Steric effects on deprotonative generation of cyclohexynes and 1,2-cyclohexadienes from cyclohexenyl triflates by magnesium amides

Article abstract of DOI:10.1016/j.tet.2020.131103

Steric effects on the deprotonative generation of cyclohexynes and 1,2-cyclohexadienes from cyclohexenyl triflates are described. A cyclohexenyl triflate, which is readily available from nonsubstituted cyclohexanone, was selectively converted to cyclohexy

Full text of DOI:10.1016/j.tet.2020.131103

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Steric effects on deprotonative generation of cyclohexynes and 1,2-cyclohexadienes
from cyclohexenyl triflates by magnesium amides
Yuto Hioki, Atsunori Mori, Kentaro Okano
PII:
S0040-4020(20)30224-6
https://doi.org/10.1016/j.tet.2020.131103
TET 131103
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 February 2020
Revised Date: 29 February 2020
Accepted Date: 2 March 2020
Please cite this article as: Hioki Y, Mori A, Okano K, Steric effects on deprotonative generation of
cyclohexynes and 1,2-cyclohexadienes from cyclohexenyl triflates by magnesium amides, Tetrahedron
(2020), doi: https://doi.org/10.1016/j.tet.2020.131103.
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Graphical Abstract
Steric effects on deprotonative generation of
cyclohexynes and 1,2-cyclohexadienes from
cyclohexenyl triflates by magnesium amides
Leave this area blank for abstract info.
a
a,b
a,
Yuto Hioki , Atsunori Mori , and Kentaro Okano ∗
a
Department of Chemical Science and Engineering, Kobe University
-1 Rokkodai, Nada, Kobe 657-8501, Japan
1
b
Research Center for Membrane and Film Technology, Kobe University
-1 Rokkodai, Nada, Kobe 657-8501, Japan
1

1
Tetrahedron
journal homepage: www.elsevier.com
Steric effects on deprotonative generation of cyclohexynes and 1,2-cyclohexadienes
from cyclohexenyl triflates by magnesium amides
a
a,b
a,
Yuto Hioki , Atsunori Mori , and Kentaro Okano ∗
a
Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
Research Center for Membrane and Film Technology, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Steric effects on the deprotonative generation of cyclohexynes and 1,2-cyclohexadienes from
cyclohexenyl triflates are described. A cyclohexenyl triflate, which is readily available from
nonsubstituted cyclohexanone, was selectively converted to cyclohexyne using magnesium
bis(2,2,6,6-tetramethylpiperidide) as base. The generated cyclohexyne was trapped by 1,3-
diphenylisobenzofuran to afford the cycloadduct. This method was also applied to a benzo-fused
cyclohexenyl triflate prepared from α-tetralone. A cyclohexenyl triflate bearing two methyl
substituents at the 3-position was selectively transformed into the corresponding 1,2-
cyclohexadiene. This 1,2-cyclohexadiene reacted with 1,3-diphenylisobenzofuran, styrene, and
nitrone to provide the corresponding cycloadducts in good yields.
Available online
Keywords:
Cycloalkyne
Cycloallene
Deprotonation
Magnesium amide
Steric effect
2
009 Elsevier Ltd. All rights reserved.
—
——
∗
Corresponding author. Tel.: +81-78-803-6167; e-mail: okano@harbor.kobe-u.ac.jp

2
Tetrahedron
1
. Introduction
cyclohexyne (1) itself was not isolable owing to ring strain.
According to the seminal work of Wittig, cyclohexenyl triflate
3a was treated with PhLi at −78 °C, which afforded no desired
cycloadduct with concomitant formation of unidentified products
Table 1, entry 1).
As seven-membered or smaller cycloalkynes and cycloallenes
1
are generally not isolable owing to inherent ring strain, these
reaction intermediates have rarely been utilized. In contrast,
arynes and relatively stable cycloalkynes have been used in
natural product synthesis, ligand synthesis, and copper-free
Huisgen cycloaddition. Among the limited approaches to
generating cyclohexynes and 1,2-cyclohexadienes reported since
1
(
2
3
Table 1. Generation of cyclohexyne by deprotonation of
cyclohexenyl triflate.
a
4
the seminal works of Wittig and Roberts, the fluoride ion-
induced generation of cyclohexyne (1) and 1,2-cyclohexadiene
(
2) has been synthetically reliable regarding regiochemistry and
5
functional group compatibility (Scheme 1). The only drawback
of this method is the multistep preparation of α-silyl
cyclohexenyl triflates 4 and 5 from cyclohexenone. However, our
group has recently reported a novel method for the preparation of
these α-silyl cyclohexenyl triflates by retro-Brook rearrangement
Entry
Base
Triflate
Cycloadduct
b
b
13a (%)
19a (%)
6
of silyl enol ether 3. In contrast, a deprotonative approach
c
1
2
3
4
5
6
7
8
PhLi
<1
<1
<1
84
<1
<1
91
<1
<1
56
<1
40
<1
–
starting from cyclohexenyl halide 7, which would be more atom-
economical, led to the generation of a mixture of cyclohexyne 8
LDA
18
14
7
and 1,2-cyclohexadiene 9. Our group has reported that metal
LiTMP
amides allow the deprotonative generation of cyclohexyne (1)
from cyclohexenyl triflate 13a, which can be prepared from
c
TMPMgCl·LiCl
–
8
cyclohexanone (12) in one step. The present study now reports
Mg(Ni-Pr
Mg(Ni-Prt-Bu)
Mg(Nt-Amt-Bu)
Mg(DMP) ·2LiCl
Mg(TMP) ·2LiCl
Zn(TMP) ·2LiCl·2MgCl
2
)
2
·2LiCl
·2LiCl
·2LiCl
38
24
the effect of substituents of cyclohexenyl triflates on the
deprotonative generation of cyclohexyne and 1,2-cyclohexadiene.
The selective generation of 1,2-cyclohexadiene 16 from
cyclohexenyl triflate 15 is also described as an example.
2
c
2
–
2
51
56
9
2
d
c
1
1
1
1
0
1
2
3
2
2
–
e
e
e
Et
Et
2
3
Zn(TMP)Li
Al(TMP)Li
6
32
48
3
i-Bu Al(TMP)Li
a
Reaction conditions: cyclohexenyl triflate 13a (1.0 equiv), base (3
b
equiv), 1,3-diphenylisobenzofuran (18) (1.5 equiv), THF, rt, 3 h.
Yields determined from H NMR spectra using 1,1,2,2-
tetrachloroethane as internal standard. Not detected in the crude H
NMR spectra. Reaction time: 19 h. Reaction conditions: 60 °C, 3
1
c
1
d
e
h.
Scheme 1. Representative methods for generating
cyclohexyne and 1,2-cyclohexadiene.
2
. Results and Discussion
Fig. 1. Structure of metal amides.
9
Both lithium diisopropylamide (LDA) and lithium 2,2,6,6-
2
.1. Deprotonative generation of cyclohexynes using metal
10
tetramethylpiperidide (LiTMP)
resulted in complete
8a,8b
amides
consumption of starting cyclohexenyl triflate 13a to afford
desired cycloadduct 19a in 18% and 14% yields, respectively
Initially, metal amides were investigated in the generation
of cyclohexyne/1,2-cyclohexadiene for achieving high yields
(entries 2 and 3). This observation indicated that proposed
lithiated intermediate 17 was reactive, causing undesired
reactions. The same reaction was then performed using the
corresponding magnesium amide, Knochel–Hauser base
(
Table 1). The efficacy for cyclohexyne (1) generation was
evaluated by comparing the yields of the cycloadduct of
cyclohexyne (1) and 1,3-diphenylisobenzofuran (18), because

3
1
1
(
TMPMgCl·LiCl), as a milder base. However, cycloadduct 19a
Table 2. Substrate scope of cyclic enol triflates.
1
was not observed in the H NMR spectrum of the crude mixture,
with recovery of starting triflate 13a (entry 4). These results
prompted us to investigate more basic magnesium bisamides.
12
The use of Mg(Ni-Pr ) ·LiCl led to the formation of 19a in 38%
2
2
yield (entry 5). Sterically demanding magnesium bisamides did
not improve the product yield (entries 6 and 7). Magnesium
1
3
bis(cis-2,6-dimethylpiperidide)·2LiCl (Mg(DMP) ·2LiCl) and
2
14
Mg(TMP) ·2LiCl bearing cyclic amide moieties provided the
2
product in 51% and 56% yields, respectively (entries 8 and 9). In
addition to magnesium bisamides, related zinc and aluminum
1
5
bases were tested. The reaction using Zn(TMP) ·2LiCl·2MgCl
2
2
16
did not give the desired product, while Et Zn(TMP)Li led to the
2
formation of cycloadduct 19a, albeit in 6% yield at 60 °C (entries
17
1
0 and 11). Furthermore, Et Al(TMP)Li and i-Bu Al(TMP)Li
3
3
provided cycloadduct 19a in 32% and 48% yields, respectively,
under heating (entries 12 and 13). Although cyclohexenyl triflate
1
3a has two allylic protons at the 6-position, no cycloadducts
derived from 1,2-cyclohexadiene (2) and isobenzofuran 18 were
observed.
We next investigated the scope of the deprotonative
generation of cyclohexynes using Mg(TMP) ·2LiCl (Table 2). In
2
addition to compound 19a, cycloadducts 19b and 19c derived
from cycloheptyne and cyclooctyne were obtained in 58% and
9
6% yields, respectively. Cyclohexenyl triflate 13d, bearing an
ethyl group at the 4-position, was converted into cycloadduct 19d
in 62% yield as a 1:1 diastereomeric mixture. Next, cyclohexenyl
triflates bearing substituents at the α-position of the triflate group
were tested. Cyclohexenyl triflate 13e, bearing a benzyl group,
was transformed into corresponding cycloadduct 19e in 65%
yield. Cyclohexenyl triflate 13f was also converted into
compound 19f in the same manner. Cyclohexenyl triflates 13g–
1
3i, bearing a quaternary carbon center at the 6-position,
proceeded in the reaction to give corresponding cycloadducts
9g–19i in satisfactory yields. This method was also applied to
benzo-fused cyclohexenyl triflate 13j to give cycloadduct 19j in
1% yield.
1
9
This deprotonative generation using TMP bases proceeded
smoothly, owing to the low nucleophilicity of the anionic species
bearing a bulky TMP group. However, the [4+2] cycloaddition of
isobenzofuran 18 with cyclohexyne (1) generated by
Mg(TMP) ·2LiCl furnished corresponding cycloadduct 19a in
2
5
6% yield, along with a substantial amount of enamine 20 that
was decomposed during attempted chromatographic purification
Scheme 2). These results indicated that the nucleophilic addition
(
of TMP base or its conjugate acid (TMPH) could not be
completely suppressed.
Scheme 2. Formation of enamine through deprotonative
generation of cyclohexyne.
a
b
1
c
Isolated yield. Ratio of diastereomers determined by H NMR.
d
e
Reaction time: 5 h. Reaction time: 7 h. Reaction time: 5 h.

4
Tetrahedron
2
.2. Steric effects on deprotonative generation of cyclohexynes
2.2.2. Effect of methyl group at the 3-position on the ratio of
and 1,2-cyclohexadienes from cyclohexenyl triflates
cyclohexyne and 1,2-cyclohexadiene generated
2
.2.1. Generation of 1,2-cyclohexadiene from cyclohexenyl
We next investigated the reaction of cyclohexenyl triflate bearing
a methyl group at the 3-position (Table 3). Under the established
conditions, cyclohexenyl triflate 24 resulted in the formation of
cycloadducts of both 1,2-cyclohexadiene and cyclohexyne. The
ratios of cycloadducts of cyclohexyne 25 and 1,2-cyclohexadiene
triflate bearing a phenyl group at the 2-position
Cyclohexenyl triflate 21, bearing a phenyl group at the 2-
position, was converted into cycloadducts endo-23 and exo-23 in
6
corresponding H NMR spectra and melting points were in good
agreement with those reported by Johnson
0% and 20% yields, respectively (Scheme 3). The
2
6 obtained when using cyclohexenyl triflate 24 with various
1
magnesium bisamides are summarized in Table 3. The ratios of
these two intermediates were determined from the yields of
corresponding cycloadducts 19f, 27, and 28 that were generated
by reacting with isobenzofuran 18. We first performed the
18a
18b
and Ceylan.
These structures were confirmed by X-ray crystallography
19,20
(
Figures 2 and 3).
These results indicated that 1,2-
cyclohexadiene 22 was generated through allylic deprotonation.
The generated 1,2-cyclohexadiene 22 underwent [4+2]
cycloaddition with isobenzofuran 18 regioselectively at the
carbon–carbon double bond bearing the phenyl group, which was
12
reaction at room temperature with Mg(Ni-Pr ) ·2LiCl, but the
2
2
cycloadducts were obtained in 46% combined yield with the
recovery of cyclohexenyl triflate 24 (entry 1). Heating at 60 °C
led to the consumption of 24 to give a 2:1 mixture of the
cycloadducts in 51% yield (entry 2). Mg(NEt ) ·2LiCl also gave
18
consistent with the reports of Johnson and Ceylan.
2
2
the products in lower yields (entry 3), while sterically demanding
Mg(Ni-Prt-Bu) ·2LiCl gave no conversion (entry 4).
2
14
Mg(TMP) ·2LiCl gave the products in 73% yields (entry 5),
2
11
while the Knochel–Hauser base gave no cycloadducts with 82%
recovery of cyclohexenyl triflate 24 (entry 6). The use of
10
9,21
LiTMP or LDA
provided the cycloadducts as a mixture in
comparable yields at 0 °C (entries 7 and 8).
Table 3. Effects of bases on the ratio of cycloadducts from
cyclohexyne and 1,2-cyclohexadiene.
Scheme 3. Generation of 1,2-cyclohexadiene 22 from
cyclohexenyl triflate 21.
a
b
h
Entry
Base
19f (%)
27+28 (%)
c,e
1
Mg(Ni-Pr
2
2
)
2
2
·2LiCl
·2LiCl
36
10
17
12
2
3
Mg(Ni-Pr
)
34
Fig. 2. ORTEP drawing of the molecular structure of (±)-
endo-23 with thermal ellipsoids at 30% probability levels.
Mg(NEt
Mg(Ni-Prt-Bu)
Mg(TMP) ·2LiCl
2
)
2
·2LiCl
22
f
d
d
4
2
·2LiCl
–
–
5
2
38
35
g
d
d
6
TMPMgCl·LiCl
LiTMP
–
–
h
7
13
48
33
14
h
8
LDA
a
Reaction conditions: cyclohexenyl triflate 24 (0.60 mmol), base
1.8 mmol), 1,3-diphenylisobenzofuran (18) (0.90 mmol), THF, 60
(
b
1
°
C, 3 h. Yields determined from H NMR spectra using 1,1,2,2-
c
d
tetrachloroethane as internal standard. Reaction conditions: rt, 8 h.
e
f
g
Not observed. Recovery of 24: 10%. Recovery of 24: 8%.
Recovery of 24: 82%. Reaction conditions: 0 °C, 30 min.
h
2
.2.3. Generation of 1,2-cyclohexadiene from cyclohexenyl
triflate bearing two methyl groups at the 3-position
Encouraged by these results, we envisaged that cyclohexenyl
triflate 15, bearing two methyl substituents at the same allylic
position, would favor the generation of 1,2-cyclohexadiene rather
Fig. 3. ORTEP drawing of the molecular structure of (±)-exo-
2
3 with thermal ellipsoids at 30% probability levels.

5
than cyclohexyne. Cyclohexenyl triflate 15 was readily prepared
from inexpensive 3-methyl-2-cyclohexenone (14) by one-pot 1,4-
addition using MeLi/CuI followed by triflation of the resulting
enolate (Scheme 4). The starting triflate 15 was treated with
The generated 4,4-dimethyl-1,2-cyclohexadiene (16) also
underwent [3+2] cycloaddition with nitrone 31 under heating to
give a mixture of isoxazolidines endo-32 and endo-33 in 57%
combined yield (Scheme 5). The regioisomers were identified
1
Mg(TMP) ·2LiCl in the presence of isobenzofuran 18 at 60 °C
from the coupling pattern of the alkenyl proton in the H NMR
2
22
for 3 h to give cycloadducts 29 and 30 in 49% and 38% yields
Table 4, entry 1). These results showed that the additional
spectrum. The endo stereochemistry was confirmed by nuclear
Overhauser effect (NOE) experiments, with an NOE observed
between the allylic methine proton on the cyclohexene ring and
the proton on the phenyl group, in accordance with a previous
(
methyl group led to exclusive generation of 1,2-cyclohexadiene.
Using Mg(Ni-Pr ) ·2LiCl resulted in a slight improvement in the
2
2
1ai
yields of cycloadducts 29 and 30 (entry 2). The combined yield
of cycloadducts 29 and 30 was increased to 98%, compared to
report by the Garg group.
Mg(TMP) ·2LiCl (entry 3).
2
Scheme 4. Synthesis of 3,3-dimethylcyclohexenyl triflate (15)
from commercially available enone 14.
Scheme 5. [3+2] Cycloaddition of 1,2-cyclohexadiene 16 and
nitrone 31.
Table 4. Exclusive generation of 1,2-cyclohexadiene from
cyclohexenyl triflate 15.
a
These results prompted us to conduct [2+2] cycloaddition
using styrene. Mg(TMP) ·2LiCl was added to a THF solution of
2
cyclohexenyl triflate 15 and styrene (34), and the resulting
solution was heated at 60 °C for 3 h to provide a mixture of four
diastereomers 35 and 36 in 82% combined yield (Scheme 6). The
1
structures of the four cycloadducts were assigned using H NMR
24a
spectra, according to a previous report of Moore and Moser
that describes the reaction of nonsubstituted 1,2-cyclohexadiene
and styrene. First, regioisomers 35 and 36 were identified from
their alkenyl proton coupling patterns. Both exo-35 and endo-35
showed a singlet signal corresponding to the alkenyl proton,
while exo-36 and endo-36 showed a multiplet signal in the
olefinic region. The exo/endo stereochemistry was determined by
the chemical shift of the benzylic proton, with endo isomers
showing signals at δ 3.90 and 3.65 ppm (ddd). The downfield
chemical shift was attributed to the deshielding effect of the
carbon–carbon double bond. The ratio of exo- to endo-isomers
was 1.7:1.0.
b
b
Entry
Base
29 (%)
30 (%)
(
endo:exo)
(endo:exo)
38 (28:10)
45 (26:19)
1
2
Mg(TMP)
2
·2LiCl
49 (34:15)
55 (36:19)
60 (44:16)
Mg(Ni-Pr ) ·2LiCl
2 2
c
d
d
3
LiTMP
38 (28:10)
a
Reaction conditions: cyclohexenyl triflate 15 (0.30 mmol), base
0.90 mmol), 1,3-diphenylisobenzofuran (18) (0.45 mmol), THF (1.3
mL), 60 °C, 3 h. Isolated yield. Reaction conditions: 0 °C, 30 min.
(
b
c
d
1
Yields determined from H NMR spectra using 1,1,2,2-
tetrachloroethane as internal standard.
As shown in Table 2, cyclohexenyl triflate 13g, in which the
allylic carbon was substituted with two methyl groups, was
Scheme 6. [2+2] Cycloaddition of 1,2-cyclohexadiene 16 and
styrene (34).
treated with Mg(TMP) ·2LiCl at room temperature in the
2
presence of 1,3-diphenylisobenzofuran (18), affording
23
The 1,2-cyclohexadiene 16 generated using this deprotonative
method underwent various cycloaddition reactions, although the
corresponding cyclohexyne (1) from cyclohexenyl triflate 13a
only reacted smoothly with 1,3-diphenylisobenzofuran (18)
under these conditions. In contrast, a cyclohexyne generated by a
combination of a silylated cyclohexenyl triflate and fluoride ion
underwent [3+2] cycloaddition with nitrone 31 based on the
corresponding cycloadduct 19g in 75% yield. In contrast,
cyclohexenyl triflate 15 was exclusively converted to 1,2-
cyclohexadiene 16, despite bearing an olefinic proton.
Subsequent cycloaddition gave a mixture of cycloadduct 29 and
1
3
0 in 87% combined yield. Careful inspection of the H NMR
spectrum of the crude product indicated no formation of
cycloadduct 19g derived from the corresponding cyclohexyne
and isobenzofuran 18. These contrasting results were attributed
to the steric effect of the two methyl substituents, which
prohibited access of the sterically demanding amide base to the
congested olefinic proton. Furthermore, these results excluded
the possibility of in-situ isomerization between 1,2-
cyclohexadiene 16 and cyclohexyne.
1ai
report of Garg. These results implied that the cycloaddition of
cyclohexynes with various ynophiles, except for 18, was
inhibited by the faster formation of enamine 20 in our
magnesium bisamide-mediated deprotonative method. In the
case of 1,2-cyclohexadiene 16, cyclohexenyl triflate 15 was
converted into cycloadducts 29 and 30 in 87% yield without
detection of the corresponding enamines. These observations
indicated that 1,2-cyclohexadienes were not susceptible to
nucleophilic attack by the amide base, and that the deprotonative
2
.3. [3+2] and [2+2] cycloadditions of cycloallene.

6
Tetrahedron
generation of 1,2-cyclohexadienes has applications in the
construction of such fused cyclic systems.
4.3.1. 6-Methylcyclohex-1-en-1-yl trifluoromethanesulfonate
(13f). A flame-dried two-necked 50-mL flask equipped with a
Teflon-coated magnetic stirring bar and a rubber septum was
charged with THF (3.0 mL). After the flask was cooled to –78
3
. Conclusions
°
C, LDA (1.5 M in THF/heptane/ethylbenzene, 3.7 mL, 5.6
In conclusion, we have developed
a
deprotonative
mmol) was added. To the resulting solution was added 2-
methylcyclohexanone (0.61 mL, 5.0 mmol) in THF (1.0 mL)
dropwise over 3 min, and the resulting solution was stirred at –
generation of highly strained cyclohexyne and 1,2-
cyclohexadiene using magnesium bisamides. When the reaction
was conducted using nonsubstituted cyclohexenyl triflate or
cyclohexenyl triflates bearing substituents at the 6-position,
cyclohexynes were generated. We have also reported the steric
effects of substituents at the 2- and 3-positions of the
cyclohexenyl triflate. Selective allylic deprotonation was
accomplished by introducing two methyl groups at the α-position
of the alkenyl proton in the starting triflate. The resultant 1,2-
cyclohexadiene reacted with nitrone or styrene to afford the
corresponding cycloadducts, apart from cyclohexyne, under the
same reaction conditions. This method allows cyclohexynes and
7
8 °C for 20 min. N-Phenyl-bis(trifluoromethanesulfonimide)
(1.89 g, 5.3 mmol) in THF (6.0 mL) was added, and the reaction
mixture was allowed to warm to room temperature for 40 min.
After the solution was treated with water and diethyl ether, the
resulting mixture was extracted twice with diethyl ether (10 mL).
The combined organic extracts were washed with 1 M aqueous
sodium hydroxide and brine, dried over anhydrous sodium
sulfate, and filtered. The filtrate was concentrated under reduced
pressure to give a crude material, which was purified by silica gel
column chromatography (hexane) to afford the corresponding
cyclohexenyl triflate 13f (0.638 g, 2.61 mmol, 52%) as a
1
,2-cyclohexadienes to be generated in a two-pot conversion
from readily available ketones or enones. Further synthetic
applications of this method will be reported in due course.
colorless oil. R = 0.26 (hexane); The spectroscopic data were
f
25
1
corresponding with those reported in the literature. H NMR
400 MHz, CDCl ): δ 5.73 (td, 1H, J = 4.0, 1.2 Hz), 2.60–2.48 (m,
(
1
4
4
. Experimental Section
3
H), 2.20–2.13 (m, 2H), 1.98–1.88 (m, 1H), 1.72–1.51 (m, 2H),
13
.1. General
1.51–1.41 (m, 1H), 1.14 (d, 3H, J = 6.8 Hz); C NMR (100 MHz,
CDCl ): δ 135.5, 118.7 (q, J = 318 Ηz), 118.4, 32.5, 31.6,
2
1
3
C–F
Analytical thin layer chromatography (TLC) was performed
19
4.6, 19.3, 17.9; F NMR (376 MHz, CDCl ): δ –77.3.
3
on Merck 60 F254 aluminum sheets precoated with a 0.25 mm
thickness of silica gel. Melting points (m.p.) were measured on a
Yanaco MP-J3 and are uncorrected. Infrared (IR) spectra were
recorded on a Bruker Alpha with an ATR attachment (Ge) and
4.3.2. 2-Phenylcyclohex-1-en-1-yl trifluoromethanesulfonate (21).
A flame-dried two-necked 50-mL flask equipped with a Teflon-
coated magnetic stirring bar and a rubber septum was charged
with NaH (60% in oil, 0.234 g, 5.9 mmol) and DMF (15 mL).
After the resulting suspension was cooled to 0 °C, 2-
phenylcyclohexanone (0.869 g, 5.0 mmol) in DMF (5.0 mL) was
added dropwise. After the reaction mixture was allowed to warm
–1
1
13
are reported in wave numbers (cm ). H NMR (400 MHz),
C
19
NMR (100 MHz), and F NMR (376 MHz) spectra were
measured on a JEOL ECZ400 spectrometer. Chemical shifts for
1
H NMR are reported in parts per million (ppm) downfield from
tetramethylsilane with the solvent resonance as the internal
to room temperature and stirred for
1
h, N-Phenyl-
standard (CHCl : δ 7.26 ppm) and coupling constants are in
bis(trifluoromethanesulfonimide) (1.82 g, 5.1 mmol) in DMF
(8.0 mL) was added to the flask, at which time the reaction was
stirred for 22 h. The reaction was quenched with water and
diluted with diethyl ether. After the resulting mixture was
extracted twice with diethyl ether (15 mL), the combined organic
extracts were washed twice with water and brine. The organic
extracts were dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to give a
crude material, which was purified by silica gel column
3
Hertz (Hz). The following abbreviations are used for spin
multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m =
13
multiplet, and br = broad. Chemical shifts for C NMR are
reported in ppm from tetramethylsilane with the solvent
resonance as the internal standard (CDCl : δ 77.16 ppm).
3
19
Chemical shifts for F NMR are reported in ppm from CFCl3
where C F (δ –164.9 ppm) was used as the internal standard.
6
6
High-resolution mass spectra (HRMS) were performed on a
JEOL JMS-T100LP AccuTOF LC-Plus (ESI) with a JEOL MS-
chromatography (hexane/Et O = 9:1) to afford the corresponding
2
5
414DART attachment. The experimental protocol of preparation
cyclohexenyl triflate 21 (1.00 g, 3.26 mmol, 65%) as a colorless
of the metal amides and the physicochemical data of cyclic enol
oil. R = 0.44 (hexane/Et O = 9:1); The spectroscopic data were
corresponding with those reported in the literature. H NMR
f
2
26 1
triflates 13a-e and 13g-j, cycloadducts 19a-e, 19g-j were
8a,8b
described in our previous report.
.2. Materials
Unless otherwise stated, all reactions were conducted in
(400 MHz, CDCl ): δ 7.41–7.21 (m, 5H), 2.53–2.44 (m, 4H),
3
13
1
.92–1.83 (m, 2H), 1.83–1.73 (m, 2H); C NMR (100 MHz,
CDCl ): δ 143.9, 137.1, 131.2, 128.4, 128.2, 128.0, 118.2 (q, J
4
1
3
C–
19
=
318 Ηz), 31.4, 28.2, 23.1, 22.1; F NMR (376 MHz, CDCl3):
F
δ –78.3.
flame-dried glassware under an inert atmosphere of argon. All
work-up and purification procedures were carried out with
reagent solvents in air. Unless otherwise noted, materials were
obtained from commercial suppliers and used without further
purification. Flash column chromatography was performed on
4
.3.3. 3-Methylcyclohex-1-en-1-yl trifluoromethanesulfonate (24).
A flame-dried two-necked 500-mL flat-bottomed flask equipped
with a Teflon-coated magnetic stirring bar and a rubber septum
was charged with CuI (1.90 g, 10 mmol) and anhydrous diethyl
ether (10 mL). After the resulting suspension was cooled to 0 °C,
MeLi (3.0 M in diethoxymethane, 6.7 mL, 20 mmol) was added
dropwise over 3 min. The pale yellow solution was stirred for 30
min, at which time the flask was cooled to –78 °C. To the
solution was added 2-cyclohexen-1-one (0.96 mL, 10 mmol) in
THF (10 mL) dropwise over 3 min, and the resulting solution
was stirred at –78 °C for 2 h. The reaction mixture was allowed
®
Wakogel C-300 (45–75 µm, Fujifilm Wako Pure Chemical
Co.). Recycling preparative SEC-HPLC was performed with LC-
9
201 (Japan Analytical Industry Co., Ltd.) equipped with
preparative SEC columns (JAI-GEL-1H and JAI-GEL-2H).
Anhydrous THF was purchased from Wako Pure Chemical
Industries, Ltd.
4
.3. Preparation of cyclohexenyl triflates
to warm to
0
°C and stirred for
2
h. N-Phenyl-
bis(trifluoromethanesulfonimide) (3.76 g, 10.5 mmol) in THF (21

7
mL) was added to the flask via cannula, and the reaction mixture
was stirred at 0 °C for 3 h. The reaction mixture was allowed to
warm to room temperature and stirred for 2 h. The reaction was
quenched with saturated aqueous ammonium chloride. To the
reaction mixture was added hexane, and the mixture was
transferred to a separatory funnel. After separation of the organic
layer, and the aqueous layer was extracted with hexane three
times. The combined organic extracts were washed with brine,
dried over anhydrous magnesium sulfate, and filtered. The filtrate
was concentrated under reduced pressure to give a crude
material, which was purified by silica gel column
chromatography (hexane) to afford the corresponding
cyclohexenyl triflate 24 (1.17 g, 4.79 mmol, 48%) as a colorless
over anhydrous sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material,
which was purified by silica gel column chromatography
hexane/CH Cl2 = 5:1 to 3:1, gradient) to afford the title
compound the endo-23 (white solid, 129 mg, 0.302 mmol, 60%)
and exo-23 (pale greenish yellow solid, 43.4 mg, 0.102 mmol,
(
2
2
0%), respectively.
4
.4.2. rac-(9R,9aS,10S)-9,9a,10-triphenyl-1,2,3,9,9a,10-
18b
hexahydro-9,10-epoxyanthracene (endo-23)
Rf
=
0.12
–1
(
hexane/CH Cl = 5:1); M.p. 192–193 °C; IR (ATR, cm ): 3060,
034, 2941, 1601, 1494, 1456, 1306, 1001, 909, 741, 699; H
NMR (400 MHz, CDCl ): δ 8.04–7.99 (m, 2H), 7.62–7.48 (m,
H), 7.46–7.40 (m, 2H), 7.31–7.12 (m, 6H), 7.01–6.91 (m, 5H),
5.95 (dd, 1H, J = 4.8, 3.2 Hz), 2.67 (dt, 1H, J = 12.0, 3.6 Hz).
.03–1.81 (m, 2H), 1.57– 1.47 (m, 1H), 1.34–1.19 (m, 1H), 0.95
(td, 1H, J = 12.8, 4.0 Hz); C NMR (100 MHz, CDCl ): δ 150.2,
147.7, 145.3, 142.3, 137.9, 135.2, 129.7, 128.8, 128.7, 128.5,
127.9, 127.5, 127.0, 126.8, 125.7, 125.6, 125.4, 123.5, 122.1,
2
2
1
3
3
4
–1
oil. R = 0.22 (hexane); IR (ATR, cm ): 2936, 2873, 1416, 1244,
f
1
1
205, 1142, 978, 958, 882, 810, 609; H NMR (400 MHz,
2
13
CDCl ): δ 5.62 (m, 1H), 2.47–2.21 (m, 3H), 1.93–1.83 (m, 1H),
3
3
1
.82–1.62 (m, 2H), 1.23–1.12 (m, 1H), 1.05 (d, 3H, J = 6.8 Hz);
13
1
C NMR (100 MHz, CDCl ): δ 149.3, 124.2, 118.7 (q, J
=
3
C–F
19
+
3
18 Hz), 30.0, 29.8, 27.6, 21.5, 21.0; F NMR (376 MHz,
117.5, 93.5, 89.3, 56.7, 32.1, 24.1, 18.8; HRMS (DART ) m/z:
+
+
CDCl ): δ –77.0; HRMS (DART ) m/z: calcd. for C H F O S,
2
calcd. for C32
H
27O, 427.2062 [M+H] ; found, 427.2063.
3
8
12
3
3
+
45.0459 [M+H] ; found, 245.0448.
4
.4.3.
rac-(9R,9aR,10S)-9,9a,10-triphenyl-1,2,3,9,9a,10-
18b
4
.3.4. 3,3-Dimethylcyclohex-1-en-1-yl trifluoromethanesulfonate
hexahydro-9,10-epoxyanthracene (exo-23)
(hexane/CH Cl = 5:1); M.p. 230–231 °C; IR (ATR, cm ): 3031,
2947, 1602, 1497, 1447, 1305, 998, 909, 743, 700; H NMR (400
MHz, CDCl ): δ 7.88–7.83 (m, 2H), 7.77–7.72 (m, 2H), 7.58 (dd,
R
f
=
0.21
–
1
(
15). A flame-dried 100-mL Schlenk tube equipped with a
2
2
1
Teflon-coated magnetic stirring bar and a rubber septum was
charged with CuI (2.82 g, 14.8 mmol) and anhydrous diethyl
ether (15 mL). After the resulting suspension was cooled to 0 °C,
MeLi (3.0 M in diethoxymethane, 9.9 mL, 30 mmol) was added
dropwise over 4 min. The pale yellow solution was stirred for 30
min, at which time it was cooled to –78 °C. To the solution was
added 3-methyl-2-cyclohexen-1-one (1.68 mL, 14.8 mmol) in
THF (15 mL) dropwise over 10 min, and the resulting solution
was stirred at –78 °C for 1.5 h. The reaction mixture was allowed
3
2H, J = 7.6, 7.6 Hz), 7.49 (dd, 2H, J = 7.6, 7.6 Hz), 7.47–7.34
(m, 4H), 7.32–7.27 (m, 1H), 7.13–7.04 (m, 2H), 6.90–6.82 (m,
2H), 6.76 (brs, 1H), 6.01 (brs, 1H), 5.78 (dd, 1H, J = 6.8, 2.8 Hz),
1
3
2.01–1.83 (m, 2H), 1.55–1.35 (m, 3H), 1.32–1.15 (m, 1H);
C
NMR (100 MHz, CDCl ): δ 148.9, 146.9, 144.8, 141.3, 137.6,
3
136.6, 128.6, 128.1, 127.6, 127.5, 127.0, 126.7, 126.5, 126.4,
126.1, 126.0, 120.9, 119.7, 119.2, 92.1, 89.9, 56.3, 30.5, 21.3,
17.6 (one aromatic signal is missing due to overlapping); HRMS
to warm to
0 °C and stirred for 2.5 h. N-Phenyl-
+
+
bis(trifluoromethanesulfonimide) (5.57 g, 15.6 mmol) in THF (21
mL) was added, and the reaction mixture was allowed to warm to
room temperature for 4 h. The reaction was quenched with
saturated aqueous ammonium chloride. To the reaction mixture
was added hexane, and the mixture was transferred to a
separatory funnel. After separation of the organic layer, and the
aqueous layer was extracted with hexane three times. The
combined organic extracts were washed with 1 M aqueous
sodium hydroxide and brine, dried over anhydrous sodium
sulfate, and filtered. The filtrate was concentrated under reduced
pressure to give a crude material, which was purified by silica gel
column chromatography (hexane) to afford the corresponding
cyclohexenyl triflate 15 (2.03 g, 7.86 mmol, 53%) as a colorless
(DART ) m/z: calcd. for C32
H
27O, 427.2062 [M+H] ; found,
427.2053.
4
.4.4. Generation of cyclohexyne 25 and cycloallene 26 from
cyclohexenyl triflate 24. A flame-dried 20-mL Schlenk tube
equipped with a Teflon-coated magnetic stirring bar and a rubber
septum was charged with cyclohexenyl triflate 24 (146.5 mg,
.600 mmol), 1,3-diphenylisobenzofuran (18) (246 mg, 0.91
mmol), and anhydrous THF (2.3 mL). To the mixture was added
0
Mg(TMP) ·2LiCl (0.305 M, 5.9 mL, 1.8 mmol, 3.0 equiv) at
2
room temperature. After stirring at 60 °C for 3 h, the reaction
mixture was treated with saturated aqueous ammonium chloride.
The resulting mixture was extracted twice with diethyl ether (2
mL). The combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material,
which was purified by silica gel column chromatography
(hexane/CH Cl = 5:1 to 1:1, gradient) to afford a mixture of
cycloadducts with cyclohexyne (19f: 38%) and 1,2-
cyclohexadiene (27 and 28: 35%). The yields of cycloadducts
9f, 27 and 28 were determined by H NMR analysis using
,1,2,2-tetrachloroethane (50.2 mg, 0.299 mmol) as an internal
–
1
oil. R = 0.22 (hexane); IR (ATR, cm ): 2961, 2871, 1417, 1245,
f
1
1
5
6
142, 1025, 952, 880, 849, 608; H NMR (400 MHz, CDCl ): δ
.51 (s, 1H), 2.27 (td, 2H, J = 6.4, 1.6 Hz), 1.79 (tt, 2H, J = 6.4,
.0 Hz), 1.45–1.40 (m, 2H), 1.06 (s, 6H); C NMR (100 MHz,
CDCl ): δ 148.4, 128.1, 118.7 (q, J
3
13
1
2
2
= 318 Ηz), 36.0, 33.1,
3
C–F
19
2
9.3, 27.7, 19.9; F NMR (376 MHz, CDCl ): δ –76.9; HRMS
3
+ +
(
DART ) m/z: calcd. for C H F O S, 259.0616 [M+H] ; found,
9 14 3 3
1
1
2
59.0607.
1
4
.4. [4+2] Cycloaddition with 1,3-Diphenylisobenzofuran
standard by comparing relative values of integration for the peaks
observed at 0.73 ppm and 0.60 ppm (19f: 3 protons) and 5.74–
4
.4.1. Generation of 1-phenyl-1,2-cyclohexadiene (22) from the
5
.45 ppm 27 and 28: 1 proton) with that of 1,1,2,2-
cyclohexenyl triflate 21. A flame-dried 20-mL Schlenk tube
equipped with a Teflon-coated magnetic stirring bar and a rubber
septum was charged with cyclohexenyl triflate 21 (155.2 mg,
tetrachloroethane observed at 5.96 ppm. Cycloadducts endo-19f
and exo-19f were prepared by the same reaction of 6-
methylcyclohex-1-en-1-yl trifluoromethanesulfonate (13f) and
isobenzofuran 18.
0
.507 mmol), 1,3-diphenylisobenzofuran (18) (207 mg, 0.77
mmol), and anhydrous THF (1.5 mL). To the mixture was added
Mg(TMP) ·2LiCl (0.272 M, 5.6 mL, 1.5 mmol) at room
4.4.5.
1-Methyl-9,10-diphenyl-1,2,3,4,9,10-hexahydro-9,10-
2
temperature. After stirring at 60 °C for 3 h, the reaction mixture
was treated with saturated aqueous ammonium chloride. The
resulting mixture was extracted twice with diethyl ether (2 mL).
The combined organic extracts were washed with brine, dried
epoxyanthracene (19f). The title compound was synthesized in
72% yield as a 3:2 diastereomeric mixture from cyclohexenyl
triflate 13f and isobenzofuran 18. R = 0.15–0.10 (hexane/CH Cl
2
f
2
–1
= 5:1); IR (ATR, cm ): 2931, 2869, 1451, 1307, 998, 909, 745,

8
Tetrahedron
1
7
33, 702; H NMR (400 MHz, CDCl ): δ 7.88–7.79 (m, 2H),
1H), 2.12–2.01 (m, 1H), 1.99–1.84 (m, 1H), 1.39–1.28 (m, 1H),
3
13
7
7
.75–7.70 (m, 1H), 7.68–7.63 (m, 1H), 7.55–7.31 (m, 7H), 7.24–
.15 (m, 1H), 7.05–6.91 (m, 2H), 2.88–2.76 (m, 0.6H), 2.53–2.43
1.18–1.14 (m, 1H), 0.78 (s, 3H), 0.64 (s, 3H); C NMR (100
MHz, CDCl ): δ 150.1, 145.2, 139.9, 137.8, 136.8, 128.5, 127.7,
27.5, 127.32, 127.27, 126.8, 126.6, 126.2, 119.6, 118.5, 118.3,
3
1
8
(m, 0.4H), 2.32–2.21 (m, 1H), 2.06–1.88 (m, 1H), 1.82–1.70 (m,
+
9.1, 88.6, 56.4, 38.9, 33.9, 31.0, 23.2, 18.5; HRMS (DART )
0
0
.6H), 1.66–1.55 (m, 2H), 1.44–1.32 (m, 0.8H), 1.11–1.01 (m,
.6H), 0.73 (d, 1.8H, J = 6.8 Hz), 0.60 (d, 1.2H, J = 7.2 Hz);
+
13
m/z: calcd. for C H O, 379.2062 [M+H] ; found, 379.2044.
C
28 27
NMR (100 MHz, CDCl ): δ 153.9, 153.1, 152.7, 152.1, 151.7,
3
4
1
.4.9.
rac-(9S,9aR,10S)-3,3-Dimethyl-9,10-diphenyl-
The
1
1
1
9
1
51.5, 149.7, 136.7, 135.8, 135.6, 135.5, 128.9, 128.7, 128.5,
28.44, 128.41, 127.73, 127.66, 127.5, 126.4, 126.1, 125.3,
24.74, 124.68, 124.5, 120.9, 119.2, 118.93, 118.89, 93.2, 92.01,
1.98, 91.6, 31.7, 30.6, 29.5, 27.1, 24.2, 24.0, 20.5, 19.3, 18.3,
,2,3,9,9a,10-hexahydro-9,10-epoxyanthracene (exo-30)
.
title compound was obtained as a colorless solid in 15% yield
16.9 mg, 0.045 mmol) from cyclohexenyl triflate 15 (0.299
mmol) according to the above procedure. Rf 0.15
(hexane/CH Cl = 5:1); M.p. 101–104 °C; IR (ATR, cm ): 2954,
(
+
=
–1
7.4; HRMS (DART ) m/z: calcd. for C H O, 365.1905
27
25
+
2
2
[
M+H] ; found, 365.1899.
1
2
930, 2860, 1457, 1449, 1211, 1020, 872, 739, 702, 666; H
4
.4.6. The mixture of cycloadducts 27 and 28 from 1,2-
NMR (400 MHz, CDCl ): δ 7.77–7.72 (m, 2H), 7.70–7.64 (m,
3
–1
cyclohexadiene 26. IR (ATR, cm ): 2931, 2853, 1452, 1339, 997,
7
3
2H), 7.58–7.47 (m, 4H), 7.45–7.35 (m, 2H), 7.31–7.26 (m, 1H),
7.18–7.10 (m, 3H), 5.32–5.30 (m, 1H), 2.53 (ddd, 1H, J = 12.0,
4.0, 0.8 Hz), 1.71–1.62 (m, 1H), 1.37–1.23 (m, 2H), 0.97 (s, 3H),
+
45, 702, 633; HRMS (DART ) m/z: calcd. for C H O,
27 25
+
65.1905 [M+H] ; found, 365.1896.
1
3
0
1
1
3
.95–0.85 (m, 1H), 0.77 (s, 3H); C NMR (100 MHz, CDCl ): δ
3
4
.4.7. Generation of 1,2-cyclohexadiene 16 from cyclohexenyl
50.2, 144.7, 139.9, 137.1, 136.3, 128.8, 128.5, 127.5, 127.3,
26.9, 126.6, 126.1, 125.9, 120.1, 117.8, 89.7, 88,8, 48.5, 37.8,
3.0, 31.1, 30.1, 24.6 (one aromatic signal is missing due to
triflate 15. A flame-dried 20-mL Schlenk tube equipped with a
Teflon-coated magnetic stirring bar and a rubber septum was
charged with cyclohexenyl triflate 15 (77.2 mg, 0.299 mmol),
+
overlapping); HRMS (DART ) m/z: calcd. for C H O, 379.2062
28
27
1
,3-diphenylisobenzofuran (18) (123.6 mg, 0.457 mmol), and
anhydrous THF (1.27 mL). To the mixture was added Mg(Ni-Pr-
2)2·2LiCl (0.319 M, 2.81 mL, 0.90 mmol, 3.0 equiv) at room
+
[
M+H] ; found, 379.2061.
4
1
.4.10.
rac-(9R,9aR,10R)-1,1-Dimethyl-9,10-diphenyl-
temperature. After stirring at 60 °C for 3 h, the reaction mixture
was treated with saturated aqueous ammonium chloride. The
resulting mixture was extracted twice with diethyl ether (2 mL).
The combined organic extracts were washed with brine, dried
over anhydrous sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material.
,2,3,9,9a,10-hexahydro-9,10-epoxyanthracene (endo-29) and
rac-(9S,9aS,10S)-3,3-Dimethyl-9,10-diphenyl-1,2,3,9,9a,10-
hexahydro-9,10-epoxyanthracene (endo-30). The title compounds
1
were obtained as a pale green solid in 62% H NMR yields
(endo-29/endo-30 = 36:26) (71.0 mg, 0.187 mmol) from
1
cyclohexenyl triflate 15 (0.299 mmol) according to the above
procedure. R = 0.27 (endo-30), 0.24 (endo-29) (hexane/CH Cl =
The yields of cycloadducts 29 and 30 were determined by H
f
2
2
NMR analysis using 1,1,2,2-tetrachloroethane (37.8 mg, 0.225
mmol) as an internal standard by comparing relative values of
integration for the peaks observed at 5.70–5.66 ppm (endo) and
5
5
–1
1
7
2
7
5
3
1
3
:1); IR (ATR, cm ): 2953, 2931, 1455, 1355, 1303, 988, 904,
53, 700, 562; H NMR (400 MHz, CDCl ): δ 8.00–7.93 (m,
1
3
H), 7.90–7.81 (m, 4H), 7.73–7.68 (m, 2H), 7.62–7.58 (m, 1H),
.53–7.35 (m, 12H), 7.26–7.17 (m, 5H), 7.17–7.08 (m, 2H),
.70–5.66 (m, 1H (endo-29)), 5.38 (d, 1H, J = 2.8 Hz (endo-30)),
.32–3.27 (m, 1H), 3.11–3.02 (m, 1H), 2.20–2.02 (m, 2H), 1.91–
.77 (m, 1H), 1.60–1.41 (m, 3H), 1.21–1.13 (m, 1H), 1.05 (s,
H), 0.98 (s, 3H), 0.66–0.56 (m, 1H), 0.55 (s, 3H), 0.08 (s, 3H);
.66–5.61 ppm (exo) (29: 1 proton), and 5.38 ppm (endo) and
.32–5.30 ppm (exo) (30: 1 proton) with that of 1,1,2,2-
tetrachloroethane observed at 5.96 ppm. Silica gel
chromatography (hexane/CH Cl = 5:1 to 1:1, gradient) of the
2
2
crude material provided analytically pure exo-29 (16%), exo-30
15%), and a mixture of endo-29 and endo-30.
(
13
C NMR (100 MHz, CDCl ): δ 148.6, 148.5, 144.5, 143.8,
3
1
1
42.10, 142.05, 138.2, 138.0 135.4, 134.9, 130.8, 129.0, 128.8,
28.6, 128.52, 128.46, 128.4, 128.2, 128.1, 127.3, 127.1, 127.0,
Structure elucidation of four regio- and stereoisomers. We
1
identified the structure of the four cycloadducts by H NMR
5b
spectra, according to the Guitián’s report. The regioisomers 29
and 30 were determined by their coupling pattern of the alkenyl
proton (29: multiplet, 30: doublet). In addition, the exo/endo
stereochemistry was determined by chemical shifts of the allylic
methine proton. Guitián reported that the chemical shifts of the
allylic methine proton of the cycloadducts with 1,2-
cyclohexadiene and isobenzofuran 18 was observed at 3.05 ppm
125.9, 125.7, 123.8, 121.5, 118.7, 118.3, 118.0, 90.5, 90.4, 89.9,
89.4, 58.0, 49.1, 39.8, 37.8, 33.6, 32.7, 31.1, 30.7, 29.4, 24.6,
23.9, 19.2; HRMS (DART ) m/z: calcd. for C28
[M+H] ; found, 379.2055.
+
H27O, 379.2062
+
4
.5. [3+2] Cycloaddition with nitrone
A flame-dried 20-mL Schlenk tube equipped with a Teflon-
(
endo) and 2.52 ppm (exo). They also determined the structure of
coated magnetic stirring bar and a rubber septum was charged
with cyclohexenyl triflate 15 (129 mg, 0.499 mmol), nitrone 31
endo-isomer absolutely by X-ray crystallography. In this case,
the peaks of methine proton of 29 were observed at 3.32–3.27
ppm and 2.61–2.56 ppm. We assigned the former one is endo-
isomer and the latter one is exo-isomer by comparing these
chemical shifts.
(179 mg, 1.01 mmol), and anhydrous THF (2.1 mL). To the
mixture was added Mg(TMP) ·2LiCl (0.312 M, 6.4 mL, 2.0
2
mmol) at room temperature. After stirring at 60 °C for 5 h, the
reaction mixture was treated with saturated aqueous ammonium
chloride. The resulting mixture was extracted twice with diethyl
ether (2 mL). The combined organic extracts were washed with
brine, dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude material,
which was purified by silica gel column chromatography
4
1
.4.8.
rac-(9R,9aS,10R)-1,1-Dimethyl-9,10-diphenyl-
,2,3,9,9a,10-hexahydro-9,10-epoxyanthracene (exo-29). The
title compound was obtained as a colorless solid in 16% yield
18.6 mg, 0.049 mmol) from cyclohexenyl triflate 15 (0.299
0.19
hexane/CH Cl = 5:1); M.p. 149–152 °C; IR (ATR, cm ): 2917,
(
mmol) according to the above procedure. Rf –
(
=
1
2
2
(hexane/ethyl acetate = 9:1) to afford a mixture of cycloadducts
1
2
871, 1448, 1017, 979, 741, 704, 644, 555; H NMR (400 MHz,
3
2 and 33 as major exo isomers (81.4 mg, 0.285 mmol, 57%) as a
CDCl ): δ 7.87–7.83 (m, 2H), 7.82–7.77 (m, 2H), 7.55 (t, 2H, J =
3
brown oil. The ratio of endo- and exo-isomers was determined by
7
.6 Hz), 7.48 (t, 2H, J = 7.6 Hz), 7.46–7.41 (m, 2H), 7.38–7.34
1
H NMR analysis by comparing relative values of integration for
(m, 2H), 7.20–7.11 (m, 2H), 5.66–5.61 (m, 1H), 2.61–2.56 (m,

9
the peaks observed at 4.33–4.12 ppm, according to the report by
Garg.
JP18H04413 in the Middle Molecular Strategy, the JSPS
predoctoral fellowship (for Y.H.), Tonen General Sekiyu
Research Development Encouragement Scholarship
1ai
&
4
2
.5.1.rac-(3S,7aS)-2-(tert-Butyl)-7,7-dimethyl-3-phenyl-
,3,5,6,7,7a-hexahydrobenzo[d]isoxazole (endo-32) and rac-
Foundation, the Harmonic Ito Foundation, and Foundation for
Interaction in Science & Technology. We also thank Dr. Shigeki
Mori and Ms. Rimi Konishi (Integrated Centre for Sciences,
Ehime University) for the X-ray crystallographic analysis. We
thank Simon Partridge, PhD, from Edanz Group
(
3R,7aR)-2-(tert-Butyl)-5,5-dimethyl-3-phenyl-2,3,5,6,7,7a-
0.3 – 0.4
hexahydro-benzo[d]isoxazole (endo-33). – Rf
=
1
(hexane/ethyl acetate = 9:1); IR (ATR, cm ): 2956, 2927, 2866,
1
1
7
5
3
3
454, 1362, 1222, 1084, 703; H NMR (400 MHz, CDCl ): δ
3
(
www.edanzediting.com/ac) for editing a draft of this manuscript.
.50–7.44 (m, 2H), 7.33–7.26 (m, 2H), 7.24–7.18 (m, 1H), 5.31–
.26 (m, 0.44H (endo-32)), 5.12 (d, 0.56H, J = 1.2 Hz (endo-
3)), 4.49 (brs, 0.56H (endo-33)), 4.48–4.45 (m, 0.44H (endo-
2)), 4.33–4.27 (m, 0.56H (endo-33)), 4.16–4.12 (m, 0.44H
5. References and notes
1
.
Cycloalkynes: (a) Scardiglia, F.; Roberts, J. D. Tetrahedron 1957,
, 343–344. (b) Wittig, G.; Pohlke, R. Chem. Ber. 1961, 94, 3276–
286. (c) Hoffman, R. W. Dehydrobenzene and Cycloalkynes
Academic Press, New York, 1967, pp. 317–361. (d) Buchwald, S.
L.; Nielsen, R. B. Chem. Rev. 1988, 88, 1047–1058. (e) Yoshida,
H.; Tanino, K.; Ohshita, J.; Kunai, A. Angew. Chem. Int. Ed.
(endo-32)), 2.09–1.20 (m, 4H), 1.13 (s, 1.3H (endo-32)), 1.07 (s,
1
3
4
3
.9H (endo-33)), 1.06 (s, 4.0H (endo-32)), 0.98 (s, 1.7H (endo-
3)), 0.90 (s, 1.7H (endo-33)), 0.82 (s, 1.3H (endo-32)); HRMS
+
+
(DART ) m/z: calcd. for C H NO, 286.2171 [M+H] ; found,
19 28
2
86.2167.
2
004, 43, 5052–5055. (f) Fujita, M.; Kim, W. H.; Sakanishi, Y.;
Fujiwara, K.; Hirayama, S.; Okuyama, T.; Ohki, Y.; Tatsumi, K.;
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M.; Kim, W. H.; Fujiwara, K.; Okuyama, T. J. Org. Chem. 2005,
4
.6. [2+2] Cycloaddition with styrene
A flame-dried 20-mL Schlenk tube equipped with a Teflon-
7
0, 480–488. (h) Peña, D.; Iglesias, B.; Quintana, I.; Pérez, D.;
coated magnetic stirring bar and a rubber septum was charged
with cyclohexenyl triflate 15 (79.8 mg, 0.309 mmol), styrene (34:
1
Guitián, E.; Castedo, L. Pure Appl. Chem. 2006, 78, 451–455. (i)
Gampe, C. M.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51,
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3
766–3778. (j) Sloan Devlin, A.; Du Bois, J. Chem. Sci. 2013, 4,
mixture was added Mg(TMP) ·2LiCl (0.293 M, 3.16 mL, 0.93
1059–1063. (k) Medina, J. M.; McMahon, T. C.; Jiménez-Osés,
G.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2014, 136,
2
mmol) at room temperature. After stirring at 60 °C for 5 h, the
reaction mixture was treated with saturated aqueous ammonium
chloride. The resulting mixture was extracted twice with diethyl
ether (2 mL). The combined organic extracts were washed with
brine, dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude material,
which was purified by silica gel column chromatography
1
2
2
4706–14709. (1) Tlais, S. F.; Danheiser, R. L. J. Am. Chem. Soc.
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(hexane) to afford a mixture of 35 and 36 (53.7 mg, 0.253 mmol,
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2%) as a colorless oil.
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structure of the four cycloadducts was identified by H NMR
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isomers have signals at δ 3.90 and 3.65 ppm (ddd). The
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0
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.6.1. 3,3-Dimethyl-7-phenylbicyclo[4.2.0]oct-1-ene (35) and
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.60 (hexane); IR (ATR, cm ): 3027, 2953, 2921, 2863, 1495,
452, 1361, 745, 697; H NMR (400 MHz, CDCl ): δ 7.34–7.14
1
1
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3
(
(
m, 5H), 5.38–5.30 (m, 0.15H (endo-36)+0.30H (exo-36)), 5.17
brs, 0.21H (endo-35)), 5.14 (brs, 0.34H (exo-35)), 3.89 (ddd,
2
Darzi, E. R.; Knapp, R. R.; Liu, F.; Houk, K. N.; Garg, N. K. Nat.
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0
9
1
0
2
.15H, J = 9.6, 9.6, 3.2 Hz (endo-36)), 3.64 (ddd, 0.21H, J = 9.6,
.6, 2.4 Hz (endo-35)), 3.30–2.69 (m, 3.6H), 2.10–1.86 (m,
.3H), 1.55–0.64 (m, 2.7H), 1.02, 1.00, 0.97 (s, total 3H), 0.92,
+
.89, 0.85 (s, total 3H); HRMS (DART ) m/z: calcd. for C H ,
16
21
+
13.1643 [M+H] ; found, 213.1636.
2
.
Acknowledgements
This work was financially supported by JSPS KAKENHI
Grant Numbers JP16K05774 in Scientific Research (C),
JP19H02717 in Scientific Research (B), JP16H01153 and
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140–3152. (e) Yoshida, S. Bull. Chem. Soc. Jpn. 2018, 91, 1293–

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Tetrahedron
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1986950).
1
1
1
1
5
6
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2
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1
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
1
(
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Highlights
Ms. Ref. No.: TET-D-20-00144
Steric effects on deprotonative generation of cyclohexynes and 1,2-cyclohexadienes from
cyclohexenyl triflates by magnesium amides
Corresponding author: Kentaro Okano
E-mail: okano@harbor.kobe-u.ac.jp
•
A deprotonative generation of highly strained cyclohexynes and 1,2-cyclohexadienes from
cyclohexenyl triflates using magnesium bisamides.
•
•
•
Substituted cyclohexenyl triflates readily prepared from ketones or enones.
Reaction pathway determined by steric effects of substituents on the cyclohexenyl ring.
Cycloaddition
of
a
1,2-cyclohexadiene
with
1,3-diphenylisobenzofuran,
α-phenyl-N-tert-butylnitrone, or styrene to afford the corresponding cycloadducts.

Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: