Nickel-catalyzed [3+2+2] cycloaddition of ethyl cyclopropylideneacetate and heteroatom-substituted alkynes: Application to selective three-component reaction with 1,3-diynes

Article abstract of DOI:10.1021/jo902251m

(Chemical Equation Presented) Heteroatom-substituted alkynes such as ynol ethers and ynamines turned out to be decent substrates for the Nicatalyzed [3 + 2 + 2] cocyclization of ethyl cyclopropylideneacetate (1). The three-component cocyclization of 1, 1,

Full text of DOI:10.1021/jo902251m

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a novel Ni-catalyzed three-component cocyclization reaction
Nickel-Catalyzed [3þ2þ2] Cycloaddition of Ethyl
Cyclopropylideneacetate and Heteroatom-
Substituted Alkynes: Application to Selective
Three-Component Reaction with 1,3-Diynes
among two alkynes and ethyl cyclopropylideneacetate (1),
which provides cycloheptadiene derivatives.3 Interestingly,
the reaction proceeded selectively even when two different
alkynes were applied.3b To take advantage of this trait, we
expanded the scope of this reaction by carrying out the three-
component cocyclization reaction between 1, alkynes, and
conjugated alkynes, such as 1,3-diynes3g or enynes.3h For
example, the chemo- and regioselective three-component
cocyclization reaction among 1, 1,3-diyne, and terminal al-
kynes proceeded (eq 1). Since the cocyclization reaction
between 1 and 1,3-diyne was obtained with low selectivity,
the delicate balance between steric and electronic factors of
each component is important for the selective cocyclization.
To expand the scope of the three-component reaction, we
selected heteroatom-substituted alkynes, such as ynol ether,4
ynamide, and ynamines,5 as the substrates.6,7 These hetero-
atom-substituted alkynes would be suitable substrates for
the synthesis of various cycloheptane derivatives such as
cycloheptanones. In this paper, we disclose the [3 þ 2 þ 2]
cocyclization of ynol ether and ynamines, especially focused
on the three-component reaction with 1,3-diynes.
Ryu Yamasaki, Natsuki Terashima, Ikuo Sotome,
Shunsuke Komagawa, and Shinichi Saito*
Department of Chemistry, Faculty of Science, Tokyo
University of Science, Kagurazaka, Shinjuku, Tokyo,
Japan 162-8601
ssaito@rs.kagu.tus.ac.jp
Received October 19, 2009
Heteroatom-substituted alkynes such as ynol ethers and
ynamines turned out to be decent substrates for the Ni-
catalyzed [3 þ 2 þ 2] cocyclization of ethyl cyclopropy-
lideneacetate (1). The three-component cocyclization of
1, 1,3-diynes, and heteroatom-substituted alkynes also
proceeded selectively. The study provided an efficient
method for the synthesis of heteroatom-substituted cy-
cloheptadiene and related compounds.
As a start of this study, we used ynol ethers as the alkyne
component. The [3 þ 2 þ 2] cocyclization reaction of 1 and
ynol ethers (5a-c)8 proceeded smoothly in the presence of a
catalytic amount of Ni(cod)2 and PPh3. Though we observed
the formation of 6 as the product, the E/Z isomers were
inseparable and it turned out that the fast isomerization of 6
proceeded during the purification. Compound 6 could be
converted to a more stable compound, a cyclohept-4-ene-1,3-
dione derivative (7), by treating the crude product with TFA.3i
The multicomponent reaction that allows one to construct
complex structures in a single step or construct a large
compound library is a very powerful and attractive synthetic
strategy.1,2 As one of this type of reactions, we have developed
(4) For a review of the reaction of ynolate and ynol ether, see: Shindo, M.
Tetrahedron 2007, 63, 10–36.
(5) For reviews of the reaction of ynamine and ynamide, see: (a) Ficini, J.
Tetrahedron 1976, 32, 1449–1486. (b) Zificsak, C. A.; Mulder, J. A.; Hsung,
R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575–7606.
(6) For representative examples of the reactions of ynol ether in the
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€
presence of transition metals, see: (a) Castro, J.; Sorensen, H.; Riera, A.;
(1) (a) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH:
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Wenheim, Germany, 2005. (b) D'Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev.
2007, 36, 1095-1108 and references cited therein.
(2) For reviews on Ni-catalyzed multicomponent reactions, see:
(a) Ikeda, S.-i. Acc. Chem. Res. 2000, 33, 511–519. (b) Montogomery, J.
Acc. Chem. Res. 2000, 33, 467–473.
Morin, C.; Moyano, A.; Pericas, M. A.; Greene, A. E. J. Am. Chem. Soc.
1990, 112, 9388–9389. (b) Imbriglio, J. E.; Rainier, J. D. Tetrahedron Lett.
2001, 42, 6987–6990. (c) Sanapo, G. F.; Daoust, B. Tetrahedron Lett. 2008,
49, 4196–4199. (d) Hashmi, A. S. K.; Rudolph, M.; Bats, J. W.; Frey, W.;
Rominger, F.; Oeser, T. Chem.;Eur. J. 2008, 14, 6672–6678.
(3) (a) Saito, S.; Masuda, M.; Komagawa, S. J. Am. Chem. Soc. 2004, 126,
10540–10541. (b) Komagawa, S.; Saito, S. Angew. Chem., Int. Ed. 2006, 45,
2446–2449. (c) Saito, S.; Takeuchi, K. Tetrahedron Lett. 2007, 48, 595–598.
(d) Maeda, K.; Saito, S. Tetrahedron Lett. 2007, 48, 3173–3176. (e) Saito, S.;
Komagawa, S.; Azumaya, I.; Masuda, M. J. Org. Chem. 2007, 72, 9114–
9120. (f) Komagawa, S.; Yamasaki, R.; Saito, S. J. Synth. Org. Chem. Jpn.
2008, 66, 974–982. (g) Yamasaki, R.; Sotome, I.; Komagawa, S.; Azumaya,
I.; Masu, H.; Saito, S. Tetrahedron Lett. 2009, 50, 1143–1145. (h) Komogawa,
S.; Takeuchi, K.; Sotome, I.; Azumaya, I.; Masu, H.; Yamasaki, R.; Saito, S.
J. Org. Chem. 2009, 74, 3323–3329. (i) Fukusaki, Y.; Miyazaki, J.; Azumaya,
I.; Katagiri, K.; Komagawa, S.; Yamasaki, R.; Saito, S. Tetrahedron 2009,
65, 10631–10636.
(7) For typical examples of the reaction of ynamine or ynamide with
transition metal, see: (a) Ficini, J.; d’Angelo, J.; Falou, S. Tetrahedron Lett.
1977, 19, 1645–1648. (b) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed.
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Riera, A. J. Org. Chem. 2000, 65, 7291–7301. (d) Domınguez, G.; Casarru-
guez-Noriega, J.; Perez-Catells, J. Helv. Chim. Acta 2002, 85,
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2856–2861. (e) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc.
2006, 128, 4586–4587. (f) Zhang, X.; Li, H.; You, L.; Tang, Y.; Hsung, R. P.
Adv. Synth. Catal. 2006, 348, 2437–2442. (g) Saito, N.; Katayama, T.; Sato,
Y. Org. Lett. 2008, 10, 3829–3832.
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480 J. Org. Chem. 2010, 75, 480–483
Published on Web 12/16/2009
DOI: 10.1021/jo902251m
r
2009 American Chemical Society

Yamasaki et al.
JOCNote
TABLE 1. Ni-Catalyzed [3þ 2þ 2] Cycloaddition of 1 and Ynol Ethers 5a
TABLE 2. Three-Component Reaction among 1, 1,3-Diynes (2), and5aa
2
entry
R1
n-hex
SiMe3
(CH2)2OTBS
SiMe3
R2
n-hex
SiMe3
(CH2)2OTBS
n-hex
yieldb (%)
1
2
3
4
2a
2b
2c
2d
65
63
80
32
aReaction conditions: a solution of 1 (1 mmol), 2 (1.5 mmol), and 5a
(1.5 mmol) in toluene (0.5 mL) was added dropwise over 5 h to a mixture
of Ni(cod)2 (0.1 mmol) and PPh3 (0.2 mmol) in toluene (0.5 mL) at 50 °C
under Ar. bIsolated yield.
aReaction conditions: a solution of 1 (1 mmol) and 5 (3 mmol)
in toluene (0.5 mL) was added dropwise over 5 h to a mixture of
Ni(cod)2 (0.1 mmol) and PPh3 (0.2 mmol) in toluene (0.5 mL) at 40 °C
under Ar.
Therefore, we carried out the reaction of 5a-c and isolated 7 as
the product (Table 1). Compound 5a turned out to be a
suitable substrate for the reaction, and compound 7 was
isolated in 82% yield by the treatment of the crude product
with TFA for 2 h (entry 1). Other ynol ethers such as 5b and 5c
were found to be less appropriate substrates for the reaction
(entries 2 and 3). The high yield of 7 in the reaction of 1 and 5a
could be explained in terms of the kinetic stabilization of the
substrate (5a) and the intermediate (6) by the bulky 1-methyl-
cyclohexyl group.
Since the [3 þ 2 þ 2] cocyclization reaction of 1 and 5a
proceeded successfully, we studied the three-component
cocyclization of 1, 5a, and 1,3-diynes (2). The reaction was
performed by the slow addition of a solution of 1, diyne (2),
and 5a to a mixture of the Ni catalyst in toluene at 50 °C. The
results are summarized in Table 2. The reaction of 7,9-
octadecadiyne (2a) proceeded smoothly and the product
(8a) was obtained in 65% yield (Table 2, entry 1).9 Other
symmetrically substituted 1,3-diynes, such as 2b and 2c, also
gave the product in good yields (entries 2 and 3). An
unsymmetrically substituted 1,3-diyne was also applied to
this cocyclization and the three-component reaction pro-
ceeded to afford the cycloheptadiene derivative with excel-
lent selectivity (entry 4).10 In analogy to the prior study
related to the three-component reaction of 1, 2a, and ethyl
propiolate,3g the alkyne moiety substituted with the bulky
trimethylsilyl group was kept intact.
TABLE 3. Ni-Catalyzed [3 þ 2 þ 2] Cycloaddition of 1 and Ynamide or
Ynaminea
A variety of cycloheptane derivatives were furnished from 8.
R,β-Unsaturated ketone derivatives (9a and 9b) were isolated
in excellent yields by the treatment of 8a or 8b with TFA (eq 2).
In addition, the selective removal of the terminal trimethylsilyl
group could be achieved by the treatment of 8b or 8d with
TBAF-AcOH (eq 3).
aReaction conditions: a solution of 1 (1 mmol) and 11 (3 mmol) in
toluene (0.5 mL) was added dropwise over 5 h to a mixture of Ni(cod)2
(0.1 mmol) and PPh3 (0.2 mmol) in toluene (0.5 mL) at specified
temperature under Ar. bIsolated yields.
(9) The configuration of the exocyclic double bond (E isomer) was
determined by 1H NMR spectra according to previous results (see refs 3a,
3b, and 3e). The high E-selectivity was determined at the stage of rearrange-
ment that prefers the s-trans conformation of the C(carbonyl)-C(R)-
C(β)-C(γ) bond (see ref 3e).
We next carried out the cocyclization reaction of ynamides
and ynamines. The initial studies implied that the ynamide
(10) The yield of the product decreased since the isolation of the product
from the byproducts turned out to be difficult.
J. Org. Chem. Vol. 75, No. 2, 2010 481

Yamasaki et al.
JOCNote
TABLE 4. Three-ComponentReactionamong1, 1,3-Diynes(2), and11ca
SCHEME 1. Plausible Reaction Mechanism
entry
2
R1
R2
yieldb (%)
1
2
3
2a
2b
2d
n-hex
SiMe3
SiMe3
n-hex
SiMe3
n-hex
66
53
53
aReaction conditions: a solution of 1 (1 mmol), 2 (2.0 mmol), and 11c
(1.0 mmol) in toluene (0.5 mL) was added dropwise over 5 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. bIsolated yield.
and N-alkynyl pyrrole11 were compatible substrates for this
reaction. The results of the reactions are summarized in
Table 3. The reaction of 1 with 11a proceeded and the
cocyclization product (12a) was isolated in 50% yield,
along with a significant amount of the trisubstituted
benzene 13a7a (entry 1). Though the cocyclization reaction
of 11b also proceeded, the yield of the product (12b) was
unsatisfactory (entry 2). On the other hand, the reaction of
11c took place smoothly at room temperature, and 12c was
isolated in 72% yield: no trimerization product was obtained
(entry 3).
and a more stable and/or kinetically favored isomer of A, rather
than B, would be generated as the major intermediate. Conse-
quently, compound 14d could be obtained as the major product
in the reaction of 1 with 2d (Table 4, entry 3).
After we found that pyrole type ynamine (11c) was
a suitable substrate for the [3 þ 2 þ 2] cocyclization, the
three-component reactions of 1, 1,3-diynes, and 11c were
examined (Table 4). 7,9-Octadecadiyne (2a) reacted with 1
and 11c to give 14a in 66% yield (entry 1). The reaction
of 1,4-bis(trimethylsilyl)-1,3-butadiyne (2b) also pro-
ceeded smoothly and selectively at room temperature
and 14b was isolated in 53% yield (entry 2). The unsym-
metrically substituted 1,3-diyne (2d) was also subjected to
this reaction, and a single product (14d) was obtained in
53% yield.
To study the relative reactivity of the alkyne moieties in the
reaction of 2d, a competitive experiment was performed. Thus, a
solution of 1, 2a, 2b, and 11c was subjected to the same reaction
conditions, and compound 14 was isolated as the predominant
product (eq 4). The result indicates that the reactivity of the
alkyne moiety bound to the hexyl group is much higher.12 The
selective formation of 14a in Table 4 could be reasonably
explained by the higher reactivity of an alkyne moiety and the
steric effect (less bulky alkynyl group located at the β position of
the nickelacycle, vide infra). A plausible reaction mechanism
was shown in Scheme 1. 1,3-Diyne and alkyne would form a
nickelacycle and the subsequent insertion of 1 and the rearran-
gement would give the product.3e The selectivity would be
mainly determined at the stage of the nickelacycle formation,
In conclusion, we presented the selective three-component
cocyclization with ethyl cyclopropylideneacetate (1), 1,3-
diynes, and heteroatom-substituted alkynes. Hydrolysis of
the cycloheptadiene derivatives prepared from ynol ethers
and 1,3-diynes afforded cycloheptadienone derivatives in
good yields. The study established the scope and expanded
the synthetic utility of the [3 þ 2 þ 2] cycloaddition reaction
with heterosubstituted alkynes.
Experimental Section
Nickel(0)-Catalyzed Cycloaddition of Ethyl Cyclopropylide-
neacetate (1) and Ynol Ether (5a) and Isomerization (Table 1): 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) and 5a (415 mg, 3 mmol) in dry toluene (0.5 mL) at the
designated temperature over 5 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) to give the crude product (6). The crude product
was immediately dissolved with the mixture of CH2Cl2 (4 mL)
and TFA (1 mL) and stirred for 2 h at room temperature. Water
was added, and the mixture was extracted with ether. The
organic layer was dried over MgSO4 and evaporated. The
residue was purified by silica gel column chromatography
(eluent, AcOEt:n-hexane 3:2) to give the product (7) as 82%
yield.
(11) (a) Paley, M. S.; Frazier, D. O.; Abeledeyem, H.; McManus, S. P.;
Zutaut, S. E. J. Am. Chem. Soc. 1992, 114, 3247–3251. (b) Mal’kina, A. G.;
Besten, R. d.; Kerk, A. C. H. T. M. v. d.; Brandsma, L.; Trofimov, B. A. J.
Organomet. Chem. 1995, 493, 271–273.
(12) Cheng et al. reported the alkyne moiety bound to a more bulky group
was more reactive. The difference probably stemmed from the sequence of
cocyclization. In their proposed reaction mechanism, the 1,3-diyne was
inserted into metallacycle, in our case being a component metallacycle.
See: Jeevanandam, A.; Prasad, R.; Huang, K. I.-w.; Cheng, C.-H. Org. Lett.
2002, 4, 807–810.
482 J. Org. Chem. Vol. 75, No. 2, 2010

Yamasaki et al.
JOCNote
Nickel(0)-Catalyzed Cycloaddition of Ethyl Cyclopropylide-
neacetate (1), 1,3-Diynes (2) and Ynol Ether (5a), or Ynamide or
Ynamine (Tables 2 and 4): A Representative Procedure for Three-
Component Cocyclization. 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
(1.5 mmol), and 5a (1.5 mmol) in dry toluene (0.5 mL) at the
designated temperature over 5 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) disappeared. The
mixture was passed through a short silica gel (or alumina)
column (ether). The crude product was further purified by silica
gel column chromatography to give the pure products.
Water was added, and the mixture was extracted from ether,
dried over MgSO4, and evaporated. The crude product was
purified by silica gel column chromatography to afford the
product.
AcOH-Buffered TBAF-Mediated Deprotection of the Silyl
Group (Eq 3). Compound 8b (or 8d) (0.5 mmol) was dissolved
with THF (3 mL), then AcOH (0.032 mL) and TBAF (1.0 M in
THF, 0.5 mL) were added at 0 °C. The mixture was stirred for
30 min at 0 °C, then extracted with ether. The combined organic
layer was dried over MgSO4 and evaporated. The crude product
was purified by silica gel column chromatography to afford the
product.
TFA-Mediated Isomerization (Eq 2). Compound 8a (or 8b)
was dissolved in CH2Cl2 (4.5 mL) and TFA (0.5 mL) was added
atroom temperature, then the mixturewas stirred for 30 min atrt.
Supporting Information Available: Experimental details and
compound data. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 2, 2010 483