N-Heterocyclic carbene-palladium(ii)-1-methylimidazole complex catalyzed direct C-H bond arylation of imidazo[1,2-a]pyridines with aryl chlorides

Article abstract of DOI:10.1039/C6OB02704K

We herein reported the N-heterocyclic carbene-palladium(ii)-1-methylimidazole complex catalyzed direct C-H bond arylation of imidazo[1,2-a]pyridines with aryl chlorides. Under suitable conditions, all reactions between various imidazo[1,2-a]pyridines and

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N-Heterocyclic
carbene-palladium(II)-1-methylimidazole
complex
catalyzed direct C-H bond arylation of imidazo[1,2-a]pyridines with aryl
chlorides
Qing-Xian Liu, Bang-Yue He, Peng-Cheng Qian* and Li-Xiong Shao*
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
We herein reported the N-heterocyclic carbene-palladium(II)-1-methylimidazole complex
catalyzed direct C-H bond arylation of imidazo[1,2-a]pyridines with aryl chlorides. Under the
10 suitable conditions, all reactions between various imidazo[1,2-a]pyridines and aryl chlorides
worked well to give the desired C3-H arylated products in acceptable to high yields, giving a
convenient and alternative method for the direct C-H bond arylation of imidazo[1,2-a]pyridines,
using the economic and easily available aryl chlorides as the arylating reagents.
C-H bond arylation using aryl chlorides, we then turned our
interests to the NHC-Pd(II)-Im complex 1 catalyzed direct C-
bond arylation of imidazo[1,2-a]pyridines with aryl
Introduction
H
15 During the past years, the transition metal catalyzed direct C-
H bond functionalization, which at least can avoid pre-
functionalization for one of the substrates, has proven one of
the most efficient methods to construct new carbon-carbon
and carbon-heteroatom bonds.1 As a consequence, the direct
20 C-H bond arylation has also been fully developed, and various
arylating reagents such as aryl halides, arylmetallic reagents,
phenol derivatives, etc., have been used in such
transformation.2 Among them, aryl halides seem to be the
most desirable because of their easy availability and economy.
25 However, in most cases, only the more active, while more
expensive aryl iodides and bromides were successfully
developed, and the economic, stable and easier available aryl
chlorides were rarely used, maybe partially due to the lower
catalytic activity of the metal catalysts developed during the
30 past years. Therefore, much room still remains in the direct C-
H bond arylation, especially using aryl chlorides as the
substrates. From 2011, we have developed a well-defined N-
heterocyclic carbene-palladium(II)-1-methylimidazole [NHC-
Pd(II)-Im] complex 1, and showed it to be a highly efficient
35 catalyst toward not only traditional cross-coupling reactions
such as C-C and C-N coupling reactions,3 but also direct C-H
bond arylation reactions using aryl chlorides as the
substrates.4 For instance, recently, we found that NHC-Pd(II)-
Im complex 1 was an efficient catalyst for the direct C-H bond
40 arylation of (benzo)oxazoles using aryl chlorides as the
arylating reagents, implying that this complex can really
activate the less active aryl chlorides toward C-H bond
arylation reactions very well.4b These results thus prompted us
to further investigate its application in the direct C-H bond
45 arylation of other interesting compounds to expand its impact
in organic synthesis. In this case, imidazo[1,2-a]pyridines
were chosen as the substrates, because such compounds are
frequently found in kinds of natural products and drugs.5
Undoubtedly, the direct C-H bond arylation of imidazo[1,2-
50 a]pyridines was also developed by several groups during the
past years.6 However, to the best of our knowledge, only the
more active aryl bromides, iodides and aryl triflates can be
used as the arylating reagents, and aryl chlorides were rarely
investigated so far.7 Therefore, based on our successful
55 experiences on the NHC-Pd(II)-Im complex 1 catalyzed direct
chlorides. Herein, we report these results in detail.
60 Results and discussion
At the outset of this investigation, the reaction of imidazo[1,2-
a]pyridine 2a (0.5 mmol) with chlorobenzene 3a (0.75 mmol)
catalyzed by NHC-Pd(II)-Im complex
1 (2.0 mol%) in
dioxane (0.5 mL) at 120 oC for 12 h was first carried out to
65 test various bases (3.0 equiv) (Table 1, entries 1-8). As can be
seen from Table 1, among the bases screened, NaOtBu gave
the best yield of 89% (Table 1, entry 1). In the presence of all
other bases, inferior results were found. For example,
acceptable yields (49 and 38%) can still be obtained when
70 KOtBu and KOH were used, respectively (Table 1, entries 2
and 3). In the presence of other bases such as NaOH, Cs2CO3,
K3PO4, LiOtBu and LiOH, very low yields were observed
(Table 1, entries 4-8). Using other bases such as Na2CO3,
NaHCO3, K2CO3, KHCO3, CH3COOK and Li2CO3, no
75 reaction occurred. Subsequently, using NaOtBu as the base,
kinds of solvents were then examined. For example, in these
cases, the best yield of 92% was obtained when THF was used
as the solvent (Table 1, entry 9). When toluene was chosen as
the solvent, good yield can also be obtained (Table 1, entry
80 10). In polar solvents such as DMAc and DMF, very lower
yields were obtained (Table 1, entries 11 and 12), and no
desired product was detected in CH3CN and DMSO,
respectively. Finally, it was found that 3.0 equiv NaOtBu was
necessary for such transformation. For instance, when the
85 amount of NaOtBu decreased to 2.0 equiv for the reaction
shown in entry 9, the yield drastically dropped to 41%. Using
Pd(OAc)2 or PdCl2 as the catalyst instead of NHC-Pd(II)-Im
complex 1, almost no desired product can be detected. Based
on the above tries, the optimized reaction conditions were
90 then established: 2a (0.5 mmol), 3a (0.75 mmol), NaOtBu (3.0
equiv), NHC-Pd(II)-Im complex 1 (2.0 mol%), THF (0.5 mL),
120 oC, 12 h.8
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Page 2 of 4
in all cases. Only 45% yield of the corresponding arylated
product 4k was obtained when 4-vinylphenyl chloride 3k was
30 tested (Table 2, entry 17). Satisfyingly, elevating the
o
temperature to 130 C, the corresponding yield can drastically
increase to 74% (Table 2, entry 18). Acceptable yield was
found when heteroaryl chloride such as 2-chloropyridine was
used (Table 2, entries 19 and 20).
35
Under the optimal conditions, the reactions of imidazo[1,2-
a]pyridine 2a with a variety of aryl chlorides 3 were first
investigated to test the scope and limitation of this
methodology. The results are shown in Table 2. It seems that
under the suitable conditions, all reactions can perform well to
give the desired C3-arylated products 4 in acceptable to good
yields. Substituents on the aryl chlorides 3 affected the
5
10 reactions significantly. That is, aryl chlorides having electron-
rich groups were relatively worse substrates under the optimal
conditions. For example, using 2- or 3-methoxyphenyl
chlorides 3b and 3c, and 4-methylphenyl chloride 3g as the
substrates, lower yields were obtained under identical
15 conditions (Table 2, entries 2, 5 and 12). To our pleasure,
simply increasing the catalyst loading or prolonging the
reaction time, better yields can be still observed (Table 2,
entries 4, 6 and 13). It was found that fluoro-substituted aryl
chlorides are the most suitable substrates. For instance, the
20 best yields were found when 2-, 3- or 4-fluorophenyl
chlorides 3h-j were used as the substrates under the optimal
conditions (Table 2, entries 14-16). In addition, when strongly
electron-poor group substituted aryl chlorides such as 4-
nitrophenyl chloride, 2-cyanophenyl chloride, 3-cyanophenyl
25 chloride, 4-cyanophenyl chloride, 2-acetylphenyl chloride,
were tested in the reactions with imidazo[1,2-a]pyridine 2a
under the optimal conditions, no desired product was detected
Next, the scope of this protocol was further expanded to the
direct C-H bond arylation between various substituted
40 imidazo[1,2-a]pyridines 2 and aryl chlorides 3. As can be seen
from Table 3, all reactions performed well to give the desired
C-H bond arylated products 4 in good to high yields. It seems
that compared to the results involving unsubstituted
imidazo[1,2-a]pyridine 2a illustrated in Table 2, better yields
45 can be observed in most cases (Table 3). Substituents on the
imidazo[1,2-a]pyridines 2 affected the reactions to some
extent. For instance, substrate 2e, having electron-poor 6-
fluoro group, gave relatively worse results (Table 3, entries
19-22). Substituents on the aryl chlorides 3 did not affect the
2
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reactions significantly. For instance, aryl chlorides 3 having
kinds of substituents on both substrates can be tolerated, thus
20 giving an alternative and facile methodology for the direct C-
H bond arylation of imidazo[1,2-a]pyridines.
electron-rich, -neutral and -poor groups were all suitable
substrates in the reactions investigated. In addition, sterically-
hindered 2-fluoroaryl chloride 3h were also good substrate in
such transformation to give the corresponding products 4p, 4u,
4z and 4af in good to high yields (Table 3, entries 4, 9, 16 and
22).
5
Experimental
General Remarks. Melting points are uncorrected. NMR spectra
1
were recorded at 500 MHz (for H NMR) and 125 MHz (for 13C
1
25 NMR), respectively. H and 13C NMR spectra recorded in CDCl3
solutions were referenced to TMS (0.00 ppm) and the residual
solvent peak (77.0 ppm), respectively. J-values are in Hz. All
solvents were dried by standard methods. The mass analyzer type
for the high resolution mass spectra (HRMS) is quadrupole (for
30 ESI). Other commercially obtained reagents were used without
further purification. Flash column chromatography was
performed on silica gel (300-400 mesh).
General procedure for the NHC-Pd(II)-Im complex
1
catalyzed C-H bond arylation of imidazo[1,2-a]pyridines 2
35 with aryl chlorides 3. Under N2 atmosphere, NHC-Pd(II)-Im
complex 1 (2.0 mol%), NaOtBu (3.0 equiv), THF (0.5 mL),
imidazo[1,2-a]pyridines 2 (0.5 mmol), and aryl chlorides 3 (0.75
mmol) were successively added into a sealed tube. The mixture
was stirred vigorously under the conditions shown in Tables 1-3.
40 Then the solvent was removed under reduced pressure and the
residue was purified by flash column chromatography to give the
pure products 4.
Acknowledgement
Peng-Cheng Qian thanks the Financial support from the
45 Foundation of Department of Education, Zhejiang Province
(No. Y201327597) and Natural Science Foundation of
Zhejiang Province (No. LY15B020002).
Notes and references
College of Chemistry and Materials Engineering, Wenzhou University,
50 Chashan University Town, Wenzhou, Zhejiang Province 325035,
People’s Republic of China. Fax: 86 57786689300; Tel: 86 57786689300;
E-mail: Shaolix@wzu.edu.cn
† Electronic Supplementary Information (ESI) available: [1H and 13C
NMR spectra of compounds 4.]. See DOI: 10.1039/b000000x/
55 ‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
1
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60
10 Conclusions
65
In conclusion, it was reported that NHC-Pd(II)-Im complex,
as an air- and moisture-stable catalyst, can promote the direct
C-H bond arylation of imidazo[1,2-a]pyridines using the
challenging aryl chlorides as the arylating reagents. Under the
15 suitable conditions, most reactions performed well enough to
give the desired C3-H bond arylated products in moderate to
high yields. The scope and limitation of such transformation
was fully investigated with various substrates, displaying that
70
75
2
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6
7
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60
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4
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