Nickel-catalyzed coupling of aryl bromides in the presence of alkyllithium reagents

Article abstract of DOI:10.1002/chem.200801008

An easy approach towards the synthesis of compounds using coupling reactions of bromide compounds was demonstrated. A comparison of different alkyllithium reagents was made by examining the coupling of bromobenzene (1a). The molar ratio of bromobenzene to catalyst was 138:1 using [NiCl ₂(dppp)] and bromobenzene, Bpy was added to the reaction solution as a ligand. Alkyllithium was added at half molar equivalents to that of phenyl bromide groups with the intention of generating an equimolar ratio of lithiated benzene anions to unreacted phenyl bromide groups. It was observed that decreasing the amount of [NiCl₂(dppp)] from 25 to 12 mg, while maintaining the ratio to bpy, did not have a substantial effect on the yield of biphenyl formed. The one-pot synthetic technique demonstrate the use of alkyllithium reagents with a catalytic amount of nickel to syntheisze coupled aryl compounds.

Full text of DOI:10.1002/chem.200801008

COMMUNICATION
DOI: 10.1002/chem.200801008
Nickel-Catalyzed Coupling of Aryl Bromides in the Presence of Alkyllithium
Reagents
[
a]
Sarav B. Jhaveri and Kenneth R. Carter*
Transition-metal-catalyzed coupling reactions of halogen-
ated molecules leading to formation of new carbon–carbon
bonds are a very important category of reactions used in the
synthesis of complex compounds and conjugated poly-
which is generally a substrate- and solvent-specific reaction
(working optimally in tetrahydrofuran or diethyl ether as
[6–10]
solvents).
Nickel reactions facilitated by the addition of
zinc powder have been utilized in a similar fashion in organ-
[1–3]
[11–13]
mers.
Within the past decade, this methodology has
ic synthesis,
merizations.
as well as in efficient condensation poly-
These reactions are not always well con-
[14–16]
evolved into a powerful synthetic tool for the preparation of
a wide range of specialty polymers, composite materials, and
pharmaceutically active compounds both in the laboratory
and on the industrial scale. It is also widely appreciated in
the context of parallel synthesis and combinational chemis-
trolled, require prolonged heating at high temperatures, and
the products have high levels of metal impurities that can be
difficult and costly to remove. This trace-metal contamina-
tion is especially problematic if the end use is in pharma-
ceutical or microelectronic applications in which safety, per-
formance, and reliability require stringent control of purity.
Another known aryl–halide coupling reaction involves the
use of highly reactive zinc (Rieke zinc), which is prepared
[
4,5]
try.
We desired to develop an improved catalytic method
for transition-metal-catalyzed aryl coupling reactions and
report herein the one-pot, one-step, nickel-catalyzed cou-
pling of aryl bromides in the presence of alkyllithium re-
agents [Eq. (1)].
by reduction of ZnCl with lithium naphthalenide and has
2
been shown to readily undergo oxidative addition with
alkyl, aryl, and vinyl halides under mild conditions to gener-
ate the corresponding organozinc compounds. These reac-
tive organozinc compounds are then cross-coupled with
[17]
other aryl or vinyl halides using palladium(0) catalysts.
Recently, homocoupling of bromide compounds has been fa-
cilitated through the combination of metallic magnesium
[
18]
Metallic reagents including palladium and nickel com-
plexes have demonstrated to be quite effective in CÀC cou-
and a catalytic amount of iron salts. Coupling reactions in-
volving activated dihalogenated thiophene molecules cata-
lyzed by nickel(II) complexes have also been demonstrated
pling reactions. Typically, coupling reactions of aryl halides
involving the use of catalytic amounts of nickel(II) com-
plexes require the addition of either magnesium or zinc to
facilitate efficient coupling and regeneration of active
nickel(0) catalytic species. For example, Kumada coupling
reactions use magnesium for the formation of active alkyl/
aryl magnesium bromide species (Grignard formation),
[19]
in the presence of reactive zinc (Rieke zinc) or an alkyl-
magnesium reagent (GRIM/McCullough method) to form
regioregular polythiophenes.
Coupling reactions of halogenated molecules involving
nickel(0) complexes (Yamamoto coupling) require the em-
ployment of equimolar quantities of expensive nickel(0)
complexes because the reaction pathway does not include a
catalytic cycle for the regeneration of nickel(0) from nickel-
[20]
[
a]Dr. S. B. Jhaveri, Dr. K. R. Carter
Polymer Science and Engineering Department
University of Massachusetts - Amherst
Conte Center for Polymer Research
[21–24]
A
H
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These reaction also require the use of toxic ligands
and elevated reaction temperatures. Coupling reactions of
aryl bromides catalyzed by palladium generally require
cross-coupling of a brominated aryl compound with func-
tional aryl derivatives, such as boronic acids or esters
1
20 Governors Drive, Amherst, MA 01003 (USA)
Fax : (+1)413-545-0082
E-mail: krcarter@polysci.umass.edu
[25]
(
Suzuki coupling),
terminal alkynes (Sonogashira cou-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801008.
[26]
[27]
pling), alkenes (Heck coupling), or alkyl tin compounds
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6845

[
28]
(
Stille coupling). Due to the synthetic requirements of the
2
Table 1. A summary of the results of the [NiCl (dppp)]catalyzed homo-
coupling using tBuLi.
A
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generation of the desired aryl derivatives, the synthesis of
new materials by these coupling methods is often challeng-
ing or technically arduous.
There have been few reported instances in the literature
in which combinations of nickel and lithium reagents have
been studied in coupling reactions. The reactions of nickelo-
Substrate
Product
Yield [%]
82
[29,30]
[31]
86
cene (NiCp ) with alkyllithium
and phenyllithium re-
2
agents have been studied and the products analyzed. Lithi-
um hydride has been used to generate the active nickel(0)
80
[32]
species from nickel acetate.
Rieke and Kavaliunas have
shown the formation of metallic nickel by the reduction of
nickel halides with lithium and naphthalene as an electron
carrier, and this active nickel was effective in the coupling
82
75
[33]
of benzylic halides and polyhalides.
They have demon-
strated that this reactive nickel can react at near room tem-
[34]
perature with one equivalent of iodopentafluorobenzene
and the resulting solution contained a mixture of the solvat-
ed species Ni(C F ) and NiI . It is important to note that in
ACHTREUNG
6
5
2
2
all of the above cases the reactions require a large excess of
reducing agent and often an equimolar amount of nickel
complex compared to the halogenated aromatic substrate.
Herein, we report the use of alkyllithium reagents in the
presence of catalytic amounts of [1,3-bis (diphenylphosphi-
7
8
2
5
no)propane]dichloronickel(II), [NiCl (dppp)], for coupling
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2
aryl bromide compounds in good yields. The scope of this
method has been demonstrated with a variety of aryl bro-
mides, including phenyl, pyrenyl, naphthyl, and fluorenyl
bromide compounds. We believe this easy and convenient
reaction, which only requires moderate cooling, can be em-
ployed for the synthesis of a broad range of aryl-based or-
ganic molecules and polymers. Equation 1 shows the one-
step, one-pot synthetic scheme for the synthesis of various
aryl molecules prepared by nickel-catalyzed homocoupling
of halogenated molecules using alkyllithium reagents. Aryl
bromides (1a–1g) in benzene were treated with an alkyl-
observed. It was observed that the reactions with tBuLi
were more effective (82% yield) than those using nBuLi
(72%) or secBuLi (74%). GC analysis performed on the
nBuLi reaction mixture revealed the formation of significant
amounts of nbutyl benzene as a side product, which indi-
cates the preference for alkyl cross-coupling versus lithiation
in this reaction. While the tendency for reactions to undergo
alkyl cross-coupling in place of lithiation has been shown to
be sensitive to the nature of the solvent used, secondary and
tertiary alkyllithiums do not give cross-coupled products in
appreciable yields. GC analysis performed on the tBuLi
reaction did not show the formation of t-butyl benzene.
When the coupling of bromobenzene using tBuLi was per-
formed in THF, the yield of biphenyl product formed was
observed to be slightly lower (76%) than with benzene
(82%). This small difference could be due to the competing
reaction of tBuLi with THF. Decreasing the amount of
lithium reagent, a catalytic amount of [NiCl (dppp)], and
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2
2,2’-dipyridyl (bpy) at 08C to give the expected biaryl prod-
ucts (2a–2g) in good to moderate yields (72–86%; Table 1).
First, a comparison of different alkyllithium reagents was
made by examining the coupling of bromobenzene (1a).
The molar ratio of bromobenzene to catalyst was 138:1
[35]
using [NiCl (dppp)](25 mg, 46.12 mmol) and bromobenzene
A
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2
(
1.00 g, 6.37 mmol). Bpy (18 mg, 115.24 mmol) was added to
the reaction solution as a ligand and was found to be neces-
[11]
sary for the coupling reaction to proceed in higher yields.
Commercially available nBuLi, secBuLi, and tBuLi solutions
were used for the reactions. Alkyllithium was added at half
molar equivalents to that of phenyl bromide groups with the
intention of generating an equimolar ratio of lithiated ben-
zene anions to unreacted phenyl bromide groups. The alkyl-
lithium reagents were added dropwise at 08C to reduce in-
teractions of alkyllithium with the solvent and the reactions
were allowed to proceed at room temperature for 24 h. The
reactions were monitored by TLC (with hexane as the elut-
ing solvent) and showed the formation of biphenyl (2a) as
the major product formed with no traces of bromobenzene
[NiCl2
of [NiCl
ACHTREUNG
AHCTREUNG
2
the yield of biphenyl formed (yield reduced from 82 to 78%
in benzene as a solvent).
The exact nature of the catalytic cycle (Scheme 1) is pro-
posed to involve the transmetalation of the aryllithium inter-
mediate with a nickel(II) species. This is followed by a
II
second transmetalation of the ArÀNi ÀX species to form an
II
ArÀNi ÀAr, which undergoes reductive elimination to form
the Ar–Ar coupled product and active nickel(0). The active
6846
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Chem. Eur. J. 2008, 14, 6845 – 6848

Nickel-Catalyzed Coupling of Aryl Bromides
COMMUNICATION
technique, we can obtain coupled products in good yields.
We believe this reaction has tremendous potential for use in
the synthesis of target organic molecules, cross-coupling re-
actions, as well as the synthesis of aryl-based conjugated
polymers, which will be the subject of a forthcoming publi-
cation.
Experimental Section
Detailed experimental procedures have been provided in the Supporting
Information and a representative procedure for the synthesis of biphenyl
(
[
1
2a) is given here. In a reactor flask bromobenzene (1.00 g, 6.37 mmol),
NiCl (dppp)](25 mg, 46.12 mmol), and 2,2’-dipyridyl (18 mg,
15.24 mmol) were added followed by the addition of benzene (3 mL).
2
ACHTREUNG
The flask was sealed under nitrogen and the reaction was cooled to 08C
with stirring. tBuLi (1.88 mL, 3.2 mmol, 1.7m solution in pentane) was
added to the cooled reaction mixture dropwise by using a syringe. The
mixture was allowed to warm gradually to room temperature and was
stirred for 24 h. The reaction mixture was concentrated by rotary evapo-
ration and loaded onto a silica gel column. The product was purified
using silica gel flash chromatography with hexane as the eluting solvent,
and after solvent evaporation gave biphenyl as a white powder (0.40 g,
8
2%).
Scheme 1. The proposed mechanism of the nickel-catalyzed homocou-
pling reaction showing the catalytic cycle of nickel. L denotes the pyri-
dine group of 2,2’-dipyridyl ligated to nickel.
Acknowledgements
This work was supported by the NSF Material Research Science and En-
gineering Center on Polymers at UMass (MRSEC, DMR-0213695) as
well as the NSF DMR Polymers (DMR-0606391).
nickel(0) species can subsequently undergo oxidative addi-
tion to another Ar–Br molecule. The reaction cycle allows
the use of catalytic amounts of nickel and the reaction
yields were not sensitive to the amount of [NiCl
A
T
E
N
(dppp)], al-
Keywords: alkyllithium reagents · biaryls · catalysis · C
coupling · nickel
ÀC
2
though the use of 0.5 equiv of tBuLi to Ar–Br was impor-
tant. An excess or insufficient amount of tBuLi led to lower
yields because the in situ nickel(0) species generated re-
quired sufficient amounts of aryl bromide for complete reac-
tions. While we cannot exclude the possibility of some re-
duction of nickel(II) to nickel(0) by tBuLi, this is not a
major factor in the coupling reaction. When tBuLi is first
added to a solution containing nickel(II) followed by addi-
tion of Ar–Br, no product formation is observed. The order
of addition is very important. This exact nature of the cou-
pling mechanism is currently under study.
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