A successful one-pot coupling reaction requires that the
catalyst is highly efficient and chemoselective toward the first
coupling and maintains its catalytic activity in the subseqent
coupling. Palladium complexes of N-heterocyclic carbenes
(NHCs) would be potentially suitable for double coupling
because of their wide applications in various coupling
reactions.10 Here we describe the facile and efficient one-
pot sequential reactions of aryl dihalides to afford unsym-
metrically substituted arenes.
product. Apparently, the catalyst is not sufficiently active
for Suzuki coupling of the resultant aryl chloride.
4-Bromoiodobenzene would be a more suitable substrate
for this sequential coupling since Suzuki reaction of the
resultant 4-bromocinnamate is easier, provided that the
catalyst shows good chemoselectivity in the initial Heck
coupling reaction. Fortunately, complex 1 exhibits sufficient
regioselectivity for the Heck coupling of 4-bromoiodoben-
zene and n-butyl acrylate (1:1) and allows the coupling of
aryl iodide to be completed before aryl bromide starts its
reaction giving monocoupled product n-butyl 3-(4-bro-
mophenyl)acrylate in 94% yield together with 3% double
coupled product after 30 min (Scheme 1). To ensure the
We first chose 4-chloroiodobenzene as the substrate for
the study of one-pot Heck/Suzuki couplings because of the
ease of regiocontrol. The Pd/IPr·HCl (IPr ) 1,3-bis(2,6-
diisopropylphenylimidazolylidene)) system has proved to be
one of the best catalysts for C-C couplings.11 Actually, the
coupling of 4-chloroiodobenzene and n-butyl acrylate could
proceed in DMF at 120 °C with 0.5 mol % of Pd2(dba)3 and
2 mol % of IPr·HCl affording (E)-butyl 3-(4-chloropheny-
l)acrylate in a quantitative yield within 30 min; however,
palladium black was observed in this process. After cooling
to room temperature, PhB(OH)2 and Cs2CO3 were directly
added to the reaction vessel without isolation and heated to
80 °C. Unfortunately, the Suzuki coupling could not proceed.
Although palladium black can be avoided in the presence
of a catalytic amount of pyridine or PPh3, no double coupled
product was observed. The combination of Pd(OAc)2 and
PdCl2 with IPr·HCl or IMes·HCl (Imes ) 1,3-bis(2,4,6-
trimethylphenylimidazolylidene) was also not successful.
[Pd(3-(2,4-dimethyl-1,8-naphthyrid-7-yl)-1- pycolylimi-
dazolylidene)2]-(PF6)2 (1) is a highly efficient catalyst for
Heck coupling reactions of aryl iodides and bromides.12 To
our delight, complex 1 is suitable for the Heck/Suzuki
coupling of 4-chloroiodobenzene, although the expected
unsymmetric double coupling product was obtained in only
6% yield after 24 h. Variation of catalyst loadings, bases,
and solvents did not improve the overall yields. When two
equivalent of PPh3 was added, a better yield (32%) was
obtained but accompanied by 48% of the dechlorinated
Scheme 1. Heck/Suzuki Coupling of 4-Bromoiodobenzene
complete consumption of 4-bromoiodobenzene and avoid the
difficulties in the isolation of the final product, 1.05 equiv
of n-butyl acrylate was employed in the following reactions.
Encouraged by the success of the chemoselective mono-
Heck coupling, one-pot sequential Heck/Suzuki coupling
reactions were studied in detail, and the conditions were
optimized. As shown in Table 1, without isolation of n-butyl
Table 1. Base Effect on the One-Pot Heck/Suzuki Reaction
time
(min)
yield
(%)b
time
(h)
yield
(%)d
entry
basea
basec
(8) (a) Ferraccioli, R.; Carenzi, D.; Rombola`, O.; Catellani, M. Org.
Lett. 2004, 6, 4759. (b) Chae, J.; Yun, J.; Buchwald, S. L. Org. Lett. 2004,
6, 4809. (c) Handy, S. T.; Sabatini, J. J. Org. Lett. 2006, 8, 1537. (d)
Wakchaure, V. N.; Mohanty, R. R.; Shaikh, A. J.; Nugent, T. C. Eur. J.
Org. Chem. 2007, 959. (e) Molander, G. A.; Yokoyama, Y. J. Org. Chem.
2006, 71, 2493. (f) Mio, M. J.; Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.;
Hull, K. L.; Brisbois, R. G.; Markworth, C. J.; Grieco, P. A. Org. Lett.
2002, 4, 3199. (g) Coleman, R. S.; Walczak, M. C. Org. Lett. 2005, 7,
2289. (h) Kawasaki, T.; Yamamoto, Y. J. Org. Chem. 2002, 67, 5138. (i)
Manickam, G.; Schlu¨ner, A. D. Eur. J. Org. Chem. 2000, 3475.
(9) (a) Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005, 127,
8004. (b) Wu, T. Y. H.; Schultz, P. G.; Ding, S. Org. Lett. 2003, 5, 3587.
(c) Itami, K.; Nokami, T.; Ishimura, Y.; Mitsudo, K.; Kamei, T.; Yoshida,
J.-i. J. Am. Chem. Soc. 2001, 123, 11577. (d) Itami, K.; Tonogaki, K.;
Ohashi, Y.; Yoshida, J. Org. Lett. 2004, 6, 4093.
1
2
3
4
5
NaOAc
Na2CO3
K2CO3
Cs2CO3
NaOAc
30
45
45
60
30
97/3
95/3
92/5
67/7
97/3
NaOAc
Na2CO3
K2CO3
24
12
12
31
86
80
Cs2CO3
3
92
a Aryl halide 1.0 mmol, n-butyl acrylate 1.05 mmol, base 1.2 mmol, Pd
1.0 mol %, DMF 5 mL, 120 °C. b GC yield of mono/double coupled product.
c PhB(OH)2 1.5 mmol, base 1.2 mmol, 80 °C. d Isolated yield.
4-bromocinnamate, the second coupling was started by direct
addition of PhB(OH)2 and Cs2CO3 after cooling to room
temperature, and the Suzuki reaction was completed within
3 h at 80 °C with a quantitative yield detected by GC (Table
1, entry 5). NaOAc is the most suitable base for Heck
coupling but a poor base for Suzuki reaction (Table 1, entry
1). Although Na2CO3 and K2CO3 are efficient for both Heck
and Suzuki reactions, the reactions require a longer time
(Table 1, entries 2 and 3). Cs2CO3 is known to be the best
base for Pd-catalyzed Suzuki reaction; however, the Heck
reaction of 4-bromoiodobenzene using Cs2CO3 afforded the
(10) For reviews of NHC complexes as catalysts in coupling reactions,
see: (a) D´ıez-Gonza´lez, S.; Nolan, S. P. Top. Organomet. Chem. 2007, 21,
47. (b) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606.
(c) Gade, L. H.; Bellemin-Laponnaz, S. Top. Organomet. Chem. 2007, 21,
117. (d) Herrmann, W. A.; Ko¨echer, C. Angew. Chem. 1997, 109, 2256;
Angew. Chem., Int. Ed. 1997, 36, 2162.
(11) (a) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1999, 64, 3804. (b) Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang, C.; Trudell,
M. L.; Nolan, S. P. Organometallics 2002, 21, 2866. (c) Huang, J.; Nolan,
S. P. J. Am. Chem. Soc. 1999, 121, 9889. (d) Desmarets, C.; Schneider, R.;
Fort, Y. J. Org. Chem. 2002, 67, 3029. (e) Viciu, M. S.; Kissling, R. M.;
Stevens, E. D.; Nolan, S. P. Org. Lett. 2002, 4, 2229.
(12) Zhang, X.; Xi, Z.; Liu, A.; Chen, W. Organometallics, 2008, DOI:
10.1021/om8003674.
3850
Org. Lett., Vol. 10, No. 17, 2008