Nickel-catalyzed [4 + 2] cycloaddition of enones with alkynes

Full text of DOI:10.1021/ja807952r

Published on Web 01/12/2009
Nickel-Catalyzed [4 + 2] Cycloaddition of Enones with Alkynes
Ichiro Koyama, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 615-8510, Japan
Received October 8, 2008; E-mail: tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp; matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Scheme 2. Formation of Oxa-Nickelacycle
The hetero-Diels-Alder reactions of R,ꢀ-unsaturated carbonyl
compounds (heterodiene) with electron-rich carbon-carbon unsat-
urated bonds (heterodienophile) are a useful method for the
synthesis of six-membered heterocyclic rings and have been widely
applied to natural product synthesis.1,2 However, the low reactivity
of alkynes as heterodienophiles has limited their use in the reaction,
and only ynamides were available as heterodienophiles.3 While
transition metal-catalyzed [4 + 2] cycloadditions of R,ꢀ-unsaturated
carbonyl compounds with alkynes would be a solution for the
problem, such reactions have not been studied well so far.4 We
postulated that such cycloaddition would proceed via heteromet-
allacycle intermediates,5,6 which are formed by oxidative cyclization
of low valent transition metals to R,ꢀ-unsaturated carbonyl com-
pounds, and subsequent insertion of alkynes (Scheme 1). Thus, we
attempted the addition of enone 1 and alkyne 2 using nickel(0)
catalyst to form polysubstituted pyranes 3.7
enones such as 1b, 1c, and 1d failed to participate in the reaction
due to difficulties in formation of oxa-nickelacycle intermediates
and were recovered quantitatively (entries 5-7).
Scheme 1. Transition-Metal-Catalyzed [4 + 2] Cycloaddition
Figure 1. ORTEP Drawing of 4a.
Table 1. Nickel-Catalyzed Cycloaddition of Enones with 4-Octynea
The formation of oxa-nickelacycle was investigated first by a
stoichiometric reaction of an enone and a nickel(0) complex. The
reaction of ethyl benzylidene acetoacetate (1a) with Ni(cod)2 and
TMEDA at 25 °C gave an oxa-nickelacycle (4) quantitatively
(Scheme 2).8 The molecular structure of 4 was unambiguously
confirmed by the X-ray crystal structure analysis, which showed
that the nickel(II) complex has square planar molecular geometry
(Figure 1). Treatment of oxanickelacycle 4 with 4-octyne (2a) in
the presence of PMe3 afforded the pyran 3aa in 96% isolated yield.
Neither benzyliden-substituted pentane-2,4-dione 1b nor diethyl
malonate 1c was converted into the corresponding oxanickelacycle
even for prolonged reaction times. Considering that 1d was also
inert to oxidative cyclization of nickel(0), we found R-ester-
substituted R,ꢀ-unsaturated ketone to be a suitable substrate for
oxa-nickelacycle formation.
The obtained results expanded the possibilities of the catalytic
reactions of 1a with alkynes. Indeed, the reaction of ethyl
benzylidene acetoacetate (1a) with 4-octyne (2a) in the presence
of 10 mol % of Ni(cod)2 and 40 mol % of PMe3 in toluene at 130
°C afforded the pyran 3aa in 99% yield (Table 1, entry 1). Not
even trace amounts of 3aa were obtained in the absence of nickel
catalyst. The extension of this result was examined for the reactions
of various enones with 2a; results are summarized in Table 1. The
cycloaddition of 1e with 2a gave the product 3ea in 90% yield
(entry 2). Enones 1f and 1g also reacted with 2a to furnish pyrans
in 82% and 50% yields, respectively (entries 3 and 4). Predictably,
entry
R1
R2
R3
1
3
yield (%)b
1
2
3
4
5
6
7
Me
Me
Ph
CO2Et
CO2Et
CO2Et
CO2Et
C(O)Me
CO2Et
H
Ph
Pr
Ph
Pr
Ph
Ph
Ph
1a
1e
1f
1g
1b
1c
1d
3aa
3ea
3fa
3ga
3ba
3ca
3da
99
99
82
Ph
50
Me
EtO
Me
<1
<1
<1
a Reactions were carried out using Ni(cod)2 (10 mol %), PMe3 (40
mol %), 1 (0.5 mmol), and 4-octyne (1.25 mmol) in 5 mL of toluene
(130 °C). b Isolated yields.
The scope of the cycloaddition of 1a with various alkynes is
summarized in Table 2. The reaction of 2b and 2c with 1a gave
the cycloadducts in 74% and 82% yields, respectively (entries 1
and 2). The addition of unsymmetrical alkynes 2d-2g gave the
pyrans consisting of regioisomers in a range of 1/1 to 3/1 ratio
(entries 3-6), whereas the reaction of 2h gave the pyran 3ah as a
single isomer (entry 7). Cyclopropyl-substituted alkyne 2i also
reacted with 1a to furnish 3ai in 68% yield with regioisomers in a
9
1350 J. AM. CHEM. SOC. 2009, 131, 1350–1351
10.1021/ja807952r CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
ratio of 7/2 (entry 8). Terminal alkynes failed to participate in the
reaction, presumably due to rapid oligomerization of alkynes.
Acknowledgment. This work was supported by Grants-in-Aid
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan. T.K. also acknowledges NOVARTIS Founda-
tion (Japan) for the Promotion of Science, and the Takeda
Pharmaceutical Company Award in Synthetic Organic Chemistry,
Japan. We thank Dr. T. Fujiwara for X-ray crystal structure analysis,
and Prof. S. Ogoshi for valuable discussions on the subject.
Table 2. Nickel-Catalyzed Cycloaddition of 1a with Alkynesa
Supporting Information Available: Experimental procedures in-
cluding spectroscopic and analytical data of new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
entry
R4
R5
2
3
yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
2b
2c
2d
2e
2f
2g
2h
2i
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
74
82
CH2OMe
CH2CH2OMe
CH2OMe
Me
CH2OMe
Pr
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74 (1/1)b
88 (3/2)b
84 (1/1)b
73 (3/1)b
79
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Scheme 3. Nickel-Catalyzed Intramolecular [4 + 2] Cycloaddition
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Scheme 4. Plausible Reaction Mechanism for Nickel-Catalyzed [4
+ 2] Cycloaddition of Enones with Alkynes
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In summary, we have developed a new nickel-catalyzed [4 + 2]
cycloaddition reaction of enones with alkynes to provide polysub-
stituted pyrans. We demonstrated for the first time that enones are
susceptible to oxidative cyclization of nickel(0); such reactions
allow inter- or intramolecular cycloaddition with alkynes.
JA807952R
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