Synthesis of vinylcycloheptadienes by the nickel-catalyzed three-component [3 + 2 + 2] cocyclization. Application to the synthesis of polycyclic compounds

Article abstract of DOI:10.1021/jo900189g

The nickel-catalyzed [3 + 2 + 2] cycloaddition of ethyl cyclopropylideneacetate and conjugated enynes proceeded smoothly and divinylcycloheptadienes were isolated in high yields. The three-component cocyclization of ethyl cyclopropylideneacetate, conjugat

Full text of DOI:10.1021/jo900189g

Synthesis of Vinylcycloheptadienes by the Nickel-Catalyzed
Three-Component [3 + 2 + 2] Cocyclization. Application to the
Synthesis of Polycyclic Compounds
Shinsuke Komagawa,† Kouhei Takeuchi,† Ikuo Sotome,† Isao Azumaya,‡ Hyuma Masu,‡
Ryu Yamasaki,† and Shinichi Saito*,†
Department of Chemistry, Faculty of Science, Tokyo UniVersity of Science, Kagurazaka, Shinjuku, Tokyo
162-8601, Japan, and Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri
UniVersity, Kagawa 769-2193, Japan
ssaito@rs.kagu.tus.ac.jp
ReceiVed January 28, 2009
The nickel-catalyzed [3 + 2 + 2] cycloaddition of ethyl cyclopropylideneacetate and conjugated enynes
proceeded smoothly and divinylcycloheptadienes were isolated in high yields. The three-component
cocyclization of ethyl cyclopropylideneacetate, conjugated enynes, and (trimethylsilyl)acetylene also
proceeded in a highly selective manner to afford vinylcycloheptadienes, which were reacted with various
dienophiles. This study provided a new, short-step synthesis of polycyclic compounds with cycloheptane
skeleton.
Introduction
the (partially) intramolecular cocyclization.3 Metal-catalyzed
cocyclization reactions for the formation of seven-membered
rings such as [6 + 1],4 [5 + 2],5 [4 + 3],6 [4 + 2 + 1],7 [3 +
2 + 2],8 and [3 + 3 + 1]9 cycloadditions have been reported,
and some reactions have been applied to natural product
synthesis.10 However, selective formation of the desired products
The short-step synthesis of the complex molecules from
simple compounds is an important issue in organic chemistry.
Transition-metal-catalyzed reactions are attractive tools for
multicomponent coupling, and many efficient reactions have
been investigated.1,2 In particular, cyclization reactions in the
presence of transition-metal catalysts are very useful for the
construction of complicated compounds. For example, polysub-
stituted benzene derivatives are synthesized by [2 + 2 + 2]
cycloaddition, and bi- or tricyclic compounds are formed by
(3) Reviews: (a) Shibata, T.; Tsuchikama, K. Org. Biomol. Chem. 2008, 6,
1317–1323. (b) Chopade, P. R.; Louie, J. AdV. Synth. Catal. 2006, 348, 2307–
2327. (c) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741–
4767. (d) Varela, J. A.; Sa´a, C. Chem. ReV. 2003, 103, 3787–3801. (e) Saito, S.;
Yamamoto, Y. Chem. ReV. 2000, 100, 2901–2915. (f) Lautens, M.; Klute, W.;
Tam, W. Chem. ReV. 1996, 96, 49–92. (g) Schore, N. E. Chem. ReV. 1988, 88,
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556.
† Tokyo University of Science.
‡ Tokushima Bunri University.
(1) For recent reviews of multicomponent reactions, see: (a) Zou, Y.; Wang,
Q.; Goeke, A. Chem.sEur. J. 2008, 14, 5335–5345. (b) D’Souza, D. M.; Mu¨ller,
T. J. J. Chem. Soc. ReV. 2007, 36, 1095–1108. (c) Do¨mling, A. Chem. ReV.
2006, 106, 17–89. (d) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602–1634. (e) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–
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Weinheim, 2005.
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Chemistry; Tamaru, Y., Ed.; Wiley-VCH: Weinheim, 2005. (b) Montgomery, J.
Angew. Chem., Int. Ed. 2004, 43, 3890–3908. (c) Ikeda, S. Acc. Chem. Res.
2000, 33, 511–519. (d) Jolly, P. W.; Wilke, G. The Organic Chemistry of Nickel;
Academic Press: New York, 1975.
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45, 3957–3960.
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[5 + 2], [6 + 2], and [5 + 2 + 1] Cycloadditions: New Reactions for Organic
Synthesis. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.;
Wiley-VCH: Weinheim, 2005; pp 263-299. (b) Yu, Z.-X.; Cheong, P. H.-Y.;
Liu, P.; Legault, C. Y.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2008,
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10.1021/jo900189g CCC: $40.75
Published on Web 04/06/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3323–3329 3323

Komagawa et al.
by metal-catalyzed multicomponent reactions is not easy unless
the reactivity of the substrates is controlled properly.11
Conjugated enyne is a useful substrate for the synthesis of
cyclic compounds in the presence of transition-metal catalysts.12
For instance, palladium-catalyzed [4 + 2] benzannulation,12b,13
nickel-catalyzed zipper annulation,14 gold- and copper-catalyzed
[4 + 2] benzannulation,12c,d and the gold-catalyzed heterode-
hydro-Diels-Alder cycloaddition15 have been reported. Fur-
thermore, the 1,3-diene moiety has been frequently constructed
by the cycloaddition reaction of enynes, and the products formed
by these reactions could be utilized for various reactions such
as the Diels-Alder reaction. This strategy is very useful for
the concise synthesis of polycyclic compounds. For example,
Wender and co-workers described the serial [5 + 2]/[4 + 2]
cycloaddition with conjugated enyne in the presence of a
rhodium catalyst.16
FIGURE 1. Nickel-catalyzed [3 + 2 + 2] cycloaddition of ethyl
cyclopropylideneacetate (1) and alkynes.
+ 2 + 2] cycloaddition19b to afford bicyclic compounds. These
reactions provided new pathways for the synthesis of a variety
of multisubstituted cycloheptadiene derivatives. In this paper,
we report the nickel-catalyzed [3 + 2 + 2] cycloaddition of 1
and conjugated enynes and the application of the reaction to
the four-component [3 + 2 + 2]/[4 + 2] cycloaddition.
Recently, we reported the nickel-catalyzed intermolecular [3
+ 2 + 2] cycloaddition of ethyl cyclopropylideneacetate (1)
and alkynes,17 and the three-component [3 + 2 + 2] cycload-
dition was achieved by the reaction of 1 and two different
alkynes (Figure 1).18 We also accomplished the [4 + 3]
cycloaddition19a of 1 with 1,3-dienes and the intramolecular [3
Results and Discussion
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Nickel-Catalyzed [3 + 2 + 2] Cocyclization of Ethyl
Cyclopropylideneacetate and Conjugated Enynes. We ini-
tially examined the nickel-catalyzed reactions of 1 and conju-
gated enynes 2 (Table 1). The reaction of 1 and 2-methyl-1-
buten-3-yne (2a) gave 3a in 97% yield (entry 1).20 Although
the metal-catalyzed [4 + 2] benzannulation12b,13 and the zipper
annulation14 of conjugated enynes have been reported, conju-
gated enynes reacted as substituted alkynes and the [3 + 2 +
2] cycloaddition proceeded smoothly. 1-Ethynylcyclohexene
(2b) was a good substrate, and 3b was afforded in 93% yield
(entry 2). The reactions of 2-benzyl-1-buten-3-yne (2c) and
3-decen-1-yne (2d) also gave the coupling products in a selective
manner (entries 3 and 4). To examine the scope of the reaction,
the reaction of 1,2-substituted conjugated enyne (2e) was carried
out, and the product was isolated in good yields (entry 5). On
the other hand, an inseparable mixture of regioisomers was
obtained when the reaction was carried out with 2f (entry 6).
The reaction of 2-butoxy-1-buten-3-yne (2g) led to the coupling
product (3g), but the product was unstable and could not be
isolated in pure form. Instead, a ketone derivative (4g) was
isolated when the reaction mixture was treated with TsOH (eq
1).
We also found that the three-component [3 + 2 + 2] cycload-
dition with 1, conjugated enynes 2, and (trimethylsilyl)acetylene
(5) proceeded in a highly selective manner (Table 2). The reaction
of 1, 2a, and 5 gave the cycloadduct 6a in 66% yield, although
the formation of a small amount of other cycloheptadienes such
as 3a was observed (entry 1). Compound 6a was synthesized in
62% yield when the reaction was carried out on a 5 mmol scale,
and the Ni(PPh3)2Br2-PPh3-Zn catalytic system was used (entry
2).17b,21 The cycloheptadiene 6b was also isolated in good yield
when the reaction of 1, 2b, and 5 was executed (entry 3). The
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Ed. 2001, 40, 3895–3897.
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10540–10541. (b) Saito, S.; Komagawa, S.; Azumaya, I.; Masuda, M. J. Org.
Chem. 2007, 72, 9114–9120. (c) Komagawa, S.; Yamasaki, R.; Saito, S. J. Synth.
Org. Chem. Jpn. 2008, 66, 974–982.
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Maeda, K.; Saito, S. Tetrahedron Lett. 2007, 48, 3173–3176.
(20) The configuration of the product (E isomer) was determined by 1H NMR
spectra according to previous results (see refs 17 and 18). It was also confirmed
by X-ray crystallographic analyses (e.g., endo-14c and 16d).
(21) Iyoda, M.; Tanaka, S.; Otani, H.; Nose, M.; Oda, M. J. Am. Chem. Soc.
1988, 110, 8494–8500.
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[3 + 2 + 2]/[4 + 2] Cocyclization
TABLE 1. Nickel-Catalyzed [3 + 2 + 2] Cycloaddition of 1 and
TABLE 2. Nickel-Catalyzed Three-Component [3 + 2 + 2]
Conjugated Enynes 2a
Cycloaddition of 1, 2, and 5a
a Reaction conditions: a solution of 1 (1 mmol), 2 (1 mmol), and 5 (4
mmol) in toluene (0.5 mL) was added dropwise over 3 h to a mixture of
Ni(cod)2 (0.1 mmol) and PPh3 (0.2 mmol) in toluene (0.5 mL) at room
temperature under Ar. The reaction mixture was stirred for the
designated time. b Isolated yields in parentheses. c A small amount of 3a
was isolated. d The Ni(PPh3)2Br2-PPh3-Zn system was used: a mixture
of Ni(PPh3)2Br2 (0.5 mmol), PPh3 (1 mmol), and Zn dust (10 mmol) in
toluene (2.5 mL) was stirred at room temperature for 1 h. Then, to this
mixture was added dropwise a solution of 1 (5 mmol), 2a (5 mmol), and
5 (15 mmol) in toluene (2.5 mL) over 5 h.
a Reaction conditions: a solution of 1 (1 mmol) and 2 (3 mmol) in
toluene (0.5 mL) was added dropwise over 3 h to a mixture of Ni(cod)2
(0.1 mmol) and PPh3 (0.2 mmol) in toluene (0.5 mL) at room
temperature under Ar. The reaction mixture was stirred for the
designated time. b Isolated yields in parentheses. c The reaction was
carried out for a shorter reaction time to prevent the decomposition of
the product. d The formation of an inseparable mixture of regioisomers
was observed.
component reactions reported in Table 2. Diphenylacetylene (7)
was also a suitable substrate for the three-component cocyclization,
and the reaction was carried out at 50 °C to give 8 in 51% yield
though formation of the undesired coupling product 3a was
observed (eq 2). The inverse chemoselectivity was observed in the
reaction of 1, 2a, and the less congested alkyne 9, and compound
reaction of 1, 2c, and 5 proceeded in moderate yield to afford 6c
(entry 4). The enol ether (6g) was isolated in moderate yield by
the reaction of 1, 2g, and 5 (entry 5). A small amount of the
undesired coupling product (3a) was also produced in the three-
J. Org. Chem. Vol. 74, No. 9, 2009 3325

Komagawa et al.
TABLE 3. Diels-Alder Reaction of 6a and Dienophiles (11)
10 was isolated in 30% yield along with 3a (eq 3). Only a trace
amount of the [3 + 2 + 2] coupling product formed by the reaction
of 1 and 7 (eq 2) or by the reaction of 1 and 9 (eq 3) was detected.
The formation of opposite regioisomers in eqs 2 and 3 could be
explained in terms of the relative bulkiness of the substituents bound
to the alkyne moietis in the cocyclization reaction. Thus, the most
bulky substituent (phenyl group in eq 2 and isopropenyl group in
eq 3) would occupy the R position of the nickelacyclopentadiene
intermediate (vide infra).22
a Reaction conditions: A mixture of 6a (0.5 mmol) and 11 in toluene (2
mL) was stirred. b Isolated yields in parentheses. c The reaction was carried
out in 1,1,2,2-tetrachloroethane. d The formation of isomers was observed.
are summarized in Table 3. The reaction of 6a and maleic
anhydride (11a) gave endo-12a as a single isomer in 63% yield
(entry 1). The stereochemistry of endo-12a was confirmed by a
NOESY experiment (Figure S1, Supporting Information). Tetra-
cyanoethylene (11b) also reacted with 6a at room temperature
leading to the cycloadduct 12b (entry 2). A tricyclic compound
endo-12c was isolated in 89% yield when the reaction of 6a and
11c was carried out at 140 °C in 1,1,2,2-tetrachloroethane (entry
3). The reaction of 6a with 1,4-naphthoquinone (11d) also
proceeded, though the formation of isomers was observed (entry
Application to the Synthesis of Polycyclic Compounds. A
conjugated and less substituted diene moiety was incorporated in
the cycloheptadienes synthesized by these reactions. We anticipated
that these conjugated dienes would react with various dienophiles,
providing an efficient route for the synthesis of polycyclic car-
bocycles with a seven-membered ring. Accordingly, we examined
the [4 + 2] cycloaddition of 5 with various dienophiles,23 and the
results of the Diels-Alder reaction under the thermal conditions
(23) Recent reviews: (a) Takao, K.; Munakata, R.; Tadano, K. Chem. ReV.
2005, 105, 4779–4807. (b) Stocking, E. M.; Williams, R. M. Angew. Chem.,
Int. Ed. 2003, 42, 3078–3115. (c) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41,
1650–1667. (d) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogian-
nakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698.
(22) The selective formation of a nickelacyclopentadiene intermediate and
the observed regioselectivity of the product in this reaction has been previously
discussed in detail. See ref 17b.
3326 J. Org. Chem. Vol. 74, No. 9, 2009

[3 + 2 + 2]/[4 + 2] Cocyclization
4). The cycloadduct was not isolated when dimethyl acetylenedi-
carboxylate (11e) was reacted with 6a (entry 5). Other vinylcy-
cloheptadienes could be used as the substrate for the reaction, and
compound 6g reacted with 11b to give 13b in 79% yield (eq 4).
The reaction of 8 and 11c gave endo-14c (57%) and exo-14c (30%)
(eq 5). The structure of a product (endo-14c) was confirmed by an
X-ray crystallographic analysis (Figure S2, Supporting Informa-
tion). We also studied the formation of tricyclic compounds by
the double Diels-Alder reaction of 3a. The cycloadduct 15b was
obtained as a single isomer in 83% yield by the reaction of 3a and
11b (eq 6).24
1, 2a, 5, and 11c in the presence of TiCl2(O-i-Pr)2 in the second
step also gave endo-12c in 51% yield (eq 10).
Mechanistic Consideration. On the basis of our recent
studies,17-19 a plausible mechanism for the formation of
cycloheptadienes is shown in Scheme 1. The selective
formation of the nickelacyclopentadiene 17 could be ex-
plained in terms of the steric effect of the vinyl group.26,27
Two bulky substituents incorporated in the nickelacycle tend
to occupy the R- and ꢀ-positions of the nickelacycle. The
formation of 18 from 2 and 5 is also predictable, based on
our previous studies: the trimethylsilyl group is located at
the R-position due to electronic and steric effects.18,27,28 The
formation of 18 is predominant in the presence of an excess
of 5, which is the less reactive alkyne. The nickelacycles 17
and 18 would react with 1 to form 19, which would rearrange
and give the final intermediate.29-31 The desired cyclohep-
tadiene is obtained by the reductive elimination of the
nickel(0) species from 20.
Subsequently, we examined Lewis acid-promoted Diels-Alder
reactions. The reaction of 6a with 11c in the presence of
TiCl2(O-i-Pr)225 (1.2 equiv) proceeded at room temperature and
gave a single coupling product (endo-12c) in 92% yield (eq 7).
The TiCl2(O-i-Pr)2 promoted Diels-Alder reaction of 6a and
11d gave 16d (eq 8). We assume that compound 16d was
formed by the aromatization of the initially formed cycloadduct
and the acid-catalyzed desilylation. The structure of 16d was
confirmed by an X-ray crystallographic analysis (Figure S3,
Supporting Information). The yield of 16d decreased when a
catalytic amount of TiCl2(O-i-Pr)2 (0.2 equiv) or another
titanium Lewis acid (TiCl4) was used. Though other Lewis acids
such as ZnCl2 or AlCl3 also catalyzed the reaction of 6a with
11d, the formation of isomeric compounds was observed, and
the product was isolated in low yield. In the presence of
BF3 ·OEt2, the formation of a complex mixture was observed.
Finally, we demonstrated the usefulness of these reactions
by carrying out the one-pot, four-component reaction. Thus, the
nickel-catalyzed [3 + 2 + 2] cycloaddition of 1, 2a, and 5 was
carried out as the first step, and to the reaction mixture was
added 11b at room temperature. The reaction proceeded
smoothly, and the four-component coupling product (12b) was
isolated in 54% yield (eq 9). The four-component reaction of
(26) (a) Wakatsuki, Y.; Nomura, O.; Kitaura, K.; Morokuma, K.; Yamazaki,
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T. Metal-Catalyzed Cycloadditions of Methylenecyclopropanes. In Methods of
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(31) The selective formation of the E isomer has been frequently observed.
We assume that the s-trans conformation of the EtO2C-C(R)-C(ꢀ)-C(γ) bonds
of 19 would be preferred. The E isomer would be formed selectively from the
s-trans conformer. See ref 17b.
(24) The coupling product (15b) was isolated as a single isomer, but the
stereochemistry has not been determined.
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(b) Denmark, S. E.; Xie, M. J. Org. Chem. 2007, 72, 7050–7053. (c) Mikami,
K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 3949–3954.
J. Org. Chem. Vol. 74, No. 9, 2009 3327

Komagawa et al.
SCHEME 1. Plausible Mechanism for the Nickel-Catalyzed
[3 + 2 + 2] Cycloaddition
the starting material (1) disappeared. The mixture was passed
through a short silica gel column (ether). Evaporation of the solvent
gave an oil, which was further purified by silica gel column
chromatography to give 6.
(E)-1-Ethoxycarbonylmethylene-3-(1-methylethenyl)-5-tri-
methylsilyl-2,4-cycloheptadiene (6a): purified by silica gel
column chromatography (hexane/CH2Cl2 3:1); pale yellow oil;
1H NMR (300 MHz, CDCl3) 6.38 (s, 1H), 6.36 (s, 1H), 5.71 (s,
1H), 5.13 (s, 1H), 5.05 (s, 1H), 4.13 (q, J ) 7.2 Hz, 2H),
3.07-3.04 (m, 2H), 2.33-2.29 (m, 2H), 1.95 (s, 3H), 1.25 (t, J
) 7.2 Hz, 3H), 0.10 (s, 9H); 13C NMR (125 MHz, CDCl3) 166.8,
158.5, 151.7, 145.6, 143.5, 133.7, 131.6, 117.4, 115.1, 59.6, 32.3,
27.6, 21.7, 14.3, -2.2; IR (neat) 2954, 1709, 1586, 1444, 1403,
1376, 1249, 1214, 1155, 1088, 1067, 1039, 892, 838, 752 cm-1
;
HR-MS (ESI) calcd for C17H26O2NaSi [M + Na]+ 313.1594,
found 313.1594.
Diels-Alder Reaction of 6a and 11 (Table 3). A Representa-
tive Procedure. A mixture of 6a (145 mg, 0.5 mmol) and 11 (0.75
mmol) in toluene (2 mL) was stirred at the designated temperature.
After the reaction was completed, the mixture was purified by silica
gel column chromatography to give 12.
Compound endo-12a. A mixture of 6a (215 mg, 0.74 mmol)
and 11a (294 mg, 3 mmol) in toluene (1 mL) was stirred at 100 °C
for 8.5 h. The mixture was purified by silica gel column chroma-
tography (hexane/AcOEt 3:1) to give endo-12a (180 mg, 61%):
1
Conclusions
white solid; mp 67-68 °C; H NMR (500 MHz, CDCl3) 6.39 (s,
1H), 5.92 (s, 1H), 4.16 (q, J ) 7.2 Hz, 2H), 3.61 (dd, J ) 9.8, 5.8
Hz, 1H), 3.44 (ddd, J ) 9.8, 6.7, 2.4 Hz, 1H), 3.32 (m, 1H),
3.04-2.99(m, 1H), 2.83-2.78 (m, 1H), 2.68 (dd, J ) 15.5, 2.3
Hz, 1H), 2.49-2.41 (m, 3H), 1.89 (s, 3H), 1.27 (t, J ) 7.2 Hz,
3H), 0.04 (s, 9H); 13C NMR (125 MHz, CDCl3) 173.3, 170.5, 165.9,
159.1, 144.6, 134.7, 130.8, 130.4, 116.7, 59.9, 50.2, 44.8, 41.3,
31.8, 31.6, 31.2, 20.4, 14.2, -1.9; IR (KBr) 2955, 1844, 1779, 1704,
1650, 1248, 1179, 992, 937, 837 cm-1; HR-MS (EI) calcd for
C21H28O5Si 388.1706, found 388.1714.
We report the nickel-catalyzed [3 + 2 + 2] cycloaddition of
ethyl cyclopropylideneacetate and conjugated enynes. The
reaction proceeded smoothly, and the selective formation of
cycloheptadiene derivatives was observed. Furthermore, we
achieved the four-component [3 + 2 + 2]/[4 + 2] cycloaddition.
The reaction provided a new pathway for the synthesis of
polycyclic compounds with a cycloheptene ring. Further ap-
plications of these reactions are now ongoing.
One-Pot, Four-Component [3 + 2 + 2]/[4 + 2] Cycloaddi-
tion of 1, 2a, 5, and 11b (eq 9). 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
(0.5 mL) was added dropwise a solution of 1 (127 mg, 1 mmol),
2a (0.095 mL, 1 mmol), and 5 (0.57 mL, 4 mmol) in dry toluene
(0.5 mL) at room temperature over 3 h under Ar. After 16 h, toluene
(1 mL) and 11b (128 mg, 1 mmol) were added, and the mixture
was stirred at room temperature for 23 h. The crude product was
passed through a short silica gel column chromatography (ether)
and further purified by silica gel column chromatography (hexane/
AcOEt 8:1) to give 12b (227.9 mg, 54%).
Experimental Section
Nickel(0)-Catalyzed Cycloaddition of Ethyl Cyclopropylide-
neacetate (1) and Conjugated Enynes (Table 1). A Representa-
tive Procedure. 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 (0.5 mL) was
added dropwise a solution of 1 (126 mg, 1 mmol) and 2 (3 mmol)
in dry toluene (0.5 mL) at room temperature over 3 h under Ar.
The progress of the reaction was monitored by TLC and GC-MS,
and the mixture was stirred until the starting material (1) disap-
peared. The mixture was passed through a short silica gel column
(ether). Evaporation of the solvent gave an oil, which was further
purified by silica gel column chromatography to give 3.
(E)-1-Ethoxycarbonylmethylene-3,5-(di-1-methylethenyl)-2,4-
cycloheptadiene (3a): purified by silica gel column chromatography
(hexane/AcOEt 30:1 and hexane/CH2Cl2 3:1); yellow oil; 1H NMR
(300 MHz, CDCl3) 6.39 (s, 1H), 6.19 (s, 1H), 5.71 (s, 1H), 5.23
(s, 1H), 5.14 (s, 1H), 5.05 (s, 2H), 4.13 (q, J ) 7.2 Hz, 2H),
3.16-3.11 (m, 2H), 2.54-2.50 (m, 2H), 1.97 (s, 3H), 1.96 (s, 3H),
1.25 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) 166.8, 158.3,
147.3, 146.0, 143.9, 143.0, 131.0, 122.7, 117.4, 115.1, 114.1, 59.6,
31.8, 26.1, 21.8, 21.1, 14.3; IR (neat) 2976, 1706, 1585, 1444, 1374,
1264, 1213, 1154, 1040, 891 cm-1; HR-MS (EI) calcd for C17H22O2
258.1620, found 258.1611.
Nickel(0)-Catalyzed Three-Component Cycloaddition of Eth-
yl Cyclopropylideneacetate (1), Conjugated Enynes, and (Tri-
methylsilyl)acetylene (5) (Table 2). A Representative Procedure.
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 (0.5 mL) was added dropwise
a solution of 1 (126 mg, 1 mmol), 2 (1 mmol), and (trimethylsi-
lyl)acetylene (5, 4 mmol) in dry toluene (0.5 mL) at room
temperature over 3 h under Ar. The progress of the reaction was
monitored by TLC and GC-MS, and the mixture was stirred until
1
Compound 12b: colorless solid; mp 156-158 °C; H NMR
(300 MHz, CDCl3) 6.17 (s, 2H), 4.21 (qd, J ) 7.2, 3.4 Hz, 2H),
3.89 (s, 1H), 3.59 (dt, J ) 11.5, 4.1 Hz, 1H), 3.20 (d, J ) 18.4
Hz, 1H), 3.00 (d, J ) 18.4 Hz, 1H), 2.62-2.56 (m, 2H),
2.52-2.43 (m, 1H) 1.82 (s, 3H), 1.30 (t, J ) 7.2 Hz, 3H), 0.06
(s, 9H); 13C NMR (75 MHz, CDCl3) 164.5, 152.7, 150.1, 130.2,
125.7, 125.4, 124.2, 110.8, 110.7, 110.5, 109.0, 60.6, 53.4, 44.2,
38.7, 37.0, 34.1, 27.7, 19.7, 14.1, -2.1; IR (KBr) 2954, 1715,
1658, 1446, 1381, 1248, 1209, 1189, 1154, 1041, 837, 751 cm-1
.
Anal. Calcd for C23H26N4O2Si: C, 66.00; H, 6.26; N, 13.39.
Found: C, 65.97; H, 6.26; N, 13.19.
Compound 16d. To a mixture of 6a (146 mg, 0.5 mmol) and
11d (120 mg, 0.75 mmol) in toluene (2 mL) was added a solution
of TiCl2(O-i-Pr)2 (1.2 mL, 0.5 M in toluene, 0.6 mmol) at room
temperature. After the reaction was completed (21.5 h), the mixture
was purified by silica gel column chromatography (hexane/AcOEt
10:1) to give 16d (111.8 mg, 59%): red solid; mp 162-163 °C; 1H
NMR (300 MHz, CDCl3) 8.13-8.11 (m, 1H), 8.05-8.01 (m, 1H),
7.75-7.68 (m, 2H), 6.38 (d, J ) 11.5 Hz, 1H), 5.88 (dt, J ) 11.5,
3.9 Hz, 1H), 5.26 (s, 1H), 4.94 (s, 1H), 4.02 (q, J ) 7.2 Hz, 2H),
3.46-3.09 (m, 4H), 3.05-2.88 (m, 1H), 2.41-2.29 (m, 1H), 1.85
(s, 3H), 1.16 (t, J ) 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
184.0, 183.1, 166.4, 164.4, 143.5, 142.9, 133.8, 133.7, 132.1, 132.0,
3328 J. Org. Chem. Vol. 74, No. 9, 2009

[3 + 2 + 2]/[4 + 2] Cocyclization
130.7, 128.1, 127.3, 126.7, 126.5, 126.4, 113.4, 59.7, 43.2, 33.3,
31.2, 25.2, 18.7, 14.2; IR (KBr) 3444, 1705, 1659, 1631, 1591,
1331, 1294, 1216, 1175, 1142 cm-1; HR-MS (EI) calcd for
C24H22O4 374.1518, found 374.1518.
Supporting Information Available: Experimental proce-
dures and characterization data and details of X-ray structural
determination of endo-14c and 16d (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. S.K. thanks JSPS for providing Research
Fellowships for Young Scientists.
JO900189G
J. Org. Chem. Vol. 74, No. 9, 2009 3329