Nickel-Catalyzed Reductive Cross-Coupling of Benzyl Chlorides with Aryl Chlorides/Fluorides: A One-Pot Synthesis of Diarylmethanes

Article abstract of DOI:10.1021/acs.orglett.6b01134

The first nickel-catalyzed, magnesium-mediated reductive cross-coupling between benzyl chlorides and aryl chlorides or fluorides is reported. A variety of diarylmethanes can be prepared in good to excellent yields in a one-pot manner using easy-to-access mixed PPh₃/NHC Ni(II) complexes of Ni(PPh₃)(NHC)Br₂ (NHC = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, IPr, 1a; 1,3-di-tert-butylimidazol-2-ylidene, ItBu, 1b) as catalyst precursors. Activation of polychloroarenes or chemoselective cross-coupling based on the difference in catalytic activity between 1a and 1b is used to construct oligo-diarylmethane motifs.

Full text of DOI:10.1021/acs.orglett.6b01134

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Reductive Cross-Coupling of Benzyl Chlorides with
Aryl Chlorides/Fluorides: A One-Pot Synthesis of Diarylmethanes
Jie Zhang, Gusheng Lu, Jin Xu, Hongmei Sun,* and Qi Shen
The Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, People’s Republic of China
S
* Supporting Information
ABSTRACT: The first nickel-catalyzed, magnesium-mediated reductive
cross-coupling between benzyl chlorides and aryl chlorides or fluorides is
reported. A variety of diarylmethanes can be prepared in good to excellent
yields in a one-pot manner using easy-to-access mixed PPh3/NHC Ni(II)
complexes of Ni(PPh3)(NHC)Br2 (NHC = 1,3-bis(2,6-diisopropylphenyl)-
imidazol-2-ylidene, IPr, 1a; 1,3-di-tert-butylimidazol-2-ylidene, ItBu, 1b) as catalyst precursors. Activation of polychloroarenes or
chemoselective cross-coupling based on the difference in catalytic activity between 1a and 1b is used to construct oligo-
diarylmethane motifs.
ransition-metal-catalyzed Grignard cross-coupling reac-
tions have been developed over the past few decades to
version.10d Copper-catalyzed couplings of aryl bromides with
alkyl tosylates or mesylates are also notable examples of
magnesium-mediated cross-couplings.10c While these reactions
are efficient for aryl−alkyl couplings, their expansion to the
selective one-pot coupling between benzyl and aryl halides
remains challenging because of homocoupling of the benzyl
halides.10c,d Thus, catalytic systems with improved cross-
coupling selectivity are in high demand to broaden the scope
of these reactions for the successful formation of diaryl-
methanes.11
Substantial advances have been made over the past five years in
nickel-catalyzed reductive cross-coupling reactions between aryl
and alkyl electrophiles with manganese or zinc as a reductant.12
Surprisingly, until now, only two papers report the use of this
approach for the synthesis of diarylmethanes. Peng et al.12g
reported the coupling of benzyl bromide with 4-iodoanisole
using a catalytic mixture of Zn/NiCl2/pyridine/ethyl crotonate.
Weix et al.12l showed that the use of Zn/NiBr2·3H2O/bipyridine
in combination with a cobalt cocatalyst (cobalt phthalocyanine)
promoted the coupling of benzyl mesylates with aryl iodides or
bromides. However, applying the latter catalytic system to the
coupling of benzyl bromides with aryl halides resulted primarily
in the formation of bibenzyl. Undertaking this cross-coupling
reaction with a nickel−based catalyst and a magnesium reductant
has not been reported to date. Furthermore, to the best of our
knowledge, nickel-catalyzed magnesium-mediated reductive
cross-coupling reactions remain poorly explored.9c
T
become some of the most powerful tools for C−C bond
formation in organic synthesis.1 In particular, versatile copper-,2
palladium-,3 nickel-,4 and iron5-catalyzed cross-couplings of aryl
Grignard reagents with benzylic electrophiles or vice versa have
been applied for the synthesis of diarylmethanes. Diarylmethanes
are important structural motifs of several classes of functional
molecules such as pharmaceuticals, drugs, and dyes6 and are
frequently found as subunits in supramolecules.7 The use of
Grignard reactions in syntheses traditionally requires the
presynthesis of Grignard reagents as nucleophiles. Despite
their synthetic advantages (i.e., ready availability, relatively low
cost, and being environmentally benign8), the direct use of
stoichiometric amounts of Grignard reagents is constrained by
the safe processing and cost-efficiency of these inherently
moisture-sensitive and hazardous compounds. These issues
often hamper their application for large-scale reactions. The
development of alternative protocols for the synthesis of
diarylmethanes that obviate the need for the presynthesis and
intricate handling of stoichiometric amounts of Grignard
reagents is of great interest.
Recent developments of the reductive cross-coupling reactions
between two stable electrophiles offer an attractive alternative
strategy to Grignard reactions.9 In this context, the first reductive
cross-coupling of aryl bromides with alkyl bromides was reported
by Jacobi von Wangelin et al.10a using stoichiometric amounts of
magnesium turnings as the reductant and a catalytic system of
FeCl3/N,N,N′,N′-tetramethylethylenediamine. Jacobi von Wan-
gelin’s group also discovered that CoCl2/N,N,N′,N′-tetramethyl-
1,2-diaminocyclohexane is catalytically capable of the same
reductive cross-coupling.10b Both reactions featured the in situ
generation of Grignard reagents and exhibited high selectivity for
the cross-coupling product in a one-pot synthesis, lowering
hazard potential and cost while simplifying the process
operations. Very recently, we have described the extension of
this intermolecular reductive cross-coupling to an intramolecular
We recently described the easy synthesis of mixed phosphine/
N-heterocyclic carbene (NHC) Ni(II) complexes, i.e., Ni(PPh3)-
(IPr)Br2 (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-yli-
dene, 1a) and Ni(PPh3)(ItBu)Br2 (ItBu = 1,3-di-tert-butylimi-
dazol-2-ylidene, 1b) (Scheme 1), via controlled ligand
substitution reactions of easily obtainable Ni(II) complexes
Received: April 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01134
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Organic Letters
Letter
are a reductant worthy of further investigation in nickel-catalyzed
reductive cross-couplings.
Scheme 1. Mixed Phosphine/NHC Ni(II) Complexes
The increasing attention given to transition-metal-catalyzed
activation and transformation of C−F bonds15 captivated our
interest as to whether 1a and 1b could activate an aryl C−F bond
in the reaction shown in Table 1. Aryl fluorides have been little
involved in nickel-catalyzed reductive cross-coupling reactions.16
The coupling of 2a and 4-fluoroanisole was effectively promoted
by a 2 mol % loading of 1b, resulting in the desired product 4ab in
an almost quantitative yield (entry 9). The IPr-based analogue 1a
exhibited poor activity and furnished merely a 22% yield of 4ab
under the same conditions (entry 8). The reason for the
difference in catalytic behavior between 1a and 1b is not
apparent.17
[NEt4][Ni(PPh3)X3]. We demonstrated the efficient application
of 1a and 1b as catalyst precursors for the cross-coupling between
aryl Grignard reagents and aryl chlorides or fluorides.13f We
continue our studies13 by reporting herein the application of 1a
and 1b to the synthesis of diarylmethanes using readily available
and low-cost benzyl chlorides and aryl chlorides or fluorides with
reductive magnesium in a simple one-pot procedure. To the best
of our knowledge, this is the first example of a nickel-catalyzed
reductive cross-coupling of two organohalides using magnesium
turnings as the reductant.
We began our study by examining the reductive cross-coupling
reaction of benzyl chloride (2a) and 4-chloroanisole (3b) with
catalytic 1a or 1b and reductive magnesium turnings. These
initial experiments revealed extremely high selectivity for the
desired products (Table 1). In the presence of 2 mol % of 1a
The one-pot protocol proved to have quite broad generality,
and a variety of diarylmethanes were easily synthesized from
benzyl chlorides and aryl chlorides or fluorides (Scheme 2).
Effective coupling of 4-methoxybenzyl chloride with different
aryl chlorides or fluorides bearing a range of electron-donating
groups or electron-withdrawing groups afforded the correspond-
ing products with yields from 89% to 95% (4ba−bf). It is worth
noting that 1,4-difluorobenzene and its 1,2-derivative and 1-
fluoro-4-(trifluoromethyl)benzene can be selectively monofunc-
tionalized via a sp2 C−F bond activation using 1a as a catalyst,
affording fluorinated diarylmethanes 4bd, 4bd′, and 4be in
81%−92% yields. The reaction of sterically hindered aryl
chlorides did not result in lower product yields (4bf, 4bg, and
4cg). Highly hindered 2,4,6-trimethylbenzyl chloride provided
the desired product 4dg in 78% yield when subjected to a longer
reaction time. Both electron-rich and electron-poor benzyl
chlorides react smoothly with comparable yields of the desired
diarylmethanes 4bb, 4eb, 4fb, and 4gb, respectively. These
results are quite similar to those reported previously for a
palladium-catalyzed, zinc-mediated approach.18 Notably, a
number of functional groups on the coupling partners survived,
including vinyl (4bh), amine (4aj), ketal (4ak), ester (4al), and
even ketone groups (4am).19 Moreover, 2-chloronaphthalene or
its fluoro analogue, N-methyl-6-chloroindole, 2-chlorothio-
phene, 2-chloropyridine, 2-chloro-5-methoxypyridine, 5-chloro-
3-methylbenzothiophene, and N-ethyl-3,6-dichlorocarbazole are
suitable reactants, affording the desired products (4ai, 4an, 4fn,
4bo, 4bp, 4aq, 4br, and 4as, respectively) in 40−98% yields. A 50
mmol scale reaction of 2-chloronaphthalene gave a yield similar
to that of the smaller scale experiment, producing 4ai in 90%
yield.
Table 1. Ni-Catalyzed Reductive Cross-Coupling of
a
C6H5CH2Cl with 4-MeOC6H4X
b
entry
X
cat. (mol %) reductant time (h) yield 4ab/5aa (%)
b
c
1
2
3
4
5
6
7
8
9
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
1a (2)
1b (2)
1a (1)
1b (1)
1a (2)
1a (2)
1a (2)
1a (2)
1b (2)
Mg
Mg
Mg
Mg
Zn
0.5
1
99 (95 )/3
99/3
98/3
8/3
1
1
d
12
9/24
0/3
b
d
b
b
Mn
Mn
Mg
Mg
12
12
9
15/27
22/4
c
F
9
99 (96 )/3
a
Reaction conditions: 2a (0.6 mmol), 3 (0.5 mmol), magnesium
turnings (0.6 mmol), THF (1.0 mL), 10 min at 0 °C, then 1 h at 25
b
°C, GC yields using n-dodecane as an internal standard. At 25 °C.
c
d
Isolated yield. At 45 °C.
The present scope was further extended to the reaction of
polychloroarenes such as 1,3-dichloro-5-methoxybenzene and
1,3,5-trichlorobenzene. As far as we are aware, such substrates
have not been coupling partners in nickel-catalyzed reductive
cross-couplings. The precursor of naturally occurring 2,4-bis(4-
hydroxybenzyl)phenol,20 4bt, was obtained in 80% yield, and
4bu, which can be used to synthesize hexacata-hexabenzocor-
onenes,21 was isolated in 71% yield using enhanced conditions.
These results show the potential of this protocol in
polyfunctionalization syntheses because the sp2 C−OMe bond
survives the reaction and can further undergo cross-coupling
with different nucleophilic reagents.4c,d
The difference in catalytic activity between 1a and 1b was used
to chemoselectively activate the sp2 C−Cl bond or the sp2 C−F
bond on aryl halides to construct oligo-diarylmethane structures
in the para (4bd and 4abd), meta (4gb and 4agb), and ortho
(4bd′ and 4abd′) positions (Scheme 3).
loading and 1.2 equiv of magnesium turnings, the desired
product 4ab was obtained in almost quantitative yield, with only
a trace amount of homocoupling byproduct 5aa observed (Table
1, entry 1). Lowering the loading of 1a to 1 mol % still gave a high
yield of 4ab (98%) but required an extended reaction time (1 h)
to reach reaction completion (entry 3). The reaction was also
catalyzed by 1b, giving 4ab in 99% yield with 2 mol % catalyst
loading and 1 h reaction time (entry 2). The catalytic activity of
1b dropped dramatically when the dosage was lowered to 1 mol
% to give 8% yield of 4ab (entry 4).14
Replacing magnesium turnings with widely used zinc dust or
magnesium powder resulted in the primary formation of the
homocoupling byproduct 5aa with a 2 mol % loading of 1a
(entries 5−7). These results are similar to those previously
reported with a nickel/cobalt cocatalytic system.12b The different
selectivity of these reactions indicates that magnesium turnings
B
DOI: 10.1021/acs.orglett.6b01134
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Representative Benzyl−Aryl Couplings
Scheme 3. Chemoselective Benzyl−Aryl Cross-Coupling
Strategy To Synthesize oligo-Diarylmethanes
a
Reaction conditions: benzyl chloride (0.6 mmol), aryl halide (0.5
mmol), Mg turnings (0.60 mmol), 1a (1 mol %), THF (1 mL), 10 min
b
at 0 °C, then 1 h at 25 °C, isolated yield, 1b (2 mol %), 9 h at 25 °C,
c
1b (2 mol %), 24 h at 45 °C.
Scheme 4. Reactions Relevant to Mechanism
This hypothetical mechanism closely resembles the magnesium-
mediated reductive cross-coupling reactions using iron(III)10a,b,d
or copper(I) catalysts.10c In considering that a metathesis
reaction of 1a or 1b may take place to form bisphosphine and
biscarbene Ni (II) complexes,22 respectively, the reductive cross-
coupling reaction of benzyl chloride (2a) and 4-chloroanisole
(3b) with 1 mol % of Ni(PPh3)2Br2 or Ni(IPr)2Br2 was
conducted under the conditions shown in Table 1. It is
noteworthy that each of the two Ni(II) complexes showed
very low catalytic activity, affording the desired product in merely
27% and 10% yields, respectively. These results indicate that
there is a possibly synergic effect between the two kinds of
ligands on the catalytic active nickel species. However,
establishing a detailed mechanism requires further investigation.
In summary, our process is the first nickel-catalyzed,
magnesium-mediated reductive cross-coupling reaction for the
direct synthesis of diarylmethanes using stable, low-cost, and
widely available benzyl chlorides and aryl chlorides or inert aryl
fluorides in place of traditional Grignard reagents. Our one-pot
procedure utilizes catalytic amounts of a mixed PPh3/NHC
Ni(II) complex 1a or 1b and stoichiometric amounts of
magnesium turnings to cross-couple two organohalides in a
highly selective manner, avoiding the homocoupling of benzyl
chlorides and the presynthesis and handling of stoichiometric
amounts of sensitive Grignard reagents. Our reaction is a
practical protocol to synthesize a wide variety of diarylmethanes.
Very efficient chemoselective reductive cross-couplings were
developed to construct oligo-diarylmethane structures by
exploiting the difference in catalytic activity between 1a and
1b. The present study shows the great potential of nickel-
catalyzed, magnesium-mediated reductive cross-coupling in C−
C bond formation. Further investigation to extend this method
to other substrates and a detailed mechanistic study are ongoing
in our laboratory.
a
Reaction conditions: benzyl chloride (0.6 mmol), aryl halide (0.5
mmol), magnesium turnings (0.6 mmol), 1a (1 mol %), THF (1 mL),
10 min at 0 °C, then 1 h at 25 °C, isolated yields. 1b (2 mol %)
instead of 1a, 12 h at 25 °C. 12 h at 35 °C. 8 h at 25 °C. 1a (2 mol
%). 50 mmol scale. 1a (3 mol %), benzyl chloride (0.7 mmol), ZnCl2
b
c
d
e
f
g
(0.7 mmol), LiCl (0.8 mmol), magnesium turnings (0.75 mmol), THF
h
(2.5 mL), 1 h at 0 °C, then 24 h at 35 °C. 1a (2 mol %), benzyl
chloride (1.2 mmol), magnesium turnings (1.2 mmol), THF (2.0 mL).
i
1a (3 mol %), benzyl chloride (1.8 mmol), magnesium turnings (1.80
j
mmol), THF (5.0 mL), 20 min at 0 °C, then 8 h at 35 °C. 12 h at 25
°C. THF (2.0 mL), 3 h.
k
Our current experimental investigations (Scheme 4, eqs 1 and
2) suggest that the reaction proceeds by initial in situ generation
of a benzyl Grignard reagent, which then couples with the aryl
halide catalyzed by 1a or 1b through a catalytic cycle involving
oxidative addition, transmetalation, and reductive elimination.
C
DOI: 10.1021/acs.orglett.6b01134
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(b) Amatore, M.; Gosmini, C. Chem. Commun. 2008, 5019−5021.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01134.
■
́
(c) Benischke, A. D.; Knoll, I.; Rerat, A.; Gosmini, C.; Knochel, P. Chem.
S
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Detailed experimental procedures and details pertaining to
the characterization of the products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sunhm@suda.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21472134 and 21172164), the Key
Laboratory of Organic Chemistry of Jiangsu Province, and the
Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD) for financial support.
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