An unprecedented iron-catalyzed cross-coupling of primary and secondary alkyl Grignard reagents with non-activated aryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2012.06.048

The use of N-heterocyclic carbene ligands in the iron-catalyzed cross-coupling of alkyl Grignards has allowed, for the first time, coupling of non-activated, electron rich aryl chlorides. Surprisingly, the tetrahydrate of FeCl₂ was found to be a better pre-catalyst than anhydrous FeCl ₂. Primary Grignard reagents coupled in excellent yields while secondary Grignard reagents coupled in modest yields. The use of acyclic secondary Grignard reagents resulted in the formation of isomers in addition to the desired product. These isomeric products were formed via reversible β-hydrogen elimination, indicating that the cross-coupling proceeds through an ionic pathway.

Full text of DOI:10.1016/j.tetlet.2012.06.048

Tetrahedron Letters 53 (2012) 4436–4439
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unprecedented iron-catalyzed cross-coupling of primary and secondary alkyl
Grignard reagents with non-activated aryl chlorides
Marc C. Perry , Amber N. Gillett , Tyler C. Law b
a,
⇑
a
a
Department of Chemistry, Point Loma Nazarene University, 3900 Lomaland Dr., San Diego, CA 92106, USA
Department of Chemistry, University of Alaska Anchorage, 3600 Providence Dr., Anchorage, AK 99508, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of N-heterocyclic carbene ligands in the iron-catalyzed cross-coupling of alkyl Grignards has
allowed, for the first time, coupling of non-activated, electron rich aryl chlorides. Surprisingly, the tetra-
hydrate of FeCl was found to be a better pre-catalyst than anhydrous FeCl . Primary Grignard reagents
2 2
coupled in excellent yields while secondary Grignard reagents coupled in modest yields. The use of acy-
clic secondary Grignard reagents resulted in the formation of isomers in addition to the desired product.
These isomeric products were formed via reversible b-hydrogen elimination, indicating that the cross-
coupling proceeds through an ionic pathway.
Received 7 March 2012
Revised 8 June 2012
Accepted 11 June 2012
Available online 18 June 2012
Keywords:
N-Heterocyclic carbenes
Grignard
Ó 2012 Elsevier Ltd. All rights reserved.
Iron-catalyzed
Cross-coupling
The search for catalysts which are capable of forming aryl–alkyl
C–C bonds but are less expensive and more benign than palladium-
based catalysts has resulted in a significant body of work describ-
ing iron-catalyzed cross-coupling reactions utilizing both alkyl and
The development of cross-coupling reactions involving non-
activated aryl chlorides expands the scope of iron-catalyzed
cross-coupling reactions, and the ability to couple secondary alkyl
Grignard reagents through an ionic pathway would prove signifi-
cant as it paves the way toward the development of an asymmetric
variant. This paper describes the use of N-heterocyclic carbenes
(NHC’s) as ligands in the iron-catalyzed cross-coupling of non-acti-
vated aryl chlorides with primary and secondary alkyl Grignard
reagents.
1
,2
aryl Grignard reagents. The cross-couplings of alkyl halides with
aryl Grignard reagents have been demonstrated using simple iron
salts as catalyst precursors in the presence of ligands including
1
l
1d,m
1a
1a
1a
acac, amines,
phosphines, phosphites, arsines, N-hetero-
1
a
1f
cyclic carbenes, and amine-bis(phenolates). These catalytic
systems allow for the couplings of primary and secondary alkyl ha-
lides including those containing b-hydrogens. Studies have shown
In order to test the viability of using N-heterocyclic carbenes as
ligands in the iron-catalyzed cross-coupling of alkyl Grignard re-
agents and aryl chlorides, butylmagnesium chloride was added to
that the cross-couplings of alkyl halides with aryl Grignard re-
agents occur through a radical-based mechanism.1
a,o,q
The cross-
THF solutions containing chlorobenzene, anhydrous FeCl
2
couplings of aryl chlorides with alkyl Grignard reagents, on the
other hand, have been shown to couple using simple iron salts as
(5 mol %), and imidazolium chlorides or imidazolinium tetrafluoro-
borates (10 mol %). The imidazolium and imidazolinium salts were
converted into the corresponding imidazol-2-ylidines and imidaz-
olin-2-ylidines in situ upon reaction with the basic Grignard re-
agent. The different NHC’s that were generated in situ and used
in this study are shown in Scheme 1.
Reaction progress was followed by GC using naphthalene as an
internal standard. All of the ligands tested resulted in some notice-
able coupling, but ligand 2 (IPr), bearing the bulky diisopropyl-
phenyl groups, gave the best overall result at 80% as shown in
Scheme 2. We were delighted with these results as non-activated
aryl chlorides like chlorobenzene have yet to be demonstrated in
iron-catalyzed cross-coupling reactions with alkyl Grignard
reagents.
catalyst in the presence of additives such as N-methyl-2-pyrroli-
done (NMP) via an ionic mechanism.1
o,3
These cross-couplings
are highly efficient and rapid for primary alkyl Grignard reagents
with activated, electron poor heteroaryl, and aryl chlorides, but
chlorobenzene and more electron rich aryl chlorides do not couple.
Moreover, secondary alkyl Grignard reagents failed to couple using
simple iron salts, and only one example utilizing the reactive
2
-chloropyridine with an iron-salen complex was reported in poor
2
a
4
yield. Heteroaryl sulfamates and phosphates as well as vinyl and
aryl carboxylates have since been reported to participate in simi-
5
lar coupling reactions as those reported using aryl chlorides.
Cross-coupling reactions using 2 and other alkyl Grignard
reagents were then attempted, but the results were often variable,
⇑
Corresponding author. Tel.: +1 619 849 2976; fax: +1 619 849 3452.
E-mail address: mperry1@pointloma.edu (M.C. Perry).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.048

M. C. Perry et al. / Tetrahedron Letters 53 (2012) 4436–4439
4437
Cl
iBu MgCl (6 eq)
.
N
N
N
N
FeCl (H O) (5 mol%)
N
N
2
2
n
1
2
3
H-IPr (10 mol %)
THF, 70 C, 1 h
OCH3
o
OCH
3
n = 0; 17 %
n = 4; 85 %
Scheme 3. Water investigation.
IMes
IPr
I2Pr
Table 1
Cross-coupling results
Cl
R
R MgCl
N
N
N
N
.
N
N
Y
FeCl (H O) (5 mol %)
2 2 4
Y
4
5
6
H-IPr (10 mol %)
o
THF, 70 C
Entry
R
Y
eq RMgCl
Time (h)
Methoda
% Yieldb
1
2
3
4
5
6
7
8
9
0
1
2
3
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Butyl
Butyl
Butyl
Butyl
Butyl
Butyl
Butyl
Propyl
Propyl
Propyl
Propyl
Propyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
H
H
H
H
H
CH
CH
OCH
OCH
H
H
CH
CH
OCH
OCH
OCH
H
CH
CH
2
3
4
6
3
3
3
3
3
3
3
3
3
3
4
3
3
3
4
3
4
3
4
3
4
4
3
4
0.5
0.5
0.5
0.5
3
1
3
2.5
3
1
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
19
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
A
A
A
B
A
B
A
B
A
B
B
A
B
87
98
95
84
HIMes
HIPr
HI2Pr
c
92
Scheme 1. NHC ligands used.
3
97
c
3
91
3
98
c
3
86
Cl 6 eq Bu-MgCl
1
1
1
1
96
c
89
3
89
FeCl (5 mol%)
H-L (10 mol%)
THF, RT, 24h
c
2
3
81
+
L
GC Yield (%)
14
15
3
3
3
83
88
1
2
3
4
5
6
19
80
14
24
66
12
c
16
17
18
19
20
81
98
84
94
79
90
58
65
47
50
50
45
43
3
3
OCH
OCH
H
3
21
3
2
2
2
2
2
2
2
2
3
4
5
6
7
8
H
Scheme 2. Ligand screening.
CH
CH
CH
OCH
OCH
3
3
3
3
3
3
3
especially when different batches of anhydrous FeCl
Recently, Biscoe et al. reported that fresh anhydrous NiCl
not perform as well in cross-coupling reactions involving tertiary
alkyl Grignard reagents as NiCl which had been exposed to lab
air for some time. They found that it was necessary to have water
present in order for the reaction to proceed efficiently and so they
2
were used.
a
In method A all of the Grignard is added at once at the beginning of the reaction,
2
did
while in method B, half of the Grignard is added initially, and the other half is added
after 1 h.
b
2
Yields determined by GC using naphthalene as an internal standard.
Isolated yield.
6
c
the beginning of the reaction, while in method B half of the Grig-
nard was added initially and the second half was added after one
hour. The cross-coupling of chlorobenzene with varying equiva-
lents of isobutylmagnesium chloride demonstrated that using
resorted to using NiCl
2
Á(H
2
O)1.5 as the catalyst precursor. We
decided to see if the same observations could be made in our
iron-catalyzed cross-coupling. The reaction of p-chloroanisole
with isobutylmagnesium chloride using 1,3-bis(2,6-diisopropyl-
phenyl)imidazolium chloride (H-IPr) as a ligand precursor was cho-
sen to test the effects of having water present as shown in Scheme 3.
The tetrahydrate of FeCl
cross-couplings of alkyl Grignard reagents which is analogous to
the observations made by Biscoe et al. utilizing NiCl
The cross-coupling of a series of alkyl Grignard reagents was
then carried out with three non-activated aryl chlorides in THF at
3
equiv of Grignard relative to the aryl chloride gave the best re-
sults as shown in entries 1–4. A single addition of Grignard in ex-
cess of 3 equiv generally gave lower yields, but an improvement
could be achieved by reacting the aryl chloride with 4 equiv of
Grignard using method B when the use of 3 equiv of Grignard using
method A gave yields below 85%. This improvement was observed
in a number of cases throughout Table 1, but is exemplified by
comparing entries 18 and 19. In general, primary Grignard
reagents coupled in excellent yields for all three non-activated aryl
chlorides including the challenging 4-chloroanisole.
2
was found to be a superior catalyst in
6
2 2
Á(H O)1.5.
7
0 °C using FeCl
2
Á(H
2 4
O) and H-IPr as catalyst and ligand precur-
sors, respectively, (Table 1). Overall, two different methods were
employed. In method A, all of the Grignard was added at once at

4
438
M. C. Perry et al. / Tetrahedron Letters 53 (2012) 4436–4439
reagents coupled in excellent yields while the use of secondary
Grignard reagents resulted in significantly lower yields. Undesired
n-alkyl isomers were formed in couplings involving acyclic sec-
ondary Grignard reagents, suggesting that reversible b-hydrogen
elimination occurs in competition with the desired reductive
elimination. Reversible b-hydrogen elimination can also explain
the formation of reduced arenes in the couplings involving
secondary alkyl Grignard reagents. Catalyst optimization for
cross-coupling reactions involving secondary alkyl Grignard re-
agents allowing for asymmetric variants and further elucidation
of the mechanistic details of these reactions will be the focus of
future studies in our lab.
Ar-H
m
m
L Fe
n
H
m-2
n
L Fe
n
L Fe
Ar
Ar
Scheme 4. Formation of reduced arene.
R
Cl
R
X eq ClMg
R
+
.
Representative cross-coupling procedure
FeCl (H O) (5 mol%)
2
2
4
DIP-Im (10 mol%)
THF, 70 ºC, 3 h
B
L
1,3-Bis-(2,6-diisopropylphenyl)imidazoliumchloride (0.1 mmol,
0 mol %) was added to Vial 1 containing a stir bar which was then
1
fitted with a septum. FeCl O) (9.9 mg, 0.05 mmol, 5 mol %)
was added to Vial 2 containing a stir bar which was then fitted
with a septum. Both Vial 1 and Vial 2 were evacuated and back-
2
Á(H
2
4
R
CH3
CH3
X
% Yield
B:L
4
6
4
6
69 %
31 %
67 %
48 %
1.2:1
3.1:1
2.4:1
filled with argon. Chlorobenzene (102 lL, 1 mmol) was then added
2
CH CH3
via syringe to Vial 2. Freshly distilled THF (10.5 mL) was added via
syringe to Vial 1, and isobutylmagnesium chloride (1.5 mL of a 2 M
solution in THF, 3 mmol) was added with stirring. Vial 1 was
placed in an oil bath at 70 °C and stirred for 10 min. Then the con-
tents of Vial 1 were transferred to Vial 2 via syringe, and Vial 2 was
placed in the oil bath at 70 °C. After 3 h, the reaction was removed
from the oil bath and allowed to cool to room temperature. The
reaction mixture was poured into a separatory funnel followed
by 15 mL of 1 M HCl and 15 mL of pentane. The pentane layer
was washed with water (1 Â 15 mL) and brine (1 Â 15 mL). The
CH CH3
10.4:1
2
Scheme 5. Cross-coupling of secondary alkyl Grignard reagents.
Gratifyingly, the secondary cyclohexyl Grignard coupled with
all three aryl chlorides, although the yields were moderate (entries
2–28). It was found that reaction times longer than 3 h did not of-
2
fer any improvement in the yields involving secondary alkyl Grig-
nards (entries 25 and 26). Substantial amounts of the arene formed
from reduction of the aryl chloride were observed in the couplings
involving the cyclohexyl Grignard. A plausible explanation for the
formation of the reduced arene is that a cyclohexylaryliron species
undergoes reversible b-hydrogen elimination, producing an inter-
mediate arylalkenylhydridoiron complex which, in turn, gives the
arene upon reductive elimination as shown in Scheme 4.
2 4
pentane layer was dried over Na SO and the solvent was removed
in vacuo. The crude oil was purified by distillation resulting in a
1
colorless oil (122 mg, 92%). H NMR and GC–MS were consistent
with known material.
Acknowledgments
We then attempted the coupling of isopropyl- and sec-butyl-
magnesium chloride with chlorobenzene in THF at 70 °C with the
expectation that some of the isomeric n-propyl- and n-butylben-
zene would be produced, thereby supporting the hypothesis that
b-hydrogen elimination occurs during the coupling. The linear n-
alkyl isomers (L) were observed in both cases as shown in Scheme
We would like to thank the donors of the American Chemical
Society Petroleum Research Fund and Research Associates of PLNU
(
an alumni group) for funding of this research. We would also like
to thank Ben Applegate for his help with the GC–MS and Brody
Besirre for his help in the lab.
5
. This result is not surprising, as b-hydrogen elimination is known
References and notes
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7
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