Direct C-H bond arylation of (benzo)oxazoles with aryl chlorides catalyzed by N-heterocyclic carbene-palladium(II)-1-methylimidazole complex

Article abstract of DOI:10.1021/ol500531m

The direct C-H bond arylation of (benzo)oxazoles with aryl chlorides was achieved catalyzed by a well-defined NHC-Pd(II)-Im complex. Under the optimal conditions, various aryl chlorides were successfully applied as the arylating reagents to achieve the 2-aryl (benzo)oxazoles in acceptable to high yields, providing a convenient and alternative method for the direct C-H bond arylation of (benzo)oxazoles and enriching the chemistry of the NHC-Pd(II) complex in organic synthesis.

Full text of DOI:10.1021/ol500531m

Letter
pubs.acs.org/OrgLett
Direct C−H Bond Arylation of (Benzo)oxazoles with Aryl Chlorides
Catalyzed by N‑Heterocyclic Carbene−Palladium(II)−1-
Methylimidazole Complex
Xiao-Bao Shen,† Yun Zhang,† Wen-Xin Chen,† Zheng-Kang Xiao,† Ting-Ting Hu,‡
and Li-Xiong Shao*,†,§
†College of Chemistry and Materials Engineering, Wenzhou University, Chashan University Town, Wenzhou, Zhejiang Province
325035, People’s Republic of China
‡Oujiang College, Wenzhou University, Chashan University Town, Wenzhou, Zhejiang Province 325035, People’s Republic of China
§College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang Province 321004, People’s Republic of China
S
* Supporting Information
ABSTRACT: The direct C−H bond arylation of (benzo)oxazoles
with aryl chlorides was achieved catalyzed by a well-defined NHC−
Pd(II)−Im complex. Under the optimal conditions, various aryl
chlorides were successfully applied as the arylating reagents to
achieve the 2-aryl (benzo)oxazoles in acceptable to high yields,
providing a convenient and alternative method for the direct C−H
bond arylation of (benzo)oxazoles and enriching the chemistry of
the NHC−Pd(II) complex in organic synthesis.
2-Aryl substituted (benzo)oxazoles are very important moieties
due to their biological or physical properties and are also
important backbones for the synthesis of natural products,
pharmaceutically active compounds, and functional materials.1
Recently, the direct C−H bond arylation of (benzo)oxazoles,
which represents an environmental, economical, and potential
alternative method, has proven to be one of the most versatile
methods.2,3 Among the arylating reagents such as aryl halides,4
phenol derivatives,5 sodium arylsulfinates,6 aryl organometallic
reagents,7 etc.,8 aryl halides possess the advantages of easy
availability, being economical, and easy operation. However, in
the successful direct C−H bond arylation of (benzo)oxazoles
using aryl halides as the arylating reagents, only the more
activated aryl iodides and bromides were fully developed. In
addition, in most cases, free tertiary phosphines were used as
ligands with transition metal salts, thus usually excessive ligands
were necessary compared to transition metal salts. Besides air-,
thermal-, and moisture-sensitive tertiary phosphine ligands and
metal salts systems, Arslan and co-workers reported a mixed
halide N-heterocyclic carbene (NHC)−Pd complex, which has
a strict 2:1 NHC/Pd ratio, and have examined its catalytic
activity toward the direct C−H bond arylation of benzox-
azoles.9 However, only aryl bromides were examined as the
arylating reagents and only moderate yields were obtained. Due
to the economy and easy availability of aryl chlorides,10
development of the phosphine-free, highly efficient direct C−H
bond arylation of (benzo)oxazoles using aryl chlorides as the
arylating reagents is still in great demand.
traditional coupling reactions using aryl chlorides as the
substrates.11 These results thus prompted us to further
investigate its application toward the direct C−H bond
arylation of (benzo)oxazoles using aryl chlorides as the
arylating reagents. Herein, we report these results in detail.
At the outset of our investigations, the screening reactions
were performed with respect to the bases and the solvents with
benzoxazole 2a (1.0 mmol) and chlorobenzene 3a (0.5 mmol)
as the model substrates in the presence of NHC−Pd(II)−Im
complex 1 (5.0 mol %) at 130 °C for 12 h, and some
representative results are shown in Table 1. For example, in the
first round, dioxane was chosen as the solvent to find the most
suitable base (Table 1, entries 1−6). It seems that LiOtBu was
the best base to give the desired arylated product 4a in 16%
yield (Table 1, entry 3). In the presence of other bases such as
KOtBu, NaOtBu, KOH, Li2CO3, NaHCO3, Cs2CO3, K3PO4·
3H2O, NaF, and CH3COONa, very low yields (<5%) of
product 4a were obtained. In the second round, using LiOtBu
as the base, the solvent effects were then investigated and
toluene was the best choice (58%) over DMSO (<5%), DMF
(11%), THF (<5%), and CH3CN (8%). By increasing the
amounts of LiOtBu to 4.0 and 5.0 equiv, the yields can be
increased to 69% and 75%, respectively (Table 1, entries 12 and
13). Further studies showed that the yield can be increased to
82% when the reaction time was prolonged to 18 h in the
presence of 5.0 equiv of LiOtBu (Table 1, entry 14), which was
not disturbed when the reaction time was prolonged to 24 h
(Table 1, entry 15). In addition, no reaction occurred in the
Recently, we have developed a well-defined N-heterocyclic
carbene−palladium(II)−1-methylimidazole [NHC−Pd(II)−
Im] complex 1 and have shown it to be a good catalyst in
Received: February 19, 2014
Published: March 26, 2014
© 2014 American Chemical Society
1984
dx.doi.org/10.1021/ol500531m | Org. Lett. 2014, 16, 1984−1987

Organic Letters
Letter
Table 1. Optimization for the Complex 1 Catalyzed Reaction
of Benzoxazole 2a with Chlorobenzene 3a
Table 2. NHC−Pd(II)−Im Complex 1 Catalyzed Reactions
of Benzoxazole 2a with Aryl Chlorides 3
a
b
entry
solvent
base (equiv)
time (h)
yield (%)
1
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMSO
DMF
KOtBu (3.0)
NaOtBu (3.0)
LiOtBu (3.0)
KOH (3.0)
12
12
12
12
12
12
12
12
12
12
12
12
12
18
24
24
<5
<5
16
<5
<5
<5
<5
11
58
<5
8
2
3
4
5
Li2CO3 (3.0)
NaHCO3 (3.0)
LiOtBu (3.0)
LiOtBu (3.0)
LiOtBu (3.0)
LiOtBu (3.0)
LiOtBu (3.0)
LiOtBu (4.0)
LiOtBu (5.0)
LiOtBu (5.0)
LiOtBu (5.0)
LiOtBu (5.0)
6
7
8
9
toluene
THF
a
10
11
12
13
14
15
All reactions were carried out using 2a (1.0 mmol), 3 (0.5 mmol), 1
(5.0 mol %), and LiOtBu (5.0 equiv) in toluene (2.0 mL) at 130 °C for
18 h. Isolated yields.
CH3CN
toluene
toluene
toluene
toluene
toluene
b
69
75
82
83
NR
give products 4h−4k in good to high yields, respectively (Table
2, entries 7−10).
c
16
Encouraged by these results, various other benzoxazoles 2
were then subjected to the reactions with aryl chlorides 3 under
identical conditions (Table 3). As can be seen from Table 3, all
reactions took place smoothly to give the desired arylated
products 4 in good to high yields. Substituents on the
benzoxazoles 2 and aryl chlorides 3 almost have no effect on
the reactions investigated. For example, good to high yields of
products 4l, 4m, 4o, 4p, 4t, and 4z can be achieved when aryl
chlorides 3 possessing sterically hindered ortho-substituents
were used as the substrates. Heteroaryl chlorides such as 2-
chlorothiophene, 3-chloropyridine, and 2-chloropyridine were
also suitable substrates in these reactions to afford products
4q−4s and 4v−4x in good to high yields, respectively.
Finally, 5-aryloxazoles 2 were also tested with aryl chlorides 3
under the optimal conditions. As can be seen from Table 4, all
reactions performed smoothly to give the desired C2-arylated
products 4 in good to high yields. Electron-rich, -withdrawing,
and -poor substituents on the phenyl rings of 5-aryloxazoles 2
did not affect the reactions. It seems that such substituents on
the aryl chlorides 3 also did not affect the reactions. Heteroaryl
chlorides such as 2-chloropyridine and 3-chloropyridine also
worked very well to give the corresponding arylated products
4al−4aq in high yields.
In conclusion, to the best of our knowledge, we report herein
the first example of a phosphine-free, NHC−Pd(II) complex
catalyzed direct C−H bond arylation of (benzo)oxazoles using
aryl chlorides as the arylating reagents. By using the readily
available NHC−Pd(II)−Im complex 1 as the catalyst, a variety
of (benzo)oxazoles can be arylated with aryl chlorides under
the optimal reaction conditions. The reaction can tolerate
various substrates. For example, aryl chlorides with electron-
donating, -neutral, -withdrawing, and -sterically hindered
substituents are all proven to be suitable substrates. The results
a
Otherwise specified, all reactions were carried out using 2a (1.0
mmol), 3a (0.5 mmol), 1 (5.0 mol %), and base (3.0−5.0 equiv) in the
solvent (2.0 mL) at 130 °C. Isolated yields. No catalyst was added.
b
c
absence of NHC−Pd(II)−Im complex 1 (Table 1, entry 16),
implying that the introduction of the palladium catalyst was
essential for such a transformation, although a metal-free
system for direct C−H bond arylation has been well-defined
during the past years.12
Having established the optimal reaction conditions, we then
first carried out the reaction between benzoxazole 2a and a
variety of aryl chlorides 3 to test the generality (Table 2). As
can be seen from Table 2, benzoxazole 2a can be smoothly
arylated using this methodology. Substituents on the aryl
chlorides 3 affected the reaction to some extent. For instance,
aryl chlorides 3 with an electron-donating group such as a
methyl group on the para- or meta-position of the phenyl ring
only gave the corresponding products 4b and 4c in 53 and 58%
yields, respectively (Table 2, entries 1 and 2). However, when
the electron-donating groups such as methyl and methoxy
groups were attached on the ortho-position of aryl chlorides 3,
good and high yields of products 4d and 4g can be achieved
(Table 2, entries 3 and 6). Sterically hindered substituents on
the aryl chlorides 3 have less effect on the reaction to afford
products 4d, 4e, and 4g in good to high yields, respectively
(Table 2, entries 3, 4, and 6). Electron-withdrawing
substituents on the aryl chlorides are tolerant in these reactions
to provide products 4e and 4f in good yields, respectively
(Table 2, entries 4 and 5). Heteroaryl chlorides such as 3-
chloropyridine 3h, 2-chloropyridine 3i, 2-chlorothiophene 3j,
and 3-chlorothiophene 3k were also good reaction partners to
1985
dx.doi.org/10.1021/ol500531m | Org. Lett. 2014, 16, 1984−1987

Organic Letters
Letter
(benzo)oxazoles and will also enrich the chemistry of the
NHC−Pd(II) complexes in organic synthesis.
Table 3. NHC−Pd(II)−Im Complex 1 Catalyzed Reactions
of Benzoxazoles 2 with Aryl Chlorides 3
ASSOCIATED CONTENT
* Supporting Information
Full experimental details, spectra data, and copy of H and 13C
■
S
1
NMR spectra of compounds 4. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Shaolix@wzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of
Zhejiang Province (No. LY12B02012) and the Open Research
Fund of Top Key Discipline of Chemistry in Zhejiang
Provincial Colleges and Key Laboratory of the Ministry of
Education for Advanced Catalysis Materials (Zhejiang Normal
University) (No. ZJHX201305) is greatly appreciated.
REFERENCES
■
(1) (a) Yeh, V. S. C. Tetrahedron 2004, 60, 11995−12042.
(b) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991−9016.
(c) Palmer, D. C. Oxazoles: Synthesis, Reactions, and Spectroscopy, Vol.
1; Wiley: NJ, 2003. (d) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975,
75, 389−437.
a
All reactions were carried out using 2 (1.0 mmol), 3 (0.5 mmol), 1
(5.0 mol %), and LiOtBu (5.0 equiv) in toluene (2.0 mL) at 130 °C for
18 h. Isolated yields.
b
(2) For some recent selected reviews on the transition metal
catalyzed direct C−H bond functionalization, please see: (a) Kuhl, N.;
Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int.
Ed. 2012, 51, 10236−10254. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.;
Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788−802. (c) Arockiam, P. B.;
Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879−5918. (d) Yu,
D.-G.; Li, B.-J.; Shi, Z.-J. Tetrahedron 2012, 68, 5130−5136.
(e) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992−2002. (f) Gutekunst,
W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976−1991.
(g) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011,
40, 1885−1898.
Table 4. NHC−Pd(II)−Im Complex 1 Catalyzed Reactions
of 5-Aryloxazoles 2 with Aryl Chlorides 3
́ ́ ́
(3) Verrier, C.; Lassalas, P.; Theveau, L.; Queguiner, G.; Trecourt, F.;
Marsais, F.; Hoarau, C. Beilstein J. Org. Chem. 2011, 7, 1584−1601.
(4) (a) Mahuteau-Betzer, F.; Piguel, S. Tetrahedron Lett. 2013, 54,
3188−3193. (b) Williams, T. J.; Fairlamb, I. J. S. Tetrahedron Lett.
2013, 54, 2906−2908. (c) Ackermann, L.; Barfusser, S.; Kornhaass, C.;
̈
Kapdi, A. R. Org. Lett. 2011, 13, 3082−3085. (d) Zhang, W.; Zeng, Q.-
L.; Zhang, X.-M.; Tian, Y.-J.; Yue, Y.; Guo, Y.-J.; Wang, Z.-H. J. Org.
Chem. 2011, 76, 4741−4745. (e) Yan, X.-M.; Mao, X.-R.; Huang, Z.-Z.
Heterocycles 2011, 83, 1371−1376. (f) Verrier, C.; Fiol-Petit, C.;
Hoarau, C.; Marsais, F. Org. Biomol. Chem. 2011, 9, 6215−6218.
(g) Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamaguchi,
J.; Itami, K. Chem.Eur. J. 2011, 17, 10113−10122. (h) Thev
́
eau, L.;
Verrier, C.; Lassalas, P.; Martin, T.; Dupas, G.; Querolle, O.; Hijfte, L.
V.; Marsais, F.; Hoarau, C. Chem.Eur. J. 2011, 17, 14450−14463.
(i) Shibahara, F.; Yamaguchi, E.; Murai, T. Chem. Commun. 2010, 46,
2471−2473. (j) Strotman, N. A.; Chobanian, H. R.; Guo, Y.; He, J.-F.;
Wilson, J. E. Org. Lett. 2010, 12, 3578−3581. (k) Dong, J.-J.; Roger, J.;
Verrier, C.; Martin, T.; Le Goff, R.; Hoarau, C.; Doucet, H. Green
̀
Chem. 2010, 12, 2053−2063. (l) Besselievre, F.; Mahuteau-Betzer, F.;
a
All reactions were carried out using 2 (1.0 mmol), 3 (0.5 mmol), 1
Grierson, D. S.; Piruel, S. Synthesis 2009, 3511−3518. (m) Hachiya,
H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737−1740.
(n) Yoshizumi, T.; Satoh, T.; Hirano, K.; Matsuo, D.; Orita, A.; Otera,
J.; Miura, M. Tetrahedron Lett. 2009, 50, 3273−3276. (o) Derridj, F.;
Djebbar, S.; Benali-Baitich, O.; Doucet, H. J. Organomet. Chem. 2008,
693, 135−144. (p) Yoshizumi, T.; Tsurugi, H.; Satoh, T.; Miura, M.
(5.0 mol %), and LiOtBu (5.0 equiv) in toluene (2.0 mL) at 130 °C for
18 h. Isolated yields.
b
reported in this paper provide an economical, convenient, and
alternative method for the direct C−H bond arylation of
1986
dx.doi.org/10.1021/ol500531m | Org. Lett. 2014, 16, 1984−1987

Organic Letters
Letter
̀
Tetrahedron Lett. 2008, 49, 1598−1600. (q) Besselievre, F.; Mahuteau-
Betzer, F.; Grierson, D. S.; Piruel, S. J. Org. Chem. 2008, 73, 3278−
3280. (r) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2008,
10, 2717−2720. (s) Verrier, C.; Martin, T.; Hoarau, C.; Marsais, F. J.
Org. Chem. 2008, 73, 7383−7386. (t) Ohnmacht, S. A.; Mamone, P.;
Culshaw, A. J.; Greaney, M. F. Chem. Commun. 2008, 1241−1243.
(u) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404−
12405.
(5) (a) Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012,
134, 169−172. (b) So, C. M.; Lau, C. P.; Kwong, F. Y. Chem.Eur. J.
2011, 17, 761−765. (c) Ackermann, L.; Barfusser, S.; Pospech, J. Org.
̈
Lett. 2010, 12, 724−726. (d) Ackermann, L.; Althammer, A.; Fenner,
S. Angew. Chem., Int. Ed. 2009, 48, 201−204. (e) Roger, J.; Doucet, H.
Org. Biomol. Chem. 2008, 6, 169−174.
(6) (a) Wang, M.; Li, D.-K.; Zhou, W.; Wang, L. Tetrahedron Lett.
2012, 68, 1926−1930. (b) Liu, B.; Guo, Q.; Cheng, Y.-Y.; Lan, J.-B.;
You, J.-S. Chem.Eur. J. 2011, 17, 13415−13419.
(7) (a) Han, W.; Mayer, P.; Ofial, A. R. Chem.Eur. J. 2011, 17,
6904−6908. (b) Yang, F.-Z.; Xu, Z.-Q.; Wang, Z.; Yu, Z.-K.; Wang, R.
Chem.Eur. J. 2011, 17, 6321−6325. (c) Ranjit, S.; Liu, X.-G.
Chem.Eur. J. 2011, 17, 1105−1108. (d) Hachiya, H.; Hirano, K.;
Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2010, 49, 2202−2205.
(e) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. ChemCatChem 2010,
2, 1403−1406.
(8) (a) Li, C.-L.; Li, P.-H.; Yang, J.; Wang, L. Chem. Commun. 2012,
48, 4214−4216. (b) Yu, P.; Zhang, G.-Y.; Chen, F.; Cheng, J.
Tetrahedron Lett. 2012, 53, 4588−4590. (c) Yu, X.-G.; Li, X.-W.; Wan,
B.-S. Org. Biomol. Chem. 2012, 10, 7479−7482. (d) Yuen, O. Y.; So, C.
M.; Wong, W. T.; Kwong, F. Y. Synlett 2012, 23, 2714−2718.
(e) Zhang, M.-L.; Zhang, S.-H.; Liu, M.-C.; Cheng, J. Chem. Commun.
2011, 47, 11522−11524.
̈
̇
(9) Arslan, H.; Ozdemįr, I.; Vanderveer, D.; Demįr, S.; C
̧etįnkaya, B.
J. Coord. Chem. 2009, 62, 2591−2599.
(10) (a) Grushin, V. V.; Alper, H. In Activation of Unreactive Bonds
and Organic Synthesis; Murai, S., Ed.; Springer: Berlin, 1999; pp 193−
226. (b) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047−1062.
(c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176−
4211. (d) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. Rev.
2004, 248, 2283−2321.
(11) (a) Yin, H.-Y.; Liu, M.-Y.; Shao, L.-X. Org. Lett. 2013, 15, 6042−
6045. (b) Xiao, Z.-K.; Yin, H.-Y.; Shao, L.-X. Org. Lett. 2013, 15,
1254−1257. (c) Gao, T.-T.; Jin, A.-P.; Shao, L.-X. Beilstein J. Org.
Chem. 2012, 8, 1916−1919. (d) Chen, W.-X.; Shao, L.-X. J. Org. Chem.
2012, 77, 9236−9239. (e) Zhu, L.; Ye, Y.-M.; Shao, L.-X. Tetrahedron
2012, 68, 2414−2420. (f) Xiao, Z.-K.; Shao, L.-X. Synthesis 2012, 44,
711−716. (g) Gu, Z.-S.; Shao, L.-X.; Lu, J.-M. J. Organomet. Chem.
2012, 700, 132−134. (h) Zhu, L.; Gao, T.-T.; Shao, L.-X. Tetrahedron
2011, 67, 5150−5155. (i) Tang, Y.-Q.; Lu, J.-M.; Shao, L.-X. J.
Organomet. Chem. 2011, 696, 3741−3744. (j) Zhou, X.-X.; Shao, L.-X.
Synthesis 2011, 3138−3142.
(12) For some recent selected papers, please see: (a) Cuthbertson, J.;
Gray, V. J.; Wilden, J. D. Chem. Commun. 2014, 50, 2575−2578.
(b) Chan, T. L.; Wu, Y.-N.; Choy, P. Y.; Kwong, F. Y. Chem.Eur. J.
2013, 19, 15802−15814. (c) Zhao, H.-Q.; Shen, J.; Guo, J.-J.; Ye, R.-J.;
Zeng, H.-Q. Chem. Commun. 2013, 49, 2323−2325. (d) Shirakawa, E.;
Hayashi, T. Chem. Lett. 2012, 41, 130−134. (e) Liu, H.-L.; Yin, B.-L.;
Gao, Z.-Q.; Li, Y.-W.; Jiang, H.-F. Chem. Commun. 2012, 48, 2033−
2035. (f) Tanimoro, K.; Ueno, M.; Takeda, K.; Kirihata, M.; Tanimori,
S. J. Org. Chem. 2012, 77, 7844−7849. (g) Thruong, T.; Daugulis, O.
Org. Lett. 2012, 14, 5964−5967. (h) Wu, Y.-N.; Wong, S. M.; Mao, F.;
Chan, T. L.; Kwong, F. Y. Org. Lett. 2012, 14, 5306−5309. (i) Qiu, T.-
T.; Liu, Y.-H.; Yang, K.; Hong, W.-K.; Li, Z.; Wang, Z.-Y.; Yao, Z.-Y.;
Jiang, S. Org. Lett. 2011, 13, 3556−3559. (j) Thruong, T.; Daugulis, O.
J. Am. Chem. Soc. 2011, 133, 4243−4245. (k) Yanagisawa, S.; Itami, K.
ChemCatChem 2011, 3, 827−829. (l) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu,
M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, Z.-J.
Nat. Chem. 2010, 2, 1044−1049. (m) Lei, A.-W.; Liu, W.; Liu, C.;
Chen, M. Dalton Trans. 2010, 39, 10352−10361.
1987
dx.doi.org/10.1021/ol500531m | Org. Lett. 2014, 16, 1984−1987