Palladium(0)-catalyzed methylenecyclopropanation of norbornenes with vinyl bromides

Article abstract of DOI:10.1021/ol500829t

Highly strained methylenecyclopropane derivatives have been achieved via a novel and efficient Pd(0)-catalyzed domino reaction. The formal [2 + 1] cycloaddition reaction of vinyl bromides to norbornenes involves a Heck-type coupling and a C(sp²)-H bond activation.

Full text of DOI:10.1021/ol500829t

Letter
pubs.acs.org/OrgLett
Palladium(0)-Catalyzed Methylenecyclopropanation of Norbornenes
with Vinyl Bromides
Jiangang Mao†,‡ and Weiliang Bao*,†
†Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡School of Metallurgy and Chemical Engineering, Jiangxi University of Science and Technology, Ganzhou 341000, China
S
* Supporting Information
ABSTRACT: Highly strained methylenecyclopropane deriva-
tives have been achieved via a novel and efficient Pd(0)-
catalyzed domino reaction. The formal [2 + 1] cycloaddition
reaction of vinyl bromides to norbornenes involves a Heck-
type coupling and a C(sp2)−H bond activation.
Norbornene9 and cyclopropane-fused norbornene moiety10
ethylenecyclopropane (MCP) is the smallest carbocycle
1
have been discovered in some bioactive compounds such as
Mwith an exo-methylene moiety. The construction and
pharmaceuticals and natural products. Cyclopropane-fused
norbornene also served as a significant building block in
organic synthesis.11
transformation of MCP unit has attracted much attention from
organic chemists for its sufficient stability, significant strain (40
kcal/mol), and conferring on them an unusually high
reactivity.2 A MCP subunit as a basic skeleton presents in
many natural products and biologically active compounds.3
Numerous efficient and straightforward syntheses of various
MCPs have been reported.4 The [2 + 1] cycloaddition of
carbene (or carbenoid) to an unsaturated bond is undoubtedly
the most common method for constructing methylene and
alkylidenecyclopropane subunit.5 The elimination reaction of
HX, XX, XY Group as well as N2 from Pyrazolines is also a
powerful tool in the synthesis of MCPs.6 A few peculiar
rearrangement reactions of designed compounds for installing
MCP units have appeared in the literature since the 1980s.7
Recently a few examples of transition metal-catalyzed
methylenecyclopropanation via C−H or C−C bond activation
have been reported.8 Buono and co-workers first reported
Pd(II)-catalyzed methylenecyclopropanation of terminal al-
kynes to norbornenes via C(sp)−H bond activation (Scheme
1).8a However, to our knowledge, transition metal-catalyzed
methylenecyclopropanation of monohalo-molecules via C-
(sp2)−H bond activation has not been reported. Herein, we
reported the first example of Pd(0)-catalyzed intermolecular
C(sp2)−H activation methylenecyclopropanation (Scheme 1).
On the basis of our previous studies12 and our interest in
methylenecyclopropanation of norbornenes via Pd(0)-catalyzed
C(sp2)−H bond activation,13 we evaluated the outcomes of the
coupling of (Z)-1-(2-bromovinyl)-4-methoxybenzene 1a with
endo-N-(p-tolyl)norbornenesuccinimide 2a using a Pd(0)
catalyst system. To our delight, the desired methylenecyclo-
propanation compound 3a was obtained as the final products
instead of benzene-fused norbornene compounds (Scheme 1).
Therefore, the reaction conditions were screened to achieve the
best yield of MCPs. The results were summarized in Table 1.
First, metal catalysts and ligands were screened in the
methylenecyclopropanation reaction. Pd(OAc)2 was better
than PdCl2, Pd(PPh3)4, and Pd(dppf)Cl2 (Table 1, entries
1−4, 97% yield compared with 58−81%). The ligand effect was
also examined. In contrast to PPh3, dppf and BINAP resulted in
a lower yield of 3aa (Table 1, entries 5−6). Base also had a
significant effect on product yield. Compared with K3PO4 and
NaOAc, K2CO3 was the best in promoting this reaction (Table
1, entries 7−8). The reaction could proceed successfully in
toluene (Table 1, entry 2). Other polar aprotic solvents, such as
DMSO, dioxane, and CH3CN, only gave moderate or low
yields (Table 1, entries 9−11).
With the optimized reaction conditions in hand, some
representative substrates were selected to explore the scope of
the reaction (Scheme 2). Substituted (Z)-2-bromovinylarene
bearing electron-donating substituents (methyl and methoxy)
afforded product 3 in excellent yields (Scheme 2, 3aa, 3ca, 3da,
3cb−3db, 3ac, 3cc), while (Z)-2-bromovinylarenes bearing
electron-withdrawing groups (chloro and fluoro) also provided
products 3 in good to high yields (Scheme 2, 3ea−3ha, 3eb−
3fb, 3ec, 3fc, 3hc). The ortho-chloro vinylarene produced 3ga
Scheme 1. Transition Metal-Catalyzed
Methylenecyclopropanation
Received: March 19, 2014
Published: April 30, 2014
© 2014 American Chemical Society
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Letter
Table 1. Optimization of Reaction Conditions for
Methylenecyclopropanation
Scheme 2. Substrate Scope of Pd-Catalyzed
Methylenecyclopropanation
a
a
b
entry
[Pd]
PdCl2
ligand
base
solvent
yield (%)
1
PPh3
PPh3
PPh3
PPh3
dppf
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
NaOAc
K2CO3
K2CO3
K2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
dioxane
CH3CN
58
97
73
81
46
14
53
62
42
65
52
2
Pd(OAc)2
Pd(PPh3)4
Pd(dppf)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
3
4
5
6
BINAP
PPh3
PPh3
PPh3
PPh3
PPh3
7
8
9
10
11
a
Reaction conditions unless otherwise noted: 1a (0.55 mmol), 2a (0.5
mmol), catalyst (0.05 mmol), ligand (0.11 mmol), base (0.25 mmol),
b
solvent (3.0 mL), 110 °C, 12 h in sealed tube. Isolated yields.
in 88% yield due to weaker electron-withdrawing effect
compared with meta- one (3fa 85% yield) and stronger steric
hindrance effect compared with para- one (3ea 91% yield).
Heterocyclic and aliphatic vinyl bromides were also employed
as substrates to enlarge this process. (Z)-1-Bromooct-1-ene
yielded vinylidenecyclopropane as product (Scheme 2, 3ja, 76%
yield) because of the regioselective β-H elimination, while (Z)-
3-(2-bromovinyl)pyridine produced methylenecyclopropane
compound 3ia in 68% yield. Subsequently, (E)-2-bromoviny-
larene substrates 4 were tested, and the corresponding products
3aa, 3ba, 3ha, 3ea, 3bc (Scheme 3, 56, 50, 42, 31, and 54%
yield) were obtained under the same reaction condition.
Obviously the (Z)-2-bromovinyl substrates were more active
than (E)-ones. Maybe the aromatic ring of (Z)-2-bromoviny-
larene stabilized the intermediate of norbornenylpalladium via
favorable interaction of the aromatic π system with the Pd
center.14 However, (E)-2-bromovinyl-arenes have no such a
space advantage to exert the same stabilizing role. The
isomerization of (Z)- and (E)-alkenes is still quite dubious
now under the reaction condition. Obviously, The isomer-
ization of (E)-alkenes to (Z)- ones generally needs a higher
activation energy and is difficult to achieve.15
a
Reaction conditions unless otherwise noted: 1 (0.55 mmol), 2 (0.5
mmol), Pd(OAc)2 (0.05 mmol), PPh3 (0.11 mmol), K2CO3 (0.25
mmol), toluene (3.0 mL), 110 °C, 12 h in sealed tube. Isolated yields
b
are shown. Reaction conditions: K2CO3 (0.5 mmol), toluene (2.0
mL). Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), K2CO3 (0.5
mmol), toluene (2.0 mL).
c
Scheme 3. Methylenecyclopropanation of (E)-2-Bromo-
vinylarene
a
After investigating the scope of the (Z)-2-bromovinylarenes,
another coupling partner of norbornene was examined. endo-N-
(Isobutyl) norbornenesuccinimide 2b was smoothly reacted
with (Z)-vinyl bromides to afford corresponding products
3cb−3fb in good to high yields under the above optimized
reaction conditions. Norbornene itself 2c showed lower
reactivity. However, by doubling the base dosage, the
corresponding methylenecyclopropane products were obtained
in good to high yields (Scheme 2, 3ac−3cc, 3ec−3fc, 3hc−
3ic). Dicyclopentadiene 2d provided product 3id in 72% yield.
Cyclohexene was also employed as the alkene to undergo this
cycloaddition; however, the reaction did not proceed
successfully. The structure of 3da is further unambiguously
elucidated by X-ray crystallography (see the Supporting
Information, Figure S1), the formed methylenecyclopropane
moiety took the exo-face of norbomene. On the basis of the
chemical shifts and coupling constants (J) of all the products, it
can be ascertained that the stereochemistry of all the
a
Reaction conditions unless otherwise noted: 4 (0.55 mmol), 2 (0.5
mmol), Pd(OAc)2 (0.05 mmol), PPh3 (0.11 mmol), K2CO3 (0.25
mmol), toluene (3.0 mL), 110 °C, 12 h in sealed tube. Isolated yields
are shown. Reaction conditions: K2CO3 (0.5 mmol), toluene (2.0
b
mL).
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compounds is the same with that of 3da.12 In addition, a sole
diastereomer was obtained in all cases.
On the basis of the experiment results and earlier
precedents,12,16 a putative mechanism was proposed (Figure
1). The oxidative addition of palladium(0) species to (Z)-vinyl
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ASSOCIATED CONTENT
* Supporting Information
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This material is available free of charge via the Internet at
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AUTHOR INFORMATION
Corresponding Author
(11) Shi, Y.; Wilmot, J. T.; Nordstrøm, L. U.; Tan, D. S.; Gin, D. Y. J.
Am. Chem. Soc. 2013, 135, 14313.
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*E-mail: wlbao@zju.edu.cn.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Natural Science Foundation of
China (No. 21072168) is greatly appreciated.
■
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