NiCl2(dppe)-Catalyzed Cross-Coupling of Aryl Mesylates, Arenesulfonates, and Halides with Arylboronic Acids

Article abstract of DOI:10.1021/jo049940i

An investigation of the NiCl₂(dppe)-, NiCl₂(dppb)-, NiCl₂(dppf)-, NiCl₂(PCy₃)_2-, and NiCl₂(PPh₃)_2- catalyzed cross-coupling of the previously unreported aryl mesylates, and of aryl arenesulfonates, chlorides, bromides, and iodides containing electron-withdrawing and electron-donating substituents with aryl boronic acids, in the absence of a reducing agent, is reported. NiCl₂(dppe) was the only catalyst that exhibited high and solvent-independent activity in the two solvents investigated, toluene and dioxane. NiCl₂(dppe) with an excess of dppe, NiCl ₂(dppe)/dppe, was reactive in the cross-coupling of electron-poor aryl mesylates, tosylates, chlorides, bromides, and iodides. This catalyst was also efficient in the cross-coupling of aryl bromides and iodides containing electron-donating substituents. Most surprisingly, the replacement of the excess dppe from NiCl₂(dppe)/dppe with excess PPh₃ generated NiCl₂(dppe)/PPh₃, which was found to be reactive for the cross-coupling of both electron-rich and electron-poor aryl mesylates and chlorides. Therefore, the solvent-independent reactivity of NiCl₂(dppe) provides an inexpensive and general nickel catalyst for the cross-coupling of aryl mesylates, tosylates, chlorides, bromides, and iodides with aryl boronic acids.

Full text of DOI:10.1021/jo049940i

NiCl2(d p p e)-Ca ta lyzed Cr oss-Cou p lin g of Ar yl Mesyla tes,
Ar en esu lfon a tes, a n d Ha lid es w ith Ar ylbor on ic Acid s
Virgil Percec,* Geoffrey M. Golding, J an Smidrkal, and Oliver Weichold
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323
percec@sas.upenn.edu
Received J anuary 8, 2004
An investigation of the NiCl2(dppe)-, NiCl2(dppb)-, NiCl2(dppf)-, NiCl2(PCy3)2-, and NiCl2(PPh3)2-
catalyzed cross-coupling of the previously unreported aryl mesylates, and of aryl arenesulfonates,
chlorides, bromides, and iodides containing electron-withdrawing and electron-donating substituents
with aryl boronic acids, in the absence of a reducing agent, is reported. NiCl2(dppe) was the only
catalyst that exhibited high and solvent-independent activity in the two solvents investigated,
toluene and dioxane. NiCl2(dppe) with an excess of dppe, NiCl2(dppe)/dppe, was reactive in the
cross-coupling of electron-poor aryl mesylates, tosylates, chlorides, bromides, and iodides. This
catalyst was also efficient in the cross-coupling of aryl bromides and iodides containing electron-
donating substituents. Most surprisingly, the replacement of the excess dppe from NiCl2(dppe)/
dppe with excess PPh3 generated NiCl2(dppe)/PPh3, which was found to be reactive for the cross-
coupling of both electron-rich and electron-poor aryl mesylates and chlorides. Therefore, the solvent-
independent reactivity of NiCl2(dppe) provides an inexpensive and general nickel catalyst for the
cross-coupling of aryl mesylates, tosylates, chlorides, bromides, and iodides with aryl boronic acids.
In tr od u ction
tosylates have been shown to be active in cross-coupling
reactions,12-14 aryl mesylates and tosylates are not suf-
ficiently reactive15 for conventional Suzuki reaction con-
ditions. Recently, the cross-coupling of alkyl tosylates
with alkyl 9-BBN boranes16 and a Pd-catalyzed cross-
coupling of aryl tosylates with aryl boronic acids were
reported.17
Palladium-catalyzed Suzuki-type cross-coupling is one
of the most powerful methods to form carbon-carbon
bonds1-3 originally, mostly from aryl bromides, iodides,
and triflates.4 Developments from different laboratories5-9
have provided methods to activate palladium toward the
less expensive and reactive aryl chlorides. However, the
high cost of palladium10 and the ligands required to
activate it11 limits its use at least in the large-scale
synthesis of inexpensive compounds. Although vinyl
Ni(0)-catalyzed homocoupling of aryl mesylates18 and
the Ni(0)-catalyzed cross-coupling of aryl boronic acids
with aryl mesylates and other sulfonates15 were reported
in 1995 from our laboratory. NiCl2(dppf)/Zn/K3PO4/diox-
ane was found to be the most suitable catalytic system
for this Suzuki-type cross-coupling. Zinc was used to
generate Ni(0) species in situ. Other groups have ex-
panded the scope of the Ni(0)-catalyzed cross-coupling
reaction. For example, exchanging n-BuLi for Zn as
reducing agent allowed the cross-coupling of aryl chlo-
ride19,20 and aryl mesylates21 with aryl boronic acids.
Subsequently, the cross-coupling of aryl chlorides with
(1) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513.
(2) For recent reviews, see: (a) Suzuki, A. J . Organomet. Chem.
1999, 576, 147. (b) Buchwald, S. L.; Fox, J . M. Strem Chem. 2000, 18
(1), 1. (c) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633.
(3) For a recent book chapter, see: (a) Suzuki, A. In Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P., Eds.; Wiley-VCH:
Weinheim, Germany, 1998.
(4) Oh-e, T.; Miyaura, N.; Suzuki, A. J . Org. Chem. 1993, 58, 2201.
(5) (a) Old, P. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 9722. (b) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int.
Ed. 1999, 38, 2413. (c) Wolfe, J . P.; Singer, R. A.; Yang, B. H.;
Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 9550.
(6) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122, 4020.
(7) . Kataoka, N.; Shelby, Q.; Stambuli, J . P.; Hartwig, J . F. J . Org.
Chem. 2002, 67, 5553.
(8) (a) Beller, M.; Fischer, H.; Herrmann, W. A.; O¨ fele, K.; Brossiner,
D. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848. (b) Zhang, C.; Huang,
J .; Trudell, M. L.; Nolan, S. P. J . Org. Chem. 1999, 64, 3804. (c) Bei,
X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S. J . Org. Chem. 1999,
64, 6797.
(11) For example, the cost of 2-(di-tert-butylphosphino)biphenyl is
$49.50/g (Strem).
(12) Fu, X.; Zhang, S.; Yin, J .; McAllister, T. L.; J iang, S. A.; Tann,
C.-H.; Thiruvengadam, T. K.; Zhang, F. Tetrahedron Lett. 2002, 43,
573.
(13) (a) Wu, J .; Liao, Y.; Yang, Z. J . Org. Chem. 2001, 66, 3642. (b)
Fu, X.; Zhang, S.; Yin, J .; Schumacher, D. P. Tetrahedron Lett. 2002,
43, 6673.
(14) (a) Huffman, M. A.; Yasuda, N. Synlett 1999, 471. (b) Wu, J .;
Zhu, Q.; Wang, L.; Fathi, R.; Yang, Z. J . Org. Chem. 2003, 68, 670.
(15) Percec, V.; Bae, J .-Y.; Hill, D. H. J . Org. Chem. 1995, 1066.
(16) Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
3910.
(9) For a recent review on activation of aryl chlorides, see: Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(10) Comparing the cost of PdX2 and NiX2 where X ) Cl or Br. For
example, NiCl2 is $82.00 for 250 g, PdCl2 is $725.00 for 25 g (Aldrich
catalogue, 2003-2004).
(17) . Nguyen, H. N.; Huang, X.; Buchwald, S. L. J . Am. Chem. Soc.
2003, 125, 11818.
(18) Percec, V.; Bae, J .-Y.; Zhao, M.; Hill, D. H. J . Org. Chem. 1995,
60, 1066.
10.1021/jo049940i CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/16/2004
J . Org. Chem. 2004, 69, 3447-3452
3447

Percec et al.
TABLE 1. In flu en ce of Lea vin g Gr ou p , Ca ta lyst,
Liga n d , a n d Solven t on th e Ni(II)-Ca ta lyzed
Cr oss-Cou p lin g Rea ction
aryl boronic acids in dioxane/water with use of the
catalytic system NiCl2(dppe)/TPPTS/Zn/K3PO4 and by
generating Ni(0) from Ni(II) on charcoal with n-BuLi/
PPh3/dioxane23 have been demonstrated. Additional phos-
phine-free systems such as NiCl2/bpy or NiCl2/NEt3/
Na3PO4 have also been elaborated.24
22
An important advance on the nickel-catalyzed reaction
was generated when aryl chlorides have been shown to
cross-couple without the need of an external reducing
agent.25 By adapting our original reaction conditions,15
it was demonstrated that NiCl2(dppf)/dioxane as well as
NiX2 together with other solvents and ligands have
efficiently catalyzed this cross-coupling reaction. Soon
after, electron-deficient aryl chlorides have been shown
to undergo the Suzuki cross-coupling in the presence of
NiCl2(PPh3)2/PPh3/K3PO4/toluene at 80 °C.26 While this
work was in progress, the cross-couplings of aryl tosylates
with NiCl2(PCy3)2/PCy3/K3PO4/dioxane27 and of aryl bro-
mides with the ligandless system NiCl2‚6H2O/K3PO4/
dioxane28 have been reported. These two catalysts are
active at 130 °C. A catalytic cycle related to Pd(0)-
catalyzed cross-coupling has been suggested for the Ni-
(II)-catalyzed reaction (Scheme S1, Supporting Informa-
tion).26 In the first step of this cycle self-coupling of aryl
boronic acid reduces Ni(II) to Ni(0) via a Pd(II)-related
mechanism.29
solvent and conv (%)
entry
X
catalyst
ligand/%
dioxane
PhMe
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cl
NiCl2(PCy3)2 PCy3/10
NiCl2(PPh3)2 PPh3/10
NiCl2(dppe)
NiCl2(dppb)
NiCl2(dppf)
>95
19
91
>95
Cl
Cl
Cl
Cl
95
>95, 92a
10
dppe/5
dppb/5
dppf/5
80
>95
>95
18
>95
70
87
22
88
OMs NiCl2(PCy3)2 PCy3/10
OMs NiCl2(PPh3)2 PPh3/10
OMs NiCl2(dppe)
OMs NiCl2(dppb)
OMs NiCl2(dppf)
OTs
OTs
OTs
OTs
OTs
dppe/5
dppb/5
dppf/5
77, 70a
50
57
12
NiCl2(PCy3)2 PCy3/10
NiCl2(PPh3)2 PPh3/10
NiCl2(dppe)
NiCl2(dppb)
NiCl2(dppf)
95
52
24
75
dppe/5
dppb/5
dppf/5
82
87
traces
20
50
20
a
Reactions carried out with 1 mol % of catalyst and 1 mol % of
dppe.
external reducing agent pre-dates this report.20 Here we
report our investigations on the influence of a diversity
of leaving groups (mesylates, tosylates, chlorides, bro-
mides and iodides), catalysts [NiCl2(PPh3)2, NiCl2(PCy3)2,
NiCl2(dppe), NiCl2(dppf), and NiCl2(dppb)], excess ligands
(PPh3, PCy3, dppe, dppf, and dppb), and two solvents
(toluene and dioxane) on the Ni(II)-catalyzed cross-
coupling of aryl derivatives containing electron-with-
drawing and electron-donating substituents, in the ab-
sence of a reducing agent.
An inspection of the previous reports on the Ni-
catalyzed cross-coupling reaction showed that different
results were generated by minor changes of the experi-
mental conditions. For example, it was reported24 that
in the cross-coupling of aryl chlorides NiCl2(dppe) was
not active in anisole while NiCl2(dppf) was efficient both
in anisole and dioxane. Toluene was found to be the best
solvent when the cross-coupling of aryl chlorides was
catalyzed by NiCl2(PPh3)2 and NiCl2(PCy3)2,25 while di-
oxane was the most suitable solvent when the cross-
coupling of aryl tosylates was catalyzed by NiCl2(PCy3)2.26
(Table S1, Supporting Information). Surprisingly, NiCl2
complexes with ligands such as dppb, dppp, and dppe
were reported to be less efficient than NiCl2(dppf) and
NiCl2(PPh3)2 both in the presence18,20 and in the absence
of a reducing agent.24 This is unexpected since dppb,
dppe, and dppp are more electron rich than PPh3.
Aryl mesylates are much less expensive and more
stable than aryl triflates. Therefore, their entry into the
Ni(II)-catalyzed cross-coupling would provide a desirable
method for the creation of carbon-carbon bonds starting
from phenols. A single example of Ni(II)-catalyzed cross-
coupling of an aryl mesylate without the use of an
Resu lts a n d Discu ssion
Five catalysts, NiCl2(PPh3)2, NiCl2(PCy3)2, NiCl2(dppe),
NiCl2(dppf), and NiCl2(dppb), were investigated (Table
1). Each catalyst was tested in both dioxane and toluene.
Three leaving groups (X ) -OMs, -OTs, and -Cl) were
first compared for activity. 4-Substituted methyl benzoate
was selected as a model substrate. Cross-coupling reac-
tions were performed at 80 °C for 14 h with 5 mol %
catalyst.
Effect of Ca ta lyst. In view of the previous results
reported for cross-couplings catalyzed by NiCl2(dppe) in
the presence18,20 and absence24 of a reducing agent, it was
surprising to find that NiCl2(dppe) was the most reactive
catalyst for electron-poor aryl mesylates and chlorides
in both dioxane and toluene, when 1 equiv of dppe was
added per equivalent of catalyst (Table 1, entries 3, 8,
and 13). Previously, NiCl2(dppe) was reported to be
reactive for cross-coupling reactions carried out in the
presence of zinc as reducing agent and the additional
ligand TPPTS.21 NiCl2(PPh3)2 and NiCl2(PCy3)2 are also
efficient in these cross-coupling reactions. However, their
reactivity is very sensitive to the nature of solvent (Table
1). NiCl2(dppf) was reactive in the cross-coupling of aryl
chlorides carried out in dioxane and toluene (Table 1,
entry 5). However, NiCl2(dppf) was less reactive for the
cross-coupling of aryl mesylates and tosylates when no
(19) Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37,
2993.
(20) Saito, S.; Oh-tani, S.; Miyaura, N. J . Org. Chem. 1997, 62, 8024.
(21) Ueda, M.; Saitoh, A.; Oh-tani, S.; Miyaura, N. J . Org. Chem.
1997, 62, 8024.
(22) Galland, J .-C.; Savignac, M.; Geneˆt, J .-P. Tetrahedron Lett.
1999, 40, 2323.
(23) Lipshutz, B. H.; Sclafani, J . A.; Blomgren, P. A. Tetrahedron
2000, 56, 2139.
(24) Massicot, F.; Schneider, R.; Fort, Y.; Illy-Cherrey, S.; Tillement,
O. Tetrahedron 2001, 57, 531.
(25) Indolese, A. F. Tetrahedron Lett. 1997, 38, 3513.
(26) Inada, K.; Miyaura, N. Tetrahedron 2000 56, 8657.
(27) Zim, D.; Lando, V. R.; Dupont, J .; Monterio, A. L. Org. Lett.
2001, 3, 3049.
(28) Zim, D.; Monteiro, A. L. Tetrahedron Lett. 2002, 43, 4009.
(29) Moreno-Manas, M.; Pe´rez, M.; Pleixats, R. J . Org. Chem. 1996,
61, 2346.
3448 J . Org. Chem., Vol. 69, No. 10, 2004

NiCl2(dppe)-Catalyzed Cross-Coupling
TABLE 2. In flu en ce of th e Su bstr a te Su bstitu en t on th e
Ni(II)-Ca ta lyzed Cr oss-Cou p lin g of Ar yl Mesyla tes
reducing agent was added. NiCl2(dppb) was the least
general catalyst, giving good yields only for the cross-
coupling of aryl mesylates and chlorides in dioxane (Table
1, entries 4 and 9).
Effect of th e Lea vin g Gr ou p . Aryl chlorides pro-
duced high conversions with nearly all catalysts. NiCl2-
(PCy3)2 and NiCl2(dppe) were active in both dioxane and
in toluene with aryl chlorides, while NiCl2(PPh3)2, NiCl2-
(dppb), and NiCl2(dppf) showed solvent-dependent activ-
ity. The reactivity of aryl mesylates is dependent on the
choice of both catalyst and solvent. Aryl tosylates gener-
ate modest conversions in reactions catalyzed by NiCl2-
(dppe) and NiCl2(PPh3)2 and high conversions in reactions
catalyzed by NiCl2(PCy3)2 above 80 °C.
Effect of Solven t. Except for the case of NiCl2(dppe)
the nature of the solvent had a strong influence on the
cross-coupling reaction. NiCl2(PCy3)2 was very efficient
for the cross-coupling of aryl chlorides in both dioxane
and toluene. However, the cross-coupling of aryl sul-
fonates in dioxane produced higher conversions when
NiCl2(PCy3)2 was used as catalyst. Regardless of the
nature of the leaving group, toluene produced the highest
conversions in the NiCl2(PPh3)2-catalyzed reactions (Table
1).
entry
R
catalyst
ligand/% solvent yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CN
NiCl2(dppe)
dppe/5
dppe/5
PhMe
dioxane 88 (>99)
84
- (50)
NiCl2(PCy3)2 PCy3/10 dioxane 72 (80)
92 (>99)
CN
Ac
Ac
Ac
NiCl2(dppe)
NiCl2(PPh3)2 PPh3/10 PhMe
NiCl2(dppe) dppe/5 dioxane
CO2Me NiCl2(PPh3)2 PPh3/10 PhMe
CO2Me NiCl2(dppe)
CO2Me NiCl2(dppe)
96 (>99)
dppe/5
dppe/5
PhMe
96 (>99)
dioxane 90 (>99)
OMe
OMe
NiCl2(PCy3)2 PCy3/10 dioxane 89 (>99)
NiCl2(PPh3)2 PPh3/10 PhMe
63 (67)
63 (68)
1-nphb NiCl2(PPh3)2 PPh3/10 PhMe
1-npfb
1-npfb
NHAc
OBn
NiCl2(dppe)
dppe/5
dioxane 55 (76)
NiCl2(PCy3)2 PCy3/10 dioxane 95 (>99)
NiCl2(PCy3)2 PCy3/10 dioxane 76 (>99)
NiCl2(PCy3)2 PCy3/10 dioxane 73 (>99)
OBn
NiCl2(dppe)
dppe/5
dioxane 28 (40)
a
Isolated yields; 1H NMR determined conversions are in
b
parentheses. 1-Naphthyl.
Op tim iza tion of th e Cr oss-Cou p lin g for Electr on -
Deficien t Ar yl Mesyla tes a n d Ch lor id es. The absence
of additional ligand decreased the reactivity of all cata-
lysts. However, most of their reactivity was restored
when half of the original amount of ligand was added
(Table S2, compare entries 4-6 with 7-9). When less and
electron-rich ligand was used, a significant amount of
self-coupling product of the aryl mesylate or chloride was
observed (Table S2, entries 1 and 2).
TABLE 3. Op tim iza tion of th e NiCl2(d p p e)/d p p e
Ca ta lytic System for Electr on -Rich Ar yl Mesyla tes a n d
Ch lor id es
Catalyst concentrations as low as 1 mol % were
sufficient for the efficient cross-coupling of electron-
deficient aryl chlorides (Table 1, entry 3 and footnote a).
However, in the cross-coupling of electron-poor aryl
mesylates a lower catalyst concentration decreased the
conversion (Table 1, entry 8 and footnote a). In addition,
although the NiCl2(PPh3)2 system could be used to cross-
couple aryl chlorides at 60 °C, aryl mesylates were not
reactive at this temperature (Table S2, Supporting
Information, entries 1and 2). However, the NiCl2(dppe)
system could be used for the cross-coupling of both
activated aryl mesylates and chlorides at 60 °C (Table
S2, Supporting Information, entry 3). Neither NiCl2-
(PPh3)2, nor NiCl2(dppe) were efficient in the cross-
coupling of aryl chlorides and aryl mesylates at 40 °C
(Table S2, Supporting Information, entries 4-6).
Electr on ic In flu en ce of th e Ar yl Mesyla te Su b-
str a te. A selected series of aryl mesylates containing
various substituents was studied in cross-coupling reac-
tions catalyzed with NiCl2(PPh3)2, NiCl2(PCy)3, and NiCl2-
(dppe). High yields were obtained when either cyano or
acetyl groups were present in the para position of the
aryl mesylate (Table 2, entries 1-5). Methyl-4-phenyl-
benzoate was obtained in 88% and 98% yields with NiCl2-
(PPh3)2 and NiCl2(dppe), respectively (Table 2, entries
6-8). However, electron-neutral and electron-rich aryl
mesylates did not provide preparative yields in the NiCl2-
(PPh3)2- and NiCl2(dppe)-catalyzed reactions (Table 3,
entries 10-12 and 16). As expected, the more electron-
rich ligand, NiCl2(PCy3)2 in dioxane, was very efficient
(Table 2, entries 9 and 13-15) in these reactions.
entry
X
solvent Ni(II) (%) dppe (%) T (°C) yield (%)
1
2
3
4
5
6
7
8
Cl
PhMe
PhMe
PhMe
PhMe
5
5
5
5
5
5
5
5
2.5
7.5
5
7.5
5
80
80
10
66
63
Cl
Cl
Cl
100
100
100
100
100
100
84
OMs PhMe
OMs PhMe
OMs PhMe
OMs dioxane
25
10
7.5
5
<10
28, 40a
31
a
Conversion determined by 1H NMR spectroscopy.
Op tim iza tion of NiCl2(d p p e) Ca ta lyst for th e
Cr oss-Cou p lin g. The influence of temperature, nature
of catalyst, catalyst, and excess ligand concentrations on
the cross-coupling reaction of 4-chloroanisole and 4-meth-
oxy-phenyl mesylate with phenyl boronic acid were
investigated (Table 3). At elevated temperature with a
higher ligand concentration only 4-chloroanisole reacted
in good yields. Methoxy-substituted aryl mesylates did
not couple more efficiently even with increased ligand
concentration and temperature.
Cr oss-Cou p lin g w ith Ni(II) Ca ta lysts Con ta in in g
Mixed Liga n d s. The cross-coupling reaction catalyzed
by NiCl2(dppe) was most efficient when an excess of
ligand that provided two additional phosphorus atoms
per Ni(II) was used. In previous examples, the excess
ligand used was identical with the ligand bound to the
Ni(II) species. A series of experiments in which the NiCl2-
(dppe) catalyst was stabilized by an excess of a mono-
dentate ligand such as PPh3 was also performed. Unex-
pectedly, the experiments reported in Table 4 demonstrate
J . Org. Chem, Vol. 69, No. 10, 2004 3449

Percec et al.
TABLE 4. Effect of Excess Mon od en ta te P P h 3 a s
Ad d ition a l Liga n d to NiCl2(d p p e)-Ca ta lyzed
Cr oss-Cou p lin g Rea ction s
TABLE 5. Ar yl Br om id es a n d Iod id es in th e
Nick el-Ca ta lyzed Cr oss-Cou p lin g
entry
X
R
solvent
Ni (%) dppe (%) yield (%)
conv (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
Br CO2Me PhMe
Br CO2Me dioxane
Br CO2Me PhMe
Br CO2Me PhMe
Br CO2Me dioxane
5
5
5
1
1
5
5
5
1
1
5
5
5
5
5
10
1
1
5
10
5
1
2
5
85, 71a
83
73
88
66
cat. PPh3
entry
R
X
solvent (%) (%) biphenylb biaryl
1
2
3
4
5
6
7
8
9
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
OMs PhMe
Cl PhMe
OMs PhMe
Cl PhMe
OMs PhMe
Cl PhMe
OMs PhMe
5
5
5
5
10
10
10
10
5
ndc
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
<5
nd
<3
<6
<6
4
80
78
30d
71d
75
I
I
I
I
I
I
CO2Me PhMe
CO2Me PhMe
82
73
83, 72a
27, 50b
52, 77c
75
5
OMe
OMe
OMe
OMe
PhMe
PhMe
PhMe
dioxane
PhMe
PhMe
5
5
10
5
74
54
89
57
75
86
99 (89)
58
56
82
82
90 (86)
96 (89)
85 (76)
73
5e
5g
5g
5
Cl
PhMef
OMs PhMef
OMs PhMe
5
Br OMe
Br OMe
5
10
73
66
10 o-OMe
11 1-naphthyl OMs PhMe
12 3,5-OMe
13 p-OMe
14 p-OMe
15 p-CO2Me
16 p-CO2Me
17 p-CO2Me
18 o-CO2Me
10
10
10
6
5
5
3
a
b
NiCl2(PPh3)2 with 10 mol % of PPh3 was used. Reaction
temperature, 100 °C. c Reaction time, 22 h.
OMs PhMe
OMs PhMe
OMs PhMe
Cl
Cl
1
2
PhMe
dioxane
5
5
5
5
5
1
10
10
10
10
10
2
NiCl2(NEt3)2 and NiCl2(bpy) catalysts.30 Both aryl bro-
mides and iodides containing electron-withdrawing and
electron-donating substituents were efficiently cross-
coupled in high conversions with use of NiCl2(dppe)
catalyst. Side products derived from the reduction or
homocoupling of the aryl halides were not detected at all
or were observed only in trace amounts. The NiCl2(dppe)
system exhibited higher reactivity than NiCl2(PPh3)2
(Table 5, entries 1 and 8). Catalyst concentrations could
be reduced to 1 mol % when methyl-4-bromobenzoate was
used (Table 5, entries 4 and 5). Iodoanisole was an
effective cross-coupling partner under standard reaction
conditions. Furthermore, a larger excess of ligand and
an extended reaction time allowed the cross-coupling of
iodoanisole with phenyl boronic acid when only 1 mol %
of NiCl2(dppe) was used.
OMs PhMe
OMs PhMe
nd
nd
2
19 m-CO2Me OMs PhMe
20 p-CO2Me
21 p-CO2Me
22 p-CO2Me
23 p-CO2Me
24 p-CO2Me
25 p-CO2Me
Cl
dioxane
OMs PhMe
1
2
3
3
82
78
OMs dioxane
OMs PhMe
1
2
0.5
5
5
1
10
20
<3
nd
5
86 (77)
16
63
OMs dioxaneh
OMs dioxaneh
Isolated yields are in parentheses. b Not determined. c Biphen-
a
d
yl from the self-coupling of ArB(OH)2. Reaction temperature 60
°C. e NiCl2(PPh3)2 as catalyst. f PCy3 as ligand. dppe as excess
g
h
ligand. As received A.C.S. reagent grade dioxane used as solvent.
that the most general catalyst for the cross-coupling of
aryl mesylates and chlorides containing electron-donating
substituents in para, meta, and ortho positions to the
leaving group was NiCl2(dppe)/PPh3. Replacing PPh3 with
the more electron-rich PCy3 reduced the reactivity of the
catalyst (compare entries 1 and 7 in Table 4). This is an
unexpected result. In addition, the catalyst concentration
could be reduced to 1 mol % for aryl chlorides and
mesylates containing electron-donating substituents and
to 0.5 mol % for electron-withdrawing derivatives. With
a 20 mol % excess of PPh3 the cross-coupling reaction was
efficient in as received A.C.S. reagent grade dioxane
(Table 4, entries 24 and 25). The small amount of biphen-
yl generated by the self-coupling of phenyl boronic acid
is proportional to the amount of catalyst used and does
not interfere with the separation of the pure cross-
coupled product by recrystallization or column chroma-
tography. Without any attempt to optimize the reaction
conditions, these experiments have demonstrated that
NiCl2(dppe)/PPh3 is the most general nickel-based cata-
lytic system for the cross-coupling of aryl mesylates and
aryl chlorides.
Syn th esis of Mu ltifu n ction a l Bip h en yls. These
nickel-catalyzed cross-coupling reaction conditions have
been employed in the preparation of several precursors
required for the synthesis of novel AB2 and AB3 self-
assembling dendritic building blocks.31 Replacing the
previously used AB2 and AB3 benzyl ether building blocks
with the corresponding biphenyl methyl ethers will
expand the dimensions, the 3-dimensional structures,
and the functions generated from the previous library of
supramolecular dendrimers.32 The very good isolated
yields obtained in the synthesis of the multifunctional
(30) . Leadbeater, N. E.; Resouly, S. M. Tetrahedron 1999, 55, 11889.
(31) (a) Percec, V.; J ohansson, G.; Ungar, G.; Zhou, J . J . Am. Chem.
Soc. 1996, 118, 9855. (b) Balagurusamy, V. S. K.; Ungar, G.; Yeardley,
D. J . P. J . Am. Chem. Soc. 1997, 119, 1539. (c) Hudson, S. D.; J ung,
H.-T.; Percec, V.; Cho, W.-D.; J ohansson, G.; Ungar, G.; Balagurusamy,
V. S. K. Science 1997, 278, 449. (d) Percec, V.; Ahn, C.-H.; Ungar, G.;
Yeardley, D. J . P.; Mo¨ller, M.; Sheiko, S. S. Nature 1998, 391, 161. (e)
Percec, V.; Cho, W.-D.; Ungar, G.; Yeardley, D. J . P. J . Am. Chem.
Soc. 2001, 123, 1302. (f) Percec, V.; Glodde, M.; Bera, T. K.; Miura, Y.;
Shiyanovskaya, I.; Singer, K. D.; Balagurusamy, V. S. K.; Heiney, P.
A.; Schnell, I.; Rapp, A.; Spiess, W.-H.; Hudson, S. D.; Duan, H. Nature
2002, 419, 384. (g) Ungar, G.; Liu, Y.; Zeng, X.; Percec, V.; Cho, W.-D.
Science 2003, 299, 1208. (h) Zeng, X.; Ungar, G.; Liu, Y.; Percec, V.;
Dulcey, A. E.; Hobbs, J . K. Nature 2004, 428, 157.
Cr oss-Cou p lin g of Ar yl Br om id es a n d Iod id es.
The capability of the NiCl2(dppe) catalyst for the cross-
coupling of aryl bromides and iodides was also investi-
gated (Table 5). Ni(II)-catalyzed cross-couplings of aryl
bromides and iodides were previously reported only with
(32) Percec, V.; Chu, P.; Ungar, G.; Zhou, J . J . Am. Chem. Soc. 1995,
117, 11441.
3450 J . Org. Chem., Vol. 69, No. 10, 2004

NiCl2(dppe)-Catalyzed Cross-Coupling
TABLE 6. Syn th esis of Mu ltifu n ction a l Bip h en yls by Nick el-Ca ta lyzed Cr oss-Cou p lin g
entry
R1
R2
R3
X
catalyst
ligand (%)
solvent
yield (%)a
79
1
2
3
4
5
6
7
H
OMe
H
H
OMe
OMe
OMe
OMe
H
Cl
Cl
Cl
Br
Br
Br
Br
NiCl2(PPh3)2
NiCl2(PPh3)2
NiCl2(dppe)
NiCl2(PPh3)2
NiCl2(dppe)
NiCl2(dppe)
NiCl2(dppe)
PPh3
PPh3
PPh3
PPh3
dppe
dppe
dppe
PhMe
PhMe
PhMe
PhMe
PhMe
dioxane
PhMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
74
86
75 (88), 85b
78 (97)
81 (93)
96
OMe
a
b
Conversions by 1H NMR spectroscopy are in parentheses. Phenyl boronic acid was used to produce the monofunctional biphenyl.
37.4. Rf (3:1 hexanes/EtOAc) 0.25. HRMS (M + Na) calcd
305.0510, found 305.0505.
biphenyls reported in Table 6 demonstrate the synthetic
utility of the NiCl2(dppe) catalytic system.
Gen er a l P r oced u r e for th e Cr oss-Cou p lin g Exp er i-
m en ts. To a 25-mL Schlenk tube equipped with a magnetic
stir bar were added 2 mmol of aryl halide or mesylate,34 0.290
g of phenyl boronic acid (2.4 mmol, 1.2 equiv), 0.10 mmol of
Nickel catalyst, 6 mmol (1.391 g) of K3PO4‚H2O, and phosphine
to give 4 equiv of P for every Ni. The reaction vessel was
equipped with a glass stopper and sealed. The Schlenk tube
was evacuated and backfilled through the sidearm with Ar
several times before being allowed to sit under Ar for at least
30 min. Solvent (10 mL) was added under Ar and the sidearm
was closed. The reaction was heated to 80 °C (oil bath
temperature) for 14 h. At the end of this time period, the
reaction was quenched by opening to air and the addition of
15 mL of Et2O or DCM. The solids were filtered off and
washed. The resultant solution was dried with MgSO4 and
filtered. The solution was concentrated under reduced pressure
to give the crude biaryl. Purification via column chromotog-
raphy gave the title compounds.
Con clu sion s
The NiCl2(dppe)-, NiCl2(dppb)-, NiCl2(dppf)-, NiCl2-
(PCy3)2-, and NiCl2(PPh3)2-catalyzed Suzuki-type cross-
coupling of aryl mesylates, tosylates, chlorides, bromides,
and iodides containing electron-withdrawing and electron-
donating substituents, in the absence of a reducing agent,
was investigated. Contrary to previous publications18,20,24
reporting that NiCl2(dppe) was unreactive in the absence
of a reducing agent, we have discovered that NiCl2(dppe)
in the presence of an excess of dppe, NiCl2(dppe)/dppe,
is the most general nickel catalyst for the cross-coupling
of aryl mesylates, tosylates, chlorides, bromides, and
iodides containing electron-withdrawing substituents and
of aryl bromides and iodides containing electron-donating
substituents, in both dioxane and toluene. NiCl2(dppe)
containing an excess of PPh3, (NiCl2(dppe)/PPh3), is a
general catalyst for the cross-coupling of aryl mesylates
and chlorides containing both electron-donating and
electron-withdrawing substituents. In the two solvents
investigated, dioxane and toluene, all other nickel cata-
lysts exhibited solvent-dependent reactivity.
4′-P h en yla cet op h en on e. White plates, mp 117-119 °C
1
(lit.5b 120-121 °C). H NMR (500 MHz, CDCl3) δ 8.03 (d, J )
8.6 Hz, 2H), 7.69 (d, J ) 8.6 Hz), 7.63 (d, J ) 7.9 Hz, 2H),
7.46 (dd, J ) 7.5, 7.0 Hz, 2H), 7.40 (tt, J ) 7.3, 1.3 Hz, 1H),
2.64 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 198.0, 146.2, 140.3,
136.3, 129.3, 129.3, 128.6, 127.6, 127.6, 26.9. Rf (3:1 hexanes/
EtOAc) 0.40.
4′-P h en yla ceta n ilid e. White needles, mp 168-170 °C
(lit.35 168-170 °C). 1H NMR (500 MHz, CDCl3) δ 7.77 (br s,
1H), 7.57-7.52 (m, 6H), 7.42 (dd, J ) 7.3, 7.5 Hz, 2H) 7.32 (t,
J ) 7.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 169.0, 140.8,
137.6, 129.1, 127.9, 127.1, 120.7, 24.8. Rf (3:1 hexanes/EtOAc)
0.06.
Exp er im en ta l Section
Ma ter ia ls a n d Gen er a l Meth od s. Materials and general
methods are available in the Supporting Information.
Gen er a l P r oced u r e for th e Syn th esis of Ar yl Mesy-
la tes. A modified literature procedure was used.12 A flame-
dried round-bottom flask equipped with a magnetic stir bar
was charged with hydroquinone monobenzyl ether (25 mmol,
5.0 g), 25 mL of CH2Cl2, and 5 mL of pyridine. The homoge-
neous mixture was cooled in an ice water bath and methane
sulfonyl chloride was added dropwise (1.2 equiv, 3.4 g, 2.3 mL,
4′-Meth yl-4-Meth oxybip h en yl. White plates, mp 106-107
°C (lit.36 109 °C). 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J )
9.0 Hz, 2H), 7.45 (d, J ) 8.0 Hz, 2H), 7.22 (d, J ) 7.9 Hz, 2H),
6.97 (d, J ) 9.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 138.4,
136., 134.2, 129.8, 128.3, 126.9, 114.6, 55.7, 21.3. Rf (3:1
hexanes/EtOAc) 0.66.
4-Cya n obip h en yl. White powder, mp 84-86 °C (lit.5c 86-
1
30 mmol). After TLC or H NMR spectroscopy analysis showed
1
87 °C). H NMR (500 MHz, CDCl3) δ 7.73 (d, J ) 8.6 Hz, 2H),
total consumption of the starting material, the reaction was
quenched with H2O (40 mL). The phases were separated and
the aqueous layer was extracted with CH2Cl2 (3 × 20 mL).
The combined organic extracts were washed successively with
15% HCl (2 × 20 mL), H2O (2 × 25 mL), and saturated aqueous
NaCl solution (2 × 20 mL). After drying over MgSO4, the crude
product was recrystallized from hexane/toluene/EtOAc (2:1:
1) to afford the aryl mesylate (5.87 g, 85%).
4-(Meth an esu lfon yl)oxy Ben zyloxyben zen e. White rhom-
boids (toluene), mp 129-131 °C. H NMR (500 MHz, CDCl3)
δ 7.43-7.34 (m, 5H), 7.21 (d, J ) 8.8 Hz, 2H), 6.99 (d, J ) 8.8
Hz, 2H), 5.06 (s, 2H), 3.10 (s, 3H). 13C NMR (125 MHz, CDCl3)
δ 158.0, 143.2, 136.8, 129.0, 128.5, 127.8, 123.38, 116.2, 70.8,
7.68 (d, J ) 8.6 Hz, 2H), 7.59 (d, J ) 7.5 Hz, 2H), 7.46 (dd,
J ) 7.6, 7.5 Hz, 2H), 7.43 (tt, J ) 7.5, 2.1 Hz). 13C NMR
(33) (a) Seeman, W.; J ohnson, J . R. J . Am. Chem. Soc. 1931, 53,
711. (b) Chan, K. S.; Zhou, X.; Au, M. T.; Tam, C. Y. Tetrahedron 1995
51, 3129.
(34) If the starting material is oil, 5 mL of a 0.2 M solution of the
compound was added. The oil was evacuated and backfilled with Ar
separately from the rest of the starting materials.
(35) Hazlet, S. E.; Dornfield, C. A. J . Am. Chem. Soc. 1944, 66,
1781.
1
(36) Tinnemans, A. H. A.; Laarhoven, W. H. J . Am. Chem. Soc.
1974, 96, 4611.
J . Org. Chem, Vol. 69, No. 10, 2004 3451

Percec et al.
(125 MHz, CDCl3) δ 139.6, 132.9, 129.5, 129.o, 128.1, 127.6,
119.2. Rf (3:1 hexanes/EtOAc) 0.47.
(125 MHz, CDCl3) δ 158.8, 137.4, 129.1, 129.0, 128.5, 128.3,
128.1, 127.8, 127.1, 127.0, 115.5. Rf (3:1 hexanes/EtOAc) 0.66.
4′-Meth yl-3,4-Dim eth oxybip h en yl. White plates (EtOH),
Bip h en yl-4-Ca r boxylic Acid Meth yl Ester . White crys-
1
mp 63-65 °C (lit.37 62-64 °C). H NMR (500 MHz, CDCl3) δ
1
tals, mp 114-115 °C (lit.41 117-118 °C). H NMR (500 MHz,
7.45 (d, J ) 8.1 Hz, 2H), 7.23 (dd, J ) 8.8, 8.6 Hz, 2H), 7.12
(dd, J ) 8.3, 2.2 Hz, 1H), 7.09 (d, J ) 2.2 Hz, 1H), 6.92 (d,
J ) 8.3 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 2.38 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 149.6, 148.9, 138.6, 136.9, 134.7,
129.8, 127.1, 119.57, 112.0, 110.9, 56.4, 56.3, 21.4. Rf (3:1
hexanes/EtOAc) 0.39.
3,4-Dim eth oxybip h en yl. White needles (EtOH), mp 68-
70 °C (lit.38 70.5 °C). 1H NMR (500 MHz, CDCl3) δ 7.57 (d,
J ) 7.9 Hz, 2H), 7.42 (dd, J ) 7.9, 7.7 Hz, 2H), 7.32 (tt, J )
7.3, 1.3, 1H), 7.15 (dd, J ) 8.3, 2.0 Hz, 1H), 7.13 (d, J ) 2.3
Hz, 1H), 6.95 (d, J ) 8.3 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H).
13C NMR (125 MHz, CDCl3) δ 149.6, 149.1, 141.5, 134.07,
129.1, 127.2, 127.2, 119.8, 112.0, 111.0, 56.4, 56.3. Rf (3:1
hexanes/EtOAc) 0.39.
4-Meth oxybip h en yl. White powder (EtOH), mp 85-87 °C
(lit.5a 83-84 °C). 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J ) 7.3
Hz, 2H), 7.58 (d, J ) 8.8 Hz, 2H), 7.45 (dd, J ) 7.8, 7.8 Hz,
2H), 7.34 (dd, J ) 7.3, 1.3 Hz), 7.02 (d, J ) 8.6 Hz, 2H), 3.88
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 159.5, 141.2, 134.1,
129.0, 128.5, 128.0, 127.0, 114.6, 55.7. Rf (3:1 hexanes/EtOAc)
0.67.
CDCl3) δ 8.10 (d, J ) 8.4 Hz, 2H), 7.65 (d, J ) 8.4 Hz, 2H),
7.61 (d, J ) 7.2 Hz, 2H), 7.47 (dd, J ) 7.5, 7.2 Hz, 2H), 7.38
(tt, J ) 7.4, 1.5 Hz, 1H), 3.94 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 167.3, 146.0, 140.4, 130.4, 129.3, 129.3, 128.5, 127.6,
127.4, 52.4. Rf (3:1 hexanes/EtOAc) 0.64.
3′,4′,5′-Tr im eth oxy-4-m eth ylbip h en yl. Hexane, mp 65 °C.
1
Purity (HPLC) 99+ %. H NMR (500 MHz, CDCl3) δ 2.41 (s,
3H), 3.89 (s, 3H), 3.93 (s, 6H), 6.78 (s, 2H), 7.25 (d, 2H, J )
8.0 Hz), 7.46 (d, 2H). 13C NMR (125 MHz, CDCl3, 20 °C) δ
153.7, 138.7, 137.8, 137.4, 137.3, 129.7, 127.2, 104.7, 61.2, 21.3.
Anal. Calcd for C16H18O3: C, 74.39; H, 7.02. Found: C, 74.16;
H, 7.08.
1-P h en yln a p h th a len e. Colorless viscous liquid.42 1H NMR
(500 MHz, CDCl3) δ 7.96 (m, 2H), 7.93 (d, J ) 8.2 Hz, 1H),
7.56 (m, 9H). 13C NMR (125 MHz, CDCl3) δ 141.1, 140.6, 134.2,
132.01, 130.4, 128.6, 128.0, 127.6, 127.5, 127.3, 126.4, 126.4,
126.1, 125.7. Rf (5:1 hexanes/EtOAc) 0.53.
Ack n ow led gm en t. Financial support by the Na-
tional Science Foundation is gratefully acknowledged.
J .S. thanks the Isabel and Alfred Bader Foundation for
a graduate fellowship and O.W. the Alexander von
Humboldt-Stiftung for a postdoctoral fellowship.
4′-Meth yl-3,5-Dim eth oxybip h en yl. White needles (hex-
1
ane), mp 55-56 °C (lit.39 57.3-57.5 °C). H NMR (500 MHz,
CDCl3) δ 7.50 (d, J ) 8.0 Hz, 2H), 7.25 (d, J ) 7.9 Hz, 2H),
6.75 (d, J ) 2.2 Hz, 2H), 6.48 (t, J ) 2.2 Hz, 1H), 3.86 (s, 6H),
2.41 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.4, 143.8, 138.7,
137.7, 129.7, 127.3, 105.6, 99.4, 55.7, 21.4. Rf (3:1 hexanes/
EtOAc) 0.60.
Su p p or tin g In for m a tion Ava ila ble: Materials and gen-
eral methods, a scheme showing the catalytic cycle proposed
for the Ni(II)-catalyzed Suzuki-type reaction, three tables of
experimental results, NMR spectra of 4-(methanesulfonyl)oxy
benzyloxybenzene and 3′,4′,5′-trimethoxy-4-methylbiphenyl,
and additional supporting references. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
4-Ben zyloxybip h en yl. White rhomboids, mp 131-133 °C
1
(lit.40 136 °C). H NMR (500 MHz, CDCl3) δ 7.54 (d, J ) 7.2
Hz, 2H), 7.52 (d, J ) 8.8 Hz, 2H), 7.45 (2H, J ) 7.3 Hz), 7.42-
7.28 (m, 6H), 7.04 (d, J ) 8.8 Hz, 2H), 5.14 (s, 2H). 13C NMR
(37) Elix, J . A.; Murphy, D. P. Aust. J . Chem. 1975, 1559.
(38) Allen, G.; Bruce, J . M. J . Chem. Soc. 1963, 1757.
(39) Dol, G. C.; Kamer, P. C. J .; van Leeuwen, P. W. N. M. Eur. J .
Org. Chem. 1998, 1, 359.
(40) Reusch, W.; J ohnson, C. K.; Manner, J . A. J . Am. Chem. Soc.
1966, 88, 2803.
J O049940I
(41) Barba, I.; Chinchilla, R.; Gomez, C. Tetrahedron 1990, 46, 7813.
(42) . Bergbreiter, D. E.; Osburn, P. L.; Wilson, A.; Sink, E. M. J .
Am. Chem. Soc. 2000, 122, 9058.
3452 J . Org. Chem., Vol. 69, No. 10, 2004