Synthesis of alkylidenecyclopropanes by palladium-catalyzed reaction of propargyl-substituted malonate esters with aryl halides by anti-carbopalladation pathway

Article abstract of DOI:10.1021/ja203062z

Palladium-catalyzed arylative cyclization of propargyl-substituted malonate esters with aryl halides offers a stereoselective approach to alkylidenecyclopropanes. The reaction proceeds by an anti-carbopalladation pathway, which guarantees the exclusive st

Full text of DOI:10.1021/ja203062z

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Synthesis of Alkylidenecyclopropanes by Palladium-Catalyzed
Reaction of Propargyl-Substituted Malonate Esters with Aryl Halides
by Anti-carbopalladation Pathway
Daishi Fujino,†,‡ Hideki Yorimitsu,*,‡ and Koichiro Oshima*,†,§
†Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
‡Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan
§Environment, Safety, and Health Organization, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
S Supporting Information
b
Scheme 1. Conventional Synthesis of ACPs
ABSTRACT: Palladium-catalyzed arylative cyclization of
propargyl-substituted malonate esters with aryl halides
offers a stereoselective approach to alkylidenecyclopro-
panes. The reaction proceeds by an anti-carbopalladation
pathway, which guarantees the exclusive stereocontrol of the
resulting double bond. The highly strained as well as densely
substituted skeletons of the products facilitate further
versatile transformations, which underscores the impor-
tance of the products as synthetic intermediates.
Table 1. Effect of Ligand on Palladium-Catalyzed Cyclopro-
panative Arylationa
lkylidenecyclopropanes (ACPs) are useful building blocks1
A
and are found in many bioactive compounds.2 Preparations
of ACPs have hence been investigated over the past few decades.3,4
However, the conventional syntheses of multisubstituted ACPs are
usually achieved by multistep preparations, which require preforma-
tion of cyclopropane derivatives or allenes (Scheme 1).5 These
methods often encounter difficulty in controlling the stereochemistry
of the carbonÀcarbon double bond of ACPs.6
yield (%)
Palladium-catalyzed intramolecular arylative cyclization of un-
saturated compounds having a nucleophilic moiety with aryl halides
represents an attractive method to construct cyclic compounds.7
Although the method has provided a number of five-membered cyclic
compounds so far, preparation of strained three-membered rings has
remained a considerable challenge.8 Recently, we reported palladium-
catalyzed cyclization reactions of allylic alcohols and allylic amines
with aryl halides, which yielded arylated epoxides and aziridines,
respectively.8j,k During the course of our study, we envisioned that
propargyl-substituted malonate esters would undergo palladium-
catalyzed intramolecular cyclization to afford multisubstituted ACPs.9
The reaction should represent facile and stereoselective synthesis of
multisubstituted ACPs from readily available starting materials.
entry
ligand
x (mol %)
1a
2a
1
Xantphos
Xantphos
RuPhos
10
5
23
23
0
51
27
30
45
12
78
2
3
10
10
10
10
4
DavePhos
DPEPhos
Xantphos
13
0
5
6b
0
a A mixture of Pd2(dba)3 (0.0075 mmol), ligand (0.030 mmol), Cs2CO3
(0.6 mmol), 1a (0.3 mmol), and PhBr (0.6 mmol) was boiled in toluene
1
(0.75 mL) for 4 h. Yields are determined by H NMR using tetra-
bromoethane as an internal standard. b Pd2(dba)3 (0.0025 mmol) and
Xantphos (0.010 mmol) were added three times at t = 0, 3, and 6 h.
entry 1). Several ligands were screened, and Xantphos proved to be
most effective for the cyclization. Biaryl-based bulky phosphines
(RuPhos and DavePhos) also gave the product (entries 3 and 4).
DPEPhos, which is structurally similar to Xantphos yet lacks the
bridging dimethylmethylene backbone, resulted in lower yield
Treatment of propargyl malonate ester 1a with bromobenzene
in the presence of cesium carbonate under palladium/Xantphos
catalysis afforded phenyl-substituted ACP 2a in 51% yield (Table 1,
Received: April 4, 2011
Published: June 01, 2011
r
2011 American Chemical Society
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Table 2. Scope of Aryl Halidesa
Table 3. Scope of Propargyl Malonate Estersa
entry
1, R
1b, Me
1c, c-C3H5
1d, t-Bu
1e, Ph
1f, 4-CF3C6H4
3
yieldb (%)
entry
ArX
2
yieldb (%)
1c
2
3
4
PhOTf
2a
2b
2c
2d
2e
2f
2g
2h
2i
77
85
91
76
90
71
72
60
61
74
1
2
3
4
5
3b
3c
3d
3e
3f
73
83
0
70
53
2-MeC6H4Br
1-naphthyl-Br
4-ClC6H4Br
4-CF3C6H4Br
4-EtOC(dO)C6H4Br
4-NCC6H4Br
2-MeOC6H4Br
4-MeOC6H4OTf
3-pyridinyl-Br
5
6
7
8
a The reaction conditions are the same as those in Table 2. b Isolated yields.
9d
10
2j
a A mixture of Cs2CO3 (1.0 mmol), 1a (0.5 mmol), and ArX (1.0 mmol)
was boiled in toluene (1.25 mL) for 8 h. Pd2(dba)3 (0.0042 mmol) and
Xantphos (0.017 mmol) were added three times at t = 0, 3, and 6 h.
b Isolated yields. c Pd2(dba)3 (0.0125 mmol) and Xantphos (0.05 mmol)
were present from the beginning, not added separately. d 5 mol %
RuPhos was used as a ligand instead of Xantphos.
(entry 5). Other ligands such as triphenylphosphine, tricyclohexyl-
phosphine, and XPhos failed to afford the product. After further exa-
mination of the reaction conditions, we found that adding the cata-
lyst and ligands in three portions gave 2a in 78% yield (entry
6).10À12 It is worth noting that a cyclopropane ring and an arylated
carbonÀcarbon double bond were formed in a single operation.
Additionally, the products were obtained without notable decom-
position, although ACPs were reactive under palladium catalysis.1,13
The scope of aryl halides is summarized in Table 2. The
reaction of phenyl triflate provided the product in good yield
without separately adding the catalyst and ligand in three portions
(Table 2, entry 1).14 Sterically demanding aryl bromides also
participated in the cyclization reaction (entries 2 and 3). Electron-
deficient aryl bromides were smoothly converted to the correspond-
ing products (entries 4 and 5). Ethoxycarbonyl and cyano groups
were well-tolerated under the reaction conditions (entries 6 and 7).
The reaction of 1a with electron-rich aryl halides resulted in modest
yields of ACPs (entries 8 and 9). Notably, heteroaryl bromide was
also applicable to this reaction (entry 10).
The scope of the substituents at the alkyne terminal was
investigated (Table 3). Propargyl malonate esters bearing a methyl
or cyclopropyl terminal underwent the cyclization smoothly to yield
the corresponding products (Table 3, entries 1 and 2). However, a
tert-butyl group was too bulky for the cyclization reaction (entry 3).
The reactions of malonates having an aryl moiety also furnished the
corresponding products (entries 4 and 5).15
We determined the configuration of the carbonÀcarbon
double bond in the product on the basis of the X-ray diffraction
analysis of 3f (Figure 1).16 The introduced phenyl group is located
at the trans position of the quaternary carbon bearing two carbonyl
groups. It should be noted that these ACPs would be difficult to
synthesize with high stereoselectivity by the known methods.3,4
A plausible mechanism is illustrated in Scheme 2, based on the
stereochemistry of the products and Gore’s report.17 Initial oxidative
addition of aryl halide to zerovalent palladium occurs to afford aryl-
palladium bromide or triflate A. Intermediate A would then activate
the alkyne moiety of 1a through π-coordination. Deprotonation of
Figure 1. ORTEP drawing of compound 3f.
Scheme 2. Reaction Mechanism
the acidic methyne proton by cesium carbonate would induce
intramolecular cyclization onto the activated alkyne to form vinyl-
palladium C by anti-carbopalladation. The subsequent reductive
elimination from C yields 2 and regenerates the initial palladium
complex. In comparison with aryl bromides as an arylating agent,
the cyclopropanative cyclization step would be more favorable in
the reaction of aryl triflates because the palladium center of B is
more cationic to activate the alkyne more efficiently. The modest
efficiency in the reactions of electron-rich aryl bromides (Table 2,
entries 8 and 9) and the higher reactivity of aryl triflates (entry 1)
experimentally justify the importance of the cationic character of the
palladium center.
The ACPs thus synthesized are expected to be useful inter-
mediates in organic synthesis, and transformations of ACPs were
hence explored. The Yb(OTf)3-catalyzed ring-opening intramo-
lecular FriedelÀCrafts reaction of dimethyl benzylidenecyclo-
propane-1,1-dicarboxylate reported by Wang18 was applicable
also to 2a, having a tetrasubstituted alkene unit, to yield dimethyl
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2-(3-butyl-1H-inden-2-yl)malonate (4) (eq 1). ACP 2e was con-
verted to allylic methyl ether 5 under Yb(OTf)3 catalysis19 in
methanol (eq 2). Notably, the ring-opening etherification pro-
ceeded with perfect retention of the configuration of the double
bond, making it useful as a new stereo- and regioselective
approach to tetrasubstituted alkenes. Lanthanide triflate-cata-
lyzed insertion of silyl enolate and aldehyde into 2e took place
(eqs 3 and 4), representing the first examples of ring-expanding
insertion of silyl enolate and aldehyde to 2-alkylidenecyclopro-
pane-1,1-dicarboxylate.20À22 Carbocyclic intermediate 6 was
unstable for purification and was converted to linear alkenone 7.
In these insertion reactions, the geometry of the tetrasubstituted
double bond was again satisfactorily or perfectly retained.
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propargyl-substituted malonate esters with aryl halides. The products
bear a stereodefined double bond, electron-withdrawing functional
groups, and a strained ring, which facilitate further transformations.
The syntheses of other strained hetero- and carbocycles by this
methodology are currently under investigation in our laboratory.
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S
Supporting Information. Spectroscopic data, general pro-
b
cedure, and 1H/13C NMR spectra of all the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yori@kuchem.kyoto-u.ac.jp; oshima@orgrxn.mbox.media.
kyoto-u.ac.jp
’ ACKNOWLEDGMENT
This work was supported by Grants-in-Aid (No. 22106523,
“Integrated Organic Synthesis”) from MEXT. D.F. acknowl-
edges a JSPS Fellowship for Young Scientists. H.Y. thanks
financial support from The Uehara Memorial Foundation,
NOVARTIS Foundation (Japan) for the Promotion of Science,
and Takeda Science Foundation.
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7.919(2) Å, b = 12.674(5) Å, c = 18.528(7) Å, β = 100.482(15)°, V =
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