Synthesis of nine-membered carbocycles by the [4+3+2] cycloaddition reaction of ethyl cyclopropylideneacetate and dienynes

Article abstract of DOI:10.1002/anie.200907052

(Figure Presented) Various dienynes reacted efficiently with ethyl cyclopropylldeneacetate in the presence of [Ni(cod)₂]/PPh ₃, and cyclononadienes were synthesized In a selective manner. Dienynes tethered with aromatic rings were very good substrates, and the corresponding tricyclic compounds were isolated In high yields. The reaction provides a new route for the synthesis of nine-membered carbocycles (see scheme).

Full text of DOI:10.1002/anie.200907052

Communications
DOI: 10.1002/anie.200907052
Cycloaddition Reactions
Synthesis of Nine-Membered Carbocycles by the
[4+3+2] Cycloaddition Reaction of Ethyl Cyclopropylideneacetate
and Dienynes**
Shinichi Saito,* Kyotaro Maeda, Ryu Yamasaki, Takuya Kitamura, Minami Nakagawa,
Korehito Kato, Isao Azumaya, and Hyuma Masu
Medium-sized carbocycles are frequently incorporated in
various natural products and the efficient construction of the
carbocycle motif is an important issue.[1] Some transition-
metal-catalyzed cycloaddition reactions provided unique and
promising solutions for the preparation of the medium-sized
rings.[2] For example, seven-membered carbocycles were
prepared by the [5+2],[3] [4+3],[4] [3+2+2],[5] and other[6]
cycloaddition reactions. Some reactions are also available
for the synthesis of eight-[7] and ten-membered[8] carbocyclic
compounds. On the other hand, the synthesis of nine-
membered carbocyclic compounds by transition-metal-cata-
lyzed cycloaddition reactions remains a very challenging
issue.[9,10]
Recently, our research group has examined the cyclo-
addition reactions of ethyl cyclopropylideneacetate (1) in the
presence of a nickel catalyst and disclosed the high and
unique reactivity of 1.[11] For example, the nickel(0)-catalyzed
[3+2+2] cycloaddition between 1 and alkyne derivatives
proceeded and cycloheptadiene compounds were isolated in
good yields.[12] We also reported the [4+3] cycloaddition
between 1 and conjugated diene derivatives.[4i] These results
prompted us to examine the reactions of 1 with other
unsaturated hydrocarbon compounds. Herein we report the
unprecedented [4+3+2] cycloaddition of ethyl cyclopropyli-
deneacetate (1) and dienynes.
Table 1: [4+3+2] Cycloaddition between 1 and dienynes 2 in the
presence of [Ni(cod)2]/PPh3.
Entry Dienyne
X
R
R’
Cond.[a]
A[c]
t
Yield of
[h] 3+4 [%][b]
1
2a
(EtO2C)2C
H
H
14 87
(82,5)
2
3
2b
2c
TsN
O
H
H
H
H
B
17 32[d]
14 76
(67,9)
A[c]
74
22
4
2d
H
H
B
(48,26)
5
6
7
8
9
2e
2 f
2g
2h
2i
(EtO2C)2C
TsN
O
TsN
O
Me
Me
Me
H
H
H
H
Me
Me
B
B
A
B
B
8
8
3
57
65
47
12 38
6 35
H
The results of the [4+3+2] cycloaddition reactions are
summarized in Table 1. The [4+3+2] cycloaddition between 1
and dienyne (2a) proceeded smoothly in the presence of
[Ni(cod)2] (10 mol%) and PPh3 (20 mol%). The dropwise
addition of a solution of 1 (1.5 equiv) and 2a in toluene to a
solution of the nickel catalyst at room temperature was the
[a] Conditions A: a solution of 1 (1.5 equiv) and 2 (1.0 equiv) was added
slowly over 10 h. The final concentration of 1 was 0.1m. Conditions B: a
solution of 1 (1.0 equiv) and 2 (1.2 equiv) was added slowly over 5 h. The
final concentration of 1 was 1.0m. [b] The yields of isolated 3 and 4 are
shown in parentheses when compound 4 was isolated. The formation of
4 was not observed in the other reactions. [c] The reaction was carried
out at room temperature. [d] A small amount of an intramolecular
cycloadduct of 2 was isolated. cod=1,5-cyclooctadiene, Ts=4-toluene-
sulfonyl.
[*] Prof. Dr. S. Saito, K. Maeda, Dr. R. Yamasaki, T. Kitamura,
M. Nakagawa, K. Kato
Department of Chemistry, Faculty of Science
Kagurazaka, Shinjuku, Tokyo, 162-8601 (Japan)
Fax: (+81)3-5261-4631
E-mail: ssaito@rs.kagu.tus.ac.jp
Homepage: http://www.rs.kagu.tus.ac.jp/sslab/
best procedure, and the product 3a was isolated in 82% yield
(entry 1). A small amount of an isomer 4a was also isolated
(5% yield). Notably, the intramolecular [4+2] cycloaddi-
tion[13–15] between the alkyne and the diene moieties was not
observed. The use of 1 as a substrate for this cycloaddition
reaction is critical: if other alkylidenecyclopropanes such as
unsubstituted methylenecyclopropane or benzylidenecyclo-
propane were used as the substrates, no cyclononadiene
derivative was isolated.
Prof. Dr. I. Azumaya, Dr. H. Masu
Faculty of Pharmaceutical Sciences at Kagawa Campus
Tokushima Bunri University
1314-1 Shido, Sanuki, Kagawa 769-2193 (Japan)
[**] Support form the Society of Synthetic Organic Chemistry (Japan) is
gratefully acknowledged (Tanabe Seiyaku Award in Synthetic
Organic Chemistry (Japan)).
The reactions of 1 with various dienyne derivatives were
also examined. The reaction of a dienyne tethered with an N-
tosyl group (2b) proceeded, though the yield of the corre-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907052.
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sponding cyclononadiene decreased (entry 2). The reaction of
1 with an oxygen-tethered dienyne (2c) also proceeded and
gave the corresponding cycloadduct (entry 3). The reaction of
a spirodienyne 2d gave a mixture of isomeric cyclononadienes
in 74% combined yield (entry 4). We introduced a methyl
group to the diene moiety of the dienyne and studied the
[4+3+2] cycloaddition (entries 5–9). When dienyne 2e was
employed as the substrate, the cocyclization proceeded and a
single isomer (3e) with a quaternary carbon center was
isolated (entry 5). The reaction of 2 f as well as 2g proceeded
and the products were isolated in moderate yields (entries 6–
7). The cocyclization reaction also proceeded in lower yields
when the methyl group was introduced to the terminal carbon
of the diene moiety (entries 8–9). In these reactions, the
formation of one stereoisomer (a compound with the
cis configuration of the methyl group and the annulated
five-membered ring) was observed.[16,17] The structure of 3i
was confirmed by an X-ray crystallographic analysis
(Figure 1).[18,19]
We confirmed that the mixture of E and Z isomers was not
formed by the isomerization of the initially formed E or
Z isomer in the reaction mixture. Thus, when compound 3j or
4j was treated with [Ni(cod)2]/PPh3 in THF at 508C, no
isomerizaiton was observed and the starting material was
recovered.
A working hypothesis of this reaction is shown in
Scheme 2. We assume that the reaction would proceed
through the formation of a nickelacycle 6[20,21] by the reaction
Scheme 2. Proposed mechanism of the [4+3+2] cycloaddition.
Figure 1. X-ray crystal structure of 3i.
of 2 with the Ni0 species. The insertion of 1 to 6 occurred
regioselectively: the reactive vinyl nickel moiety would
undergo Michael-type addition to 1, and 7 would be formed
as an intermediate. The ester group bound to 1 would play a
crucial role for this process. Finally, the cyclopropylmethyl-
butenyl rearrangement[22] and the reductive elimination of the
Ni0 species from 8 would proceed to give 3 (4) as the final
product. The stereochemistry of the exomethylene group of
the product would be determined when the rearrangement of
7 to 8 takes place. In most examples, the predominant
formation of 3 was observed. This could be explained by
considering the conformation of 7. Thus, the dihedral angle
This reaction was applied to the synthesis of tricyclic
compounds (Scheme 1). Thus, the reaction of 1 with 2j, the
alkyne moiety and the diene moiety of which are tethered
with an aniline derivative, proceeded efficiently at 508C and
the E isomer (3j) was isolated in 92% yield, together with a
small amount of the Z isomer (5%; 4j). A phenol derivative
2k was also treated with 1 and the E and Z isomers were
isolated in 98% combined yield. In this reaction, however, no
E/Z selectivity was observed.
À
À
À
between the two C C bonds (C1 C2 and C3 C4 in
Scheme 2) would be important. When the angle is large, the
selective formation of 8 would be observed (path a). On the
other hand, the formation of 9 would proceed when the
dihedral angle is small (path b). The dihedral angle would be
large and the s-trans conformer is predominant in most
reactions because of the cyclic structure of 7, and compound
3 would be isolated as the major product. In the reactions
of some dienynes, however, a significant amount of the
s-cis conformer would be present and compound 4 would be
isolated. We assume that the linkers and substituents intro-
duced to the dienyne would affect the conformation of 7, thus
leading to the observed stereochemistry.[23,24]
In summary, we have developed a new [4+3+2] cyclo-
addition of ethyl cyclopropylideneacetate with dienynes in
the presence of a Ni0 catalyst. The reaction provided a new
route for the synthesis of nine-membered carbocyclic rings.
Scheme 1. Synthesis of tricyclic compounds. THF=tetrahydrofuran.
Boc=tert-butoxycarbonyl.
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Communications
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Detailed studies related to the scope and mechanism of this
reaction is in progress.
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Experimental Section
General procedure for the synthesis of 3: A solution of 1 (1.5 mmol)
and 2 (1 mmol) in dry toluene (5 mL) at 508C under Ar was added
dropwise over 10 h to a dark red mixture of [Ni(cod)2] (27.5 mg,
0.1 mmol) and PPh3 (52.5 mg, 0.2 mmol) in dry toluene (5 mL). The
progress of the reaction was monitored by TLC and GC-MS, and the
reaction mixture was stirred until the starting material 2 disappeared.
The mixture was passed through a short silica gel column (eluent:
diethyl ether). Evaporation of the solvent gave an oil, which was
further purified by column chromatography on silica gel and gave 3
(and 4).
Received: December 15, 2009
Published online: February 9, 2010
À
Keywords: C C coupling · cycloaddition ·
medium-ring compounds · nickel · synthetic methods
.
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for 3i: C16H22O3 ; Mr = 262.34 gmolÀ1, colorless prism measuring
0.4 ꢅ 0.4 ꢅ 0.35 mm, triclinic, P1, a = 10.481(2), b = 10.876(2), c =
ꢀ
13.831(2) ꢆ, a = 103.367(2), b = 110.059(2), g = 90.337(2)8, V=
1434.6(4) ꢆ3, Z = 4, 1calcd = 1.215 gcmÀ3
, 2qmax = 56.568, T=
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biphenyl phosphite as the ligand (Ref. [14a]). We assume that
the bulky phosphite ligand accelerated the reductive elimination
of the Ni species from the nickelacycloheptadiene intermediate.
On the other hand, the reductive elimination is slow in the
presence of PPh3, and the insertion of 1 to the nickelacyclohep-
tadiene would occur.
[16] The attempted reactions of dienynes with internal alkyne moiety
did not proceed.
[17] The details of the observed regioselectivity will be studied in due
course.
[18] X-ray data were collected on a CCD detector. The crystal
structure was solved by direct methods SHELXS-97 and refined
by full-matrix least-squares SHELXL-97 (Ref. [17]). All non-
hydrogen atoms were refined anisotropically. All hydrogen
atoms were included as their calculated positions. Crystal data
150 K, 8014 reflections measured, 6094 unique (Rint = 0.0157),
m = 0.082 mmÀ1. The final R1 and wR2 was 0.0584 and 0.1323 (all
data). The residual electron densities (peak and hole) were 0.284
and À0.197 eꢆÀ3. Two independent molecules are included in an
asymmetric unit of the crystal. CCDC 741408 contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
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[21] Alternatively, a nickelacycle might be formed by the reaction of
the alkyne or diene moiety of the dienyne with 1. We assume that
the formation of 6 is more likely since this is a partially
intramolecular reaction and the formation of [4+2] cycloadduct
under closely related reaction conditions could be reasonably
explained.
[22] P. Binger, M. J. Doyle, R. Benn, Chem. Ber. 1983, 116, 1 – 10.
[23] The formation of the stereoisomers was occasionally observed in
the closely related [3+2+2] cycloaddition reaction. In these
reactions, the conformation of the nickelacycle would affect the
configuration of the product. See Ref. [12a] and [12c].
[24] For example, the conformation of the nickelacycle formed by the
reaction of 2j would be different from the nickelacycle prepared
from 2k owing to the presence of the bulky Boc group, and it
would affect the outcome of the reaction. The electronic effect of
the substituents might also influence the outcome of the
reaction.
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