High ortho preference in Ni-catalyzed cross-coupling of halophenols with alkyl Grignard reagents

Article abstract of DOI:10.1021/ol802824b

(Chemical Equation Presented) High preference of substitution at the position ortho to the hydroxy group was observed for Ni-catalyzed cross-coupling reactions of dihalophenols with alkyl Grignard reagents. Reactions of 2,4-dihalophenols, with various com

Full text of DOI:10.1021/ol802824b

ORGANIC
LETTERS
2009
Vol. 11, No. 3
741-744
High Ortho Preference in Ni-Catalyzed
Cross-Coupling of Halophenols with
Alkyl Grignard Reagents
Jia-Rui Wang and Kei Manabe*
Manabe InitiatiVe Research Unit, RIKEN AdVanced Science Institute,
2-1 Hirosawa, Wako 351-0198, Japan
keimanabe@riken.jp
Received December 8, 2008
ABSTRACT
High preference of substitution at the position ortho to the hydroxy group was observed for Ni-catalyzed cross-coupling reactions of dihalophenols
with alkyl Grignard reagents. Reactions of 2,4-dihalophenols, with various combinations of F, Cl, and Br, were shown to afford ortho-cross-
coupled products selectively. In addition, high ortho preference was also observed in competitive cross-coupling reactions between 2-halophenols
and other halophenols.
Transition-metal-catalyzed cross-coupling reactions in which
haloarenes react with nucleophilic organometallic reagents
Scheme 1. Site-Selective Cross-Coupling Reaction
constitute an important and practical synthetic methodology
of multisubstituted arenes.1 Unfortunately, the selective
conversion of one halogen atom (mono-cross-coupling reac-
tions) for dihalobenzenes that possess two identical halo
groups has proven to not always be easy. In many cases,
the reaction results in double-cross-coupling that involves
both halo groups, even when the amount of the nucleophilic
reagents was limited.2 Furthermore, site-selective mono-
cross-coupling reactions of dihalobenzene derivatives (Scheme
1) remain to be investigated in detail.3 In general, the site-
selective mono-cross-coupling reactions have been achieved
using dissimilar halogen substituents (Scheme 1, X1 * X2)
that exploit the differences in their reactivities (reactivity
order: I > Br > Cl > F). It would be highly desirable,
however, to employ substrates having two identical halo
groups (X1 ) X2) due to facile preparation and/or com-
mercially availability.
Recently, we developed the ortho-selective cross-coupling
of dihalobenzenes that possess electron-donating ortho-
directing groups using Grignard reagents in the presence of
palladium-based catalysts.4 Our methodology sharply differs
from most other ortho-selective cross-coupling reactions in
which electron-withdrawing groups act as ortho-directing
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Corbet, J.-P.;
Mignani, G. Chem. ReV. 2006, 106, 2651.
(2) (a) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka,
A.; Kodama, S.-i.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc.
Jpn. 1976, 49, 1958. (b) Sinclair, D. J.; Sherburn, M. S. J. Org. Chem.
2005, 70, 3730. (c) Dong, C.-G.; Hu, Q.-S. J. Am. Chem. Soc. 2005, 127,
10006.
10.1021/ol802824b CCC: $40.75
Published on Web 01/14/2009
2009 American Chemical Society

groups.5 Although electron-donating groups typically retard
the oxidative addition of a C-X bond to a transition metal
in cross-coupling reactions, the presence of such groups is
essential for the acceleration at the ortho position in our
reactions. Aryl, alkenyl, and benzyl Grignard reagents were
successfully utilized. For alkyl Grignard reagents that possess
ꢀ-hydrogens, however, the reaction resulted in only the
reduction of the starting halobenzenes, without the formation
of the desired cross-coupled products. To overcome this
problem, we tested various nickel catalysts that bear a
bidentate phosphine ligandsas a note, such catalysts were
employed in the original investigations of cross-coupling
reactions using alkyl Grignard reagents, as reported by
Tamao, Kumada, and co-workers.2a,6 Although such nickel-
based catalysts tend to undergo double cross-coupling,2a
several catalysts have shown promising results toward
promoting ortho-selective mono-cross-coupling of dihalophe-
nols. Herein, we report such selective reactions, along with
the high ortho preference in competitive cross-coupling
reactions between two substrates.
For these reactions, the hydroxy group of the substrate,
which is deprotonated to form the corresponding magnesium
phenoxide upon addition of the Grignard reagent, was shown
to play an essential role for achieving high efficiencies. Using
the methyl ether analogue (2,4-dichloroanisole) as a substrate,
under the conditions shown in Table 1 (entry 5, 1.5 equiv
of the Grignard reagent), the double-cross-coupled product
was obtained in 44% yield, along with the ortho-cross-
coupled product in 35% yield. Therefore, although a methoxy
group can function as a directing group, it is significantly
less effective than a magnesium oxido group.
As shown in Table 2, our catalytic system was applied to
other substrates. In the cases of 2,4-dichloro-, 2,4-difluoro-,
Table 2. Ortho-Selective Cross-Coupling of Substrates Having
Two Identical Halo Groupsa
We first tested nickel catalysts using the model reaction
of 2,4-dichlorophenol with dodecylmagnesium bromide in
ether. Representative examples are shown in Table 1.
Table 1. Optimization of Ortho-Selective Cross-Coupling
Conditions
entry
catalyst
solvent
T (°C)
yielda (%)
1
2
3
4
5
NiCl2(dppf)
NiCl2(dppp)
NiCl2(dppe)
NiCl2(dppbz)
NiCl2(dppbz)
Et2O
Et2O
Et2O
Et2O
reflux
reflux
reflux
rt
0 (8)b
13 (15)b
24 (11)b
64 (9)b
76 (2)b
toluene
rt
a The yield of the isolated product. b The yield of the double cross-
coupled product (2,4-didodecylphenol).
Although the use of NiCl2(dppf) resulted in the formation
of the double-cross-coupled product in a low yield (entry
1), the use of NiCl2(dppp) or NiCl2(dppe) afforded the ortho-
selective cross-coupling product, albeit in low yields (entries
2 and 3). For these reactions, the isomer, 2-chloro-4-
dodecylphenol, was not obtained at all. Encouraged by these
results, various multidentate phosphines were screened as
ligands, and as a result, 1,2-bis(diphenylphosphino)benzene
(DPPBZ)7 was determined as the optimal ligand. The desired
product was obtained in a high yield even at rt (entry 4).
The yield was further improved when toluene was used as
the solvent (entry 5).8 Moreover, the formation of the double-
cross-coupled product was effectively suppressed. Under
these conditions, neither the cross-coupling nor the reduction
was catalyzed by PdCl2(dppbz), indicating the higher activity
of the nickel species.
a Reaction conditions: substrate (0.5 mmol), Grignard reagent (1.5
mmol), NiCl2(dppbz) (0.025 mmol) in toluene at rt for 22 h unless otherwise
indicated. b The yield of the isolated product. c At 75 °C. d NiCl2(dippbz)
was used instead of NiCl2(dppbz).
and 2,4-dibromophenol, reactions with alkyl Grignard re-
agents occurred ortho-selectively (entries 1-6). Although the
yields of the desired products were modest in most cases,
742
Org. Lett., Vol. 11, No. 3, 2009

the corresponding isomeric products were not obtained. With
the exception of entry 1 (7%) and entry 6 (12%), only trace
amounts of the double cross-coupled products were obtained.
In the cases of difluoro- and dibromophenol (entries 5 and
6), the use of NiCl2(dippbz) was slightly more effective than
NiCl2(dppbz) (DIPPBZ ) 1,2-bis[di(4-isopropylphenyl)phos-
phino]benznene). Interestingly, the cross-coupling of a fluo-
robenzene derivative having an electron-donating group was
shown to proceed at rt. For 2,5-dichlorophenol, the yield of
the ortho-cross-coupled product was significantly lower
(entry 7), while a significant amount of the double cross-
coupled product was obtained (26%).9
and double-cross-coupled products were obtained in trace
amounts. These results indicate that the directing effects of
the hydroxy group take priority over the intrinsic reactivity
order of the halo groups.10 As expected, the reactions
involving substrates shown in entries 5 and 6 selectively
afforded the ortho-cross-coupled products.
High ortho preference was also observed in the competitive
cross-coupling between two substrates.11 As shown in Table
4 (entry 1), the cross-coupling reaction involving a 1:1
Table 4. Competitive Cross-Coupling of Two Substratesa
As shown in Table 3, unusual behavior was observed using
substrates that have two different halo groups. For the
Table 3. Ortho-Selective Cross-Coupling of Substrates Having
Two Different Halo Groupsa
a Reaction conditions: substrate (0.5 mmol), dodecylmagnesium bromide
(1.5 mmol), NiCl2(dppbz) (0.025 mmol) in toluene at rt for 22 h unless
otherwise indicated. b The yield of the isolated product. c NiCl2(dippbz)
was used instead of NiCl2(dppbz).
a Reaction conditions: two substrates (0.5 mmol each), dodecylmagne-
sium bromide (2.0 mmol), NiCl2(dppbz) (0.025 mmol) in ether at rt for
22 h. b The yields after separation. c NiCl2(dippbz) was used instead of
NiCl2(dppbz).
reaction of 4-bromo-2-chlorophenol or 4-bromo-2-chloro-
5-methylphenol (entries 1 and 2), an o-chloro group was
found to be more reactive than a p-bromo group. Accord-
ingly, the reaction strongly favored the formation of the
ortho-cross-coupled over the para-cross-coupled product, but
a small amount of the double-cross-coupled product was
formed (3%, entry 1; 8%, entry 2). More surprisingly, an
o-fluoro group was more reactive than a p-chloro and even
a p-bromo group (entries 3 and 4). In these cases, the para-
mixture of 2-chlorophenol and 4-chlorophenol favored the
former substrate. Similarly, preference for the ortho substrate
was also observed for the competitive reactions between
2- and 3-chlorophenol (entry 2), between 2- and 4- (or
3-)bromophenol (entries 3 and 4), and between 2- and
4-fluorophenol (entry 5). Furthermore, 2-chlorophenol and
Org. Lett., Vol. 11, No. 3, 2009
743

2-fluorophenol were found to be more reactive than 4-bro-
mophenol (entries 6 and 7). These results clearly demonstrate
that the ortho-directing effect of the hydroxy group is
effective, not only for intramolecular differentiation between
two halo groups but also for intermolecular differentiation
between two halobenzene substrates.
Despite the following assumptions, the mechanism of the
high ortho preference in these nickel-catalyzed cross-coupling
reactions remains unclear. For the ortho-selective reactions
of dihalophenols, the oxidative addition of the ortho-C-X
bond to nickel(0) is presumably the selectivity-determining
step. The oxidative addition step is assumed to be facilitated
by the Lewis acidic magnesium of the magnesium phenoxide
(substrate) (Figure 1).10a,12,13 On the other hand, we cannot
In summary, the catalytic system involving NiCl2(dppbz)
and NiCl2(dippbz) was shown to enhance the ortho-selective
cross-coupling reactions of dihalophenols with alkyl Grignard
reagents. Furthermore, high ortho preference was also
observed in competitive cross-coupling between two sub-
strates. Our studies show that the directing effects of the
hydroxy group can override the intrinsic reactivities of halo
groups. Although the mechanism of the high ortho preference
has yet to be clarified, we believe that the unusual behavior
described herein contributes to further development of cross-
coupling methodology.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research on Priority Areas
“Advanced Molecular Transformation of Carbon Resources”
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Experimental pro-
cedures, spectral data, and copies of NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. Proposed transition state of the oxidative addition step
in which Lewis acidic Mg facilitates the C-X bond cleavage.
OL802824B
(5) Deprotonative ortho-metalation is frequently directed by an electron-
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4374.
rule out the possibility that the nickel(0)/arene η2-complex
formation step,14 prior to the oxidative addition, is the
selectivity-determining step especially for the competitive
cross-coupling of two substrates. Further studies are currently
underway to gain insight into the origin of the high ortho
preference.
(7) Levason, W.; McAuliffe, C. A. Inorg. Chim. Acta 1974, 11, 33.
(8) See the Supporting Information for experimental details.
(9) Dichlorobenzene derivatives having other functional groups such as
-CH2OH, -NH2, and -NHAc resulted in poor yields and ratios of the
desired ortho-substituted and the disubstituted products. The yields of the
desired ortho-substituted products (and the disubstituted products in
parenthesis): 2,4-dichlorobenzyl alcohol, 6% (28%); 2,4-dichloroaniline,
19% (8%); 2,4-dichloroacetanilide, trace (13%).
(10) Reversal of the reactivity order of halo groups in transition-metal-
catalyzed cross-coupling has been reported. See: (a) Terao, J.; Ikumi, A.;
Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646. (b) Arisawa,
M.; Suzuki, T.; Ishikawa, T.; Yamaguchi, M. J. Am. Chem. Soc. 2008, 130,
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(13) One of the reviewers of this paper suggested possibilities of SNAr
and radical mechanisms instead of concerted oxidative addition of C-X
bond to Ni(0). We cannot completely exclude these possibilities, although
the SNAr mechanism is unlikely because of the presence of the strongly
electron-donating oxido group. We thank the reviewer for pointing out these
possibilities.
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