Nickel-catalyzed cross-coupling of aryl bromides with tertiary grignard reagents utilizing donor-functionalized N-heterocyclic carbenes (NHCs)

Article abstract of DOI:10.1002/chem.201100909

Metal-catalyzed cross-coupling reactions are among the most important transformations in organic synthesis, allowing the efficient construction of complex structures from simpler, readily available building blocks.Many applications in large and small-scale synthesis can be found in different areas such as agrochemicals, pharmaceuticals and supramolecular chemistry. Whereas the coupling of sp2-hybridized carbon atoms in either reaction partner is well established, the use of CACHTUNGTRENUNG(sp³)-hybridized substrates presents some challenges. Catalytic cross-coupling of sterically hindered tertiary alkyl substrates is especially difficult, generally resulting in low yields, and thus, only few reports exist.[27] A big challenge in this field is not only to get the required level of reactivity, but also to overcome competing pathways like β-hydride elimination, hydrodehalogenation or isomerization

Full text of DOI:10.1002/chem.201100909

DOI: 10.1002/chem.201100909
Nickel-Catalyzed Cross-Coupling of Aryl Bromides with Tertiary Grignard
Reagents Utilizing Donor-Functionalized N-Heterocyclic Carbenes (NHCs)
Claudia Lohre, Thomas Drçge, Congyang Wang, and Frank Glorius*[a]
Metal-catalyzed cross-coupling reactions are among the
most important transformations in organic synthesis, allow-
ing the efficient construction of complex structures from
simpler, readily available building blocks.[1] Many applica-
tions in large and small-scale synthesis can be found in dif-
ferent areas such as agrochemicals, pharmaceuticals and
supramolecular chemistry. Whereas the coupling of sp2-hy-
bridized carbon atoms in either reaction partner is well es-
tablished, the use of CACTHNUTRGNEUNG
(sp3)-hybridized substrates presents
some challenges.[2] Catalytic cross-coupling of sterically hin-
dered tertiary alkyl substrates is especially difficult, general-
ly resulting in low yields, and thus, only few reports exist.[2–7]
A big challenge in this field is not only to get the required
level of reactivity, but also to overcome competing pathways
like b-hydride elimination, hydrodehalogenation or isomeri-
zation.[8]
Scheme 1. Challenging cross-couplings of tertiary alkyl Grignard re-
agents.
In an early report, Kumada et al.[4] have shown a nickel-
catalyzed cross-coupling of tertiary alkyl Grignard reagents
with b-bromostyrene. Cahiez et al.[5] could obtain the same
product in similar yield using an Fe catalyst, however, b-hy-
dride elimination became competitive. Furthermore, the
group of Bell used a stoichiometric amount of a copper(I)
salt to alkylate pyridines and quinolines.[6] Recently, Hinter-
mann et al. reported an impressive selective copper-cata-
lyzed cross-coupling of tertiary Grignard reagents of certain
azacyclic electrophiles, but this protocol is limited to chlor-
oazacycles such as pyridines, pyrimidines, quinazolines and
quinoxalines (Scheme 1).[7]
A general method for the coupling of tertiary alkyl metal
reagents with aryl halides would be very desirable. Due to
their attractive properties[9] N-heterocyclic carbene (NHC)
ligands have found widespread applications in organometal-
lic chemistry and transition-metal catalysis.[10] NHCs have al-
ready been successfully applied in Kumada–Corriu–
Tamao[11] reactions.[12] Herein we report the Kumada–
Corriu–Tamao-type nickel-catalyzed cross-coupling of aryl
halides with tertiary Grignard reagents. This practical ad-
vance provides selective access to highly substituted tertiary
alkyl benzene derivatives, an interesting class of chemical
compounds. The coupling of 4-bromobiphenyl with
tBuMgCl was used as the initial model system. The high re-
activity of Grignard reagents is desirable in this coupling, as
is their easy accessibility. Functional group compatibility,
often a problem in reactions of Grignard reagents, can be
expanded, if sufficiently mild reaction conditions can be re-
alized. Using NHC ligands, we tried to prevent the forma-
tion of undesired side products. Thus, the sterically demand-
ing easily synthesized ligand precursor L1, IAd·HBF4, was
selected for the first screening reactions.
Screening of L1 together with various commercial Ni, Pd
and Cu sources showed [NiACTHNUTRGNE(UNG acac)2] to be a uniquely suited
metal precursor, with all other complexes giving lower or no
catalytic activity (Table 1, entries 1 and 3). Naturally, no
product was obtained in the absence of any metal source
(entry 2). In addition, different solvents, bases and reaction
temperatures were evaluated.[13] The reaction can be suc-
cessfully run at 08C, and changing the temperature to +40
or À788C did lower the yield significantly (entries 4 and
5).[13] The solvent played an important role, non-coordinat-
ing solvents only afforded poor or no conversion. On the
contrary, ethers, especially THF, were suitable (entries 7, 14,
16). Without an NHC ligand, the desired product could be
obtained in decreased yield and selectivity after rather long
reaction time (entry 8).[13] For many other substrates this
effect was even more pronounced, as became obvious upon
studying the substrate scope of this reaction (see below).
[a] C. Lohre, T. Drçge, Dr. C. Wang, Prof. Dr. F. Glorius
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Organisch-Chemisches Institut, Corrensstrasse 40
48149 Mꢁnster (Germany)
Fax : (+49)251-833-3202
E-mail: glorius@uni-muenster.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100909.
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Chem. Eur. J. 2011, 17, 6052 – 6055

COMMUNICATION
ble ligands (L1–L5, Figure 1),[15] consisting of a donor func-
tion flexibly tethered to one nitrogen and a more rigid sub-
stituent such as mesityl or 2,6-diisopropylphenyl on the
other nitrogen resulting in a bifunctional NHC (Figure 1).
Using the O-donor functionalized ligand L2, reactivity and
selectivity towards the formation of product 2 of the current
transformation could be improved (entry 9). Switching from
a hydroxy to a carboxylic acid group led to a decrease in
yield whereas elongation of the carboxylic acid alkyl chain
again improved the yield (entries 10 and 11). Comparing the
selectivity for different substrates we observed a beneficial
influence of L4 on the suppression of the protodebromina-
tion and isomerization. Ligand L5 containing a 2,6-diisopro-
pylphenyl group instead of a mesityl group gave a similar
amount of isomerized product 3, but an increased yield of
dehalogenated by-product 4 (entry 12). Neither varying the
ligand to metal ratio nor higher catalyst loading increased
the yield of the desired product (entry 23). The addition of
50 mol% of benzonitrile to the standard conditions was
found to result in nearly complete inhibition of the reaction,
indicating that the nitrile group can coordinate to the
metal.[13] Obviously, LiOtBu plays an important role, since
its replacement by KOtBu or LiCl resulted in lower reactivi-
ty (entries 6 and 17). Finally, using 5 mol% of L4, 5 mol%
Table 1. Optimization of experimental conditions.
Entry Variation from the conditions[a]
Yield [%][b]
2
3
4
1
–
65
–
5
–
3
6
28
–
2
no [NiACHTUNGTRENNUNG(acac)2]
3[c]
4
Ni
N
A
20
47
48
21
–
74
À788C
47[d]
5
+408C
13 39[d]
6
KOtBu (instead of LiOtBu)
8
–
71[d]
–
46
21
8
7
toluene as solvent
no ligand
L2
8[e]
9
49
72
66
80
62
3
7
10
L3
26
18
15 23
11
L4
2
12
L5
13[f]
14[f]
15[f]
16[f]
17[f]
18[f]
19[f]
20[f]
21[f]
22[f]
23[f]
L4
85 (83) 10
5
L4, Et2O as solvent
L4, DMF as solvent
L4, dioxane as solvent
L4, LiCl (instead of LiOtBu)
L4, added CsOAc (50 mol%)
L4, added COD (50 mol%)
L4, [NiCl2ACHTUNGTRENNUNG(glyme)] (instead of [NiACHTUNGTRENNUNG
L4, no LiOtBu
no ligand, no LiOtBu
L4 (10 mol%)
12
–
27
36
62
11
20 68[d]
–
8
–
65[d]
14 50[d]
13 25
of [NiACTHUNTRGEN(UNG acac)2] and 1.5 equiv of LiOtBu and Grignard we ob-
tained 83% isolated yield of the desired product after 3 h
starting from cheap, commercially available starting materi-
als.
24 65[d]
13 36[d]
40 30[d]
30
25
64
6
69[d]
To illustrate the potential of ligand L4, we commenced
our substrate scope studies with electron-donating groups
such as methyl and phenyl ether. A wide range of functional
groups is tolerated ranging from electron-donating groups
like silyl[16] and alkyl ethers, over electron-neutral to elec-
tron-withdrawing substituents like an ester, a halogen or a
trifluoromethyl group yielding the corresponding products
in moderate to good yields.
17 19
[a] Reactions were carried out on a 0.2–0.4 mmol scale. [b] Determined
by 1H NMR spectroscopy. Isolated yields in parentheses. [c] Pd
(OAc)2,
Cu(OAc)2, Ni(COD)2, Fe(acac)3 and Mn(OAc)2 showed no conversion.
AHCTUNGTRENNUNG
A
E
N
ACHTUNGTRENNUNG
[d] No full conversion, mixture of 4-bromobiphenyl and biphenyl deter-
mined by GC-MS analysis. [e] After 12 h reaction time. [f] Reactions
were carried out with 1.5 equiv tBuMgCl, 1.5 equiv LiOtBu.
Unfortunately, in many cases the isomerization product
could not be separated from the main product (due to simi-
lar RF values) and in some other cases the isolated yield was
deteriorated by the volatility of the products. Notably,
ortho-substituted compound 2n and the polyaromatic com-
pound 2o were obtained in moderate to good yield
(Scheme 2).
Remarkably, under our optimized conditions aryl chlor-
ides are well tolerated, which facilitates a further functional-
ization of the product. The marked reactivity difference be-
tween sp2- and sp3-hybridized organic halides, becomes ap-
parent in the compatibility of alkyl bromides in this reac-
tion, as shown for substrate 2k. Most remarkable, not only
aryl bromides 1 are suitable for this attractive reaction, in
some cases readily available triflate 1p and benzylic bro-
mide 1r showed proper reactivity. Obvious limitations arise
from protic functional groups, for example, alcohols, and
groups with high reactivity toward Grignard reagents such
as nitriles.
This importance of the NHC ligand led us to investigate a
series of other NHC ligands (Figure 1).
Hoveyda et al. developed a series of bidentate NHC-
based ligands containing a free hydroxyl group, and, more
recently Alexakis et al. reported a copper-free asymmetric
alkylation with Grignard reagents using alkoxy-substituted
NHCs.[14] Inspired by this, we utilized several easily prepara-
The synthetic flexibility of this new method is supported
by the ability to use diverse sterically demanding Grignard
Figure 1. NHCs used in this study.
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F. Glorius et al.
Scheme 4. Simplified mechanism for the cross-coupling of aryl bromides
with tert-butyl Grignard reagents and the hydrodehalogenation via b-hy-
dride elimination.
The efficiency of the Ni/Mg/NHC system can be ex-
plained by the following mechanism (Scheme 4). The imida-
zolium salt is first deprotonated by the base and leads to the
formation of a Ni-NHC complex; reduction of the Ni source
by the Grignard reagent leads to A. Intermediate B is then
formed by oxidative addition, followed by transmetalation
and reductive elimination. An undesired b-hydride elimina-
tion from intermediate C would generate a Ni–H species
that can undergo a direct reductive elimination to give 4 or
a re-addition to the formed isobutene followed by reductive
elimination to give 3 (not shown).[18] Our optimization of re-
action conditions shows that the b-hydride elimination can
be partially avoided by utilizing the donor-functionalized
L4. It seems that the carboxylate group prevents b-hydride
elimination by occupying a free coordination site on the Ni.
On the contrary, b-hydride elimination increased in most
cases when the reactions were run without NHC (Scheme 2)
(entries 2a, 2d).
However, it is important to note that the addition of stoi-
chiometric amounts of either TEMPO or galvinoxyl inhibit-
ed the reaction, indicating a participation of radicals in this
nickel-catalyzed process, which is not accounted for in
Scheme 4. Similarly, Knochel[19] and Vicic[20] reported about
radical-chain mechanisms in palladium- and nickel-catalyzed
cross-coupling reactions of aryl Grignard or alkylzinc re-
agents.
Scheme 2. Substrate scope. Reactions were carried out on a 0.4–1.0 mmol
scale. Isolated yields are given. [a] Together with additional 12–15% in-
separable iBu isomer. [b] OTf instead of Br: 19% NMR yield. [c] With-
out NHC: 2a/3a/4a 14:8:78; 2d/3d/4d 16:0:84; 2j/3j/4j 56:16:28; NMR
yield. [d] Determined by 1H NMR spectroscopy. [e] Starting material
with R=TMS. [f] OTf instead of Br employed.
reagents like iPrMgCl, iBuMgCl, tAmylMgCl and 1-
AdMgBr (Scheme 3). 1-AdMgBr is tolerant to a wide range
of functional groups and led to very good isolated yields.
Further examples are known from Szeimies et al. They re-
ported
a
nickel-catalyzed cross-coupling of (tricy-
clo[4.1.0.02,7]hept-1-yl)-magnesiumbromide with aryl, vinyl
and alkynyl halides in moderate yields.[17]
In conclusion, we have developed a nickel-catalyzed
method for the challenging cross-coupling of aryl bromides
and triflates with sterically demanding tertiary Grignard re-
agents. Bifunctional NHC ligands were shown to result in
especially selective and efficient transformations. Good
yields of the coupled products were obtained and a wide
range of functional groups is well tolerated. Further applica-
tions of this catalyst system and asymmetric couplings of ter-
tiary alkyl species seem to be within reach.
Scheme 3. Catalytic cross-coupling with different Grignard reagents. Re-
actions were carried out on a 0.4–1.0 mmol scale. Isolated yields are
given. [a] 2.0 equiv of 1-AdMgBr.
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Nickel-Catalyzed Cross-Coupling of Aryl Bromides
COMMUNICATION
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Experimental Section
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General procedure: A flame-dried sealed tube equipped with a stirring
bar was heated and cooled under vacuum and back-filled with argon.
Ligand L4 (5.9 mg, 0.02 mmol, 5 mol%), [NiACTHNUTRGNEN(UG acac)2] (5.1 mg, 0.02 mmol,
5 mol%) and LiOtBu (48 mg, 0.6 mmol, 1.5 equiv) were weighed into the
reaction vessel in the glovebox. Anhydrous THF (4.0 mL) was added
under a stream of argon and the mixture was stirred for 15 min. A solu-
tion of the Grignard reagent (0.6 mmol, 1.7m in Et2O) was added slowly,
and the reaction mixture stirred for 10 min at 08C followed by addition
of the aryl halide (0.4 mmol, 1.0 equiv). The solution was stirred slowly
warming from 08C to room temperature until GC/MS analysis indicated
completion of the reaction. Afterwards the mixture was filtered through
a small pad of silica and washed with CH2Cl2 (2ꢃ10 mL). Evaporation of
the solvent afforded the crude product, which was purified by column
chromatography and pure fractions were checked by GC/MS analysis.
[13] For further experimental details, see Supporting Information.
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Acknowledgements
We thank Mrs. Cornelia Weitkamp and Christian Richter for experimen-
tal support. Generous financial support by the Deutsche Forschungsge-
meinschaft (DFG), especially for the IRTG Mꢁnster-Nagoya. The re-
search of F.G. was supported by the Alfried Krupp Prize for Young Uni-
versity Teachers of the Alfried Krupp von Bohlen und Halbach Founda-
tion.
Keywords: aryl bromides
·
cross-coupling
·
Grignard
reagents · N-heterocyclic carbenes · nickel
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Received: February 18, 2011
Published online: April 20, 2011
Chem. Eur. J. 2011, 17, 6052 – 6055
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6055