Nickel-Catalyzed Enantioselective Synthesis of Cyclobutenes via [2+2] Cycloaddition of α,β-Unsaturated Carbonyls with 1,3-Enynes

Article abstract of DOI:10.1055/s-0035-1561669

A Ni(0)/chiral N-heterocyclic carbene (NHC) catalyzed enantioselective and intermolecular [2+2] cycloaddition of α,β-unsaturated carbonyl compounds with conjugated enynes was investigated to produce enantioenriched cyclobutenes (up to 89% ee). The present

Full text of DOI:10.1055/s-0035-1561669

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
A
special topic
R. Kumar et al.
Special Topic
Synthesis
Nickel-Catalyzed Enantioselective Synthesis of Cyclobutenes via
[2+2] Cycloaddition of α,β-Unsaturated Carbonyls with 1,3-Enynes
Ravindra Kumara
Eri Tamaia
Akira Ohnishia
Akira Nishimuraa
Yoichi Hoshimotoa,b
Masato Ohashia
Sensuke Ogoshi*a
Ni(0)-catalyzed First Enantioselective [2+2] Cycloaddition
Cy Cy
5 mol% Ni(cod)2
5 mol% (R,R)-L*12·HBF4
5 mol% NaOtBu
R3
R3
R1
R2
R1
R2
BF4
*
*
+
N
N
C6D6, 60 °C
18–72 h
R4
R4
Cy
Cy
Ph
Ph
up to 79% yield
89% ee
(R,R)-L*12·HBF4
a Department of Applied Chemistry, Faculty of Engineering, Osaka
University, Suita, Osaka 565-0871, Japan
b Frontier Research Base for Global Young Researchers, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-0871,
Japan
Received: 10.03.2016
Accepted after revision: 09.05.2016
Published online: 23.06.2016
of four-membered rings, and those were developed for
non-enantioselective syntheses.8 We previously reported
the Ni(0)-catalyzed intermolecular [2+2] cycloaddition of
an alkene/α,β-unsaturated carbonyl with an alkyne/conju-
gated enyne to synthesize cyclobutenes with the generation
of one or two stereogenic centers [Scheme 1,(1) and (2)].9 In
contrast, cyclohexenes were obtained by the reaction of
two enones and an alkyne with the generation of four con-
tiguous stereogenic centers [Scheme 1,(3)].10 These two dis-
tinct products were formed due to the structural differenc-
es in nickelacycles A, B, and C generated by the oxidative cy-
clization of α,β-unsaturated carbonyl compounds with a
1,3-enyne and an alkyne, respectively. In the course of the
[2+2]-cycloaddition reaction, the coordination of another
enone to the nickelacycle might be hampered because of to
the pre-occupation of the coordination site of the nickel
center either with the conjugated double bond of an enyne
[A or B (1)] or with a bulky substituent (R1) at the β-posi-
tion of an enone [C (2)]. Since the pioneering discovery of
C2-symmetric chiral N-heterocyclic carbenes (NHCs) by
Grubbs et al.,11 which relied on the transfer of the inherent
central chirality from the NHC backbone to unsymmetrical-
ly N-substituted aryl side chains and ultimately to the met-
al-coordination sphere, a number of metal–chiral NHC sys-
tems have been designed. Recently, these NHCs have also
been recognized as effective ligands for nickel-catalyzed en-
antioselective reactions.12 Very recently, we explored the
Ni(0)-catalyzed enantioselective [2+2+2] cycloaddition of
two enones and an alkyne in the presence of a chiral NHC
[Scheme 1,(3)].13 Herein, we report the development of an
enantioselective variant of a Ni(0)-catalyzed [2+2] cycload-
dition of α,β-unsaturated carbonyls with 1,3-enynes to pro-
duce enantioenriched cyclobutenes [Scheme 1,(1)].
DOI: 10.1055/s-0035-1561669; Art ID: ss-2016-c0174-st
Abstract A Ni(0)/chiral N-heterocyclic carbene (NHC) catalyzed enan-
tioselective and intermolecular [2+2] cycloaddition of α,β-unsaturated
carbonyl compounds with conjugated enynes was investigated to pro-
duce enantioenriched cyclobutenes (up to 89% ee). The present report
reveals the first example of a nickel-catalyzed enantioselective [2+2]-cy-
cloaddition reaction.
L*12·HBF4, was the most effective NHC precursor for the present cata-
lytic reactions.
A newly synthesized imidazolinium salt,
Key words nickel catalysis, N-heterocyclic carbenes, enantioselective,
intermolecular, [2+2] cycloaddition, cyclobutenes
Cyclobutene rings are of particular relevance in chemi-
cal synthesis due to the unique reactivity that originates
from ring strain.1 In addition, cyclobutene is also a key com-
ponent in many natural and pharmaceutically important
molecules.2 The [2+2] cycloaddition of an alkene and an
alkyne is the most straightforward method for the synthe-
sis of cyclobutenes. Brønsted or Lewis acid catalyzed and
transition-metal-catalyzed [2+2] cycloadditions have been
well developed.3,4 Whereas ample examples of racemic syn-
theses of cyclobutenes have been reported, catalytic enantio-
selective syntheses have been significantly less studied.4c,d
Furthermore, transition-metal-catalyzed enantioselective
[2+2]-cycloaddition reactions have been limited to highly
strained norbornene types of molecules, that are catalyzed
by rhodium5 and iridium.6
Nickel is a prominent candidate as a catalyst for the syn-
thesis of carbo- and heterocycles, and it has been extensive-
ly studied for five-, six-, and larger-membered rings.7 Con-
versely, there have been few examples of the construction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
R. Kumar et al.
Special Topic
Synthesis
O
(L*10)16a gave 3aa in good yield with an increase in enanti-
O
oselectivity (78%, 43% ee).
R1
R
R1
R
10 mol% Ni(cod)2
O
Ni(0)/L
R1
Ni(0)/L
O
11 mol% (R,R)-L*n·HBF4
10 mol% NaOtBu
*
R
R
+
O
Hex
C6D6, 80 °C
R
R1
*
Hex
R1
O
O
1a
2a
3aa
Ni
L
L
L
1.5 equiv
Ar =
B
C
A
BF4
O
Ar
Ar
R1 = Bulky
substituent
N
N
R
R1
Ph
Ph
(R,R)-L*n·HBF4
R
O
O
L*1
0%, 48 h
L*2
0%, 24 h
L*3
0%, 24 h
L*4
0%, 48 h
∗
R1
∗
∗
∗
∗
R
∗
O
R
∗
R1
O
Et
Et
∗
R1
R1
iPr
R
Cy
(1)
iPr
(2)
(3)
Cy
Scheme 1 Nickel(0)-catalyzed cycloaddition of enone and alkyne
L*5a
23%, 30 h
L*6
72%, 5 h
2% ee
L*8
85%, 5 h
29% ee
L*7
54%, 24 h
6% ee
L*9
94%, 5 h
30% ee
Our study commenced with a survey of chiral NHCs
generated in situ from the corresponding C2-symmetric im-
idazolinium salts, L*n·HBF4, in the presence of NaOtBu and
Ni(cod)2 at 80 °C using cyclopent-2-en-1-one (1a) and dec-
1-en-3-yne (2a) as model substrates (Scheme 2).14 First, we
examined the reaction with N-biphenyl-2-yl-substituted
NHC L*1, which was an optimal ligand in the case of our
Ni(0)-catalyzed enantioselective [2+2+2]-cycloaddition re-
action.13 However, this NHC did not give 3aa at all. In a sim-
ilar manner, N-2-isopropylphenyl-12d and N-1-naphthyl-
substituted NHCs L*2 and L*3 were also unsuccessful,
which suggested that mono-ortho-substituted NHCs might
not be suitable to deliver the desired product, 3aa. In addi-
tion, a mixture of cotrimerization products was detected.15
It was probably due to the spatial accessibility of the nickel
center complexed with less-hindered NHC to another
alkyne. In the presence of N-2-naphthyl-substituted NHC
L*4, no reaction occurred. We examined 2,6-disubstituted
(bis-ortho) NHC L*5, which led to the formation of 3aa in
23% yield along with inseparable cotrimerization prod-
ucts.15 N-2,6-Diethylphenyl-substituted NHC L*6 gave 3aa
in good yield, albeit with very poor enantioselectivity (72%
yield, 2% ee). N-Mesityl-substituted NHC L*7 also gave 3aa
in 54% yield and 6% ee. Montgomery et al. developed a high-
ly efficient chiral NHC L*8 for the nickel-catalyzed reductive
coupling of aldehydes and alkynes.12a Indeed, NHC L*8
worked effectively in our system to afford 3aa in high yield
with a significant improvement in enantioselectivity (85%
yield, 29% ee). An analogous NHC salt, L*9·HBF4, was syn-
thesized by replacing the cyclohexyl groups with the iso-
propyl units, giving 3aa in optimal chemical yield with al-
most the same degree of enantioselectivity (94% yield, 30%
iPr
Cy
Cyoct
R
R
BF4
N
N+
iPr
Cy
Cyoct = cyclooctyl
L*13; R = iPr; trace
L*14; R = Me; trace
L*10
L*11
L*12
78%, 6 h
43% ee
83%, 14 h
73%, 12 h
43% ee
10% ee
Scheme 2 Catalytic enantioselective [2+2] cycloaddition: Survey of
imidazolinium salts. General reaction conditions: (R,R)-L*n·HBF4 (0.22
mmol), NaOtBu (0.02 mmol), Ni(cod)2 (0.02 mmol), 1a (0.2 mmol), 2a
(0.3 mmol), and C6D6 (0.5 mL). Experiments were conducted in an NMR
tube equipped with a J. Young valve. Isolated yields are given. The enan-
tiomeric excess (ee) was determined by HPLC using a chiral stationary
phase. a NMR yield, ee was not determined.
Dorta et al. reported that enantioselectivity and reactiv-
ity are attributed from all the atropisomers, generated from
the respective orientation of naphthyl wingtips (L*10·HBF4
consists of three atropisomers).16a They also reported that
2-cyclooctyl-1-naphthyl-substituted NHC (L*11·HBF4 exists
as almost a single atropisomer) was an optimal ligand in
the Pd-catalyzed α-arylation of amides.17 However, it was
not appropriate to improve the enantioselectivity of 3aa
(83%, 10% ee). This was probably due to the smaller coordi-
nation sphere of the nickel center than that of palladium,
which resulted an increase of flexibility of the N-2-cyclooc-
tyl-1-naphthyl rings in the nickel/L*11-complex. Thus, the
N-(2,7-dicyclohexyl-1-naphthyl)-substituted NHC precur-
sor L*12·HBF4 was synthesized having cyclohexyl groups
(smaller than cyclooctyl but bulkier than isopropyl) at the
ee).
N-(2,7-Diisopropyl-1-naphthyl)-substituted
NHC
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
R. Kumar et al.
Special Topic
Synthesis
2- and 7-positions of the naphthyl wingtips to restrict the
flexibility of the naphthyl rings in the nickel–L*12 complex.
The newly synthesized NHC salt L*12·HBF4 also appeared
virtually as a single major atropisomer in NMR analy-
ses,16b,18 and superior enantioselectivity (73%, 43% ee) was
obtained using the present system (cf. 10% ee in the case of
L*11·HBF4). Although the efficiency of L*12·HBF4 and
L*10·HBF4 was almost the same in the case of 3aa,
L*12·HBF4 emerged as a promising NHC precursor in the
present nickel-catalyzed reactions. Chiral NHCs of the fused
ring system were also examined for their role in restricting
the flexible behaviors of N-substituents (L*13 and L*14).19
However, only a trace amount of 3aa was obtained.15
An extensive survey of NHC salts and further optimiza-
tion provided the best results with L*10·HBF4 at 60 °C (en-
try 12). Since comparable results were obtained with
L*12·HBF4 (entry 5), the scope of the substrates was investi-
gated with both ligands, L*10 and L*12.18 Notably, superior
results were obtained with our newly synthesized NHC
salts (L*12·HBF4) for most of the substrates (Scheme 3).18
A
bulky alkyne, 3-methyl-1-(trimethylsilyl)but-3-en-1-yne
(2b), gave the corresponding cyclobutene 3ab in 65% yield
and 65% ee. Cyclohex-2-en-1-one (1b) gave the respective
bicyclic cyclobutene 3ba with 2a in 56% yield and 34% ee.
However, superior enantioselectivity was achieved with
L*10·HBF4 (41% yield, 53% ee). On the other hand, the reac-
tion of 1b with sterically hindered enyne 2c gave 3bc with a
significantly higher enantioselectivity using L*12·HBF4
(41% yield, 59% ee; cf. 14% ee with L*10·HBF4). N-tert-Butyl-
maleimide (3c) gave the corresponding annulated cyclobu-
tene 3ca in good enantioselectivity (65% yield, 89% ee). N,N-
Dimethylacrylamide (1d) afforded 3da in good yield and
enantioselectivity (61% yield and 78% ee), whereas N-meth-
yl-N-phenylacrylamide (1e) gave 3ea in 59% yield and 53%
ee. The reaction of diethyl vinylphosphonate (1f) was also
examined with 2a, which gave a phosphonate containing
cyclobutene 3fa in 69% yield and 50% ee. Remarkably, acry-
lates 1g and 1h also worked well to give the corresponding
cyclobutenes 3ga and 3hc with 2a and 2c, respectively in
good chemical yields (3ga: 76% and 3hc: 66%).20
Ethyl acrylate (1g) reacted with 2a to give 3ga with 45%
ee, whereas 3hc was obtained with only 13% ee from the
reaction of methyl acrylate (1h) with a sterically hindered
enyne 2c. We also examined the catalytic enantioselective
[2+2] cycloaddition reaction between an enone with a tert-
butyl group at the β-position (1i) and oct-4-yne (2d) or
dec-1-en-3-yne(2a), but the desired [2+2] cycloaddition
product was not obtained.
The plausible reaction mechanism depicted in Scheme 4
is based on our previous report.9a The simultaneous regio-
selective coordination of an α,β-unsaturated carbonyl and
an 1,3-enyne with a nickel(0)/L*n moiety followed by oxi-
dative cyclization gives an enantioenriched η3-butadienyl
intermediate A. Subsequent reductive elimination from A
gives cyclobutene 3 with the generation of one or two ste-
reogenic centers.
a
Table 1 Further Optimization with L*10·HBF4 and L*12·HBF4
Entry L*n
Solvent
Temp (°C) Time (h) Yieldb (%) eec (%)
1
2
L*10
C6D6
C6D6
C6D6
C6D6
C6D6
THF
80
60
40
80
60
60
60
60
60
60
60
60
60
6
30
144
12
25
24
24
24
24
24
24
72
24
78
79
50
73
75
63
72
67
46
50
13
75
73
43
48
50
43
44
44
47
50
29
50
43
48
46
L*10
L*10
L*12
L*12
L*10
L*10
L*10
L*10
L*10
L*10
L*10
L*10
3
4
5
6
7
dioxane
toluene
MeCN
Et2O
8
9
10
11
12d
13e
DMI
C6D6
C6D6
a General reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), L*10·HBF4 or
L*12·HBF4, (0.22 mmol), NaOtBu (0.02 mmol), Ni(cod)2 (0.02 mmol). All
experiments were conducted in an NMR tube equipped with a J. Young
valve in C6D6. Isolated yields are given; ee was determined by SFC/HPLC us-
ing a chiral stationary phase.
b Isolated yields are given.
c Enantioselectivities were determined by SFC using a chiral stationary
phase.
d 5 mol% L*10·HBF4, NaOtBu, and Ni(cod)2 were employed.
e 20 mol% L*10·HBF4, NaOtBu, and Ni(cod)2 were employed.
Since the NHCs L*10 and L*12 were the most effective
ligands, they were subjected to further possible optimiza-
tion (Table 1). Lowering the temperature to 60 °C was help-
ful in slightly improving the enantioselectivity (48 and 44%
ee with L*10·HBF4 and L*12·HBF4, respectively) without
loss in chemical yield (entries 2 and 5). In the case of
L*10·HBF4, a further decrease in temperature to 40 °C had
no significant influence on the ee (entry 3). Solvent screen-
ing with L*10·HBF4 at 60 °C was also not beneficial (entries
6–11). A catalyst loading of 5 mol% gave identical results
(entry 12, cf. entry 2). A slight influence on yield and enan-
tioselectivity was observed with a catalyst loading of 20
mol% (entry 13, cf. entries 2 and 12).
In summary, the nickel(0)–NHC-catalyzed enantioselec-
tive [2+2]-cycloaddition reaction of α,β-unsaturated car-
bonyl compounds with 1,3-enynes was studied. A survey of
chiral imidazolinium salts suggested that 2,6-disubstitution
on the N-aryl group of the NHC was essential for an enantio-
selective reaction. A wide range of enantioselectivities were
obtained for different substrates. However, a newly synthe-
sized chiral NHC L*12 proved to be the most effective ligand
in our study. This also represents the first example of a
nickel-catalyzed enantioselective [2+2] cycloaddition reac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

D
R. Kumar et al.
Special Topic
Synthesis
All manipulations were conducted under a nitrogen atmosphere us-
ing standard Schlenk or dry box techniques. All commercially avail-
able reagents were distilled and degassed prior to use. Ni(cod)2 was
purified by recrystallization from toluene. All products were charac-
terized by 1H and 13C NMR spectra, which were recorded on a Bruker
Avance III AV 400 MHz spectrometer. Chiral NHC salts were synthe-
sized according to reported procedures.11,12a,16,17,19 Optical rotations
were measured in Jasco-DIP 1000 polarimeter with a path length of 1
dm using the Na D line. Enantioselectivities were recorded by means
of Jasco-Supercritical Fluid chromatography (SFC), equipped with PU-
2080-CO2 plus CO2 delivery pump and MD-2018 plus as a photodiode
array detector using chiral columns of Diacel Chiralpak (λ = 244–264
nm; temp. = 25 °C; back pressure = 15 MPa).
5 mol% Ni(cod)2
5 mol% (R,R)-L*12.HBF4
5 mol% NaOtBu
O
R4
R3
O
R4
R1
+
*
*
R1
C6D6, 60 °C
18–72 h
R3
R2
R2
2
1
3
1.5 equiv
O
O
O
O
*
*
*
*
*
*
*
Hex
Ph
TMS
Hex
*
3aa
79%, 48% eea
3ba
41%, 53% eea
3ab
65%, 65% ee
3bc
41%, 59% ee
Ni-Catalyzed Enantioselective [2+2] Cycloaddition of α,β-Unsatu-
rated Carbonyl and 1,3-Enyne; General Procedure
O
tBuN
O
P
O
O
To a vial in a glove box was added chiral NHC salt L*n·HBF4 (0.020
mmol, 5 mol%), NaOtBu (0.020 mmol, 5 mol%), and C6D6 (0.5 mL). This
suspension was stirred at r.t. for 10 min. Ni(cod)2 (0.020 mmol, 5
mol%) was added and the suspension was further stirred at r.t. for 5–
10 min. Finally, to the solution was added enone 1 (0.4 mmol) fol-
lowed by enyne 2 (0.4–0.6 mmol, 1.2–1.5 equiv). The mixture was
transferred to a J. Young tube, and heated at 60 °C until complete re-
action of the α,β-unsaturated carbonyl compounds, as monitored by
1H NMR (18–72 h). The resultant mixture was cooled to r.t., filtered
directly through a short plug of silica gel and washed with EtOAc. Vol-
atiles were removed under reduced pressure and the residue was pu-
rified by flash column chromatography (silica gel, 5% to 35% EtOAc–
hexanes). All cyclobutenes were obtained as single diastereomers and
regioisomers. Enantioselectivities were determined via SFC using a
chiral stationary phase.
*
Ph
*
EtO
*
*
Me2N
N
EtO
*
Hex
Hex
Hex
Hex
O
3ca
3ea
59%, 53% ee
3fa
3da
65%, 89% ee
69%, 50% ee
61%, 78% ee
O
O
O
iPr
iPr
Ph
*
EtO
*
MeO
Hex
Ph
3ga
76%, 45% ee
3hc
66%, 13% ee
3id
0%
Scheme 3 Nickel(0)-catalyzed cycloaddition of α,β-unsaturated car-
bonyl and 1,3-enyne. General reaction conditions: 1 (0.4 mmol), 2 (0.6
mmol), L*12·HBF4 (0.02 mmol), NaOtBu (0.02 mmol), Ni(cod)2 (0.02
mmol). All experiments were conducted in an NMR tube equipped with
a J. Young valve in C6D6. Isolated yields are given. Enantioselectivities
were determined by SFC using a chiral stationary phase. Absolute con-
figuration was not determined. a Results are obtained with L*10·HBF4.
(1R*,5S*)-6-Hexyl-7-vinylbicyclo[3.2.0]hept-6-en-2-one (3aa)9a
Following the general procedure, cyclopent-2-en-1-one (1a, 32.8 mg,
0.40 mmol), dec-1-en-3-yne (2a, 81.8 mg, 0.60 mmol), Ni(cod)2 (5.3
mg, 0.020 mmol), chiral NHC precursor L*10·HBF4 (14.3 mg, 0.020
mmol), and NaOtBu (1.7 mg, 0.018 mmol) were heated at 60 °C for 72
h. Purification by column chromatography (EtOAc/hexane, 5:95) gave
3aa (65.8 mg, 0.30 mmol, 75%; 48% ee) as a pale yellow oil. Spectro-
scopic data were identical to that previously reported.9a
tion. The initial study would definitely encourage the pur-
suit of the most suitable chiral NHCs and reaction condi-
tions, and is presently ongoing in our laboratory.
SFC (Daicel Chiralpak IC, CO2: 3.0 mL/min, CH2Cl2: 0.3 mL/min): tR
7.0 (minor), 7.9 min (major).
=
[α]D24 +84.53 (c 0.10, CHCl3).
O
R1
O
(1R*,5S*)-7-(Prop-1-en-2-yl)-6-(trimethylsilyl)bicyclo[3.2.0]hept-
[Ni0L*]
R2
*
*
R1
1
+
6-en-2-one (3ab)9a
R2
Following the general procedure, cyclopent-2-en-1-one (1a, 32.0 mg,
0.39 mmol), 3-methyl-1-(trimethylsilyl)but-3-en-1-yne (1b, 86.9 mg,
0.63 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), chiral NHC precursor
L*12·HBF4 (18.4 mg, 0.021 mmol), and NaOtBu (2.0 mg, 0.021 mmol)
were heated at 60 °C for 72 h. Purification by column chromatography
(hexane/EtOAc, 95:5) gave 3ab (57.0 mg, 0.26 mmol, 65%; 65% ee) as a
pale yellow oil. Spectroscopic data were identical to that previously
reported.9a
3
Reductive
Elimination
2
R1
O
O
R2
*
L*
R1
*
Ni
L*
Ni
SFC (Daicel Chiralpak IC, CO2: 3.0 mL/min, CH2Cl2: 0.3 mL/min): tR
=
R2
4.8 (major), 5.8 min (minor).
[α]D24 +131.76 (c 0.10, CHCl3).
A
Oxidative
Cyclization
Scheme 4 A plausible mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

E
R. Kumar et al.
Special Topic
Synthesis
(1R*,6S*)-7-Hexyl-8-vinylbicyclo[4.2.0]oct-7-en-2-one (3ba)9a
°C for 24 h. Purification by column chromatography [Rf = 0.4 (EtOAc/
hexane, 20:80)] gave 3ea (70.1 mg, 0.24 mmol, 59%; 53% ee) as a col-
orless oil.
Following the general procedure, cyclohex-2-en-1-one (1b, 38.4 mg,
0.40 mmol), dec-1-en-3-yne (2a, 81.5 mg, 0.60 mmol), Ni(cod)2 (5.6
mg, 0.02 mmol), chiral NHC precursor L*10·HBF4 (14.2 mg, 0.019
mmol), and NaOtBu (1.9 mg, 0.02 mmol) were heated at 60 °C for 48
h. Purification by column chromatography (EtOAc/hexane, 5:95) gave
3ba (38.0 mg, 0.16 mmol, 41%; 53% ee) as a pale yellow oil. Spectro-
scopic data were identical to that previously reported.9a
SFC (Daicel Chiralpak IA, CO2: 2.4 mL/min, i-PrOH: 0.6 mL/min): tR
=
5.2 (major), 7.1 min (minor).
[α]D24 + 19.0 (c 0.26, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.42 (t, J = 7.5 Hz, 2 H, m-H-Ph), 7.33 (t,
J = 7.5 Hz, 1 H, p-H-Ph), 7.19 (d, J = 7.5 Hz, 2 H, o-H-Ph), 6.36 (dd, J =
10.6, 17.3 Hz, 1 H, -CH=CH2), 4.98 (d, J = 10.6 Hz, 1 H, CH=CH2), 4.89
(d, J = 17.3 Hz, 1 H, -CH=CH2), 3.43 (br s, 1 H, COCH), 3.30 (s, 3 H,
NCH3), 2.28 (d, J = 13.4 Hz, 1 H, CHCH2CH), 2.26 (d, J = 13.4 Hz, 1 H,
CHCH2CH), 2.13 (t, J = 7.2 Hz, 2 H, CHCH2CH2), 1.42–1.24 (m, 8 H), 0.85
(t, J = 6.8 Hz, 3 H, CH2CH3).
13C{1H} NMR (100 MHz, CDCl3): δ = 173.0, 145.9, 144.1, 137.5, 129.6,
128.1, 127.5, 127.1, 113.0, 39.6, 37.3, 33.8, 31.6, 29.1, 28.7, 26.9, 22.5,
14.0.
SFC (Daicel Chiralpak IA, CO2: 4.0 mL/min, CH2Cl2: 0.3 mL/min): tR
2.6 (minor), 3.3 min (major).
[α]D24 –61.60 (c 0.23, CHCl3).
=
(1R*,6S*)-7-Phenyl-8-(prop-1-en-2-yl)bicyclo[4.2.0]oct-7-en-2-
one (3bc)9a
Following the general procedure, cyclohex-2-en-1-one (1b, 38.2 mg,
0.4 mmol), 3-methyl-1-phenylbut-3-en-1-yne (2c, 68.2 mg, 0.48
mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), chiral NHC precursor L*12·HBF4
(17.0 mg, 0.019 mmol), and NaOtBu (2.0 mg, 0.02 mmol) were heated
at 60 °C for 72 h. Purification by column chromatography (EtOAc/hex-
ane, 5:95) gave 3bc (39.0 mg, 0.16 mmol, 41%; 59% ee) as a pale yel-
low oil. Spectroscopic data were identical to that previously report-
ed.9a
HRMS (EI): m/z [M+] calcd for C20H27NO: 297.2093; found: 297.2090.
Diethyl 3-Hexyl-2-vinylcyclobut-2-en-1-ylphosphonate (3fa)
Following the general procedure, diethyl vinylphosphonate (1f, 64.7
mg, 0.39 mmol), dec-1-en-3-yne (2a, 80.6 mg, 0.59 mmol), Ni(cod)2
(5.6 mg, 0.020 mmol), chiral NHC precursor L*12·HBF4 (17.8 mg, 0.02
mmol), and NaOtBu (1.8 mg, 0.019 mmol) were heated at 60 °C for 24
h. Purification by column chromatography [Rf = 0.3 (EtOAc/hexane,
35:65)] gave 3fa (81.0 mg, 0.27 mmol, 69%; 50% ee) as a pale yellow
oil. Spectroscopic data were identical to that previously reported.9a
SFC (Daicel Chiralpak IA, CO2: 4.0 mL/min, CH2Cl2: 0.3 mL/min): tR
4.8 (major), 6.4 min (minor).
[α]D24 +116.63 (c 0.10, CHCl3).
=
(1R*,5S*)-3-tert-Butyl-6-hexyl-7-vinyl-3-azabicyclo[3.2.0]hept-6-
SFC (Daicel Chiralpak IE, CO2: 2.4 mL/min, i-PrOH: 0.3 mL/min): tR
5.4 (major), 6.0 min (minor).
=
ene-2,4-dione (3ca)9a
Following the general procedure, N-tert-butylmaleimide (1c, 60.1 mg,
0.39 mmol), dec-1-en-3-yne (2a, 83.6 mg, 0.61 mmol), Ni(cod)2 (5.6
mg, 0.02 mmol), chiral NHC precursor L*12·HBF4 (17.5 mg, 0.02
mmol), and NaOtBu (2.0 mg, 0.02 mmol) were heated at 60 °C for 36
h. Purification by column chromatography (hexane/EtOAc, 95:5) gave
3ca (75.5 mg, 0.26 mmol, 65%; 89% ee) as a pale yellow oil. Spectro-
scopic data were identical to that previously reported.9a
[α]D24 + 27.76 (c 0.45, CHCl3).
Ethyl 3-Hexyl-2-vinylcyclobut-2-enecarboxylate (3ga)
Following the general procedure, ethyl acrylate (1g, 41.2 mg, 0.42
mmol), dec-1-en-3-yne (2a, 67.9 mg, 0.5 mmol), Ni(cod)2 (6.2 mg,
0.023 mmol), chiral NHC precursor L*12·HBF4 (18.3 mg, 0.021 mmol),
and NaOtBu (2.0 mg, 0.02 mmol) were heated at 60 °C for 24 h. Purifi-
cation by column chromatography (EtOAc/hexane, 5:95) gave 3ga
(75.6 mg, 0.32 mmol, 76%; 45% ee) as a colorless oil. Spectroscopic
data were identical to that previously reported.9a
SFC (Daicel Chiralpak IA, CO2: 3.0 mL/min, i-PrOH: 0.1 mL/min): tR
=
2.1 (major), 2.3 min (minor).
[α]D24 +105.82 (c 0.33, CHCl3).
SFC (Daicel Chiralpak IE, CO2: 3.5 mL/min, CH2Cl2: 0.1 mL/min): tR
6.3 (major), 6.9 min (minor).
[α]D24 –4.93 (c 0.13, CHCl3).
=
3-Hexyl-N,N-dimethyl-2-vinylcyclobut-2-ene-1-carboxamide
(3da)9a
Following the general procedure, N,N-dimethylacrylamide (1d, 38.2
mg, 0.39 mmol), dec-1-en-3-yne (2a, 86.8 mg, 0.64 mmol), Ni(cod)2
(5.5 mg, 0.02 mmol), chiral NHC precursor L*12·HBF4 (17.2 mg, 0.021
mmol), and NaOtBu (2.0 mg, 0.02 mmol) were heated at 60 °C for 18
h. Purification by column chromatography (EtOAc/hexane, 30:70)
gave 3da (56.1 mg, 0.24 mmol, 61%; 78% ee) as a colorless oil. Spec-
troscopic data were identical to that previously reported.9a
Methyl 3-Phenyl-2-(prop-1-en-2-yl)cyclobut-2-ene-1-carboxylate
(3hc)
Following the general procedure, methyl acrylate (1h, 35.0 mg, 0.41
mmol), 3-methyl-1-phenylbut-3-en-1-yne (2c, 68.2 mg, 0.48 mmol),
Ni(cod)2 (5.5 mg, 0.020 mmol), chiral NHC precursor L*12·HBF4 (19.6
mg, 0.022 mmol), and NaOtBu (2.0 mg, 0.02 mmol) were heated at 60
°C for 24 h. Purification by column chromatography [Rf = 0.4 (EtOAc/
hexane, 5:95)] gave 3hc (62.0 mg, 0.27 mmol, 66%; 13% ee) as a color-
less oil.
SFC (Daicel Chiralpak IC, CO2: 2.4 mL/min, i-PrOH: 0.6 mL/min): tR
=
6.7 (major), 7.2 min (minor).
[α]D24 +81.31 (c 0.12, CHCl3).
SFC (Daicel Chiralpak IA, CO2: 4.0 mL/min, CH2Cl2: 0.3 mL/min): tR
2.2 (minor), 2.7 min (major).
[α]D24 +8.40 (c 0.38, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 7.6 Hz, 2 H, Ar-H), 7.31 (t, J =
7.6 Hz, 2 H, Ar-H), 7.23 (m, 1 H, Ar-H), 5.11 [s, 1 H, CH=C(CH3)], 4.99
[s, 1 H, CH=C(CH3)], 3.68–3.70 (m, 4 H, OCH3, CH2CH), 2.82 (br s, 2 H,
CH2CH), 1.89 (s, 3 H, CH3).
=
3-Hexyl-N-methyl-N-phenyl-2-vinylcyclobut-2-ene-1-carboxam-
ide (3ea)
Following the general procedure, N-methyl-N-phenylacrylamide (1e,
64.2 mg, 0.40 mmol), dec-1-en-3-yne (2a, 86.0 mg, 0.63 mmol),
Ni(cod)2 (5.4 mg, 0.02 mmol), chiral NHC precursor L*12·HBF4 (19.1
mg, 0.021 mmol), and NaOtBu (2.0 mg, 0.02 mmol) were heated at 60
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

F
R. Kumar et al.
Special Topic
Synthesis
13C{1H} NMR (100 MHz, CDCl3): δ = 174.1, 140.8, 138.7, 138.5, 135.2,
128.1, 127.8, 127.3, 115.1, 51.7, 41.9, 30.9, 20.8.
HRMS (EI): m/z (M+) calcd for C15H16O2: 228.1150; found: 228.1146.
N.; Takaya, H. J. Am. Chem. Soc. 1973, 95, 1674. (d) Takaya, H.;
Yamakawa, M.; Noyori, R. Bull. Chem. Soc. Jpn. 1982, 55, 852.
(e) Lautens, M.; Edwards, L. G.; Tam, W.; Lough, A. J. J. Am. Chem.
Soc. 1995, 117, 10276. Between two allenes, see: (f) Saito, S.;
Hirayama, K.; Kabuto, C.; Yamamoto, Y. J. Am. Chem. Soc. 2000,
122, 10776. Intramolecular using ene-allene, see: (g) Noucti, N.
N.; Alexanian, E. J. Angew. Chem. Int. Ed. 2015, 54, 5447.
(9) (a) Nishimura, A.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2012,
134, 15692. (b) Abulimiti, A.; Nishimura, A.; Ohashi, M.; Ogoshi,
S. Chem. Lett. 2013, 42, 904.
(10) Ogoshi, S.; Nishimura, A.; Ohashi, M. Org. Lett. 2010, 12, 3450.
(11) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225.
(12) Examples of Ni-chiral NHC catalysis, see: (a) Chaulagain, M. R.;
Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129,
9568. (b) Sato, Y.; Hinata, Y.; Seki, R.; Oonishi, Y.; Saito, N. Org.
Lett. 2007, 9, 5597. (c) Ahlin, J. S. E.; Donets, P. A.; Cramer, N.
Angew. Chem. Int. Ed. 2014, 53, 13229. (d) Kumar, R.;
Hoshimoto, Y.; Yabuki, H.; Ohashi, M.; Ogoshi, S. J. Am. Chem.
Soc. 2015, 137, 11838. Chiral NHC with NiH complex, see:
(e) Ho, C.-Y.; Chan, C.-W.; He, L. Angew. Chem. Int. Ed. 2015, 54,
4512.
Acknowledgment
This work was supported by Grant-in-Aid for Young Scientists (A) (No.
25708018), and Grant-in-Aid for Scientific Research on Innovative Ar-
eas (15H05803) from MEXT and by JST, Advanced catalytic Transfor-
mation Program for carbon utilization (ACT-C), Japan. Y. H.
acknowledges support from the Frontier Research Base for Global
Young Researchers, Osaka University, on the Program of MEXT.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561669.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(13) Kumar, R.; Tokura, H.; Nishimura, A.; Mori, T.; Hoshimoto, Y.;
Ohashi, M.; Ogoshi, S. Org. Lett. 2015, 17, 6018.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F