Two-carbon ring expansion of cyclobutanone skeletons by nickel-catalyzed intermolecular alkyne insertion

Article abstract of DOI:10.1016/j.tet.2006.03.118

The reaction of cyclobutanone with an alkyne in the presence of a nickel(0) catalyst formally achieves intermolecular alkyne insertion between the carbonyl carbon and the α-carbon of a cyclobutanone, providing a six-membered carbocyclic skeleton.

Full text of DOI:10.1016/j.tet.2006.03.118

Tetrahedron 62 (2006) 7540–7546
Two-carbon ring expansion of cyclobutanone skeletons
by nickel-catalyzed intermolecular alkyne insertion
*
Masahiro Murakami, Shinji Ashida and Takanori Matsuda
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
Received 30 November 2005; revised 8 March 2006; accepted 8 March 2006
Available online 12 June 2006
Dedicated to Professor Gunther Wilke for his contribution to the field of organonickel chemistry as the pioneer
¨
Abstract—The reaction of cyclobutanone with an alkyne in the presence of a nickel(0) catalyst formally achieves intermolecular alkyne
insertion between the carbonyl carbon and the a-carbon of a cyclobutanone, providing a six-membered carbocyclic skeleton.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
As a result of our intensive studies along this line, we have
achieved intramolecular olefin insertion into cyclobutan-
ones,5 which proceeds through insertion of rhodium(I)
between the carbonyl carbon and the a-carbon of cyclo-
butanone, subsequent intramolecular migratory insertion of
an olefin into the resulting Rh–C linkage, and reductive
elimination. We attempted to realize analogous olefin inser-
tion also in intermolecular reactions. However, the reactions
examined have all failed so far. Then, another idea to achieve
intermolecular insertion reactions occurred to us, which
exploits a different elementary step for carbon–carbon
bond cleavage, that is, b-carbon elimination.6 A number
of reactions are known in which the four-membered carbo-
cycle of a cyclobutylmethyl- or (cyclobutyloxy)metal is
opened through b-carbon elimination.7 On the other hand,
there have recently appeared several reports on the nickel-
catalyzed carbon–carbon bond forming reactions of carbonyl
compounds with other unsaturated bonds like carbon–
carbon double and triple bonds.8,9 In the initial step,
nickel(0) acts as a template to promote oxidative cyclization
of a carbonyl group with an unsaturated bond on it.10 We
envisaged that an intermolecular insertion of alkynes into
cyclobutanones would be achieved by combining a process
of oxidative cyclization with a process of b-carbon elimina-
tion. A five-membered oxanickelacyclopentene resulting
from oxidative cyclization of a cyclobutanone and an alkyne
contains a nickel cyclobutanolate skeleton as a spiro appen-
dant. The five- and four-membered rings can be merged into
a seven-membered ring nickelacycle through b-carbonelimi-
nation. The following reductive elimination completes a
formal alkyne insertion. We herein describe the details of
our studies on the nickel-catalyzed intermolecular alkyne
insertion reaction into cyclobutanones, which expands
the four-membered ring skeleton by two carbons to six-
membered ring skeletons.11,12
A variety of transformations of organic compounds are cur-
rently available for synthetic chemists. The introduction of
transition metals in organic synthesis has greatly expanded
the repertoire of organic reactions to such an extent to in-
clude those, which are otherwise difficult to achieve.1 We
discovered that the carbon–carbon bond between the car-
bonyl carbon and the a-carbon of cyclobutanones was cata-
lytically cleaved by rhodium in 1994.2 Since then, we have
pursued our studies to develop various kinds of carbon–
carbon bond cleavage reactions.3 Those investigations led
us to think that it would be a potentially useful protocol of
considerable novelty if a carbon–carbon single bond is
cleaved by inserting an unsaturated organic functionality4
like a carbon–carbon triple bond. Two carbon–carbon single
bonds are newly formed in one chemical operation without
wasting any unwanted material. Such an insertion reaction
is highly atom-economical, making a sharp contrast to cross-
coupling reactions, for example, which produce a stoichio-
metric amount of an unnecessary metal salt (Scheme 1).
C
C
C
C
transition metal
C
C
C
C
C
X
C
C
transition metal
+
+
M
C M
X
C
C
C
C
Scheme 1.
Keywords: Alkyne; b-Carbon elimination; Cyclobutanone; Nickel; Oxida-
tive cyclization; Ring expansion.
* Corresponding author. Tel.: +81 75 383 2747; fax: +81 75 383 2748;
e-mail: murakami@sbchem.kyoto-u.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.118

M. Murakami et al. / Tetrahedron 62 (2006) 7540–7546
7541
2. Results and discussion
approximately 120ꢀ, changes to a sp3 carbon, whose ideal
angle is 108ꢀ, thereby diminishing the ring strain of the
four-membered carbocycle. Another mechanistic pathway
leading to intermediate 4 through insertion of nickel(0)
between the carbonyl carbon and the a-carbon is also con-
ceivable. In this case, seven-membered nickelacycle 6 is
formed by migratory insertion of an alkyne into the Ni–C
bond of intermediate 5.
Various ligands of nickel(0) were examined for the formal
insertion of an alkyne into cyclobutanone. A mixture of
3-methyl-3-phenylcyclobutanone (1a) and 4-octyne (2a,
1.5 equiv) was heated in the presence of a nickel catalyst
prepared in situ from bis(1,5-cyclooctadiene)nickel(0)
(10 mol %) and an additional ligand (Table 1). Whereas no
reaction occurred without any additional ligand (entry 1),
an intermolecular alkyne insertion reaction took place to
produce six-membered ring ketone 3a when a phosphine
ligand was added to Ni(cod)2. Especially, tricyclohexylphos-
phine showed excellent reactivity (entries 2–5). The best
yield of 3a was obtained when the reaction was carried
out in toluene at 100 ꢀC for 3 h using 2 equiv of P(c-Hex)3
to nickel (entry 2). Similar ligands such as tricyclopentyl-
phosphine and triisopropylphosphine worked equally well
to give 3a in 92% and 94% yields, respectively (entries 6
and 7). Use of tri-n-butylphosphine resulted in incomplete
conversion and afforded an inseparable mixture of 3a
(82%) and 1a (13%) (entry 8). Triphenylphosphine and tri-
tert-butylphosphine gave only a trace amount of 3a (entries
9 and 10).
O
R1
O
R2
R1
+
R
R2
2
R´
R
R´
Ni(0)
3
1
R1
O
Ni(0)
R2
R1
O
R
R´
R2
R´
Ni
6
R
β-carbon
elimination
oxidative
cyclization
Ni
O
R1
R2
We assumed the catalytic cycle shown in Scheme 2 for
this insertion reaction on the basis of the mechanism pro-
posed for the nickel-catalyzed reactions of aldehydes with
alkynes.7a,b,d Oxanickelacyclopentene 4 having a four-
membered ring spiro appendant is initially formed by oxida-
tive cyclization of the carbonyl group of cyclobutanone 1
and alkyne 2 on nickel(0). The four-membered ring is then
opened by b-carbon elimination, resulting in ring expansion
to form seven-membered ring nickelacycle 6. Finally, reduc-
tive elimination gives the product 3 with nickel(0) regener-
ated. Although oxidative cyclization of an alkyne with a
ketonic carbonyl group on nickel(0) is more difficult to occur
than the one with an aldehydic carbonyl group in general, the
ketonic carbonyl group of 1 possesses a relatively high
reactivity presumably due to its ring strain. Upon oxidative
cyclization, the carbonyl sp2 carbon, whose ideal angle is
R
4
R´
R2
O
or
Ni
R1
R
R´
5
Scheme 2.
Next, various alkynes were subjected to the insertion reaction
into 1a under the optimized reaction conditions (Table 2).
Symmetrical internal alkynes, such as 3-hexyne (2b) and
diphenylacetylene (2c), reacted with cyclobutanone 1a to
give cyclohexenones 3b and 3c, respectively, in good yield
(entries 1 and 2). With unsymmetrical 1-phenyl-1-propyne
(2d), fairly regioselective alkyne insertion (92:8) was
observed under the standard conditions. The methyl group
was located a to the carbonyl group in the major product
(entry 3). In order to see if any electronic effect impacts the
regioselectivity, alkynes 2e and 2f having electron-donating
and -withdrawing substituents at the para-positions of the
phenyl group were subjected to the insertion reaction
(entries 4 and 5). The regioisomeric ratios hardly changed
depending on the electronic nature of the substituents.
These results suggest that a steric factor rather than an elec-
tronic one dominates in determining the regioselectivity
of this insertion reaction. In the case of aryl-substituted
alkynes 2c–f, which otherwise underwent rapid self-oligo-
merization on nickel(0), slow addition of 3.0 equiv of the
alkyne to the reaction mixture was required to attain a
high product yield.
Table 1. Optimization of reaction conditions
O
O
Pr
Pr
Pr
10 mol% Ni(cod)2–ligand
3 h
+
Ph
Me
Ph Me
1a
Pr
2a
3a
(1.5 equiv)
Entry
Liganda (mol %)
Solvent
Temp/ꢀC
%Yieldb
1
2
3
4
5
6
7
8
9
10
None
Toluene
Toluene
Toluene
Toluene
1,4-Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
100
100
100
80
100
100
100
100
100
100
0
P(c-Hex)3 (20)
P(c-Hex)3 (10)
P(c-Hex)3 (20)
P(c-Hex)3 (20)
P(c-Pent)3 (20)
P(i-Pr)3 (20)
P(n-Bu)3 (20)
PPh3 (20)
95
70c
50c
39c
92
94
82c
Trace
Trace
P(t-Bu)3 (20)
a
P(c-Hex)3: tricyclohexylphosphine; P(c-Pent)3: tricyclopentylphosphine.
Isolated yield.
Obtained as an inseparable mixture of 1a and 3a. The yields of 3a were
Terminal alkynes, such as 1-octyne and phenylacetylene,
failed to participate in the reaction due to rapid self-oligo-
merization of the alkynes (Fig. 1). Internal silylalkynes as
b
c
calculated by 1H NMR.

7542
M. Murakami et al. / Tetrahedron 62 (2006) 7540–7546
Table 2. Reaction of 3-methyl-3-phenylcyclobutanone (1a) and alkynes 2b–fa
Entry
1
2 (equiv)
Product 3 (%Yieldb)
O
Et
Et
Et
2b (1.5)
2c (3.0)
3b (97)
3c (84)
Ph
Me
Et
O
Ph
Ph
Ph
2
3
Ph
Me
Ph
Ph
O
O
Me
Ph
Ph
2d (3.0)
3dc (78)
Ph
Me
Ph
Me
Me
Me
92:8
OMe
O
OMe
O
O
Me
Ph
Me
4
2e (3.0)
3ec (58)
Ph
OMe
90:10
Me
Me
Me
CF3
O
CF3
Me
3fc (65)
Ph
Me
5
2f (3.0)
Ph
Me
Me
CF3
91:9
Me
a
Cyclobutanone 1, alkyne 2 (1.5–3.0 equiv to 1), Ni(cod)2 (10 mol %), and P(c-Hex)3 (20 mol %) were heated in toluene at 90–110 ꢀC for 3–6 h.
Isolated yield.
b
c
Regioisomeric ratios were determined by 1H NMR.
Table 3. Nickel-catalyzed reaction of 1 and 2 forming cyclohexenone 3a
Entry
1
2 (equiv) Mol % Ni
3 (%Yieldb)
O
O
Pr
O
O
Pr
Ph
H
Hex
H
SiMe3
Me
SnBu3
Pr
B
1
10
Ph
Ph
3g (91)
Pr
Ph Ph
1b
Pr
2a (1.5)
Pr
O
O
Figure 1.
O
Ph
Me
Ph
Ph
2
3
10
Ph
Ph
Ph
Ph
Me
Me
a surrogate of terminal alkynes also failed to join, probably
due to steric reasons. Other internal functionalized alkynes,
including borylalkynes and stannylalkynes, were not suit-
able coupling partners either.
Ph Ph
93:7
1b
2d (3.0)
3hc (69)
O
O
Pr
Pr
Pr
20
Cyclobutanone 1b possessing two phenyl groups at the 3-
position showed reactivity similar to that of 1a and reacted
with 2a and 2d to afford the corresponding six-membered
ring products in 91% and 69% yields, respectively (Table 3,
entries 1 and 2). The reaction of 3,3-diethylcyclobutanone
(1c) required 20 mol % of the nickel catalyst to gain an
acceptable yield due to its lower reactivity than the phenyl-
substituted 1a and 1b (entries 3 and 4).
Et
Et
Et Et
1c
Pr
2a (1.5)
3i (91)
O
O
O
Ph
Me
Me
Ph
4
20
Et
Et
Et
Et
Ph
90:10
3jc (47)
Me
Et Et
1c
2d (3.0)
The reaction pathway with a cyclobutanone having a hydro-
gen at the 3-position turned out to be somewhat different
(Table 4). The reaction of 3-octylcyclobutanone 1d in
the presence of the nickel(0)–P(c-Hex)3 catalyst afforded
a
Cyclobutanone 1, alkyne 2 (1.5–3.0 equiv to 1), Ni(cod)2, and P(c-Hex)3
(2 equiv to Ni) were heated in toluene at 90–110 ꢀC for 3–6 h.
Isolated yield.
b
c
Regioisomeric ratios were determined by 1H NMR.

M. Murakami et al. / Tetrahedron 62 (2006) 7540–7546
Table 4. Reaction of 3-monosubstituted cyclobutanones and 4-octyne (2a)a
7543
O
O
O
Pr
cat. Ni(cod)2–ligand
Pr
Pr
+
+
2a
R
Me Pr
R
R
1
3
7
O
O
β
-hydride
1) reductive
elimination
Pr
Pr
Pr
Pr
elimination
R
H
R
2) olefin
Ni
Ni
isomerization
H
6
Entry
1 (R)
Mol % Ni
Ligand (mol %)
Toluene/mL
Conditions
3 (%Yieldb)
7 (%Yieldb)
1
2
3
4
5
6
7
1d (n-C8H17
1e (Ph)
1e (Ph)
1e (Ph)
1e (Ph)
)
10
10
10
10
10
20
10
P(c-Hex)3 (20)
P(c-Hex)3 (20)
PPh3 (20)
IPrd (20)
IPr (10)
IPr (20)
IPr (10)
1.0
1.0
1.0
2.0
2.0
4.0
2.0
100 ꢀC, 3 h
100 ꢀC, 3 h
100 ꢀC, 3 h
110 ꢀC, 18 h
110 ꢀC, 18 h
110 ꢀC, 15 h
110 ꢀC, 15 h
3k (37)
3l (41)
3l (37)
3l (59)
3l (61)
3l (79)
3m (32)
7ac (37)
7b (54)
7b (26)
—
—
—
1e (Ph)
1f (2-naphthyl)
—
a
Cyclobutanone 1 (0.20 mmol), alkyne 2a (0.30 mmol), and nickel catalyst were heated in toluene.
Isolated yield.
A mixture of Z- and E-isomers with respect to the 2-methyldec-1-enyl moiety was obtained.
IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
b
c
d
a mixture of the desired product 3k (37%) and linear un-
it possible for alkynes to insert intermolecularly between the
carbonyl carbon and the a-carbon of cyclobutanone. This
new reaction demonstrated the potential of cyclobutanones
as a 1-oxobutane-1,4-diyl unit to build carbocyclic frame-
works in a concise and efficient way (Fig. 3).
saturated ketone 7a (37%) (entry 1). Similar results were
obtained for the reaction of 3-phenylcyclobutanone (1e),
affording two products 3l and 7b (entries 2 and 3). The for-
mation of the linear ketones 7 is explained by assuming that
the hydrogen at the 3-position of cyclobutanone undergoes
b-hydride elimination from intermediate 6. The following
reductive elimination and subsequent olefin isomerization
give 7.13 Ligands of nickel(0) were again screened to im-
prove the product selectivity in favor of 3. To our delight,
the use of a N-heterocyclic carbene ligand (IPr) afforded cy-
clohexenone 3l selectively without any detectable formation
of 7, although the reaction became slower (entries 4 and 5).14
Sterically bulkier IPr ligand might hinder an agostic inter-
action with the hydrogen on the b-carbon, suppressing the
formation of 7. The yield increased to 79% when 20 mol %
of the nickel catalyst was employed (entry 6). The reaction of
3-(2-naphtyl)cyclobutanone (1f) with 2a using the Ni–IPr
catalyst produced cyclohexenone 3m also selectively but in
lower yield (entry 7).
O
C
O
C
C
C
Figure 3.
4. Experimental
4.1. General
All manipulations were carried out in a nitrogen-filled gloved
box or with standard Schlenk techniques under a nitrogen
atmosphere. Preparative thin-layer chromatography was per-
1
formed with silica gel 60 PF254 (Merck). H and 13C NMR
spectra were recorded on a Varian Gemini 2000 (1H at
300.07 Hz and 13C at 75.46 Hz) spectrometer. All NMR
data were obtained in CDCl3. Proton chemical shifts were
referenced to the residual proton signal of the solvent at
7.26 ppm. Carbon chemical shifts were referenced to the
carbon signal of the solvent at 77.00 ppm. High resolution
mass spectra were recorded on a JEOL JMS-SX102A spec-
trometer. IR spectra were recorded on a Shimadzu FTIR-
8100 spectrometer. Cyclobutanones 1 were prepared by
[2+2] cycloaddition of the corresponding olefins with di-
chloroketene and the subsequent dechlorination with zinc
dust in acetic acid.15 1,3-Bis(2,6-diisopropylphenyl)imida-
zol-2-ylidene (IPr) was prepared according to the literature
procedure.16 Toluene was distilled over sodium–benzophe-
none ketyl prior to use. All other commercially available
chemical resources were used without further purifications.
The reaction failed to take place with cyclobutanones
possessing substituents at the 2-position shown in Figure 2,
presumably due to steric reasons.
H
O
O
Ph
Ph
Figure 2.
3. Conclusions
Combining a process of the carbonyl–alkyne oxidative cycli-
zation on nickel(0) with a process of the nickel(II) cyclo-
butanolate ring opening by b-carbon elimination rendered

7544
M. Murakami et al. / Tetrahedron 62 (2006) 7540–7546
4.2. Nickel-catalyzed reactions of cyclobutanones 1 with
alkynes 2
0.60 mmol) was added dropwise via syringe over 2 h. After
being stirred for 4 h, the reaction mixture was concentrated,
and the residue was purified by preparative thin-layer chro-
matography of silica gel (hexane/AcOEt ¼ 9:1) to afford
3d (39.2 mg, 72%) and 30d (3.2 mg, 6%). Compound 3d:
1H NMR d 1.44 (s, 3H), 1.68 (t, J¼1.8 Hz, 3H), 2.76 (dd,
J¼16.1, 1.1 Hz, 1H), 2.92 (ddd, J¼17.7, 1.9, 1.2 Hz, 1H),
3.07 (dd, J¼16.1, 1.5 Hz, 1H), 3.13 (dt, J¼17.7, 1.5 Hz,
1H), 7.14–7.17 (m, 2H), 7.22–7.26 (m, 1H), 7.30–7.43 (m,
7H); 13C NMR d 12.5, 29.5, 40.3, 46.3, 49.8, 125.2, 126.3,
126.9, 127.8, 128.4, 128.5, 131.6, 141.2, 146.8, 153.8,
199.3; HRMS (EI) calcd for C20H20O (M+) 276.1514, found
4.2.1. 5-Methyl-5-phenyl-2,3-dipropyl-2-cyclohexenone
(3a). To a toluene solution (1.0 mL) of Ni(cod)2 (5.5 mg,
0.02 mmol) and P(c-Hex)3 (11.2 mg, 0.04 mmol) were
added 1a (32.7 mg, 0.20 mmol) and 4-octyne (2a, 33 mg,
0.30 mmol). After being stirred for 3 h at 100 ꢀC, the reac-
tion mixture was concentrated, and the residue was purified
by preparative thin-layer chromatography of silica gel
(hexane/AcOEt ¼ 9:1) to afford 3a (52.4 mg, 95%): IR
1
(neat) 1663 cmꢁ1; H NMR d 0.81 (t, J¼7.4 Hz, 3H), 0.91
1
(t, J¼7.4 Hz, 3H), 1.19–1.29 (m, 2H), 1.33 (s, 3H), 1.47
(sext, J¼7.5 Hz, 2H), 2.12–2.31 (m, 4H), 2.58 (d,
J¼18.2 Hz, 1H), 2.59 (dd, J¼16.2, 1.2 Hz, 1H), 2.80 (d,
J¼18.2 Hz, 1H), 2.89 (dd, J¼16.1, 1.2 Hz, 1H), 7.15–7.20
(m, 1H), 7.27–7.32 (m, 4H); 13C NMR d 14.1, 14.2, 20.8,
22.6, 26.8, 29.0, 36.9, 39.6, 44.0, 49.9, 125.1, 126.1,
128.3, 135.2, 147.1, 155.7, 198.4; HRMS (EI) calcd for
C19H26O (M+) 270.1984, found 270.1982. Anal. Calcd for
C19H26O: C, 84.39; H, 9.69. Found: C, 84.55; H, 9.85.
276.1512. Compound 30d: H NMR d 1.45 (s, 3H), 1.82
(s, 3H), 2.76 (d, J¼16.8 Hz, 1H+1H), 2.97 (d, J¼18.0 Hz,
1H), 3.05 (d, J¼15.9 Hz, 1H), 6.93–6.96 (m, 2H), 7.22–
7.35 (m, 8H).
4.2.5. Stereochemical assignment of 3d and 30d. The two
regioisomers 3d and 30d were subjected to NOE experi-
ments. No NOE between the methyl protons (d 1.68) and
the C4 and C6 methylene protons (d 2.76, 2.92, 3.07, and
3.13) was observed for 3d. On the other hand, a NOE
between the methyl protons (d 1.82) and the C4 methylene
protons (d 2.76 and 2.97) was observed for 30d.
4.2.2. 2,3-Diethyl-5-methyl-5-phenyl-2-cyclohexenone
(3b). To a toluene solution (0.5 mL) of Ni(cod)2 (5.5 mg,
0.02 mmol) and P(c-Hex)3 (11.2 mg, 0.04 mmol) were
added 1a (32.1 mg, 0.20 mmol) and 3-hexyne (2b,
24.6 mg, 0.30 mmol). After being stirred for 6 h at 90 ꢀC,
the reaction mixture was concentrated, and the residue was
purified by preparative thin-layer chromatography of silica
gel (hexane/AcOEt ¼ 9:1) to afford 3b (47.2 mg, 97%):
1H NMR d 0.87 (t, J¼7.5 Hz, 3H), 1.04 (t, J¼7.7 Hz, 3H),
1.33 (s, 3H), 2.17–2.33 (m, 4H), 2.58 (d, J¼17.7 Hz, 1H),
2.60 (dd, J¼16.1, 1.1 Hz, 1H), 2.79 (d, J¼17.7 Hz, 1H),
2.88 (dd, J¼16.1, 1.1 Hz, 1H), 7.17–7.21 (m, 1H), 7.27–
7.30 (m, 4H); 13C NMR d 12.0, 14.0, 17.9, 27.7, 28.8,
39.5, 43.6, 49.9, 125.1, 126.1, 128.2, 136.0, 147.1, 156.7,
198.4; HRMS (EI) calcd for C17H22O (M+) 242.1671, found
242.1670.
4.2.6. 3-(4-Methoxyphenyl)-2,5-dimethyl-5-phenyl-2-
cyclohexenone (3e) and 2-(4-methoxyphenyl)-3,5-
dimethyl-5-phenyl-2-cyclohexenone (30e).
A
toluene
solution (0.4 mL) of Ni(cod)2 (5.5 mg, 0.02 mmol), P(c-
Hex)3 (11.2 mg, 0.04 mmol), and 1a (31.3 mg, 0.20 mmol)
was stirred at 110 ꢀC for a few minutes. A toluene solution
(0.1 mL) of 1-(4-methoxyphenyl)-1-propyne (2e, 87.7 mg,
0.60 mmol) was added dropwise via syringe over 2 h. After
being stirred for 4 h, the reaction mixture was concentrated,
and the residue was purified by preparative thin-layer chro-
matography of silica gel (hexane/AcOEt ¼ 8:1) to afford 3e
1
(31.1 mg, 52%) and 30e (3.5 mg, 6%). Compound 3e: H
NMR d 1.43 (s, 3H), 1.71 (t, J¼1.8 Hz, 3H), 2.74 (dd,
J¼16.1, 0.8 Hz, 1H), 2.90 (ddd, J¼17.9, 1.7, 0.8 Hz, 1H),
3.05 (dd, J¼16.1, 1.2 Hz, 1H), 3.12 (dt, J¼17.9, 1.6 Hz,
1H), 3.83 (s, 3H), 6.90–6.95 (m, 2H), 7.09–7.14 (m, 2H),
7.19–7.24 (m, 1H), 7.32–7.34 (m, 4H); 13C NMR d 12.7,
29.5, 40.2, 46.3, 49.8, 55.3, 113.7, 125.2, 126.2, 128.4,
128.6, 131.3, 133.4, 146.8, 153.5, 159.2, 199.3; HRMS
(EI) calcd for C21H22O2 (M+) 306.1620, found 306.1621.
Compound 30e: 1H NMR d 1.44 (s, 3H), 1.84 (s, 3H),
2.75 (d, J¼16.5 Hz, 1H+1H), 2.96 (d, J¼18.9 Hz, 1H),
3.04 (dd, J¼15.9, 1.2 Hz, 1H), 3.80 (s, 3H), 6.83–6.90
(m, 4H), 7.20–7.27 (m, 1H), 7.30–7.35 (m, 4H); HRMS
(EI) calcd for C21H22O2 (M+) 306.1620, found 306.1617.
4.2.3. 5-Methyl-2,3,5-triphenyl-2-cyclohexenone (3c). A
toluene solution (0.3 mL) of Ni(cod)2 (5.5 mg, 0.02 mmol),
P(c-Hex)3 (11.2 mg, 0.04 mmol), and 1a (31.6 mg,
0.20 mmol) was stirred at 110 ꢀC for a few minutes. A tolu-
ene solution (0.2 mL) of diphenylacetylene (2c, 106.9 mg,
0.60 mmol) was added dropwise via syringe over 2 h. After
being stirred for 4 h, the reaction mixture was concentrated,
and the residue was purified by preparative thin-layer chro-
matography of silica gel (hexane/AcOEt ¼ 9:1) to afford 3c
(56.0 mg, 84%): 1H NMR d 1.57 (s, 3H), 2.91 (dd, J¼16.1,
0.6 Hz, 1H), 3.15 (d, J¼18.0 Hz, 1H), 3.24 (dd, J¼16.1,
1.7 Hz, 1H), 3.35 (dd, J¼18.0, 1.7 Hz, 1H), 6.83–6.86 (m,
2H), 6.98–7.03 (m, 2H), 7.11–7.19 (m, 6H) 7.24–7.30 (m,
1H) 7.36–7.45 (m, 4H); 13C NMR d 29.5, 40.3, 46.3, 50.3,
125.4, 126.4, 126.7, 127.4, 127.7, 127.8, 127.9, 128.5,
130.7, 134.9, 137.4, 140.7, 146.3, 155.2, 197.6; HRMS
(EI) calcd for C25H22O (M+) 338.1671, found 338.1671.
4.2.7. 2,5-Dimethyl-5-phenyl-3-(4-trifluoromethyl-
phenyl)-2-cyclohexenone (3f) and 3,5-dimethyl-5-phe-
nyl-2-(4-trifluoromethylphenyl)-2-cyclohexenone (30f). A
toluene solution (0.4 mL) of Ni(cod)2 (5.5 mg, 0.02 mmol),
P(c-Hex)3 (11.2 mg, 0.04 mmol), and 1a (31.8 mg,
0.20 mmol)was stirredat110 ꢀC forafew minutes. A toluene
solution (0.1 mL) of 1-(4-trifluoromethylphenyl)-1-propyne
(2f, 110.4 mg, 0.60 mmol) was added dropwise via syringe
over 2 h. After being stirred for 4 h, the reaction mixture
was concentrated, and the residuewas purified by preparative
thin-layer chromatography of silica gel (hexane/AcOEt ¼
10:1) to afford 3f (40.8 mg, 60%) and 30f (3.9 mg, 6%).
4.2.4. 2,5-Dimethyl-3,5-diphenyl-2-cyclohexenone (3d)
and 3,5-dimethyl-2,5-diphenyl-2-cyclohexenone (30d). A
toluene solution (0.4 mL) of Ni(cod)2 (5.5 mg, 0.02 mmol),
P(c-Hex)3 (11.2 mg, 0.04 mmol), and 1a (31.7 mg,
0.20 mmol) was stirred at 110 ꢀC for a few minutes. A tolu-
ene solution (0.1 mL) of 1-phenyl-1-propyne (2d, 69.6 mg,

M. Murakami et al. / Tetrahedron 62 (2006) 7540–7546
7545
1
Compound 3f: H NMR d 1.44 (s, 3H), 1.65 (t, J¼1.8 Hz,
4.2.11. 5,5-Diethyl-2-methyl-3-phenyl-2-cyclohexenone
(3j) and 5,5-diethyl-3-methyl-2-phenyl-2-cyclohexenone
(30j). A toluene solution (0.4 mL) of Ni(cod)2 (11.0 mg,
0.04 mmol), P(c-Hex)3 (22.4 mg, 0.08 mmol), and 1c
(24.5 mg, 0.19 mmol) was stirred at 110 ꢀC for a few min-
utes. A toluene solution (0.1 mL) of 1-phenyl-1-propyne
(2d, 69.6 mg, 0.60 mmol) was added dropwise via syringe
over 2 h. After being stirred for 4 h, the reaction mixture
was concentrated, and the residue was purified by prepara-
tive thin-layer chromatography of silica gel (hexane/
AcOEt ¼ 20:1) to afford 3j (20.3 mg, 43%) and 30j
(2.1 mg, 4%). Compound 3j: 1H NMR d 0.83 (t, J¼7.4 Hz,
6H), 1.45 (q, J¼7.5 Hz, 4H), 1.69 (t, J¼2.0 Hz, 3H), 2.39
(s, 2H), 2.49 (d, J¼1.8 Hz, 2H), 7.16–7.19 (m, 2H), 7.32–
7.42 (m, 3H); 13C NMR d 7.8, 12.5, 28.8, 38.4, 43.0, 47.5,
127.0, 127.7, 128.3, 130.9, 141.6, 153.9, 200.3; HRMS
(EI) calcd for C17H22O (M+) 242.1671, found 242.1671.
Compound 30j: 1H NMR d 0.85 (t, J¼7.5 Hz, 6H), 1.46 (q,
J¼7.4 Hz, 4H), 1.80 (s, 3H), 2.36 (s, 2H), 2.41 (s, 2H),
7.04–7.07 (m, 2H), 7.25–7.38 (m, 3H).
3H), 2.77 (d, J¼15.9 Hz, 1H), 2.90 (dd, J¼18.2, 2.0 Hz,
1H), 3.04–3.14 (m, 2H), 7.20–7.28 (m, 3H), 7.30–7.38 (m,
4H), 7.66 (d, J¼8.4 Hz, 2H); 13C NMR d 12.4, 29.6, 40.5,
1
46.1, 49.7, 123.9 (q, JC–F¼271.5 Hz), 125.2, 125.5
3
2
(q, JC–F¼3.8 Hz), 126.4, 127.3, 128.6, 129.9 (q, JC–F
¼
32.4 Hz), 132.3, 144.7, 146.4, 151.9, 198.8;HRMS(EI) calcd
for C21H19F3O (M+) 344.1388, found 344.1386. Compound
30f: 1H NMR d 1.46 (s, 3H), 1.82 (s, 3H), 2.76 (d,
J¼16.2 Hz, 1H), 2.78 (d, J¼18.0 Hz, 1H), 2.99 (d,
J¼18.0 Hz, 1H), 3.08 (dd, J¼16.2, 1.5 Hz, 1H), 7.06 (d,
J¼8.4 Hz, 2H), 7.21–7.29 (m, 1H), 7.31–7.40 (m, 4H), 7.58
(dd, J¼8.4, 0.6 Hz, 2H); HRMS (EI) calcd for C21H19F3O
(M+) 344.1388, found 344.1385.
4.2.8. 5,5-Diphenyl-2,3-dipropyl-2-cyclohexenone (3g).
To a toluene solution (0.5 mL) of Ni(cod)2 (5.5 mg,
0.02 mmol) and P(c-Hex)3 (11.2 mg, 0.04 mmol) were added
1b (44.5 mg, 0.20 mmol) and 4-octyne (2a, 33 mg,
0.30 mmol). After being stirred for 3 h at 110 ꢀC, the reaction
mixture was concentrated, and the residue was purified by
preparative thin-layer chromatography of silica gel (hexane/
AcOEt ¼ 10:1) to afford 3g (60.7 mg, 91%): 1H NMR d 0.73
(t, J¼7.5 Hz, 3H), 0.88 (t, J¼7.4 Hz, 3H), 1.11–1.23 (m, 2H),
1.39–1.51 (m, 2H), 2.16–2.22 (m, 2H), 2.24–2.29 (m, 2H),
3.14 (s, 2H), 3.15 (s, 2H), 7.13–7.19 (m, 6H), 7.22–7.28
(m, 4H); 13C NMR d 14.0, 14.2, 20.7, 22.4, 26.8, 37.1,
42.6, 47.6, 49.9, 126.2, 126.7, 128.2, 136.3, 146.3, 155.4,
197.7; HRMS (EI) calcd for C24H28O (M+) 332.2140, found
332.2143.
4.2.12. 5-Octyl-2,3-dipropyl-2-cyclohexenone (3k). To a
toluene solution (0.5 mL) of Ni(cod)2 (5.5 mg, 0.02 mmol)
and P(c-Hex)3 (11.2 mg, 0.04 mmol) were added 1d
(36.3 mg, 0.20 mmol) and 4-octyne (2a, 33 mg, 0.30 mmol).
After being stirred for 3 h at 110 ꢀC, the reaction mixture
was concentrated, and the residue was purified by preparative
thin-layer chromatography of silica gel (hexane/AcOEt ¼
10:1) to afford 3k (21.7 mg, 37%) and 6a (21.3 mg, 37%):
1H NMR d 0.85–0.98 (m, 9H), 1.26–1.35 (m, 16H), 1.42–
1.54 (m, 2H), 1.96–2.08 (m, 3H), 2.19–2.26 (m, 4H), 2.30–
2.37 (m, 1H), 2.47–2.51 (m, 1H); 13C NMR d 14.1, 14.3,
21.3, 22.7, 22.9, 26.5, 27.1, 29.3, 29.6, 29.7, 31.9, 34.6,
35.9, 37.0, 37.3, 44.5, 135.3, 158.1, 199.6 [one carbon signal
is missing due to overlapping]; HRMS (EI) calcd for
C20H36O (M+) 292.2766, found 292.2770.
4.2.9. 2-Methyl-3,5,5-triphenyl-2-cyclohexenone (3h)
and 3-methyl-2,5,5-triphenyl-2-cyclohexenone (30h). A
toluene solution (0.1 mL) of Ni(cod)2 (5.5 mg, 0.02 mmol),
P(c-Hex)3 (11.2 mg, 0.04 mmol), and 1b (44.5 mg,
0.20 mmol) was stirred at 110 ꢀC for a few minutes. A tolu-
ene solution (0.1 mL) of 1-phenyl-1-propyne (2d, 69.6 mg,
0.60 mmol) was added dropwise via syringe over 2 h. After
being stirred for 4 h, the reaction mixture was concentrated,
and the residue was purified by preparative thin-layer
chromatography of silica gel (hexane/AcOEt ¼ 10:1) to
afford 3h (43.2 mg, 64%) and 30h (3.4 mg, 5%). Compound
3h: 1H NMR d 1.66 (s, 3H), 3.34 (s, 2H), 3.46 (s, 2H), 7.12–
7.44 (m, 15H); 13C NMR d 12.5, 45.0, 48.3, 49.7, 126.3,
126.6, 126.9, 128.0, 128.4, 132.6, 141.0, 146.1, 153.4,
198.5 [one carbon signal is missing due to overlapping];
HRMS (EI) calcd for C25H22O (M+) 338.1671, found
4.2.13. 5-Phenyl-2,3-dipropyl-2-cyclohexenone (3l). A
toluene solution (1.5 mL) of 1e (29.3 mg, 0.20 mmol) and
4-octyne (2a, 33 mg, 0.30 mmol) was stirred for 10 min
at 110 ꢀC. To the stirring solution, a toluene solution
(0.5 mL) of Ni(cod)2 (5.5 mg, 0.02 mmol) and IPr (7.8 mg,
0.02 mmol), which was stirred for 6 h at room temperature
in glove box, was added. After being stirred for 18 h at
110 ꢀC, the reaction mixture was concentrated, and the
residue was purified by preparative thin-layer chromato-
graphy of silica gel (hexane/AcOEt ¼ 10:1) to afford 3l
1
1
338.1671. Compound 30h: H NMR d 1.87 (s, 3H), 3.27
(s, 2H), 3.33 (s, 2H), 6.85–6.88 (m, 2H), 7.20–7.32 (m, 13H).
(31.4 mg, 61%): H NMR d 0.94 (t, J¼7.5 Hz, 3H), 0.97
(t, J¼7.4 Hz, 3H), 1.32–1.44 (m, 2H), 1.47–1.60 (m, 2H),
2.23–2.36 (m, 4H), 2.52–2.62 (m, 3H), 2.71 (dd, J¼16.2,
4.2 Hz, 1H), 3.17–3.28 (m, 1H), 7.22–7.26 (m, 3H), 7.31–
7.37 (m, 2H); 13C NMR d 14.2, 14.3, 21.1, 22.8, 27.1,
36.8, 38.5, 40.4, 44.6, 126.5, 126.7, 128.5, 135.4, 143.6,
157.6, 198.5; HRMS (EI) calcd for C18H24O (M+)
256.1827, found 256.1829.
4.2.10. 5,5-Diethyl-2,3-dipropyl-2-cyclohexenone(3i). To a
toluene solution (1 mL) of Ni(cod)2 (11.0 mg, 0.04 mmol)
and P(c-Hex)3 (22.4 mg, 0.08 mmol) were added 1c
(24.4 mg, 0.19 mmol) and 4-octyne (2a, 33 mg, 0.30 mmol).
After being stirred for 3 h at 110 ꢀC, the reaction mixture was
concentrated, and the residue was purified by preparative
thin-layer chromatography of silica gel (hexane/AcOEt ¼
10:1) to afford 3i (28.1 mg, 61%): 1H NMR d 0.77 (t,
J¼7.4 Hz, 6H), 0.89 (t, J¼7.4 Hz, 3H), 0.96 (t, J¼7.5 Hz,
3H), 1.25–1.38 (m, 6H), 1.42–1.55 (m, 2H), 2.16–2.25 (m,
8H); 13C NMR d 7.7, 14.3, 14.4, 21.2, 22.8, 26.9, 28.7,
36.9, 37.8, 40.4, 47.8, 134.6, 155.7, 199.5; HRMS (EI) calcd
for C16H28O (M+) 236.2140, found 236.2143.
4.2.14. (2E,5E)-2-Phenyl-5-propyl-2,5-nonadien-4-one
(7b). The title compound was obtained by the reaction
1
with Ni(cod)2–P(c-Hex)3. H NMR d 0.94 (t, J¼7.8 Hz,
3H), 0.96 (t, J¼7.8 Hz, 3H), 1.35–1.56 (m, 4H), 2.25 (q,
J¼7.4 Hz, 2H), 2.33–2.39 (m, 2H), 2.40 (d, J¼1.2 Hz,
3H), 6.62 (t, J¼7.4 Hz, 1H), 6.78 (d, J¼1.2 Hz, 1H), 7.34–
7.42 (m, 3H), 7.48–7.52 (m, 2H); 13C NMR d 14.0, 14.2,

7546
M. Murakami et al. / Tetrahedron 62 (2006) 7540–7546
5. (a) Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002,
124, 13976–13977; (b) Matsuda, T.; Fujimoto, A.; Ishibashi,
M.; Murakami, M. Chem. Lett. 2004, 33, 876–877.
18.4, 22.3, 22.5, 27.8, 31.0, 123.3, 126.2, 128.4, 128.5,
142.8, 143.1, 143.6, 150.5, 194.7; HRMS (EI) calcd for
C18H24O (M+) 256.1827, found 256.1826.
6. For recent examples of b-carbon elimination, see: (a) Zhao, P.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 11618–11619; (b)
Siriwardana, A. I.; Kamada, M.; Nakamura, I.; Yamamoto, Y.
J. Org. Chem. 2005, 70, 5932–5937; (c) Funayama, A.;
Satoh, T.; Miura, M. J. Am. Chem. Soc. 2005, 127, 15354–
15355 and references therein.
7. Pd: (a) Nishimura, T.; Uemura, S. Synlett 2004, 201–216; (b)
Nishimura, T.; Nishiguchi, Y.; Maeda, Y.; Uemura, S. J. Org.
Chem. 2004, 69, 5342–5347; (c) Satoh, T.; Miura, M.
Palladium in Organic Synthesis; Tsuji, J., Ed.; Topics in
Organometallic Chemistry; Springer: Berlin, 2005; Vol. 14,
pp 1–20; Rh: (d) Matsuda, T.; Makino, M.; Murakami, M.
Angew. Chem., Int. Ed. 2005, 44, 4608–4611; (e) Matsuda,
T.; Makino, M.; Murakami, M. Bull. Chem. Soc. Jpn. 2005,
78, 1528–1533.
8. For recent examples, see: (a) Mahandru, G. M.; Liu, G.;
Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698–3699;
(b) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004,
126, 15342–15343; (c) Tekavec, T. N.; Louie, J. Org. Lett.
2005, 7, 4037–4039; (d) Knapp-Reed, B.; Mahandru, G. M.;
Montgomery, J. J. Am. Chem. Soc. 2005, 127, 13156–13157;
(e) Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127,
14194–14195; For a review, see: (f) Montgomery, J. Angew.
Chem., Int. Ed. 2004, 43, 3890–3908.
9. For related reactions with carbon dioxide, see: (a) Takimoto,
M.; Shimizu, K.; Mori, M. Org. Lett. 2001, 3, 3345–3347; (b)
Tekavec, T. N.; Arif, A. M.; Louie, J. Tetrahedron 2004, 60,
7431–7437 and references therein.
4.2.15. Stereochemical assignment of 7b. Divinylketone
7b was subjected to NOE experiments. No NOE between
the vinyl proton (d 6.78) and the methyl protons (d 2.40)
was observed. On the other hand, a NOE between the vinyl
proton (d 6.78) and the aromatic ortho protons (d 7.48–7.52)
was observed.
4.2.16. 5-(2-Naphthyl)-2,3-dipropyl-2-cyclohexenone(3m).
A toluene solution (1.5 mL) of 1f (39.2 mg, 0.2 mmol) and
4-octyne (2a, 33 mg, 0.3 mmol) was stirred for 10 min
at 110 ꢀC. To the stirring solution, a toluene solution
(0.5 mL) of Ni(cod)2 (5.5 mg, 0.02 mmol) and IPr (7.8 mg,
0.02 mmol), which was stirred for 6 h at room temperature
in glove box, was added. After being stirred for 15 h at
110 ꢀC, the reaction mixture was concentrated, and the resi-
due was purified by preparative thin-layer chromatography
of silica gel (hexane/AcOEt ¼ 10:1) to afford 3m (19.5 mg,
32%): 1H NMR d 0.95 (t, J¼7.2 Hz, 3H), 0.98 (t, J¼7.6 Hz,
3H), 1.33–1.46 (m, 2H), 1.48–1.59 (m, 2H), 2.28–2.38 (m,
4H), 2.63–2.73 (m, 3H), 2.80 (dd, J¼16.1, 4.1 Hz, 1H),
3.35–3.46 (m, 1H), 7.37–7.40 (m, 1H), 7.43–7.51 (m, 2H),
7.66–7.67 (m, 1H), 7.79–7.84 (m, 3H); 13C NMR d 14.3,
21.3, 22.9, 27.2, 36.9, 38.5, 40.5, 44.7, 124.9, 125.3, 125.6,
126.2, 127.6, 127.6, 128.3, 132.4, 133.5, 135.5, 141.1,
157.7, 198.6 [one carbon signal is missing due to overlap-
ping]; HRMS (EI) calcd for C22H26O 306.1984, found
306.1985.
10. For mechanistic studies, see: (a) Hratchian, H. P.; Chowdhury,
S. K.; Gutierrez-Garcia, V. M.; Amarasinghe, K. K. D.; Heeg,
M. J.; Schlegel, H. B.; Montgomery, J. Organometallics 2004,
23, 4636–4646; (b) Ogoshi, S.; Oka, M.-a.; Kurosawa, H.
J. Am. Chem. Soc. 2004, 126, 11802–11803; (c) Ogoshi, S.;
Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem. Soc. 2005,
127, 12810–12811.
11. A part of this work appeared as a preliminary communication:
Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc.
2005, 127, 6932–6933.
Acknowledgements
We thank H. Fujita for his assistance in the structure determi-
nation by NMR and H. Ushitora for obtaining the HRMS
data. This work was supported by a Grant-in-Aid for Young
Scientists (B) (No. 15750085) from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
References and notes
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Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1990,
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mediate from cyclobutenones, which are much more labile
thermally as well as catalytically than cyclobutanones.
13. The E-isomer is more stable than the Z-isomer because the
maximum conjugative stabilization is achieved with the
OaC–CaC–Ph moiety of the E-isomer for which it is easier
to take a planar conformation. With the Z-isomer, steric inter-
action of the acyl and the phenyl groups causes deviation of the
conjugated moiety from planarity, reducing such stabilization.
The more stable E-isomer was formed as a result of isomeriza-
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W. D. Organometallics 2002, 21, 1975–1981; (b) Kondo, T.;
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