Iron-copper cooperative catalysis in the reactions of alkyl grignard reagents: Exchange reaction with alkenes and carbometalation of alkynes

Article abstract of DOI:10.1021/ja206745w

Iron-copper cooperative catalysis is shown to be effective for an alkene-Grignard exchange reaction and alkylmagnesiation of alkynes. The Grignard exchange between terminal alkenes (RCH=CH₂) and cyclopentylmagnesium bromide was catalyzed by FeCl₃ (2.5 mol %) and CuBr (5 mol %) in combination with PBu₃ (10 mol %) to give RCH₂CH ₂MgBr in high yields. 1-Alkyl Grignard reagents add to alkynes in the presence of a catalyst system consisting of Fe(acac)₃, CuBr, PBu₃, and N,N,N″,N″-tetramethylethylenediamine to give β-alkylvinyl Grignard reagents. The exchange reaction and carbometalation take place on iron, whereas copper assists with the exchange of organic groups between organoiron and organomagnesium species through transmetalation with these species. Sequential reactions consisting of the alkene-Grignard exchange and the alkylmagnesiation of alkynes were successfully conducted by adding an alkyne to a mixture of the first reaction. Isomerization of Grignard reagents from 2-alkyl to 1-alkyl catalyzed by Fe-Cu also is applicable as the first 1-alkyl Grignard formation step.

Full text of DOI:10.1021/ja206745w

Article
pubs.acs.org/JACS
Iron−Copper Cooperative Catalysis in the Reactions of Alkyl
Grignard Reagents: Exchange Reaction with Alkenes and
Carbometalation of Alkynes
Eiji Shirakawa,* Daiji Ikeda, Seiji Masui, Masatoshi Yoshida, and Tamio Hayashi*
Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S
* Supporting Information
ABSTRACT: Iron−copper cooperative catalysis is shown to be
effective for an alkene−Grignard exchange reaction and
alkylmagnesiation of alkynes. The Grignard exchange between
terminal alkenes (RCHCH2) and cyclopentylmagnesium
bromide was catalyzed by FeCl3 (2.5 mol %) and CuBr (5 mol
%) in combination with PBu3 (10 mol %) to give
RCH2CH2MgBr in high yields. 1-Alkyl Grignard reagents add
to alkynes in the presence of a catalyst system consisting of
Fe(acac)3, CuBr, PBu3, and N,N,N′,N′-tetramethylethylenediamine to give β-alkylvinyl Grignard reagents. The exchange reaction
and carbometalation take place on iron, whereas copper assists with the exchange of organic groups between organoiron and
organomagnesium species through transmetalation with these species. Sequential reactions consisting of the alkene−Grignard
exchange and the alkylmagnesiation of alkynes were successfully conducted by adding an alkyne to a mixture of the first reaction.
Isomerization of Grignard reagents from 2-alkyl to 1-alkyl catalyzed by Fe−Cu also is applicable as the first 1-alkyl Grignard
formation step.
silyl10 group, except for intramolecular reactions.11 Although
Jousseaume and co-workers reported that the nickel-catalyzed
INTRODUCTION
Alkyl Grignard reagents are in a remarkable position among
■
methylmagnesiation of alkynes having no heteroatoms
organometallic compounds in organic synthesis because of their
high availability and ease of handling.1 When an alkyl halide is
proceeds in yields of up to 65%, alkyl Grignard reagents
having β-hydrogen atoms add to alkynes in only ≤22%
available, we can obtain the corresponding alkyl Grignard
reagent simply by mixing the alkyl halide with magnesium
yields.12−14
Two catalysts sometimes work cooperatively to promote a
metal (direct method). However, the desired alkyl halides are
reaction that does not take place with either of the catalysts
not always readily available, and it is difficult to apply the direct
alone.15 Two of the most famous examples of cooperative
method to the synthesis of alkyl Grignard reagents having C−X
(X = halogen) or O−H bonds, which are not compatible with
catalysis are the Wacker oxidation16 and the Sonogashira−
Hagihara coupling,17 each of which represents a major type of
the Grignard formation step. Thus, there is still room for
cooperative catalysis.18 In the former type, the first catalyst
development of other synthetic methods. Primary alkyl
contacts essentially with all of the substrates and transforms
Grignard reagents are known to be produced by isomerization
them into the desired products, whereas the second catalyst
of secondary alkyl Grignard reagents, which are otherwise
structurally stable,2 under the influence of transition-metal
restores the first catalyst back to the original state. In the
catalysis by Ti(IV)3 or Ni(II)4 through a β-hydride
Wacker oxidation, a palladium(II) complex transforms ethylene
elimination−hydrometalation sequence.5 As a mechanistically
and water into acetaldehyde and is transformed into a
palladium(0) complex, which is oxidized back to the palladium-
related reaction, the exchange between alkyl Grignard reagents
(II) complex by a copper(II) catalyst with the aid of oxygen as a
and alkenes gives primary alkyl Grignard reagents derived from
alkenes.6 Although both the isomerization and exchange
terminal oxidant. There have been many reports on this type of
cooperative catalysis, in particular on oxidation reactions. In the
reactions are attractive alternatives to the direct method, their
efficiencies were not sufficient in the reported examples.3,4,6
latter type, the first and second catalysts contact with substrates
A and B, respectively, to give two distinct intermediates, which
Carbometalation of alkynes is one of the most convenient
methods for constructing alkene-based frameworks.7 Among
are combined into one species leading to the product. The
Sonogashira−Hagihara coupling employs palladium(0) and
these, many examples of the addition of alkyl Grignard reagents
to alkynes have been presented, probably because of the high
availability of the starting alkyl Grignard reagents and the high
utility of the resulting β-alkylvinyl Grignard reagents. However,
copper(I) catalysts that react with an organic halide (R−X) and
a terminal alkyne (R′−CC−H), respectively. Transmetala-
high yields of alkylmagnesiation have been attained only for
Received: July 20, 2011
Published: November 30, 2011
alkynes having a specific group such as a heteroatom8,9 or a
© 2011 American Chemical Society
272
dx.doi.org/10.1021/ja206745w | J. Am. Chem.Soc. 2012, 134, 272−279

Journal of the American Chemical Society
Article
tion between the resulting R−PdII−X and R′−CC−CuI
species gives R−PdII−CC−R′, which undergoes reductive
elimination to give the coupling product R−CC−R′ and
regenerate the palladium(0) and copper(I) catalysts. Cooper-
ative catalysis of this type should offer ample opportunities not
only for improvement of the known transformation but also for
the development of new reactions that are not possible with
any single catalyst.
We have reported that Fe−Cu cooperative catalysis is
effective for arylmagnesiation of dialkylacetylenes having no
heteroatoms.19 In this cooperative catalysis, which is classified
into the group of the Sonogashira−Hagihara coupling, iron is
engaged in addition to alkynes, and copper takes charge of
exchange of organic groups between iron and magnesium by
transmetalation. The Fe−Cu cooperative catalysis has also been
applied to the isomerization of alkyl Grignard reagents from 2-
alkyl to 1-alkyl.20 For example, 2-hexylmagnesium bromide
(1IIa) was fully isomerized to the 1-hexyl derivative (1Ia) in
83% yield by reaction at −25 °C for 10 min in tetrahydrofuran
(THF) in the presence of FeCl3 (2.5 mol %), CuBr (5 mol %),
and PBu3 (10 mol %) (Scheme 1). In contrast, the reaction in
alkylcuprate 4IIa generated from CuBr and 1IIa, giving 1-
alkylcuprate 4Ia and regenerating 2IIa. Further transmetalation
of 4Ia with 1IIa gives isomerized 1-alkyl Grignard reagent 1Ia
and regenerates 4IIa.
Here we report that iron−copper cooperative catalysis is
effective for the alkene−Grignard exchange reaction and
alkylmagnesiation of alkynes. Terminal alkenes are transformed
into the corresponding 1-alkyl Grignard reagents in high to
moderate yields through the use of cyclopentylmagnesium
bromide as an exchanging alkyl Grignard reagent.21 Alkylme-
talation of alkynes, including those having no heteroatoms,
proceeded with alkyl Grignard reagents having β-hydrogen
atoms. Furthermore, under iron−copper cooperative catalysis,
it is possible to perform the alkene−Grignard exchange and the
alkylmagnesiation sequentially just by adding an alkyne to the
mixture of the first reaction, where the isomerization of 2-alkyl
Grignard reagents also can be used for the first 1-alkyl Grignard
formation step.
RESULTS AND DISCUSSION
■
Exchange Reaction between Alkyl Grignard Reagents
and Alkenes. Under the conditions that were effective for
isomerization of 2-hexylmagnesium bromide (1IIa) to the 1-
hexyl derivative 1Ia, 3-hexyl Grignard reagent 1IIIa did not
undergo efficient isomerization to 1Ia even in the presence of
twice the amount of the Fe−Cu catalyst. Thus, treatment of
1IIIa (1 equiv) with FeCl3 (5 mol %), CuBr (10 mol %), and
PBu3 (20 mol %) in THF at −25 °C for 10 min followed by the
reaction of the resulting alkyl Grignard reagents with ClSiH2Ph
(2 equiv) at 30 °C for 2 h gave 3-hexyl(phenyl)silane (6IIIa)
and 1-hexylsilane 6Ia in yields of 61 and 10%, respectively
(Scheme 3). A considerable amount of hexenes (18% yield),
Scheme 1
the absence of FeCl3 or CuBr gave only <1 or 3% yield of 1Ia.
The driving force for this reaction must be the high
thermodynamic stability of primary alkyl Grignard reagents in
comparison with secondary derivatives. Several examinations,
including D-labeling experiments and stoichiometric reactions
using FeCl3 or CuBr, showed that the roles of iron and copper
are essentially the same as in the arylmagnesiation of alkynes
(Scheme 2). Thus, the reaction of FeCl3 with 1IIa gives 2-
Scheme 3
Scheme 2
mainly consisting of internal ones, were produced, probably
through dissociation of the sterically demanding internal
alkenes from complexes 7 generated from 2IIIa (Scheme 4).
Scheme 4
hexyliron (2IIa), which undergoes β-hydride elimination to give
hydride complex 3a coordinated with 1-hexene. After rotation
of the alkene on the iron, hydroferration converts 3′a into 1-
hexyliron (2Ia), which undergoes transmetalation with 2-
273
dx.doi.org/10.1021/ja206745w | J. Am. Chem.Soc. 2012, 134, 272−279

Journal of the American Chemical Society
Article
The low catalytic activity likely can be ascribed to the instability
of free iron−hydride complex 8. To prevent decomposition of
8, the reaction of 1IIIa in the presence of 1-decene (5b) (1
equiv) was conducted, and it gave a 60% yield of 1-decylsilane
6Ib, where most of the MgBr moiety was transferred from the
C6 to the C10 component (Scheme 3).6,22 As shown in Scheme
4, the added terminal alkene probably prevents decomposition
of free iron−hydride complex 8 by forming complex 3′b, which
is converted into 2Ib through hydroferration and then to
Grignard reagent 1Ib via cycle B in Scheme 2.23
Table 1. Exchange Reaction between an Alkyl Grignard
Reagent and 1-Hexene
a
The reaction of 3-hexylmagnesium bromide (1IIIa) with 1-
decene (5b) to give a 60% yield of 1-decyl Grignard reagent 1Ib
shows the potential of the iron−copper system as a catalyst for
the alkene−Grignard exchange reaction. Thus, we looked for
more efficient exchanging alkyl Grignard reagents (R−MgBr)
than 1IIIa in the exchange reaction of 1-hexene (5a). Of several
alkyl Grignard reagents examined, cyclopentylmagnesium
bromide (1c) was the most effective, affording a high yield of
1-hexylmagnesium bromide (1Ia) upon reaction at −20 °C for
1 h (Scheme 5), which was carried out under the conditions
a
The reaction was carried out in Et2O (1.6 mL) at −20 °C for 1 h
under a nitrogen atmosphere using 1-hexene (5a) (0.44 mmol), an
alkylmagnesium bromide (R−MgBr) (0.40 mmol), and PBu3 (0.040
mmol) in the presence of FeCl3 (0.010 mmol) and CuBr (0.020
mmol), which was followed by treatment with ClSiH2Ph (0.80 mmol)
Scheme 5
b
c
at 30 °C for 2 h. Determined by GC based on R−MgBr. The yield
after isolation is given in parentheses. The yield of 1-pentyl(phenyl)-
d
silane is shown in parentheses.
Table 2. Exchange Reaction between Cyclopentylmagnesium
a
Bromide and Terminal Alkenes
used for the isomerization of Grignard reagents.20 Here again,
the cooperative catalysis was apparent. No exchange took place
with the copper catalyst alone, and only a 44% yield of 6Ia was
produced with the iron catalyst alone. Table 1 summarizes the
efficiency of alkyl Grignard reagents in the exchange reaction
with 5a. Cyclohexylmagnesium bromide (1d) was much less
effective, as 71% of the Grignard reagent remained unreacted
(entry 2). The large difference lies most likely in the
conformation of the intermediate alkyliron complex. Cyclo-
pentyliron complexes readily take conformations in which one
of the hydrogen atoms is located at the syn-periplanar position
with respect to the iron, facilitating β-hydride elimination, while
such conformations are not available with cyclohexyliron
complexes. 3-Pentylmagnesium bromide (1e) gave the second
best result of the four alkyl Grignard reagents examined.
Because primary alkyl Grignard reagents and 1-alkenes are in an
equilibrium under the Fe−Cu catalyst system, 1-propylmagne-
sium bromide (1If) was not a Grignard reagent of choice for
the present exchange reaction (entry 4).
The Fe−Cu-catalyzed exchange reaction using cyclopentyl-
magnesium bromide (1c) to give 1-alkyl Grignard reagent 1I
was applicable to various terminal alkenes (Table 2). Trapping
of the reaction mixture by ClSiH2Ph showed that MgBr is
attached exclusively to the nonsubstituted carbon atom of the
alkene. All of the alkenes used in Table 2 are more readily
accessible than the corresponding 1-alkyl halides, which are
required for the preparation of the same Grignard reagents by
the direct method. Diene 5k underwent a selective exchange
reaction at the monosubstituted alkene moiety (entry 5). A
dimagnesioalkane, which was converted to 6Il, was obtained
from diene 5l having double bonds at both terminals (entry 6).
a
The reaction was carried out in Et2O (1.6 mL) at −20 °C under a
nitrogen atmosphere using terminal alkene 5 (0.40 mmol) and
cyclopentylmagnesium bromide (1c) (0.40 mmol) in the presence of
FeCl3 (0.010 mmol), CuBr (0.020 mmol), and PBu3 (0.040 mmol),
which was followed by treatment with ClSiH2Ph (0.80 mmol) at 30 °C
for 2 h. Yields of the isolated products. 2-(Phenylsilyl)-1-
(phenyldimethylsilyl)propane also was produced in 3% yield.
b
c
The exchange reaction was applied to the synthesis of alkyl
Grignard reagents having functional groups that are not
compatible with the direct Grignard synthesis from a halide
and magnesium metal (Scheme 6). Hydroxyalkene 5m
underwent the exchange reaction to give alkyl Grignard reagent
1Im with an alcolate moiety at the expense of an extra
274
dx.doi.org/10.1021/ja206745w | J. Am. Chem.Soc. 2012, 134, 272−279

Journal of the American Chemical Society
Article
Scheme 6
Scheme 7
Scheme 8
equivalent of 1c. The reaction was applicable to the preparation
of alkyl Grignard reagent 1In, which has a chloroarene moiety
and is difficult to synthesize from the corresponding dihalo
compound through selective transformation of the haloalkane
moiety over the haloarene. In the reaction of chloroalkene 5o
under the standard conditions at −20 °C, competitive HCl
elimination at the chloroalkane moiety lowered the yield of 11-
chloroundecylmagnesium bromide (1Io). The reaction at a
lower temperature (−40 °C) using a catalyst consisting of
FeCl3, N,N-dimethyl[3-(diphenylphosphino)propyl]amine, and
[CuI(PBu3)]4 gave an improved yield of chloroalkyl Grignard
reagent 1Io.
Grignard formation from alkyl halides and Mg is sometimes
hampered by side reactions induced by alkyl radical
intermediates. The reaction of 6-bromo-1,1-diphenyl-1-hexene
(10Ip) with Mg gave a 1:1 mixture of linear and cyclic alkyl
Grignard reagents 1Ip and 1p′, respectively, the structures of
which were confirmed by quenching the reaction mixture with
D2O (Scheme 7).24 The formation of 1p′ is thought to occur
when the 6,6-diphenyl-5-hexenyl radical generated by transfer
of a single electron from Mg to haloalkene 10Ip cyclizes before
receiving one more electron from Mg. In contrast, the exchange
reaction between 1,1-diphenyl-1,5-hexadiene (5p) and 1c gave
only linear Grignard reagent 1Ip in a high yield.
Subjecting an isomeric mixture of 1-butene and (Z)- and
(E)-2-butene to the Fe−Cu cooperative catalysis gave isomeri-
cally pure 1-butyl Grignard reagent 1Iq, the structure of which
was confirmed after transformation to 1-butylsilane 6Iq
(Scheme 8).
In addition to ClSiH2Ph and D2O, carbon and heteroatom
electrophiles react with alkyl Grignard reagents obtained by
exchange reactions with alkenes. Thus, a reaction mixture of 4-
(4-chlorophenyl)-1-butene (5n) and 1c under the iron−copper
catalysis was treated with carbon dioxide at −20 °C for 30 min
to give 5-phenylpentanoic acid in 75% yield after acidic workup
(Table 3, entry 1). Benzaldehyde also reacted as a carbon
electrophile, giving the benzylic alcohol (entry 2). The reaction
with iodine gave the 1-alkyl iodide, corresponding to anti-
Markovnikov hydrohalogenation of a terminal alkene (entry 3).
Alkylmagnesiation of Alkynes. The reaction conditions
that were effective for the arylmagnesiation of alkynes,19 which
was carried out in THF at 60 °C, did not work efficiently in the
present alkylmagnesiation. Thus, the reaction of butylmagne-
sium bromide (1Iq) (2 equiv) with 1-phenyl-1-hexyne (12a) (1
equiv) in THF in the presence of Fe(acac)3 (5 mol %), CuBr
(10 mol %), and PBu3 (40 mol %) at 60 °C for 3 h followed by
methanolysis gave only a 20% yield of 2-butyl-1-phenyl-1-
hexene (14qa) with 65% conversion of 12a (Table 4, entry 1).
Changing the solvent from THF to Et2O drastically improved
the yield and the reaction rate, giving 14qa in 78% yield at −20
°C (entry 2).25 A large amount of a yellowish-brown precipitate
was observed in the reaction in THF at −20 °C, and the yield
of 14qa was only 2% after 3 h (entry 3). Although reduction of
the amount (20 mol %) of PBu3 severely lowered the yield, a
combination of PBu3 (20 mol %) with N,N,N′,N′-tetramethy-
lethylenediamine (TMEDA) (20 mol %) improved the yield to
87% (entries 4 and 5). The use of TMEDA in the absence of
PBu3 was totally ineffective (entry 6). A small amount (2%) of
14qa was observed in a quenched sample of the reaction after 1
min in the presence of the iron catalyst alone, though it
disappeared after 3 h (entries 7 and 8). In contrast, 14qa was
not observed at all with the copper catalyst alone in either a
short or long reaction period, with alkyne 12a mostly remaining
unreacted (entries 9 and 10). These results clearly show that
275
dx.doi.org/10.1021/ja206745w | J. Am. Chem.Soc. 2012, 134, 272−279

Journal of the American Chemical Society
Article
a
Table 3. Reaction of an Exchange Product with Electrophiles
b
entry
electrophile (equiv)
conditions
E
yield (%)
1
2
3
CO2(g) (excess)
PhCHO (1)
I2 (2)
−20 °C, 30 min
−20 °C, 10 min
−78 °C, 15 min
CO2H
75
73
81
CH(OH)Ph
I
a
b
Grignard reagent 1In obtained as a reaction mixture was treated with an electrophile. Yields of the isolated products.
a
Table 4. Butylmagnesiation of 1-Phenyl-1-hexyne Followed by Methanolysis
amount (mol %)
b
b
entry
Fe(acac)3
CuBr
additive (mol %)
PBu3 (40)
time
conv. of 12a (%)
yield of 14qa (%)
c
,d
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
5
0
0
10
10
10
10
10
10
0
3 h
65
>99
15
53
>99
14
8
20
78
2
PBu3 (40)
3 h
c
PBu3 (40)
3 h
PBu3 (20)
3 h
34
e
PBu3 (20), TMEDA (20)
TMEDA (40)
3 h
87 (86)
3 h
<1
2
PBu3 (20), TMEDA (20)
PBu3 (20), TMEDA (20)
PBu3 (20), TMEDA (20)
PBu3 (20), TMEDA (20)
1 min
3 h
0
18
<1
1
<1
<1
<1
10
1 min
3 h
10
10
a
The reaction was carried out at −20 °C in Et2O (1.8 mL) under a nitrogen atmosphere using butylmagnesium bromide (1Iq) (0.80 mmol) and 1-
b
c
phenyl-1-hexyne (12a) (0.40 mmol) in the presence of Fe(acac)3 (0.020 mmol) and/or CuBr (0.040 mmol). Determined by GC. THF was used
as the solvent instead of Et2O. Reaction temperature = 60 °C. The yield after isolation is given in parentheses.
d
e
the cooperative catalysis is essential for the alkylmagnesiation to
take place.
group, underwent the addition (entries 13−16). The reaction
using butylmagnesium chloride and dibutylmagnesium also
gave the alkylmagnesiation products (entries 17 and 18).
The generation of alkenyl Grignard reagents by the
alkylmagnesiation was confirmed by the production of
deuterated alkene 14qa-d1 in a high deuteration ratio (98%
D) upon deuteriolysis of the reaction mixture of 1Iq and 12a
(Scheme 9). The alkylmagnesiation products are applicable to
carbon−carbon bond-forming reactions. For example, allylic
alcohol 15 was obtained in high yield by the reaction of 13qa
with benzaldehyde.
The scope of the alkylmagnesiation of alkynes is shown in
Table 5. The yields were high for the reaction of aryl alkynes
having an electron-donating or -withdrawing substituent on the
aryl group (entries 1−4). An aryl chloride moiety was
compatible with the alkylmagnesiation (entry 5). The
introduction of a bulky alkyl group at the ortho position of
the aryl group on the alkyne retarded the reaction, but
acceptable yields of the adduct were obtained (entries 6 and 7).
A heteroarylacetylene and an ynoate reacted with 1Iq in high
yields (entries 8 and 9). Dialkylacetylenes were unreactive
under these conditions. The reaction of 1Iq with 1-phenyl-1-
butyne (12k) gave a mixture of stereoisomers (14qk:14′qk =
45:55), showing that the present alkylmagnesiation unfortu-
nately does not proceed stereoselectively (entry 10). When the
reaction was quenched after a reaction time of 1 min, a nearly
equimolar isomeric mixture (14qk:14′qk = 49:51, 6% yield)
was produced. The isomerization possibly takes place at the
stage of intermediate alkenyliron and/or -copper complexes. As
the alkyl group on the alkyne became bulkier, the yield of
adduct decreased (entries 11 and 12), but even the reaction of
an isopropylacetylene gave a 59% yield of the addition product.
Other alkyl Grignard reagents, including one having a methoxy
The result that both the iron and copper catalysts are needed
to promote the alkylmagnesiation of alkynes, as in the case with
the arylmagnesiation, prompted us to consider a mechanism of
cooperative catalysis similar to that proposed for the
arylmagnesiation.19 To confirm that the iron complex is
responsible for the alkylmetalation, we conducted stoichio-
metric reactions using an iron or copper complex, as shown in
Scheme 10. Treatment of equimolar amounts of Fe(acac)3 and
1-phenyl-1-hexyne (12a) with neopentylmagnesium bromide
(1Ir) (10 equiv) in the presence of PBu3 (4 equiv) and
TMEDA (4 equiv) at 20 °C for 2 h gave a 62% yield of 14ra. In
contrast, 14ra was not produced at all in the same treatment
with CuBr instead of Fe(acac)3. These results in addition to
276
dx.doi.org/10.1021/ja206745w | J. Am. Chem.Soc. 2012, 134, 272−279

Journal of the American Chemical Society
Article
a
Table 5. Alkylmagnesiation of Alkynes Followed by Methanolysis
b
c
entry
R1
R2
R3
time (h)
yield (%)
14:14′
1
2
3
4
5
6
7
8
Bu (1Iq)
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Et
4-MeOC6H4 (12b)
3-MeOC6H4 (12c)
4-(CF3)C6H4 (12d)
3-(CF3)C6H4 (12e)
4-ClC6H4 (12f)
2-MeC6H4 (12g)
2-(i-Pr)C6H4 (12h)
2-thienyl (12i)
CO2Et (12j)
Ph (12k)
3
3
80
85
86
93
77
93
71
79
84
87
76
59
85
88
61
57

Bu (1Iq)

Bu (1Iq)
3

Bu (1Iq)
3

Bu (1Iq)
3

Bu (1Iq)
3

Bu (1Iq)
18
3

Bu (1Iq)

d
9
Bu (1Iq)
0.2
3

10
11
12
13
14
15
Bu (1Iq)
45:55
39:61
64:36
53:47
79:21
97:3
54:46

Bu (1Iq)
i-Bu
i-Pr
Bu
Bu
Bu
Hex
Bu
Bu
Ph (12l)
21
21
3
Bu (1Iq)
Ph (12m)
f
f
Hex (1Ia)
i-Bu (1Iq′)
Me3CCH2 (1Ir)
MeO(CH2)4 (1Is)
Bu (BuMgCl)
Bu (Bu2Mg)
Ph (12a)
Ph (12a)
9
Ph (12a)
3
e
16
Ph (12n)
4
g
17
18
Ph (12a)
3
89
g
Ph (12a)
3
88

a
The reaction was carried out at −20 °C in Et2O (1.8 mL) under a nitrogen atmosphere using alkylmagnesium bromide 1I (0.80 mmol) and alkyne
b
12 (0.40 mmol) in the presence of Fe(acac)3 (0.020 mmol), CuBr (0.040 mmol), PBu3 (0.080 mmol), and TMEDA (0.080 mmol). Yields of the
c
d
e
isolated products based on 12. Determined by GC and/or 1H NMR spectroscopy. Reaction temperature = −78 °C. MeO(CH2)4MgCl was used.
f
g
The configuration was not determined. Determined by GC.
Scheme 9
Scheme 11
Scheme 10
yield of 14qa generated by methanolysis of 16 is 2% or <1% in
a short or long reaction period, respectively (Table 4, entries 7
and 8), can be rationally understood. In the presence of the
copper cocatalyst, dialkylcuprate 4I generated from CuBr and 1I
undergoes transmetalation with 16 to give alkenylcuprate 17
and regenerate alkyliron species 2I. Finally, transmetalation of
cuprate 17 with 1I gives alkylmagnesiation product 13 and
regenerates dialkylcuprate 4I.
Two Successive Reactions Both Catalyzed Coopera-
tively by Iron and Copper Complexes. We have shown
that iron−copper cooperative catalysis is effective for both the
alkene−Grignard exchange reaction to give 1-alkyl Grignard
reagents and the alkylmagnesiation of alkynes to give alkenyl
Grignard reagents. Thus, successive reactions of the alkene−
Grignard exchange and the alkylmagnesiation of alkynes with
the resulting 1-alkyl Grignard reagent would be expected to
occur upon addition of the alkyne to a reaction mixture of the
other observations prompted us to draw a plausible catalytic
cycle (Scheme 11) wherein addition of alkyl groups to alkynes
takes place on iron and transmetalation of cuprates promotes
the exchange of organic groups between iron and magnesium.
Thus, the low-valent alkyliron species 2I generated from
Fe(acac)3 upon reaction with excess alkyl Grignard reagent 1I
adds to alkyne 12 to give alkenyliron 16, which cannot undergo
transmetalatation directly with 1I. Thus, the iron complex alone
cannot catalyze the alkylmagnesiation. If one supposes that 16
is unstable under the reaction conditions, the result that the
277
dx.doi.org/10.1021/ja206745w | J. Am. Chem.Soc. 2012, 134, 272−279

Journal of the American Chemical Society
Article
first reaction. This was realized by use of the catalyst system
optimized for the alkylmagnesiation, which proceeds efficiently
in the presence of PBu3 and TMEDA. Thus, treatment of 1-
hexene (5a) with cyclopentylmagnesium bromide (1c) in the
presence of Fe(acac)3 (5 mol %), CuBr (5 mol %), PBu3 (20
mol %), and TMEDA (20 mol %) in Et2O at −20 °C for 10
min was followed by addition of 1-phenyl-1-octyne (12n) (0.5
equiv), and quenching with methanol after 3 h gave 2-hexyl-1-
phenyl-1-octene (14an) in 79% yield based on 12n (Scheme
Scheme 13
Scheme 12
and brings the alkyl group of the starting Grignard reagent to
iron.
The products of the exchange reaction are 1-alkyl Grignard
reagents, which are exactly the substrates of the alkylmagne-
siation. Thus, these two types of reactions were successively
conducted in one pot by adding an alkyne after the first
reaction. This was successful because the first reaction does not
form any byproducts that would inhibit the second reaction and
the catalyst system survives after the first reaction. This
presents a rare example of a one-pot reaction consisting of two
cooperatively catalyzed reactions.
12). The addition product 14an was also obtained from 2-
hexylmagnesium bromide (1IIa) and 12n through isomerization
followed by the alkylmagnesiation. As shown in Scheme 13, the
exchange reaction with cyclopentyl Grignard reagent 1c
converted an isomeric mixture of butenes in a single step
into isomerically pure 1-butyl Grignard reagent 1Iq, which
added to alkyne 12a to give the addition product 14qa. An
isomeric mixture of butylmagnesium bromides (1Iq and 1IIq)
prepared from an isomeric mixture of butenes through
hydrobromination followed by reaction with magnesium was
treated with the iron−copper catalyst to give isomerically pure
1Iq, which underwent alkylmagnesiation of 12a without the
addition of an extra catalyst.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectroscopic and analytical data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
shirakawa@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.
ac.jp
CONCLUSION
■
■
We have disclosed that iron−copper cooperative catalysis is
effective for the exchange reaction between terminal alkenes
and cyclopentylmagnesium bromide and for alkylmagnesiation
of alkynes. Various terminal alkenes were transformed to 1-alkyl
Grignard reagents, including those having a haloarene or
haloalkane moiety and thus otherwise being not so readily
accessible. The alkylmagnesiation was applied to various
phenylalkynes having an electron-donating or -withdrawing
substituent on the benzene ring. Studies of the reaction
mechanism, including reactions using a stoichiometric amount
of an iron or copper complex, revealed the roles of the iron and
copper catalysts. In these reactions, transformation of the
organic group takes place on iron through β-hydride
elimination/hydroferration or alkylferration, whereas copper
transfers the resulting organic group from iron to magnesium
ACKNOWLEDGMENTS
■
This work was financially supported in part by a Grant-in-Aid
for Scientific Research on Priority Areas (19028029, “Chem-
istry of Concerto Catalysis”) and a Grant-in-Aid for Scientific
Research (the Global COE Program “Integrated Materials
Science” at Kyoto University) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
REFERENCES
■
(1) Handbook of Grignard Reagents; Silverman, G. S., Rakita, P. E.,
Eds.; Marcel Dekker: New York, 1996.
278
dx.doi.org/10.1021/ja206745w | J. Am. Chem.Soc. 2012, 134, 272−279

Journal of the American Chemical Society
Article
(2) Isomerization triggered by a double bond or a strained cycle, as in
allyllic and cyclopropylmethyl Grignard reagents, is known. For a
review, see: Hill, E. A. J. Organomet. Chem. 1975, 91, 123−271.
(3) (a) Finkbeiner, H. L.; Cooper, G. D. J. Org. Chem. 1961, 26,
4779−4780. (b) Cooper, G. D.; Finkbeiner, H. L. J. Org. Chem. 1962,
27, 1493−1497. (c) Fell, B.; Asinger, F.; Sulzbach, R. A. Chem. Ber.
1970, 103, 3830−3841.
(17) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467−4470. For an account, see: (b) Sonogashira, K. J.
Organomet. Chem. 2002, 653, 46−49. (c) Sonogashira, K. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley Interscience: New York, 2002; Chapter III.2.8.1, pp 493−529.
(18) According to the classification by Chang in ref 15a, the Wacker
oxidation and the Sonogashira−Hagihara coupling belong to types I
and III, respectively.
(19) (a) Shirakawa, E.; Yamagami, T.; Kimura, T.; Yamaguchi, S.;
Hayashi, T. J. Am. Chem. Soc. 2005, 127, 17164−17165. Iron−copper
cooperative catalysis is also effective for aryllithiation of alkynes (see
ref 14).
(20) Shirakawa, E.; Ikeda, D.; Yamaguchi, S.; Hayashi, T. Chem.
Commun. 2008, 1214−1216.
(21) FeCl3 has been reported to catalyze the exchange between 1-
propylmagnesium bromide and styrene to give α-phenethylmagnesium
bromide, albeit in low yield (15%) (see ref 6b).
(22) The transfer ratio of the MgBr moiety from the C6 to the C10
component was much less when 1-hexylmagnesium bromide (1Ia) was
used instead of 1IIIa. Thus, the reaction of 1Ia in the presence of 1-
decene (5b) under the same conditions as in Scheme 3 gave 6Ia (70%
yield), hexenes (11% yield), 6Ib (7% yield), and decenes (92% yield).
(23) The addition of 1-decene after premixing all of the other
components for 30 min did not affect the yields of 6IIIa, 6Ia, and
hexenes (59, 7, and 23%, respectively), and most of the 1-decene (5b)
remained unreacted (5b, 83%; 6Ib, 3%).
(24) Ashby, E. C.; Oswald, J. J. Org. Chem. 1988, 53, 6068−6076.
(25) Alkyne 12a was added 5 min after the addition of a solution of
1Iq to the other components. The yield was slightly higher using this
procedure in comparison with addition of 1Iq last.
́ ́
(4) Farady, L.; Marko, L. J. Organomet. Chem. 1971, 28, 159−165.
(5) Isomerization of the alkyl group derived from alkyl Grignard
reagents during the transition-metal-catalyzed cross-coupling reaction
with aryl halides is known. For an early example, see: Tamao, K.; Kiso,
Y.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 9268−9269.
(6) 1-Alkyl (α-arylalkyl) Grignard reagents can be obtained by metal-
catalyzed exchange between terminal alkenes (styrenes) and alkyl
Grignard reagents. For a review, see: (a) Sato, F. J. Organomet. Chem.
1985, 285, 53−64. For Ti catalysts, see: (b) Finkbeiner, H. L.;
Cooper, G. D. J. Org. Chem. 1962, 27, 3395−3400. (c) Ashby, E. C.;
Ainslie, R. D. J. Organomet. Chem. 1983, 250, 1−12. (d) Eisch, J. J.;
Galle, J. E. J. Organomet. Chem. 1978, 160, C8−C12. Also see refs 3a
and 3b. For Ni catalysts, see: (e) Farad
Organomet. Chem. 1967, 10, 505−510. (f) Farad
Marko, L. J. Organomet. Chem. 1969, 17, 107−116. Also see ref 3c.
́
y, L.; Bencze, L.; Marko,
́
L. J.
́
y, L.; Bencze, L.;
́
(7) For reviews of carbometalation of alkynes, see: (a) Knochel, P.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Semmelhack, M. F., Eds.; Pergamon Press: New York, 1991; Vol. 4,
Chapter 4.4, pp 865−911. (b) Marek, I.; Chinkov, N.; Banon-Tenne,
D. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Chapter
7, pp 395−478. (c) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57,
5899−5913.
(8) For examples, see: (a) Vermeer, P.; de Graaf, C.; Meijer, J. Recl.
Trav. Chim. Pays-Bas 1974, 93, 24−25. (b) Jousseaume, B.; Duboudin,
J.-G. J. Organomet. Chem. 1975, 91, C1−C3. (c) Shinokubo, H.;
Oshima, K. Catal. Surv. Asia 2003, 7, 39−46. (d) Chechik-Lankin, H.;
Livshin, S.; Marek, I. Synlett 2005, 2098−2100.
(9) For examples of the iron-catalyzed reaction, see: (a) Hojo, M.;
Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba, Y.; Hosomi, A. Angew.
Chem., Int. Ed. 2001, 40, 621−623. (b) Zhang, D.; Ready, J. M. J. Am.
Chem. Soc. 2006, 128, 15050−15051.
(10) For examples, see: (a) Snider, B. B.; Karras, M.; Conn, R. S. E.
J. Am. Chem. Soc. 1978, 100, 4624−4626. (b) Snider, B. B.; Conn, R. S.
E.; Karras, M. Tetrahedron Lett. 1979, 20, 1679−1682.
(11) Intramolecular alkylmagnesiation takes place in high yields. For
an example, see: (a) Richey, H. G. Jr.; Rothman, A. M. Tetrahedron
Lett. 1968, 9, 1457−1460.
For a review of rearrangements of
Grignard reagents, including intramolecular alkylmagnesiation, see:
(b) Hill, E. A. J. Organomet. Chem. 1975, 91, 123−271.
(12) (a) Duboudin, J.-G.; Jousseaume, B. J. Organomet. Chem. 1972,
44, C1−C3. (b) Duboudin, J.-G.; Jousseaume, B. J. Organomet. Chem.
1978, 162, 209−222.
(13) Heptylmagnesium bromide has been reported to add to
nonsubstituted acetylene in ca. 30% yield in the presence of a copper
catalyst. See: Alexakis, A.; Cahiez, G.; Normant, J. F. J. Organomet.
Chem. 1979, 177, 293−298.
(14) We have reported iron-catalyzed alkyllithiation of alkynes. See:
Shirakawa, E.; Ikeda, D.; Ozawa, T.; Watanabe, S.; Hayashi, T. Chem.
Commun. 2009, 1885−1887.
(15) Cooperative catalysis has recently been reviewed with an
appropriate classification. See: (a) Lee, J. M.; Na, Y.; Han, H.; Chang,
S. Chem. Soc. Rev. 2004, 33, 302−312. Also see the following review:
(b) van den Beuken, E. K.; Feringa, B. L. Tetrahedron 1998, 54,
12985−13011.
(16) (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.;
Ruttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176−182. For
̈
reviews, see: (b) Tsuji, J. Synthesis 1984, 369−384. (c) Henry, P. M. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; Wiley Interscience: New York, 2002; Chapter V.3.1.1; pp
2119−2139.
279
dx.doi.org/10.1021/ja206745w | J. Am. Chem.Soc. 2012, 134, 272−279