Table 2. Fe-catalyzed cross-coupling reaction of alkyl halides
with alkyl Grignard reagentsa
afforded the desired coupling product 3ac in 56% yield
(Entry 12). Grignard reagents having no β-H such as methyl,
phenyl, and benzyl Grignard reagents did not participate in the
coupling reaction (vide infra).
When 1-bromo-6-chlorohexane (7) was employed, the
cross-coupling reaction with n-BuMgCl (2a) took place site
selectively at the CBr carbon, providing decyl chloride (8)
in 44% yield without formation of other possible coupling
products, i.e. decyl bromide and tetradecane (eq 1). In addition,
CpFe(CO) Cl (6)
2
(
5 mol%)
(
4 equiv)
1
2
R1 R2
3
R –X
+
R MgCl
THF, 0 ºC to rt, 24 h
1
2 (1.5 equiv)
1
2
Yield/%b
Entry R –X
R –MgCl
1
2
3
4
5
6
n-Non–F 1b
n-Non–Cl 1c
n-Non–Br 1d
n-Non–I 1e
n-BuMgCl 2a
n-BuMgCl 2a
n-BuMgCl 2a
n-BuMgCl 2a
n-BuMgCl 2a
n-BuMgCl 2a
35
n.d.
54
9
5
62
1
a selectively coupled with n-BuMgCl (2a) even in the presence
4
b
of PhBr, which was completely recovered after the reaction
eq 2).
(
n-Non–OTs 1f
6
(5 mol%)
Br
1
g
7
8
Cy
Br
n-BuMgCl 2a
n-BuMgCl 2a
61
47
1
h
(4 equiv)
THF,
(1.5 equiv) 0 ºC to rt,
+
2a
ð1Þ
ð2Þ
S
Cl
4
Br
Cl
4
n-Bu
Br
7
8 44%
1
i
c
24 h
9
PhO
Br1
n-BuMgCl 2a
n-BuMgCl 2a
54(40)
42
j
Br
OTHP
n-Bu
10
Ph
3
aa 40%
as above
1
k
Br
+
PhBr
+
2a
Ph
+
Br
1
1
2
n-OctMgCl 2b
s-BuMgCl 2c
47
56
Ph
Ph
1a
1a (1 equiv) (1 equiv) (1.5 equiv)
PhBr
Br
1
>99% recov.
1a
aReaction conditions: RX (1.0 mmol), n-BuMgCl (1.5 mmol,
in THF), CpFe(CO)2Cl (0.05 mmol), 1,3-butadiene
It was reported that Fe-catalyzed cross-coupling reaction of
alkyl halides involved single electron transfer (SET) to generate
alkyl radicals arising from alkyl halides due to the facile one
b
c
(
4.0 mmol). Yields were determined by GC. Isolated yield.
4
h,15
THP: tetrahydropyranyl.
electron redox behavior of iron.
We thus examined the
reaction of 1l. It is noteworthy that the direct coupling product
lb was obtained in 50% yield accompanied by only 3% yield of
2
1
3
It has been reported that Cu impurity in Fe salts worked
as the genuine catalytic active species in cross-coupling
a linear product 9, indicating that radical intermediates are not
produced from alkyl bromides in the present catalytic reaction.
This is in sharp contrast to hitherto known Fe-catalyzed
1
6
reactions. We thus conducted ICP-AES analysis of the
reaction mixture and observed the contamination of Cu and Pd
only in 0.79 and 0.21 ppm (11 and 1.7 molppm), respectively.
Ni could not be detected in the analysis.17 In addition, when
2
1
reactions (eq 3).
6
(5 mol%)
n-Oct
lb 50%
+
1
8
iron complex 6 synthesized from distilled Fe(CO)5 was
used as a catalyst, yield of 3aa did not change. These results
rule out the effect of trace amounts of metal impurities in the
reaction.
3
(
4 equiv)
THF,
2b (1.5 equiv) 0 ºC to rt,
4 h
Br
ð3Þ
+
n-OctMgCl
n-Oct
1l
9
3%
2
Under the optimized reaction conditions,14,19 we tested the
reactivity of alkyl (pseudo)halides. Although n-Non-Cl (1c)
did not react under the present conditions (Table 2, Entry 2),
the reaction of n-Non-F (1b) and n-Non-Br (1d) afforded the
coupling product in 35% and 54% yield, respectively (Entries 1
and 3). This is the first example of an alkyl-alkyl cross-coupling
Low valent Fe(II) species, {Fe(MgX)2}n, formed by the
treatment of FeCl2 with 4 equiv of alkyl Grignard reagent
bearing β-hydrogen, were proposed to act as catalytic active
species for the cross-coupling reaction employing alkyl
2
2,23
Grignard reagents as the coupling partner.
At the early
of alkyl fluorides using iron catalyst albeit in a low yield.4t
Reaction of iodide 1e and tosylate 1f resulted in a complex
mixture including the cross-coupling product, tridecane, in a
poor yield (Entries 4 and 5). In the former case, no n-Non-I
remained, and the possible by-products formed by dehydro-
halogenation, reduction, or dimerization of n-Non-I were
observed only in 1% yield or less although other products
could not be identified by GC analysis. The cross-coupling
reaction of 1g and sterically hindered 1h smoothly proceeded to
afford the corresponding coupling products (Entries 6 and 7).
Alkyl bromides bearing thiophene 1i, ether 1j, and acetal 1k also
afforded the desired products in moderate yields (Entries 810).
While no reaction took place when secondary and tertiary alkyl
bromides were employed, secondary alkyl Grignard reagent 2c
2
0
stage of our catalytic system, similar transmetalation and β-H
elimination might occur to form the iron hydride species, which
might react with 1,3-butadiene to form CpFe(π-allyl) complexes.
To confirm the β-H elimination process, we conducted reactions
of n-Non-Br with Grignard reagents having no β-hydrogen
such as methyl, benzyl, and phenyl Grignard reagents and
revealed that no reaction took place. When reaction of n-Non-Br
with MeMgCl was conducted similarly, but with preceded pre-
treatment of the iron complex 6 with n-BuMgCl (2a) to form
iron hydride species, the cross-coupling did proceed to afford
10 in 20% yield along with tridecane in 27% yield (eq 4). These
results strongly suggest that the formation of Fe-H species is
essential to trigger this catalytic reaction.
© 2018 The Chemical Society of Japan