S.-B. Yu et al. / Tetrahedron Letters 49 (2008) 1253–1256
1255
remarkable tolerance towards the substitution pattern and
electronic properties of the substrates. Both electron-
donating substituents and sterically encumbering o-substit-
uents in the aryl ring gave good results. For examples,
various chlorotoluenes could smoothly couple with phenyl-
boronic acids, and the yields exceeded 96% (entries 1–3).
For the chlorides bearing electron-withdrawing groups,
excellent yields were obtained (entries 4–8). In particular,
the chlorides with sterically encumbering substituent such
as o-NO2, 2,6-dimethyl also coupled with phenylboronic
acid in good yields (entries 8 and 9). However, when steri-
cally encumbering phenylboronic acids were coupled with
2,6-dimethylchlorobenzene, the results were less satisfac-
tory. Thus, the reaction of 2-methylphenylboronic acid
and 2,6-dimethylchlorobenzene gave the coupling product
in 66% yield.
ties of the substituent in the phenyl ring. However, the
position of the methoxy group in the phenyl ring had some
effect in this catalytic reaction. Thus, 2-OMe substituted
substrate was coupled in 86% yield, while the correspond-
ing ones with 3- or 4-OMe group resulted in over 95% yield
of the coupling product (entries 5–7).
In conclusion, we have found that ferrocenylphosphine–
triazine ligands were highly effective for the Pd-catalyzed
Suzuki–Miyaura cross-coupling of aryl chlorides with
arylboronic acids. Under the optimized conditions, the
reaction proceeded in excellent yields, and displayed
remarkable tolerance towards the electronic properties of
the substrates. Further application of the present catalytic
system in the coupling reaction is still in progress.
Acknowledgement
To further demonstrate the scope and flexibility of the
present catalytic system, the cross-coupling of sterically
demanding o-chlorotoluene with various arylboronic acids
was also studied under the optimized conditions. The
results are summarized in Table 3. The arylboronic acids
with electron-donating and electron-withdrawing substitu-
ents were coupled smoothly with o-chlorotoluene. For the
arylboronic acids with a methyl group in the 2, 3 and 4-
position of the phenyl ring, the coupling yields exceeded
95% (entries 2–4). The yields for the coupling of substrates
with a methoxy group in the 3- or 4-position were also
excellent (entries 6 and 7). However, when 2-methoxy-
phenylboronic acid was used as a substrate, the yield was
decreased to 86% (entry 5). For the coupling of 4-CF3
and 4-F substituted substrates, 97% and 96% yields were
obtained (entries 8 and 9), respectively. These results indi-
cated that there is no major effect on the electronic proper-
The authors would like to thank the National Natural
Science Foundation of China for the financial support
(20472083).
References and notes
1. (a) Cross-Coupling Reactions; Miyaura, N., Ed.; Springer: Berlin,
2002; (b) Handbook of Organopallidium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley Interscience: New York, 2002;
Vol. 1–3; (c) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
2. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b) Suzuki, A.
Proc. Jpn. Acad. Ser. B—Phys. Biol. Sci. 2004, 80, 359; (c) Suzuki, A.
Chem. Commun. 2005, 4759; (d) Boronic Acids—Preparation and
Applications in Organic Synthesis and Medicine; Hall, D. G., Ed.;
Wiley-VCH: Weinheim, 2005.
3. For reviews, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176; (b) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord.
Chem. Rev. 2004, 248, 2283; (c) Phan, N. T. S.; Sluys, M. V. D.; Jones,
C. W. Adv. Synth. Catal. 2006, 348, 609. For recent example, see: (d)
Teo, S.; Weng, Z.; Hor, T. S. A. Organometallics 2006, 25, 1199; (e)
Punji, B.; Ganesamoorthy, C.; Balakrishna, M. S. J. Mol. Catal. A:
Chem. 2006, 259, 78; (f) Luo, Q.; Eibauer, S.; Reiser, O. J. Mol. Catal.
A: Chem. 2007, 268, 65; (g) Pal, S.; Hwang, W.-S.; Lin, I. J. B.; Lee,
C.-S. J. Mol. Catal. A: Chem. 2007, 269, 197; (h) Nonnenmacher, M.;
Kunz, D.; Rominger, F.; Oeser, T. J. Organomet. Chem. 2007, 692,
2554; (i) Cho, S.-D.; Kim, H.-K.; Yim, H.-S.; Kim, M.-R.; Lee, J.-K.;
Kim, J.-J.; Yoon, Y.-J. Tetrahedron 2007, 63, 1345; (j) Fleckenstein,
C. A.; Plenio, H. Organometallics 2007, 26, 2758; (k) Kingston, J. V.;
Verkade, J. G. J. Org. Chem. 2007, 72, 2816; (l) Li, S.; Lin, Y.; Cao,
J.; Zhang, S. J. Org. Chem. 2007, 72, 4067.
Table 3
Suzuki–Miyaura cross-coupling of 2-chlorotoluene with arylboronic
acidsa
Cl
B(OH)2
Pd(OAc)2 / 1b
K3PO4
+
R
dioxane, reflux
12 hours
R
4
2b
3
Entry
Arylboronic acid
Product
Yieldb (%)
4. (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000,
39, 4153; (b) Littke, A. F.; Dai, C. Y.; Fu, G. C. J. Am. Chem. Soc.
2000, 122, 4020; (c) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed.
2005, 44, 366; (d) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
1
2
3
4
5
6
7
8
9
3a: R = H
4b: R = H
4k: R = 2-Me
96
95
95
96
86
98
96
97
96
95
3b: R = 2-Me
3c: R = 3-Me
3d: R = 4-Me
3e: R = 2-OMe
3f: R = 3-OMe
3g: R = 4-OMe
3h: R = 4-CF3
3i: R = 4-F
4l: R = 3-Me
4m: R = 4-Me
4n: R = 2-OMe
4o: R = 3-OMe
4p: R = 4-OMe
4q: R = 4-CF3
4r: R = 4-F
ˆ
5. (a) Herrmann, W. A.; Ofele, K.; Preysing, D. V.; Schneider, S. K. J.
Organomet. Chem. 2003, 687, 229; (b) Navarro, O.; Kelly, R. A., III;
Nolan, S. P. J. Am. Chem. Soc. 2003, 125, 16194; (c) Miura, M.
Angew. Chem., Int. Ed. 2004, 43, 2201; (d) Hadei, N.; Kantchev, E. A.
B.; O’Brien, C. J.; Organ, M. G. Org. Lett. 2005, 7, 1991; (e) Kim,
J.-H.; Kim, J.-W.; Shokouhimehr, M.; Lee, Y.-S. J. Org. Chem. 2005,
70, 6714; (f) Marion, N.; Navarro, O.; Mei, J. G.; Stevens, E. D.;
Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101.
6. (a) Zim, D.; Gruber, A. S.; Ebeling, G.; Dupont, J.; Monteiro, A. L.
Org. Lett. 2000, 2, 2881; (b) Bedford, R. B.; Cazin, C. S. J.;
Hazelwood, S. L. Angew.Chem., Int. Ed. 2002, 41, 4120; (c) Botella,
10
a
3j: R = 3,5-difluoro
4s: R = 2,6-difluoro
The reactions were carried out in the presence of 1.0 mmol of o-chloro-
toluene, 1.2 mmol of arylboronic acid, 0.5 mol % of catalyst prepared
in situ from Pd(OAc)2Á3H2O and ligand 1b, and 3.0 equiv of K3PO4 in
5 mL of dioxane at refluxing temperature for 12 h.
b
Isolated yields, purity >95% was confirmed by 1H NMR.