Nickel-catalyzed regioselective carbomagnesation of methylenecyclopropanes through a site-selective carbon-carbon bond cleavage

Article abstract of DOI:10.1002/anie.200904721

chemical equation presented Unwringing the ring: Methylenecyclopropanes reacted with vinyl and aryl Grignard reagents in the presence of a nickel catalyst to afford vinyl- and arylmagnesation products, respectively, through a selective C - C bond cleavage (see scheme). The reaction provides a new method for the preparation of substituted homoallyl and allyl Grignard reagents.

Full text of DOI:10.1002/anie.200904721

Communications
DOI: 10.1002/anie.200904721
À
C C Activation
Nickel-Catalyzed Regioselective Carbomagnesation of
Methylenecyclopropanes through a Site-Selective Carbon–Carbon
Bond Cleavage**
Jun Terao,* Masahiro Tomita, Surya Prakash Singh, and Nobuaki Kambe*
Since the discovery of Grignard reagents (RMgX) by the
reaction of organic halides (RX) with magnesium metal in
1900, numerous efforts have been devoted to revealing the
reactivity of these species and to applying these reagents in
organic synthesis. The addition of organomagnesium com-
pounds across carbon–carbon unsaturated bonds (carbomag-
nesation) is one of the principal and important methods
employed for the generation of Grignard reagents with
À
concomitant C C bond formation; this method provides a
straightforward entry into Grignard reagents having a unique
carbon skeleton.[1,2] Recently, we have realized the regiose-
lective carbomagnesation of carbon–carbon unsaturated
compounds such as alkenes, 1,3-butadienes, alkynes, and
enynes with Grignard reagents in the presence of transition-
metal “ate” complexes as key catalytic species.[3] We
attempted to apply this methodology to methylenecyclopro-
panes (MCPs), because MCPs are readily accessible[4] and
highly reactive unsaturated hydrocarbons which have served
as useful building blocks in organic synthesis, especially in
transition-metal-catalyzed reactions.[5] We report herein the
nickel-catalyzed reaction of MCPs with Grignard reagents,
wherein the selective cleavage of the proximal or the distal
carbon–carbon bond of the MCPs[6] has been achieved by
using Grignard reagents to give the corresponding carbomag-
nesation products regioselectively [Eq. (1)].
2-Phenyl-1-methylenecyclopropane (1a, 0.5 mmol) was
reacted with phenylmagnesium bromide (2a, 1.0 mmol, 1m in
THF) in the presence of a catalytic amount of [Ni(PPh3)2Cl2]
(0.025 mmol) at 08C for eight hours and then an aqueous
workup was performed, delivering 2,3-diphenyl-1-butene
(3a) in 83% yield as determined by GC methods [Eq. (2)].
The pure form of 3a was obtained in 61% yield by recycling
preparative HPLC methods using CHCl3 as an eluent. The
À
selective cleavage of a less sterically hindered proximal C C
bond was observed in this reaction. Under the same reaction
conditions, the use of NiCl2, [Ni(PMe3)2Cl2], and [Ni-
(dppf)Cl2], instead of [Ni(PPh3)2Cl2], gave 3a in only 30%,
20%, and 11% yields, respectively. Using [Pd(PPh3)2Cl2] was
ineffective. Methyl and allyl Grignard reagents did not
undergo this reaction. When the reaction mixture was
quenched with D2O before the usual aqueous workup,
monodeutarated 3a (deuterium content 96%) was obtained.
This result implies that the 2,3-diphenyl-1-butenyl Grignard
reagent 4 was formed by the present reaction. Reagent 4
could be trapped with iodine, allyl bromide, and CO2 to give
the corresponding products 3b, 3c, and 3d in 61%, 66%, and
68% yields, respectively.
Table 1 summarizes the representative results obtained
using substituted MCPs and aryl Grignard reagents. 4-
Methoxyphenylmagnesium bromide (2b) gave the corre-
sponding product 3e in good yield (Table 1, entry 1). The
reaction was sluggish with respect to the chloro-substituted
phenylmagnesium bromide 2c (Table 1, entry 2). 4-Tolyl and
2-naphthyl groups on 1 did not affect this reaction system, and
the desired products 3g and 3h were obtained in 68% and
62% yields, respectively (Table 1, entries 3 and 4). An MCP
bearing an alkyl substituent gave the corresponding product
3i in a moderate yield (Table 1, entry 5).
[*] Dr. J. Terao
Department of Energy and Hydrocarbon Chemistry
Graduate School of Engineering
Kyoto University, Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2514
E-mail: terao@scl.kyoto-u.ac.jp
Homepage: http://twww.ehcc.kyoto-u.ac.jp/terao/
M. Tomita, Dr. S. P. Singh, Prof. Dr. N. Kambe
Department of Applied Chemistry, Graduate School of Engineering
Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871 (Japan)
E-mail: kambe@chem.eng.osaka-u.ac.jp
Surprisingly, the use of a vinyl Grignard reagent instead of
an aryl Grignard one led to the formation of a different
[**] This research was supported financially in part by a grant from the
Ministry of Education, Culture, Sports, Science, and Technology of
Japan, the Asahi Glass foundation, the Sumitomo foundation, and
the Mitsubishi Chemical Corporation Fund.
À
carbomagnesation product through the selective distal C C
bond cleavage reaction of the MCPs. For example, the
reaction of 1a with vinylmagnesium chloride 5a in the
presence of 5 mol% of NiCl2 at 08C for three hours with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904721.
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Table 1: Nickel-catalyzed reaction of MCPs with arylmagnesium bro-
coupling products 8a in 86% upon isolation, based on
mide.[a]
tributylchlorosilane (Table 2, entry 1). [Ni(acac)2] (acac =
acetylacetonate), [Ni(PPh3)2Cl2], and [Ni(dppf)Cl2] (dppf =
1,1-bis(diphenylphosphino)ferrocene) also afforded 8a in
84%, 63%, and 60% yields, respectively, under the same
reaction conditions, indicating phosphine-free conditions are
more suitable for the vinylation reaction. PdCl2 was not
effective. When 1-bromooctane was employed as an electro-
phile, the corresponding product 8b was obtained in 70%
yield (Table 2, entry 2). a-Methyl- and b-methyl-substituted
vinyl Grignard reagents also underwent the present coupling
reaction (Table 2, entries 3 and 4). 2-Naphthyl-, 4-tolyl-, and
4-methoxyphenyl-substituted MCPs also gave the corre-
sponding products in good yield (Table 2, entries 5–7).
Entry MCP
Ar
Product Yield [%][b]
1
1a
2b (Ar=4-
MeOC6H4)
2c
3e
72
2
3
4
5
1a
3 f
3g
3h
3i
37[c]
68
1g (R=4-tolyl)
1h (R=2-naphthyl) 2a
1i (R=n-hexyl) 2a
2a
62
37[d]
[a] Reaction conditions: MCP (0.5 mmol), ArMgBr (1.0 mmol, 1m in
THF), [Ni(PPh3)2Cl2] (0.025 mol), THF (3 mL), 08C, 8 h. [b] Yield of
isolated product based on MCP. [c] Stirring for 20 h at 108C. [d] Stirring
for 10 h at À208C.
À
To study the effect of Grignard reagents on the C C bond-
cleavage reaction, we carried out the reaction of 1a with a
Table 2: Nickel-catalyzed reaction of MCPs with vinylmagnesium chloride in the presence of electro-
subsequent quenching with D2O
yielded monodeuterated 7a in
40% yield with a deuterium atom
at the benzylic position. No evi-
dence was found for the presence
of another possible carbomagnesa-
tion product arising from the prox-
philes.[a]
1
2
=
Entry
MCP
R CH CR MgCl
EX
Product
Yield [%][b]
=
1
2
3
4
5
6
7
1a (R=Ph)
1a
1a
1a
1e (R=2-naphthyl)
1g (R=4-MeOC6H4)
1h (R=4-ClC6H4)
5a (CH2 CHMgCl)
5a
nBu3SiCl
nOctBr
8a
8b
8c
8d
8e
8 f
86
70
72
63
73
87
85
À
imal C C bond cleavage reaction.
This result suggests that the allylic
benzyl Grignard reagent 6 was
formed in situ [Eq. (3)].
=
5c (CH2 CMeMgCl)
nPr3SiCl
nPr3SiCl
nBu3SiCl
nBu3SiCl
nBu3SiCl
=
5c (MeCH CHMgCl)
5a
5a
5a
Since it is known that allylic
Grignard reagents are more reac-
tive nucleophiles toward chlorosi-
8h
1
2
=
[a] Reaction conditions: MCP (0.75 mmol), R CH CR MgCl (1.0 mmol), EX (0.5 mmol), NiCl2
lanes
than
vinyl
Grignard
(0.025 mol), THF (3 mL), 08C, 3 h. [b] Yield of isolated product based on EX.
reagents,[7] we carried out the reac-
tion of 1a (0.5 mmol) with 5a
catalytic amount of [Ni(cod)2] (cod = 1,5-cyclooctadiene) in
the presence and in the absence of PPh3 [Eqs. (4) and (5)]; the
À
C C bond-cleavage reaction of a cyclopropane ring of an
MCP was reported to occur in the presence of Ni0 to give
oligomerization products.[8] After the THF solution had been
stirred for six hours at 08C, the reaction was quenched with 1n
HCl (aq.). GC and NMR analyses of the resulting reaction
mixture did not indicate the formation of dimerization or
oligomerization products, and 1a was recovered unchanged
[Eqs. (4) and (5); top arrow]. In contrast, when PhMgBr or
=
CH2 CHMgCl and Et3SiCl were added to these reaction
mixtures, a phenylmagnesation product 3a and the three-
component-coupling product 8i were obtained in 54% and
46% yields, respectively [Eqs. (4) and (5); bottom arrow].
(1.0 mmol) in the presence of tributylchlorosilane
(0.75 mmol) as an electrophile to quench 6 in situ; the same
reaction conditions as those in Equation (3) were used for this
experiment. As expected, the three-component-coupling
product 8a was formed regioselectively and isolated in 56%
yield based on 1a. NMR and GC analyses of the resulting
reaction mixture showed no evidence for the direct coupling
of vinyl Grignard reagents with tributylchlorosilane. Optimi-
zation of the reaction conditions revealed that use of 1a
(0.75 mmol), 5a (1.0 mmol), tributylchlorosilane (0.5 mmol),
and NiCl2 (0.025 mmol) at 08C for three hours afforded
À
This result indicates that Grignard reagents promote the C C
bond-cleavage reaction.
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Communications
À
It is known that the C C bond-cleavage reaction of MCPs
proceeds through the oxidative addition or migratory inser-
[5,9]
=
tion of a C C bond and subsequent b-carbon elimination.
To investigate the reaction mechanism, the following labeling
experiment was performed. The reaction of an MCP contain-
ing deuterium at the terminal vinylic carbon atom ([D2]1a)
with a vinyl Grignard reagent and tributylchlorosilane was
conducted in THF at 08C for three hours in the presence of
NiCl2. Compound [D2]8a was formed in 79% yield with
deuterium atoms at the geminal vinylic position [Eq. (6)]. No
evidence was found for the formation of [D2]8a’, which can
possibly be obtained by migratory insertion and subsequent b-
carbon elimination (Path B). This result indicates that the
present carbomagnesation reaction could proceed through
Scheme 1. A plausible reaction pathway.
Ni0 to complete the catalytic cycle. An alternative pathway
proceeding by the insertion of the double bond of MCP into
À
the Ph Ni bond and subsequent b-carbon elimination cannot
À
the oxidative addition of a C C bond of an MCP to a Ni
be ruled out in the case of PhMgBr.
catalyst (Path A).
In conclusion, we report the first example of the nickel-
catalyzed carbomagnesation of MCPs, wherein the appropri-
ate aryl or vinyl Grignard reagents lead to the site-selective
À
À
C C bond cleavage reaction of the proximal or the distal C C
bonds of the MCPs. The present reaction provides a new
method for the preparation of substituted homoallyl or allyl
Grignard reagents from an aryl or a vinyl Grignard reagent
and MCPs in the presence of a nickel catalyst.
Experimental Section
2,3-Diphenyl-1,6-heptadiene
(3c):
[Ni(PPh3)2Cl2]
(16.3 mg,
0.025 mmol) was added to a mixture of 2-phenyl-1-methylenecyclo-
propane (65.0 mg, 0.5 mmol), phenylmagnesium bromide (1.0m,
1.0 mL, 1.0 mmol), and THF (2 mL) which was maintained at 08C
under a nitrogen atmosphere. After the reacton mixture had been
stirred for 8 h, allyl bromide (133.1 mg, 1.1 mmol) was added to the
solution at 08C, and the mixture was warmed to 208C. A saturated
aqueous NH4Cl solution (50 mL) was added, and the product was
extracted with diethyl ether (50 mL). The organic layer was dried
over MgSO4 and evaporated to give a yellow residue containing the
crude products (78% GC yield). Purification by HPLC methods using
CHCl3 as an eluent afforded 71.3 mg (66%) of 3c as a colorless oil.
2-[Phenyl(tributylsilyl)methyl]-1,4-pentadiene (8a): Vinylmag-
nesium chloride (1.25m, 0.8 mL, 1.0 mmol) was added to a mixture
of 2-phenyl-1-methylenecyclopropane (65.0 mg, 0.75 mmol), tributyl-
chlorosilane (117.4 mg, 0.5 mmol), NiCl2 (3.2 mg, 0.025 mmol), and
Although the detailed mechanism of the present carbo-
magnesation reaction has not yet been clarified, we would like
to propose the reaction pathways as shown in Scheme 1.
[LnNiCl2] could be reduced by two equivalents of Grignard
reagents to afford [LnNi0] by the reductive elimination of
[LnNiR2]. The subsequent reaction of [LnNi0] with a Grignard
reagent and an MCP would yield the nickelate complex 9.[9] In
the case of aryl Grignard reagents, the direct oxidative
THF (2 mL) which was maintained at 08C under
a nitrogen
atmosphere. After the reaction mixture had been stirred for 3 h, a
saturated aqueous NH4Cl solution was added to the solution and the
products were extracted with diethyl ether. The organic layer was
dried over MgSO4 and evaporated to give a yellow residue containing
the crude products (92% GC yield). Purification by HPLC methods
using CHCl3 as an eluent afforded 153.2 mg (86%) of 8a as a colorless
oil.
À
addition of a proximal C C bond of the MCP to the nickel
catalyst might occur to yield 10. In contrast, when vinyl
Grignard reagents were employed, the distal bond cleavage of
the MCP might predominate to form 12. The subsequent
isomerization of 10 and 12 into 11 and 13, respectively, and
then reductive coupling would afford the corresponding
carbomagnesation products 4 and 6, respectively, along with
Received: August 25, 2009
Revised: November 2, 2009
Published online: November 27, 2009
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À
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