguous confirmation of the
structure of a representative C-2-arylated product was
obtained in the form of the X-ray structure of com-
pound 3a20.
Ph
Ph
Ph
Ph
Ph
Ph
4-CF3C6H4
1-naphthyl
Ph
Ph
3u (84)
3v (98)
Ph
Ph
a The reaction was performed with 1 (0.5 mmol), 2 (1.5 mmol),
t-BuOLi (2.0 equiv), and CuCl (20 mol %) in 1 mL of DMA at 140 °C
for 18 h. b Isolated yield after column chromatography of the crude.
c Determination from 1H NMR.
unsuccessful. We then tested other alkoxide bases, t-BuOK
and t-BuONa, and yields of 24% and 59% were obtained,
respectively. No arylated product was found without
bases. Furthermore, PhBr or PhCl, instead of PhI, only
gave traces of product under optimized conditions. Opti-
mization experiments indicated that the best result for C-2
arylation of imidazo[2,1-b]thiazoles was obtained in the
presence of CuCl (20 mol %), aryl iodides (3.0 equiv), and
t-BuOLi (2.0 equiv) in DMA at 140 °C.
With optimized conditions in hand, the scope with
respect to aryl iodides and imidazo[2,1-b]thiazoles was
investigated (Table 3). A variety of functional groups on
the substituents of the aryl iodides were well-tolerated.
The electron-deficient and electron-rich aryl iodides were reac-
tive in moderate to excellent yields (entries 1ꢀ8). Electron-
rich aryl iodides gave a slightly higher yield than electron-
deficient ones under the optimized conditions (entries 2,
3 vs entries 4, 5). Substantial steric hindrance was tolerated
on the aryl iodides at the para-, meta-, and ortho-positions
(entries 3 vs 6 vs 7) and afforded good results. Most
As shown in Table 2, Cu(II) salts, CuCl2, CuCl2 2H2O,
Cu(OAc)2 2H2O, Cu(OTf)2, and Cu(acac)2, were also
3
3
tested in our studies and found to be effective but a little
less active than Cu(I) (entries 5ꢀ9). Subsequently, we
explored the effects of the solvent, base, and Cu-catalyst
loading in the arylation. Equally good results were ob-
tained in DMF or DMAꢀxylene mixtures, and DMA
afforded the highest yields (94%, entry 11). Reducing the
catalyst loading from 20 to 10 and 5 mol % lowered the
yields of product from 94% to 86% and 73%, respectively.
In the absence of the Cu catalyst, no arylated product was
found. With thesepartially optimized arylation conditions,
the bases were investigated, and a variety of weak inor-
ganic bases (K3PO4, Cs2CO3, and K2CO3) were all
(24) Lindley, J. Tetrahedron 1984, 40, 1433.
(25) (a) Do, H. O.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185. (b) Do, H. Q.; Daugulis, O. Org. Lett. 2009, 11,
421.
(23) (a) Steinkopf, W.; Leitsmann, R.; Hofmann, K. H. Liebigs Ann.
Chem. 1941, 546, 180. (b) Nilsson, M. Tetrahedron Lett. 1966, 7, 679. (c)
Bjorklund, C.; Nilsson, M. Acta Chem. Scand. 1968, 22, 2338. (d)
€
Ljusberg, H.; Wahren, R. Acta Chem. Scand. 1973, 27, 2717.
5226
Org. Lett., Vol. 13, No. 19, 2011

Scheme 1. Mechanistic Considerations
Scheme 2. Possible Mechanism for Cu-Catalyzed Arylation of
Imidazo[2,1-b]thiazoles
remarkably, the sterically hindered 1-naphthyl iodide
also gave the desired regioselective C-2 arylation pro-
duct in excellent yield (>95%, entries 8, 15, and 22). It
should be noted that the substrates with aromatic groups
at C-5 and C-3 gave better yields than the aliphatic
groups (entries 1 vs 9 vs 16). Presumably, electronic
effects rather than steric effects played a more important
role in this reaction.
substrate compared to the aliphatic substrate can also be
foreseen.
While monitoring the Cu(II)-catalyzed reaction, we
observed that the purple reaction solution turned into a
brown solution, just as the reaction with Cu(I) salt. This
color change phenomenon can be understood on the
basis of the catalytic cycle in Scheme 2. Cu(II) was
initially transformed to Cu(I) and entered the cycle13c
to accumulate the reaction. It was also understood that
Cu(II) showed somewhat low reactivity relative to
Cu(I).
In summary, an efficient, ligandless copper-catalyzed
method for the regioselective arylation of imidazo[2,1-b]
thiazole was first developed. This protocol provided a
new avenue for developing CꢀC bond-forming reac-
tions of fused heteroarene. The best result was obtained
with copper(I) catalyst, aryl iodide coupling partner,
DMA solvent, and t-BuOLi base. Mechanistic investi-
gations of the arylation process were also described.
Further research will be focused on alkylation of
imidazo[2,1-b]thiazole with aliphatic iodide in the pre-
sence of Cu(I).
Naturally, we were interested in elucidating the me-
chanism for this arylation reaction and carried out
preliminary mechanistic investigations of the coupling
process. (i) Cu-assisted benzyne-type mechanisms,24 (ii)
deprotonationꢀmetalation mechanisms, and (iii) typical
FꢀC alkylations were considered. C6D5I was applied to
the optimized conditions for mechanistic consideration
(Scheme 1). Only compound 5, instead of 4, was found in
the reaction, and no HꢀD exchange was observed. This
result could not support the assumption that the re-
action proceeded via a copper-assisted benzyne-type
mechanism. And, according to the result that no desired
arylated product was found without bases, the possibi-
lity of typical FꢀC alkylation was excluded because in
typical FꢀC alkylation a Lewis acid is always necessary
as catalyst.
Detailed mechanistic insight into this catalytic system
led to the proposition that the addition between Cu(I) and
heterocycle gavethe unstablecationicintermediates6, then
C2ꢀH proton was removed by t-BuOLi (Scheme 2) to give
the organocopper species (7).25 Reaction of 7 with aryl
iodide gave a possilble cu(III)ꢀaryl species (8), and the
desired arylation product was obtained by a reductive
elimination from 8. 8 was proposed to be involved as a
key intermediate. Imidazo[2,1-b]thiazole contains both a
π-deficient ring and a π-excessive ring. 8 formed at C-2 of
the π-excessive thiazole ring should be more stable than the
copper(III)ꢀaryl species formed at C-5 of the π-deficient
imidazole ring. Moreover, the possibility of neighbored-S
atom strong concerted coordination made 8 more stable.
Futhermore, cu(III)ꢀaryl species from electron-rich aryl
iodides were more stable than electron-deficient ones, and
as a result, electron-rich aryl iodides gave higher yields
than electron-deficient aryl iodide as shown in Table 3. In
addition, the better results provided by the aromatic
Acknowledgment. We acknowledge support from the
Natural Science Foundation of China (Nos. 20932004,
21072093), the National Basic Research Program of China
(nos. 2007CB925103, 2011CB808600), the Doctoral Fund
of Ministry of Education of China (20090091110017), and
the fundamental research funds for the central universities
(Nos. 1103020505, 1107020526). We also acknowledge
Dr. Shouyun Yu for discussions about the mechanism.
Supporting Information Available. Crystallographic
data, experimental procedures, and spectroscopic data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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