Cross-coupling reactions catalyzed by an N-heterocyclic carbene-Pd(ii) complex under aerobic and CuI-free conditions

Article abstract of DOI:10.1039/c4ra02480j

A Pd-complex, (Cat. 3), has been successfully employed as a highly efficient and recyclable catalyst for the Sonogashira and Heck reactions of aryl bromides with various terminal acetylenes and olefins. The catalytic reactions proceed with excellent yields with a low catalyst loading (1.0 mol%) under aerobic and CuI-free conditions. A plausible mechanism has also been proposed for the reaction. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra02480j

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Cross-coupling reactions catalyzed by an
N-heterocyclic carbene–Pd(II) complex under
aerobic and CuI-free conditions†
Cite this: RSC Adv., 2014, 4, 30447
a
a
a
a
b
*
*
Hongfei Lu, Lin Wang, Feifei Yang, Runze Wu and Wei Shen
Received 21st March 2014
Accepted 19th June 2014
A Pd-complex, (Cat. 3), has been successfully employed as a highly efficient and recyclable catalyst for the
Sonogashira and Heck reactions of aryl bromides with various terminal acetylenes and olefins. The catalytic
reactions proceed with excellent yields with a low catalyst loading (1.0 mol%) under aerobic and CuI-free
conditions. A plausible mechanism has also been proposed for the reaction.
DOI: 10.1039/c4ra02480j
www.rsc.org/advances
The palladium catalyzed cross-coupling reaction is one of the Organ highlighted that bulky yet exible NHC ligands were able
most powerful tools for the construction of C–C bonds.1 The to circumvent various limitations of cross-coupling reac-
exemplary cross-coupling methodologies encompass Suzuki tions.9c,12 Encouraged by the excellent yields of [Pd–NHC]
reactions,1e,2 Heck reactions and Sonogashira reactions.3 In the complex (IPr*–Pd(II)–Py, Catalyst 3) mediated Suzuki couplings
Heck and Sonogashira reactions, despite numerous other of aryl bromides and arylsulfonates with arylboronic acids
metals proved to be effective for such reactions,5 conventional under aerobic conditions, we further proceeded to investigate
palladium complexes such as PdCl2(PPh3)2,3,4 oen in combi- its application in other cross-couplings.
nation with copper(I) salts, are still the most preferred ones.
We report herein that Cat. 3 efficiently catalyzes Heck and
Although the ligands of those palladium complexes are air- Sonogashira reactions under CuI-free condition with low cata-
sensitive phosphine-based structures of limited practicality, the lyst loading (1.0 mol%) in the absence of the protection of inert
catalysts are still being widely employed because the cross- atmosphere (Schemes 1 and 2).
coupling conditions are generally compatible with a broad
In our previous study of cross-coupling reactions (Scheme 3),
library of functionalities. Most noticeably, a large number of it was found that the catalyst Cat. 3 is highly efficient for the
modied protocols have also been developed to expand the Suzuki cross-coupling reaction, and the yield of the idea prod-
scope of the applications.5a,6
ucts are measured up to 93%.13 Considering the good catalytic
Ever since the initial discovery of the cross-coupling reac-
tions, tremendous endeavor has recently been focused on
searching for alternatives, among which electrophiles and aryl
tosylates have been proven to be a new class of practical
surrogates to aryl halides.1c,7 Compared to arylhalides, aryl
tosylates are usually less expensive and more readily available
from phenols.8 Nonetheless, more efficient, moisture- and air-
insensitive palladium catalysts6a,9c,e,10 are still being called for to
affect the Sonogashira and Heck reaction with low catalyst
loadings under copper-free6e,9 and less rigorously anhydrous
and anaerobic conditions.9f,11
During the past twenty years, signicant advances have been
made to develop N-heterocyclic carbenes (NHCs) and their
metal complexes to facilitate various organic transformations.
Scheme 1 Catalysts.
aSchool of Biological and Chemical Engineering, Jiangsu University of Science and
Technology, Zhenjiang, China. E-mail: zjluhf1979@hotmail.com
bJiangsu Key Laboratory of Pesticide Science, College of Science, Nanjing Agricultural
University, Nanjing, China. E-mail: swgdj@njau.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra02480j
Scheme 2 Pd(II) catalysts.
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The base oen plays an important role in the Sonogashira
cross-coupling reactions, different kinds of bases were then
screened (entries 10–12). As shown in the Table 1, organic bases
are effective in the present catalytic system, especially TEA.
However, inorganic bases are less effective and gave moderate
yield of the target product. No conversion was observed in the
absence of base.
With the optimized reaction conditions in hand, a variety of
aryl bromides, aryl tosylates and terminal alkynes have been
examined for their generality. The results are summarized in
Tables 2 and 3.
As demonstrated in Table 2, all the reactions proceeded
smoothly under the optimum reaction conditions, and the
desired products were formed in good yields (63–89%),
showing its wide substrate tolerance. Reaction of aryl bromides
with electron-withdrawing substituents such as cyano (Table 2,
entries 4 and 9) with phenylacetylene and 4-ethynyltoluene
Scheme 3 Suzuki cross-coupling reactions.
performance of Cat. 3, we were encouraged to investigate the
catalytic activity of the present catalyst for the Sonogashira and
Heck reactions.
In the presence of substrate, Pd(II) complex catalytic system
is efficient in the reactions (Fig. 1). Great attention should be
paid to Cat. 3, which performed much better than that of the
others, and the Pd(II) catalysts (Cat. 4, Cat. 5 and Cat. 6) without
co-catalyst Cu(I) performed not well than Cat. 3. We proposed
that this phenomenon may attribute to the electron-with-
drawing group, which could improve the catalyze activity of the
complex system (Fig. 1, 4d). Therefore, in this article, we chose
Cat. 3 as the catalyst model to the following research.
To verify the solvent and base effects on Sonogashira
coupling reactions, we investigated the Sonogashira coupling
reaction with the present catalyst using the coupling of bro-
mobenzene with phenylacetylene as a model reaction to eval-
uate the reaction conditions (Table 1).
Table 1 Optimal conditions for Cat. 3 catalyzed Sonogashira reaction
of bromobenzene and phenylacetylene
Entrya Solvent Base
Temperature (ꢀC) Time (h) Yieldb (%)
We initiated our investigation by screening for reaction
conditions under which the Sonogashira reaction would
proceed in the presence of oxygen, and in the absence of copper
and phosphine. We observed that the yields of the desired
coupling products could be isolated aer 1.5 h at 25 ꢀC to 80 ꢀC
in DMSO using Cat. 3 (catalyst loading 1.0 mol%), and TEA as
base under aerobic conditions (Table 1, entries 1–4). Never-
theless, when the temperature was set up to 90 ꢀC (Table 1,
entry 5), the increasing trend of the isolated yield was dramat-
ically decreased (only 3%). Measurable yields were also
observed with the different solvents including Dioxane, DMF
and Toluene (Table 1, entries 6, 7 and 8), however, Toluene as
the solvent, gave a much lower amount of conversions than that
of other solvents (Table 1, entry 8).
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
Dioxane Et3N
DMF Et3N
Toluene Et3N
DMSO
DMSO
DMSO
DMSO
Et3N
Et3N
Et3N
Et3N
Et3N
25
40
60
80
90
80
80
80
80
1
1
1
1
1
3
2.5
4
1
Trace
21
63
86
89
78
76
20
9
K2CO3
Piperidine 80
Pyridine
No base
42
81
82
10
11
12
1
1
1
80
80
No reaction
a
Reaction conditions: 2a (1.2 mmol), 3a (0.8 mmol), base (2 equiv.),
solvent (2 mL), Cat. 3 (1.0 mol%), aerobic condition. b Isolated yields.
Fig. 1 Parallel multisubstrate for the reactions of phenylacetylene with six aryl bromides catalyzed by Pd(II) catalysts.
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Table 2 Cat. 3 catalyzed Sonogashira coupling of terminal aryl alkyne 2 with aryl bromides 3 under the optimal conditions
Entrya
Terminal acetylene
Substrate
Products
Time (h)
Temperature (ꢀC)
Yieldb (%)
1
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2c
2a
2b
3a (Ph-Br)
3b (p-OHPh-Br)
3c (o-Me-m-MePh-Br)
3d (p-CNPh-Br)
3e (2-Br-thiophene)
3f (1-Br-naphthalene)
3b
3c
3d
3e
3f
3a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4s
4t
1
6
3
0.7
1.5
3
6
5
1.5
2
4
1.5
2
4.5
5
80
85
85
80
80
80
85
85
80
80
85
80
80
80
80
86
65
75
89
85
75
60
63
83
76
65
88
74
72
67
2c
3
4
5
6
7c
8
9
10
11
12
13
14
15
3g (p-CH3Ph-Br)
3h (2-NH2-5-Br-pyrazin)
3h
a
b
Conditions: 2 (1.2 mmol), 3 (0.8 mmol), TEA (2 equiv.), DMSO (2 mL), Cat. 3 (1.0 mol%), aerobic condition. Isolated yield aer ash
chromatography. c Inert atmosphere.
Table 3 Cat. 3 catalyzed Sonogashira coupling of terminal acetylenes 2 with aryl tosylates 5 under the optimal conditions
Entrya
Terminal acetylene
Substrate
Product
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2b
2b
2b
2b
2b
5a (Ph-OTs)
5b (1-OTs-naphthalene)
5c (p-ClPh-OTs)
5d (p-NO2Ph-OTs)
4a
4f
5
7
5
4
6
7
9
5
5
82
73
83
86
72
61
60
76
77
4n
4o
4p
4q
4k
4r
5a
5e (p-CH3Ph-OTs)
5b
5c
5d
4u
a
b
Conditions: 2 (1.2 mmol), 5 (0.8 mmol), TEA (2 equiv.), DMSO (2 mL), Cat. 3 (1.0 mol%), aerobic condition. Isolated yield aer ash
chromatography.
gave excellent yields of expected products (83–89%), while aryl amine (Table 2, entries 5, 10, 14 and 15) also gave good yields
bromides with electron-donating groups such as hydroxy and (67–85%).
methyl (Table 2, entries 2, 7 and 13) gave the corresponding
Since only few examples of Sonogashira cross-coupling
coupling products in a slightly lower yield. Even sterically reactions utilizing aryl tosylates have been reported,8 we next
hindered substrates, such as 1-bromo-2,3-dimethylbenzene, wanted to investigate the coupling of various aryl tosylates with
were also successfully coupled in good yields (Table 2, entries 3 terminal alkynes. As shown in Table 3, high catalytic activity was
and 8), although a slight higher temperature and a longer observed in the coupling of aryl tosylates possessing electron-
reaction time were required. To our satisfaction, donating groups such as fused ring (Table 3, entries 2 and 7),
heterocycle, such as 2-bromothiophene and 5-bromopyrazin-2- and 1-bromo-4-nitrobenzene (Table 3, entries 4 and 9) has
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electron-decient aromatic rings also gave the corresponding
coupling product under the reaction conditions identied
above.
Generally speaking, the synthesis of skew symmetric tolanes
can be realized by employing two different measures
(Scheme 4). From a synthetic point of view it is important to ask
which of the two leads to better yields when R or R0 are sterically
demanding or undemanding or when R or R0 possess electron-
releasing or -donating character.
In the rst place, we decided to investigate which reaction
(Scheme 5) would be more strongly inuenced by electronic
effects. As the above statement, electron withdrawing groups
have an effect on increasing the reactivity of both substrates.
The reaction C (Scheme 5, Fig 2) attains 71% yield via 30 min, at
the same time, while the reaction D reaches 46%. However,
when the reaction time was prolonged to 90 min, both reactions
acquired almost 90% yields. When the reaction B achieved 81%
yield aer 90 min's reaction, reaction A only exhibited 56%
yield. Nonetheless, they all reached to 80% yields aer 180 min
reaction. For this catalyst system, the reactivity of aryl bromide
is higher than that of aryl tosylates. Aer 10 min's reaction, F
only gave 9% yield, and, the reaction E has no conversion at all.
For all this, they all could reach 80% yields aer 150 min's
reaction. Finally, the yield of reaction E is lightly lower than that
of F.
Fig. 2 Time yield curves for the reactions of Scheme 5.
Encouraged by the achievements in the Suzuki and Sono-
gashira reactions, we further tested the catalytic activity of Cat. 3
in the Heck reactions using various aryl bromides and terminal
olens as substrates. The results of the Heck reactions were
summarized in the Table 4. Taking bromobenzene and styrene
as substrates, Cat. 3 at a loading of 1.0 mol% afforded 75% yield
Table 4 Cat. 3 catalyzed Heck coupling of terminal olefins 6 and aryl
bromides 3 under the optimal conditions
Scheme 4 Potential Sonogashira routes to tolanes.
Terminal
olen
Time
(h)
Yieldb
(%)
Entrya
Substrate
Products
1
6a
6a
3a
3b
7a
7b
8
16
12
24
15
10
8
10
13
7
75
28
62
32
60
67
79
77
57
80
80
34
62
73
78
81
85
2c
3k (p-OHPh-I)
3h (p-OCH3Ph-Br)
3l (p-OCH3Ph-I)
3g
3i (p-ClPh-Br)
3j (m-FPh-Br)
3h
3i
3j
3h
3l
3g
3a
3j
3
6a
7c
4
5
6
7
8
9
10
6a
6a
6a
6b
6b
6b
6c
7d
7e
7f
7g
7h
7i
9
7j
20
14
12
8
9
7
11
12
13
14
6c
6c
6c
6c
7k
7l
7m
7n
3i
a
Conditions: 6 (1.2 mmol), 3 (0.8 mmol), TEA (2 equiv.), dioxane (2 mL),
b
Cat. 3 (1.0 mol%), aerobic condition. Isolated yield aer ash
chromatography. c DMF (2 mL), inert atmosphere.
Scheme 5 Electronic modifications of substrates and aryl tosylates or
aryl bromides for Sonogashira coupling.
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A. Prastaro, S. Niembro, A. Shar and A. Vallribera, Org.
´
Biomol. Chem., 2009, 7, 2270–2273; (c) J. F. Cıvicos,
D. A. Alonso and C. Njera, Adv. Synth. Catal., 2013, 355,
203–208; (d) L. Zhou, F. Ye, Y. Zhang and J. B. Wang, J. Am.
Chem. Soc., 2010, 132, 13590–13591; (e) K. H. Chung,
C. M. So, S. M. Wong, C. H. Luk, Z. Y. Zhou, C. P. Lau and
F. Y. Kwong, Chem. Commun., 2012, 48, 1967–1969; (f)
Z. Y. Wang, G. Q. Chen and L. X. Shao, J. Org. Chem., 2012,
77, 6608–6614.
2 (a) A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41,
4176–4211; (b) W. J. Tang, S. Keshipeddy, Y. D. Zhang,
X. D. Wei, J. Savoie, N. D. Patel, N. K. Yee and
C. H. Senanayake, Org. Lett., 2011, 13, 1366–1369.
3 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
1975, 16, 4467–4470.
4 Y. Liang, Y. X. Xie and J. H. Li, J. Org. Chem., 2006, 71, 379–
381.
5 (a) H. Plenio, Angew. Chem., Int. Ed., 2008, 47, 6954–6956; (b)
´
T. Lauterbach, M. Livendahl, A. Rosellon, P. Espinet and
A. M. Echavarren, Org. Lett., 2010, 12, 3006–3009; (c)
Scheme 6 Proposed mechanism for Sonogashira reactions catalyzed
by Cat. 3.
´
Z. Gonda, G. L. Tolnai and Z. Novak, Chem.–Eur. J., 2010,
16, 11822–11826; (d) N. E. Leadbeater, Nat. Chem., 2010, 2,
1007.
(Table 4, entry 1). For bromobenzene with electron-withdrawing
groups, including –F, –Cl, the reaction proceeded smoothly and
77–85% yields of the corresponding coupling product were
acquired. However, for bromobenzene with an electron-rich
group, such as –OCH3, –OH, –CH3, the reaction proceeded
much slower, and only 57–73% yields were obtained.
We proposed a plausible mechanism for this Cat. 3 mediated
Sonogashira and Heck coupling reactions (Scheme 6). The Pd(0)
species could be generated readily from the reaction of Cat. 3
with substrates, ligands, and TEA,2a,4,9e,14 and, followed by the
oxidative addition of Pd(0) with R1X to form intermediate (1).
On account of alkalinity of TEA is feeblish, the acetylene is not
able to deprotonation, therefore, acetylene and Pd complex
form intermediate (2), which was further involved in the typical
catalytic cycle of Sonogashira coupling reaction. The mecha-
nism is also suitable for Heck cross-coupling reactions.
6 (a) H. Doucet and J. C. Hierso, Angew. Chem., Int. Ed., 2007,
46, 834–871; (b) R. Chinchilla and C. Najera, Chem. Rev.,
2007, 107, 874–922; (c) T. Schulz, C. Torborg, S. Enthaler,
B. Schaeffner, A. Dumrath, A. Spannenberg, H. Neumann,
A. Boerner and M. Beller, Chem.–Eur. J., 2009, 15, 4528–
4533; (d) A. D. Finke, E. C. Elleby, M. J. Boyd, H. Weissman
and J. S. Moore, J. Org. Chem., 2009, 74, 8897–8900; (e)
J. L. Bolligera and C. M. Frech, Adv. Synth. Catal., 2009,
351, 891–902.
7 (a) D. Gelman and S. L. Buchwald, Angew. Chem., Int. Ed.,
2003, 42, 5993–5996; (b) O. R'kyek, N. Halland,
A. Lindenschmidt, J. Alonso, P. Lindemann, M. Urmann
´
and M. Nazare, Chem.–Eur. J., 2010, 16, 9986–9989; (c)
Y. Nishihara, D. Ogawa, S. Noyori and M. Iwasaki, Chem.
Lett., 2012, 41, 1503.
´
8 D. A. Alonso, C. Najera, I. Pastor and M. Yus, Chem.–Eur. J.,
In summary, the NHC–Pd complex featured with air-insen-
sitivity, was proved to be a highly efficient catalyst for the
Suzuki, Sonogashira and Heck coupling reactions. In a simple
one-pot procedure free of co-catalyst, this complex is available
for a wide range of substrates under mild conditions with good
to excellent product yields and a low catalyst loading.
2010, 16, 5274–5284.
9 (a) Z. Gu, Z. Li, Z. Liu, Y. Wang, C. Liu and J. Xiang, Catal.
Commun., 2008, 9, 2154–2157; (b) M. H. Sie, Y. H. Hsieh,
Y. H. Tsai, J. R. Wu, S. J. Chen, P. V. Kumar, J. H. Lii and
H. M. Lee, Organometallics, 2010, 29, 6473–6481; (c) X. Cui,
Z. Li, C. Z. Tao, Y. Xu, J. Li, L. Liu and Q. X. Guo, Org. Lett.,
¨
2006, 8, 2467–2470; (d) E. Wuttke, B. Nagele, B. Weibert
and F. Kessler, Organometallics, 2011, 30, 6270–6282; (e)
A. Kamal, V. Srinivasulu, B. N. Seshadri, N. Narkandeya,
A. Alari and N. Shankaraiah, Green Chem., 2012, 14, 2513–
Acknowledgements
The authors acknowledge the nancial support of the National
´
´
Natural Science Foundation of China (no. 21302098).
2522; (f) D. Mery, K. Heuze and D. Astruc, Chem. Commun.,
2003, 15, 1934–1935; (g) M. Bakherad, A. Keivanloo and
S. Samangooei, Tetrahedron Lett., 2012, 53, 5773–5776.
10 (a) Y. Zhang, T. F. Jamison, S. Patel and N. Mainol, Org.
Lett., 2011, 13, 280–283; (b) J. P. Huang, W. Wang and
H. Li, ACS Catal., 2013, 3, 1526–1536.
References
1 (a) J. D. Senra, L. F. B. Malta, M. E. H. M. da Costa,
R. C. Michel, L. C. S. Aguiar, A. B. C. Simas and
O. A. C. Antunes, Adv. Synth. Catal., 2009, 351, 2411–2422; 11 (a) H. J. Xu, Y. Q. Zhao and X. F. Zhou, J. Org. Chem., 2011, 76,
(b) R. Bernini, S. Cacchi, G. Fabrizi, G. Forte, F. Petrucci,
8036–8041; (b) A. Ohtaka, T. Teratani, R. Fujii, K. Ikeshita,
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 30447–30452 | 30451

View Article Online
RSC Advances
Paper
T. Kawashima, K. Tatsumi, O. Shimomura and R. Nomura, J. 13 H. F. Lu, F. F. Yang, R. Z. Wu, J. T. Zhou, Z. B. Luo and
Org. Chem., 2011, 76, 4052–4060. Y. J. Hu, submitted for publication.
12 C. Valente, S. Calimsiz, K. H. Hoi, D. Mallik, M. Sayah and 14 R. R. Tykwinski, Angew. Chem., Int. Ed., 2003, 42, 1566–
M. G. Organ, Angew. Chem., Int. Ed., 2012, 51, 3314–3332. 1568.
30452 | RSC Adv., 2014, 4, 30447–30452
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