Published on the web February 2, 2013
183
Ligand-controlled Iron-catalyzed Cross Coupling of Benzylic Chlorides
with Aryl Grignard Reagents
Shintaro Kawamura1,2,³ and Masaharu Nakamura*1,2
1Internal Research Center for Elements Science (IRCELS), Institute for Chemical Research,
Kyoto University, Uji, Kyoto 611-0011
2Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering,
Kyoto University, Uji, Kyoto 611-0011
(Received November 8, 2012; CL-121130; E-mail: masaharu@scl.kyoto-u.ac.jp)
The selective cross coupling of benzylic chlorides with aryl
Grignard reagents has been achieved by using catalytic amounts
of FeCl2 and electronically tuned ortho-phenylenebisphosphine
ligands. Although electron-deficient ligands promoted the
reductive homocoupling of benzylic halides, electron-rich
ligands effectively promoted the desired cross-coupling reaction
to afford the corresponding diarylmethanes in good to excellent
yields.
MeO
MgBr
MeO
1
3; 31%
FeCl2
(5 mol %)
(1.5 equiv)
+
+
THF
25 °C, 1 h
Cl
2
4; 64%
Scheme 1. Iron-catalyzed cross coupling of benzyl chloride
(2) with aryl Grignard reagent 1.
The diarylmethane skeleton is one of the key frameworks
frequently found in functional molecules such as pharmaceut-
icals and dyes.1,2 Hence, numerous synthetic routes to symmetric
and unsymmetrical diarylmethanes have been reported thus far.
Vingiello synthesized diarylmethanes via a simple substitution
reaction of benzylic chlorides with aryl Grignard reagents.3
Friedel-Crafts alkylation between various benzyl donors and
aryl nucleophiles has also been applied to the synthesis of
diarylmethanes.4 More recently, transition metals such as
copper,5 palladium,6 and nickel7 have been found to enhance
the synthetic utility of cross-coupling reactions that afford
diarylmethanes. Iron is an inexpensive and environmentally
friendly catalyst, which shows high reactivity for the cross
coupling of alkyl halides.8,9 However, iron catalysis has not been
extended successfully to the reaction between benzylic halides
and aryl Grignard reagents because of the competing homocou-
pling reaction;10 this was studied extensively by Kharasch11 and
was found to restrict the selective cross coupling for diaryl-
methane synthesis. Kozak demonstrated an iron-catalyzed
selective cross coupling of benzylic chlorides and bromides
with aryl Grignard reagents, which produced the corresponding
diarylmethanes in moderate yields.12 Bedford found that the use
of aryl zinc9j and aryl boron9q reagents improved the selectivity
of the reaction considerably, and high cross-coupling selectiv-
ities were attained in the presence of an o-phenylenebisphos-
phine-iron complex such as 5a. Hitherto, there has been no other
report on the ligand-mediated control of the cross-/homocou-
pling selectivity in iron-catalyzed reactions between benzylic
halides and aryl Grignard reagents. Herein, we report the
selective cross coupling achieved by electronic tuning of the
bisphosphine ligand and demonstrate the application of our
method to the synthesis of a variety of diarylmethanes.
R
R
Ar2
P
Ar2
P
Cl
Fe
Cl
R
R
R
R
P
P
P
P
Fe
Ar2
Ar2
Cl Cl
R
R
Ar = Ph; 5a
Ar = 4-FC6H4; 5b
R = t-Bu
[FeCl2(SciOPP)]; 5f
R = SiMe3
[FeCl2(TMS-SciOPP)]; 5g
Ar = 3,4,5-F3C6H2; 5c
Ar = 4-MeOC6H4; 5d
Ar = 4-Me2NC6H4; 5e
Figure 1. FeCl2-dppbz complexes and FeCl2-SciOPPs.
attempted cross coupling in the presence of a catalytic amount of
[FeCl2(dppbz)2] (5a), which is highly efficient for the reaction of
alkyl halides (including benzylic halides) with aryl zinc,9i,9j aryl
aluminum,9m or aryl boron9q reagents (Figure 1 and Table 1,
Entry 1). Catalyst 5a gave the cross- and homocoupling
products with almost 1:1 selectivity under Kharasch type
reaction conditions. We have demonstrated previously that
substituents on the phenyl moiety attached to the phosphorus
atoms in the bisphosphine ligand affect the catalyst reactivi-
ty.9a,9b,9l,9o,9p Hence, we investigated the effect of the ligand
substituents on the cross- or homocoupling selectivity in the
reaction of benzylic chlorides (Figure 1 and Table 1). Ligands
bearing a fluorine (electron-withdrawing) group at the 4- (5b)14
and 3,4,5- (5c)14 positions gave the desired cross-coupling
product in only 34% and 9% yields, respectively (Entries 2 and
3); however, in the presence of 5c, the homocoupling rate was
remarkably enhanced, and dibenzyl 4 was obtained in 86% yield
(Entry 3). In contrast, electron-donating groups on the phenyl
moiety promoted the cross-coupling reaction (Entries 4-6). The
yield of the desired product 3 increased slightly in the presence
of the methoxy-substituted 5d (52%, Entry 4)14 but increased
considerably in the presence of 5e, which had a stronger
electron-donating dimethylamino group (64%, Entry 5).
We first examined the reaction of benzyl chloride (2) with
4-methoxyphenylmagnesium bromide (1) in the presence of a
catalytic amount of FeCl2 (Scheme 1). Although the conversion
in this reaction was good, the poor selectivity resulted in a low
yield of the desired cross-coupling product 3 (31%), while the
homocoupling product 4 was obtained in 64% yield. We then
Chem. Lett. 2013, 42, 183-185
© 2013 The Chemical Society of Japan