Ligand-Effect in Gold(I)-Catalyzed Rautenstrauch Rearrangement: Regio- and Stereoselective Synthesis of Bicyclo[3.2.1]octa-3,6-dienes through Cyclodimerization of 1-Ethynyl-2-propenyl Esters

Article abstract of DOI:10.1021/acs.joc.7b02816

Gold(I) complexes bearing sterically demanding phosphine ligands such as ^tBuXphos catalyze the cascade Rautenstrauch rearrangement/[4 + 3] cycloaddition of 1-ethynyl-2-propenyl esters. The reaction provides an efficient and straightforward rout

Full text of DOI:10.1021/acs.joc.7b02816

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Article
Ligand-Effect in Gold(I)-Catalyzed Rautenstrauch Rearrangement:
Regio- and Stereoselective Synthesis of Bicyclo[3.2.1]octa-3,6-
dienes through Cyclodimerization of 1-Ethynyl-2-propenyl Esters
Jidong Zhao, Shuang Yang, Xin Xie, Xiangdong Li, and Yuanhong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02816 • Publication Date (Web): 12 Jan 2018
Downloaded from http://pubs.acs.org on January 15, 2018
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Ligand-Effect in Gold(I)-Catalyzed Rautenstrauch Rearrangement: Regio- and
Stereoselective Synthesis of Bicyclo[3.2.1]octa-3,6-dienes through Cyclodimerization
of 1-Ethynyl-2-propenyl Esters
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Jidong Zhao, Shuang Yang, Xin Xie, Xiangdong Li and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of
China
Fax: (+86) 21-64166128, E-mail: yhliu@sioc.ac.cn
R2
R1
R1
OCOR
OCOR
OCOR
R2
R2
R1
R2
R1
OCOR
cat. LAu+
ROCO
R1
(in situ-generated)
toluene, rt
R2
[4+3]-cycloaddition
Au+L
L = tBuXphos
regio- and stereoselective
Rautenstrauch rearrangement/[4+3] cascade
20 examples
up to 85% yield
Abstract: Gold(I) complexes bearing sterically demanding phosphine ligands such as
tBuXphos catalyze the cascade Rantenstrauch rearrangement/[4+3] cycloaddition of
1ꢀethynylꢀ2ꢀpropenyl esters. The reaction provides an efficient and straightforward route to
bicyclo[3.2.1]octaꢀ3,6ꢀdienes with high regioꢀ and stereoselectivity. The formation of the
[4+3] cycloadducts likely proceeds through the cycloaddition of
a
gold(I)
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carbenoid/goldꢀstabilized allyl cation intermediate with cyclopentadiene arised from
Rantenstrauch rearrangement.
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INTRODUCTION
The bridged bicyclo[3.2.1]octanes represent a ubiquitous structural motif existed
in many families of biologically active natural compounds1 such as Enaimeone A,
Clavubicyclone, and Ialibinone A. For example, Clavubicyclone showed a moderate
growth inhibition activity toward tumor cells.1b Ialibinone A exhibited an
antioxidant
activity
in
polymorphonuclear
cells.1c
In
addition,
bicyclo[3.2.1]octaꢀ3,6ꢀdienꢀ2ꢀyl anion or cation have also attracted much attention
because they have often been used for the study of the bishomoaromaticity or
bishomoantiaromaticity due to their unique structures (Figure 1).2 Although various
methods have been developed to construct these carbon bridged sevenꢀmembered
rings,3 most of them require multistep synthesis or their synthetic methods are
restricted to to specific substrates. Therefore, the straightforward access to
bicyclo[3.2.1]octane cores from readily available building blocks under mild
reaction conditions is highly desired.
O
O
O
OH
3
O
O
HO
H
H
bishomoaromate
O
HO
H
2
AcO
O
CO2Me
AcO
Clavubicyclone
bishomoantiaromate
Enaimeone A
Ialibinone A
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Figure 1. Representative Compounds Containing Bicyclo[3.2.1]octane Core
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Homogeneous gold catalysis has emerged as one of the most powerful tools for
the rapid and efficient construction of highly functionalized and architecturally
complex molecules from simple starting materials.4 A particularly attractive strategy
is based on the goldꢀcatalyzed 1,2ꢀacyloxy migration of propargyl esters.5 For
example, in 2005, Toste6a and Gagosz6b reported that PPh3ꢀligated gold(I) complex
could catalyze Rautenstrauch rearrangement7 of 1ꢀethynylꢀ2ꢀpropenyl pivaloates to
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cyclopentenones8 (Scheme 1
a). Recently, Hashmi and Lautens expanded the scope
of this reaction by addition of a proton source into the reaction mixture to facilitate
the hydrolysis of the enol ester intermediate.9 Generally, these reactions are initiated
through the activation of the propargyl moiety by gold catalyst to trigger an efficient
generation of
a
vinyl gold species
I.
Subsequent Nazarovꢀlike
cyclization/1,2ꢀacyloxy migration and hydrolysis furnish the desired
cyclopentenones.9,10 An excellent chirality transfer found in these reactions
indicated that a gold carbenoid species might not be involved.6a Later in 2015, the
Toste group has also disclosed a goldꢀcatalyzed highly enantioselective dearomative
Rautenstrauch rearrangement of the indoleꢀderived propargyl acetals,11 in which a
vinyl gold carbenoid or its resonance structure was proposed as a reaction
intermediate. During our studies on goldꢀcatalyzed cyclization of functionalized
alkynes, we found that the steric and electronic properties of ancillary ligands on
gold catalyst could have a significant impact on the reaction course such as tuning
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the reactivity of gold catalysts, stabilizing the active goldꢀcontaining intermediates
or improving the reaction selectivity.12 Ligand effects have also been found in many
excellent reports described by other groups.13 We found here that when sterically
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t
demanding ligands such as BuXphos were employed instead of PPh3 in the
goldꢀcatalyzed Rautenstrauch rearrangement, an unexpected product of
bicyclo[3.2.1]octaꢀ3,6ꢀdiene was formed with high regioꢀ and stereoselectivity
(Scheme 1
b
). We rationalized that an increase of the steric interaction between the
vinyl moiety and gold in intermediate
I
caused by the bulky ligand on the gold metal
could slow down the Nazarov cyclization process. This may result in a facile
formation of a vinyl gold(I) carbenoid II. The ligand should have played a crucial
role in the stability of gold(I) carbenoid II. The [4+3] cycloaddition of
cycopentadiene intermediate with II thus affords the cyclodimerized product.14
Herein, we disclose the details of this reaction.
Scheme 1. Goldꢀcatalyzed Rautenstrauch Rearrangement
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a. Gold-catalyzed Rautenstrauch rearrangement to cyclopentenones (previous work)
tBu
+
OPiv
O
cat.
LAu+
R2
R1
O
R2
OPiv
R2
R1
O
R2
R1
H3O+
R3
R1 LAu R3
R3
R3
L = PPh3
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I
b. Bulky ligand enabled interrupted-Rautenstrauch Rearrangement (this work)
R
+
O
R2
R2
OCOR
O
R1
slow
fast
cat.
LAu+
OCOR
R1 LAu
R1
OCOR
R2
R2
R1
ROCO
R1
I
slow
R
+
R2
O
R2
R1
OCOR
Au+L
R2
O
L = tBuXphos
[4+3]-annulation
R1 LAu
vinyl gold carbenoid
I
II
RESULTS AND DISCUSSION
We initially investigated goldꢀcatalyzed Rautenstrauch rearrangement of
phenylꢀsubstituted 1ꢀethynylꢀ2ꢀpropenyl benzoate 1a in the presence of various gold
catalysts. Treatment of 1a with 2 mol% PPh3AuNTf2 in toluene resulted in a
nonꢀclean reaction mixture, among which, only 11% NMR yield of the double bond
isomerized cyclopentenone 2a was formed, which could not be separated from other
byproducts through column chromatography (Table 1, entry 1). Gratifyingly, the
cyclization using [LAu(MeCN)]SbF6 bearing a Buchwald ligand in toluene afforded
a cyclodimerized product 3a containing a bicyclo[3.2.1]octaꢀ3,6ꢀdiene skeleton in
satisfactory yields. For example, the gold catalyst with a Johnphos, Sphos or
tBuXphos as the ligand provided 3a in 62%, 55% and 70% yields, respectively
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(entries 2ꢀ4). 3a was isolated as a single diastereomer in which the bridging atom is
oriented trans with respect to the styryl group, and the phenyl group on the
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bridgehead is cis with right side ring. The use of a
Nꢀheterocyclic carbeneꢀgold(I)
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complex IPrAuNTf2 as the catalyst afforded a complex reaction mixture, and 3a was
observed in 22% NMR yield (entry 5). We next examined the effect of the
protecting groups on this reaction. Propargyl benzoates bearing an electronꢀdonating
group (pꢀMeO) or electronꢀwithdrawing group (pꢀCF3) on the aryl ring provided the
corresponding 3b and 3c in similar yields (60ꢀ69%, entries 6ꢀ7), indicating that the
electronic nature on the aryl ring have a little influence on the reaction process.
Interestingly, the replacement of a phenyl substituent on the protecting group by a
thienyl ring resulted in a higher yield of 3e (81%, entry 9). Propargyl acetate (1f
)
and pivaloate (1g) were also transformed into the desired cyclodimerized products
3f and 3g smoothly in 63ꢀ71% yields (entries 10ꢀ11). Changing the counterions of
ꢀ
ꢀ
the gold catalysts from SbF6 to OTfꢀ, BF4 afforded 3e in 44% and 72% yields,
respectively (entries 12ꢀ13). The use of DCE or THF as the solvent led to the
diminished yields of 3e (17ꢀ53%, entries 14ꢀ15). It was noted that in most cases of
the above reactions, small amounts of inseparable isomers or byproducts were also
t
observed.15 Control experiments run with BuXphosAuCl or AgSbF6 alone did not
give the desired products (entries 16ꢀ17).
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Table 1. Optimization of Reaction Conditions
O
Ph
O
6
7
8
9
O
O
R
R
R
N
2 mol% catalyst
solvent, rt
O
O
Ph
1
3
Ph
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12
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R1
R1
N
+SbF6
Ar
Ar
A, R1 = tBu, R2 = R3 = H
B, R1 = Cy, R2 = MeO, R3 = H
C, R1 = tBu, R2 = R3 = iPr
P
Au NCMe
R2
Au
R3
NTf2
R2
Ar = 2,6-(iPr)2C6H3
D
yield
(%)a
time
(h)
product
catalyst
entry
solvent
R
b
b
-
PPh3AuNTf2
Ph (1a)
Ph (1a)
Ph (1a)
toluene
toluene
toluene
1
2
3
24
1
-
62
55
A
B
3a
3a
1
Ph (1a)
Ph (1a)
1
70
C
D
toluene
toluene
3a
3a
4
5
24
22c
p-OMeC6H4 (1b)
p-CF3C6H4 (1c)
2-furanyl (1d)
2-thienyl (1e)
Me (1f)
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C
toluene
toluene
toluene
toluene
toluene
toluene
toluene
2
2
3
2
2
1
5
3b
3c
3d
3e
3f
60
69
47
81
63
7
C
8
C
9
C
10
11
12
C
tBu (1g)
71
44
C
3g
3e
tBuXphosAuCl/AgOTf
2-thienyl (1e)
tBuXphosAuCl/AgBF4
2-thienyl (1e)
2-thienyl (1e)
2-thienyl (1e)
toluene
DCE
3e
3e
3e
13
14
3
6
5
72
53
17
C
15
16
17
C
THF
tBuXphosAuCl
AgSbF6
0 (62)d
0 (85e)d
2-thienyl (1e)
2-thienyl (1e)
toluene
toluene
12
12
3e
3e
O
aIsolated yields. bComplicated reaction mixture. 2a was observed in
11% NMR yield. cNMR yield. dThe yields of the recovered 1e are
shown in parentheses. eContaining small amounts of impurity.
Ph
2a
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Having established the effective catalytic system, we proceeded to explore the
substrate scope of this novel cascade reaction. As shown in Scheme 2, a wide range
of 1ꢀethynylꢀ2ꢀpropenyl esters containing an aryl substituent at the alkene
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terminus
were
suitable
for
this
reaction,
and
the
desired
bicyclo[3.2.1]octaꢀ3,6ꢀdienes 3h
ꢀ
r and 3t were obtained in moderate to good yields
within short reaction times at room temperature. The process is also highly
stereoselective, as trans products were obtained as the major isomers. Both
electronꢀdeficient (
3,4,5ꢀ(MeO)3) on the aryl rings tolerated well during the reaction, leading to 3h
in 56ꢀ72% yields. Substrates bearing an ortho substituent ( ꢀF) or metaꢀsubstituent
ꢀCl) on the aryl rings were also compatible, leading to 3m and 3n in 55% and 77%
p
ꢀBr,
pꢀF,
pꢀCF3) and electronꢀrich substituents (
pꢀMe,
ꢀ3l
o
(
m
yields, respectively. Interestingly, the substrate tethered with an alkynyl functional
group could be efficiently converted to the desired product 3o in moderate yield
(55%), and the alkynyl group remained intact. A sterically demanding 2ꢀnaphthyl
group as R1 was well accommodated to give the product 3p in 71% yield.
Cyclization of the substrates bearing an alkyl group as R2 such as methyl or nꢀhexyl
group occurred smoothly to give the corresponding 3q and 3r in 85% and 74%
yields, respectively. However, when a substrate bearing an alkyl group such as a
methyl group on the alkene terminus was employed, only low yield (28%) of the
desired product 3s was obtained, possibly due to the lower stability of the
goldꢀcarbenoid/goldꢀstabilized allyl cation intermediate. The structure of the
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Scheme 2. Scope of Goldꢀcatalyzed Rautenstrauch Rearrangement/[4+3] Cascadea
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6
7
8
9
2 mol%
O
R1
O
tBuXphosAu(MeCN)SbF6
(catalyst C)
S
S
O
O
R2
R1
O
S
R2
O
toluene, rt
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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R2
R1
1
3
X
Ph
O
O
3h, X = Br, 2 h, 72%
3i, X = F, 2 h, 71%
3j, X = CF3, 2 h, 65%
3k, X = Me, 1 h, 56%
O
Ar
Ar
O
O
Ar
O
Ar
O
O
Ph
3e, 2 h, 81%
Cl
X
F
MeO
OMe
OMe
O
O
O
Ar
Ar
O
O
O
Ar
Ar
O
O
O
Ar
Ar
O
O
O
F
Cl
MeO
MeO
3m, 1 h, 55%
p-MeOC6H4
3n, 2 h, 77%
OMe
3l, 1 h, 66%
O
O
Ar
O
Ar
O
Ph
O
O
O
Ar
O
Ar
O
Ar
Ar
O
O
O
Ph
p-MeOC6H4
3o, 2 h, 55%
Ph
3p, 2 h, 71%
3q, 4 h, 85%
Me
p-BrC6H4
O
O
O
O
O
O
Ar
Ar
Me
Ar
Ar
Me
O
O
O
5
O
O
O
5
Ph
Me
3s, 1 h, 28%
p-BrC6H4
3tb, 1 h, 67%
3r, 6 h 74%
aIsolated yields. Ar = 2-thienyl. bPropargyl acetate was used as the substrate.
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dimerized products was unambiguously confirmed by the Xꢀray crystallographic
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7
8
analyses of 3a
The utility of the bicyclo[3.2.1]octaꢀ3,6ꢀdienes
deprotection reactions of 3e and 3l (Scheme 3). Treatment of 3e with 2.0 equiv
ꢀtoluenesulfonic acid monohydrate in DCM resulted in the formation of ketone 4e
, .
3q and 3t 16
3
was demonstrated by the
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p
in 66% yield. The results indicated that only the protecting group at the same side
with the Ar group was removed selectively. The chemoselectivity of this reaction is
possibly influenced by the steric effect. Similarly, 4l was obtained in moderate yield,
and its structure was determined by Xꢀray crystallography.16 This process may
enlarge the utility in subsequent modification and transformations. However,
deprotection attempts of the remaining acyl group by various methods failed.
Scheme 3. Removal of the Protecting Group
Ar
O
Ar
O
O
O
S
2 equiv TsOH H2O
DCM, 50 oC, 2 h
O
O
S
S
O
Ar
Ar
4e, Ar = Ph, 66%
4l, Ar = 3,4,5-(OMe)3C6H2, 60%
3e or 3l
In order to validate the proposed gold(I)ꢀcarbenoid intermediate, the
goldꢀcatalyzed oxidative rearrangement reaction of ester 1e was performed. As we
expected, aldehyde
5
was formed in 59% yield as a (
E,E)ꢀisomer (determined by 2D
NOESY NMR spectroscopy), together with 16% of (
E,Z
)ꢀisomer in the presence
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of diphenylsulfoxide as the oxidant (Scheme 4, eq 1).17 We noted that
5
could
in
6 within 3 h under
undergo a doubleꢀbond isomerization slowly when standing a solution of
organic solvents. Interestingly, could be readily isomerized to
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5
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the irradiation of the blue light, indicating that the process was caused by the
photoꢀinduced isomerization (Scheme 4, eq 2)18,19 The structure of
6
was confirmed
).16
by the Xꢀray crystallographic analysis of its imine derivative (compound
7
Scheme 4. Formation of Enals
S
2 mol%
S
tBuXphosAu(MeCN)SbF6
O
O
O
O
O
2.0 equiv Ph2SO
(1)
+
1e
5
Ph
O
toluene, rt, 0.5 h
Ph
H
H
5, 59%
6, 16%
blue LED
(2)
6, 88%
in toluene
rt, 3 h
Although the full mechanistic details of the current cyclization reactions remain
to be elucidated, plausible mechanism for the formation of
a
bicyclo[3.2.1]octaꢀ3,6ꢀdienes is proposed based on the above results and the
literature reports (Scheme 5). Initially, nucleophilic attack of the carbonyl of the
ester group to the goldꢀcoordinated alkyne leads to the formation of vinyl gold
species 9. Although the Toste’s work supported a concerted process from 9 to
cyclopentadiene 12, our study prefers that vinyl goldꢀcarbenoid 10 or its resonance
structure goldꢀstabilized allyl cation 10’ is formed due to the stabilizing effect of the
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bulky ligand. 10 might isomerize to (
E
,
Z
)ꢀisomer 11 according to the experiment
or 10 10’ followed by elimination of the
shown in Scheme 4, eq 1. Cyclization of
9
/
7
8
9
gold catalyst gives cyclopentadiene 12. The subsequent [4+3] cycloaddition
10’20 from another substrate occurs followed by
10
11
12
13
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16
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between cyclopentadiene 12 and 10
/
deauration to deliver the product
be understood through a transition state (13
is considered to react with the ( )ꢀisomer 10 selectively since that 10 is formed as
3
(path a). The stereoselectivity observed in
3 can
/14). In this process, cyclopentadiene 12
E,E
the major isomer. In 13, R1 group on the bridgehead oriented trans with the diene
moiety to avoid the steric hindrance. Furthermore, a secondary orbital interaction
between the alkene moiety and cyclopentadiene might be involved, making the
endoꢀproduct
3 to be the major isomer. In addition, the electron rich vinyl ester
moiety may prefer to attack the gold carbenoid, thus affording the cycloadduct with
high regioselectivity. We also can not exclude the pathway through a
cyclopropanation/Cope rearrangement cascade5c as indicated in path b. In this
reaction pathway, cyclopentadiene 12 may react with the thermodynamically more
stable (
goldꢀcarbenoid moiety to give the cisꢀcyclopropane intermediate 1521, which
undergoes Cope rearrangement22 to deliver the product
E,Z
)ꢀisomer 11 preferencially5d due to the less steric hindrance of
3
. It is reported that the Cope
rearrangement of divinylcyclopropanes proceeds through a boat transition state.5c,23
Thus a boatlike transition state 16 is proposed to account for the observed
stereoselectivity.
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Scheme 5. Possible Reaction Mechanism
5
6
R
R
+
O
R
O
O
R
7
8
9
O
O
O
R2
O
R2
R1
O
R2
O
R
R2
R1
R2
R1
O
Au+L
R1
+
10
11
12
13
14
15
16
17
18
19
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L+Au
R1 LAu
Au+L
AuL
8
9
10
10'
11
R2
R1
OCOR
Au+L
R1
ROCO
R2
R1
ROCO
path b, 11
cyclopropanation
10/10'
R2
H
R1
R2
path a
OCOR
R1
R2
OCOR
12
13
15
[4+3] annulation
R1
R1
O
R2
OCOR
H
LAu
R1
O
Cope
rearrangement
OCOR
R
R
+
OCOR
ROCO
O
H
R2
O
R2
R2
LAu+
R2
R2
R1
R1
R1
14
3
16
CONCLUSION
In summary, we have developed a gold(I)ꢀcatalyzed regioꢀ and stereoselective
synthesis of bicyclo[3.2.1]octaꢀ3,6ꢀdienes through the cyclodimerization of
1ꢀethynylꢀ2ꢀpropenyl esters by modulating the steric and electronic properties of the
ligands on the gold(I) catalyst. This reaction provides a new strategy for the
construction of complex molecules from simple building blocks. The formation of
the [4+3] cycloadducts likely arises from the cycloaddition of a gold(I)
carbenoid/goldꢀstabilized allyl cation with cyclopentadiene intermediate.
EXPERIMENTAL SECTION
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General Methods. All reactions were carried out using standard Schlenk technique under
argon unless noted. DCM and DCE were distilled from CaH2. Toluene was distilled from
sodium and benzophenone. THF was distilled from sodium and benzophenone or purified
using Innovative Technology Solvent Purifier (for the synthesis of substrates). MeCN was
purified using Innovative Technology Solvent Purifier. Unless noted, all commercial
10
11
12
13
14
15
16
17
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reagents
were
used
without
further
purification.
(Acetonitrile)[(2ꢀbiphenyl)diꢀtertꢀbutylphosphine]gold(I)hexafluoroantimonate (catalyst A)
was purchased from Chemical Company. Gold complex B-C were prepared by stirring the
25
[Au(L)Cl] complex with AgSbF6 in MeCN at room temperature.24 PPh3AuNTf2 and
26
1
13
IPrAuNTf2 were prepared according to the published methods. H and C NMR spectra
were recorded at room temperature in CDCl3 (containing 0.03% TMS), Acetonitrileꢀd3
(containing 0.03% TMS), or Tolueneꢀd8 on Varian XLꢀ400 MHz spectrometer or Agilent
1
400 MHz NMR spectrometer. H NMR spectra were recorded at 400 MHz, 13C NMR
1
spectra were recorded at 100 MHz. H NMR spectra were recorded with tetramethylsilane
(δ = 0.00 ppm) or solvent residual peak (CDCl3: 7.26 ppm) as internal reference; 13C NMR
spectra were recorded with CDCl3 (δ = 77.00 ppm) as internal reference. Highꢀresolution
mass spectra was performed on a mass spectrometer with a TOF or FT analyzer. Melting
points were uncorrected. Single crystal Xꢀray diffraction data were collected at 296(2) K
for 3a, 293(2) K for 3q, 296(2) K for 3t, 273(2) for 4l and 293(2) K for 7. Photochemical
reactions were carried with 15 W blue LED (456 nm peak wavelength, 23.8 nm spectral
halfꢀwave width, composed of 30 LED units.
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Method A: Synthesis of 1-ethynyl-2-propenyl esters 1a-1i, 1q, 1o, 1s and 1t.
Typical procedure for the synthesis of (E)-1-phenylpent-1-en-4-yn-3-yl benzoate (1a).
To a solution of cinnamaldehyde (660.8 mg, 5.0 mmol) in THF (10 mL) was added
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o
ethynylmagnesium bromide (0.5 M in THF, 12.0 mL, 6.0 mmol) at 0 C, and the resulting
solution was stirred at room temperature for 1 h. After the starting material was consumed,
the mixture was quenched with water, extracted with ethyl acetate, washed with brine
solution and dried over anhydrous Na2SO4. The solvent was evaporated under the reduced
pressure and the residue was purified by column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate = 10:1) to afford the desired propargyl alcohol, which was
used directly for the next step.
Under air, to a mixture of above propargyl alcohol, DCM (20 mL), Et3N (1.52g, 15.0
mmol), DMAP (61.1 mg, 0.5 mmol) was added benzoyl chloride (1.41 g, 10 mmol) at 0 oC.
The resulting solution was warmed up to room temperature and stirred for 6 h. After the
starting material was consumed, the mixture was quenched with saturated NH4Cl solution,
extracted with dichloromethane, washed with brine and dried over anhydrous Na2SO4. The
solvent was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) to afford 1a
(1.03 g, 79% yield) as a yellow oil.
Method B: Synthesis of 1-ethynyl-2-propenyl esters 1j-1k, 1m-1n, 1p and 1r.
Typical procedure for the synthesis of (E)-1-(p-tolyl)pent-1-en-4-yn-3-yl
thiophene-2-carboxylate (1k).
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To a solution of (E)ꢀ3ꢀ(pꢀtolyl)acrylaldehyde (438.6 mg, 3.0 mmol) in THF (10 mL)
was added ethynylmagnesium bromide (0.5 M in THF, 7.2 mL, 3.6 mmol) at 0 oC, and the
resulting solution was stirred at room temperature for 1 h. After the starting material was
consumed, the mixture was quenched with water, extracted with ethyl acetate, washed with
brine solution and dried over anhydrous Na2SO4. The solvent was evaporated under the
reduced pressure and the residue was purified by column chromatography on silica gel
(eluent: petroleum ether: ethyl acetate = 5:1) to afford the desired propargyl alcohol, which
was used directly for the next step.
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Under air, to a mixture of above propargyl alcohol, DCM (10 mL), pyridine (1.19 g,
o
15.0 mmol) was added thiopheneꢀ2ꢀcarbonyl chloride (879.5 mg, 6 mmol) at 0 C. The
resulting solution was warmed up to room temperature and stirred for 4 h. After the starting
material was consumed, the mixture was quenched with saturated NH4Cl solution,
extracted with dichloromethane, washed with brine and dried over anhydrous Na2SO4. The
solvent was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) to afford 1k
(762.2 mg, 90% yield) as a white amorphous solid.
(E)-1-Phenylpent-1-en-4-yn-3-yl benzoate (1a). Method A was used. 1H NMR (400 MHz,
CDCl3) δ 8.09 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.45ꢀ7.42 (m, 4H), 7.34ꢀ7.22
13
(m, 3H), 6.97 (d, J = 14.8 Hz, 1H), 6.38ꢀ6.30 (m, 2H), 2.69 (s, 1H); C NMR (100 MHz,
CDCl3) δ 165.3, 135.5, 134.9, 133.3, 129.8, 129.5, 128.6, 128.5, 128.4, 126.9, 123.3, 79.3,
75.6, 64.5. The spectroscopic data is in agreement with that previously reported.27
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(E)-1-Phenylpent-1-en-4-yn-3-yl 4-methoxybenzoate (1b). Method A was used. 3 mmol
8
9
scale. Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10:1)
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11
12
13
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15
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1
afforded the title product in 82% yield (720.5 mg) as a yellow oil. H NMR (400 MHz,
CDCl3) δ 8.05 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.35ꢀ7.24 (m, 3H), 6.96 (d, J =
15.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.36 (dd, J = 15.6 Hz, 6.4 Hz, 1H), 6.29 (dd, J = 6.4
Hz, 0.8 Hz, 1H), 3.83 (s, 3H), 2.69 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 165.0, 163.6,
135.5, 134.6, 131.9, 128.6, 128.4, 126.9, 123.5, 121.8, 113.6, 79.5, 75.4, 64.1, 55.3. IR
(neat): 3291, 3026, 2837, 2121, 1712, 1604, 1249, 1090, 768 cmꢀ1. HRMS (EIꢀTOF) m/z:
M+ calcd for C19H16O3 292.1099; Found 292.1102.
(E)-1-Phenylpent-1-en-4-yn-3-yl 4-(trifluoromethyl)benzoate (1c). Method A was used.
3 mmol scale. Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate
= 10:1) afforded the title product in 75% yield (741.8 mg) as a light yellow amorphous
1
solid. H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H),
7.44 (d, J = 7.6 Hz, 2H), 7.36ꢀ7.27 (m, 3H), 6.99 (d, J = 15.2 Hz, 1H), 6.39ꢀ6.31 (m, 2H),
2.73 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 164.1, 135.5, 135.3, 134.7 (q,
2JCꢀF = 32.6 Hz), 132.8, 130.2, 128.7, 127.0, 125.4 (q, JCꢀF = 3.8 Hz), 123.5 (q, JCꢀF
=
3
1
271.8 Hz), 122.8, 78.9, 76.0, 65.2. IR (neat): 3294, 3056, 2923, 2126, 1721, 1246, 1094,
773 cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C19H13O2F3 330.0868; Found 330.0873.
(E)-1-Phenylpent-1-en-4-yn-3-yl furan-2-carboxylate (1d). Method A was used. 3 mmol
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scale. Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10:1)
afforded the title product in 75% yield (568.4 mg) as a light yellow oil. 1H NMR (400 MHz,
CDCl3) δ 7.59 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.35ꢀ7.25 (m, 4H), 6.96 (d, J = 15.2 Hz,
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1H), 6.51 (dd, J = 1.8 Hz , 1.2 Hz, 1H), 6.36ꢀ6.28 (m, 2H), 2.72 (d, J = 2.0 Hz, 1H); C
NMR (100 MHz, CDCl3) δ 157.2, 146.7, 143.8, 135.3, 135.3, 128.5, 128.5, 126.9, 122.8,
118.8, 111.9, 78.9, 76.0, 64.4. IR (neat): 3280, 3128, 2940, 2118, 1715, 1579, 1165, 754
cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C16H12O3 252.0786; Found 252.0781.
(E)-1-Phenylpent-1-en-4-yn-3-yl thiophene-2-carboxylate (1e). Method A was used. 10
mmol scale. Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate =
20:1) afforded the title product in 86% yield (2.31 g) as a yellow oil. 1H NMR (400 MHz,
CDCl3) δ 7.86 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 7.6 Hz, 2H),
7.35ꢀ7.23 (m, 3H), 7.09 (t, J = 4.4 Hz, 1H), 6.95 (d, J = 15.6 Hz, 1H), 6.33 (dd, J = 15.6
Hz, 6.4 Hz, 1H), 6.27ꢀ6.25 (m, 1H), 2.70 (d, J = 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 160.9, 135.4, 135.0, 134.1, 133.1, 132.9, 128.6, 128.5, 127.8, 126.9, 123.1, 79.1, 75.8,
64.7. IR (neat): 3290, 3087, 3023, 2124, 1706, 1250, 1069, 745 cmꢀ1. HRMS (EIꢀTOF) m/z:
M+ calcd for C16H12O2S 268.0558; Found 268.0560.
(E)-1-Phenylpent-1-en-4-yn-3-yl acetate (1f). Method A was used. 3 mmol scale, acetic
anhydride (2 equiv) was used. Column chromatography on silica gel (eluent: petroleum
ether: ethyl acetate = 20:1) afforded the title product in 91% yield (545.9 mg) as a yellow
oil. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.2 Hz, 2H), 7.35ꢀ7.25 (m, 3H), 6.89 (d, J =
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15.6 Hz, 1H), 6.24 (dd, J = 16.0 Hz, 6.4 Hz, 1H), 6.05 (d, J = 6.4 Hz, 1H), 2.65 (d, J = 2.0
Hz, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 135.3, 134.6, 128.4, 128.3,
126.7, 123.1, 79.2, 75.3, 63.7, 20.8. The spectroscopic data is in agreement with that
previously reported.28
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(E)-1-Phenylpent-1-en-4-yn-3-yl pivalate (1g). Method A was used. 2 mmol scale.
Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1)
1
afforded the title product in 86% yield (416.5 mg) as a yellow oil. H NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 7.6 Hz, 2H), 7.34ꢀ7.25 (m, 3H), 6.87 (d, J = 15.6 Hz, 1H), 6.22 (dd, J
= 15.8 Hz, 6.4 Hz, 1H), 6.03 (d, J = 6.4 Hz, 1H), 2.61 (d, J = 1.2 Hz, 1H), 1.24 (s, 9H);13C
NMR (100 MHz, CDCl3) δ 177.0, 135.6, 134.3, 128.6, 128.4, 126.9, 123.5, 79.5, 75.0, 63.7,
38.7, 27.0. IR (neat): 3292, 3029, 2972, 2871, 2122, 1729, 1272, 1136, 747 cmꢀ1. HRMS
(EIꢀTOF) m/z: M+ calcd for C16H18O2 242.1307; Found 242.1311.
(E)-1-(4-Bromophenyl)pent-1-en-4-yn-3-yl thiophene-2-carboxylate (1h). Method A
was used. 3 mmol scale. Column chromatography on silica gel (eluent: petroleum ether:
ethyl acetate = 20:1) afforded the title product in 77% yield (802.6 mg) as a yellow
1
amorphous solid. H NMR (400 MHz, CDCl3) δ 7.88ꢀ7.87 (m, 1H), 7.60 (d, J = 5.2 Hz,
1H), 7.46 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.12 (t, J = 4.0 Hz, 1H), 6.90 (d, J =
15.6 Hz, 1H), 6.33 (dd, J = 15.6 Hz, 6.4 Hz, 1H), 6.25 (d, J = 6.4 Hz, 1H), 2.71 (d, J = 1.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.9, 134.4, 134.2, 133.8, 133.2, 132.8, 131.8,
128.5, 127.9, 123.9, 122.5, 78.8, 76.0, 64.5. IR (neat): 3258, 3042, 2121, 1719, 1246, 1067,
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745 cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C16H11O2SBr 345.9663; Found 345.9673.
5
6
7
8
9
(E)-1-(4-Fluorophenyl)pent-1-en-4-yn-3-yl thiophene-2-carboxylate (1i). Method A was
used. 3 mmol scale. Column chromatography on silica gel (eluent: petroleum ether: ethyl
acetate = 20:1) afforded the title product in 69% yield (591.3 mg) as a yellow oil. 1H NMR
(400 MHz, CDCl3) δ 7.87 (dd, J = 3.6 Hz, 0.8 Hz, 1H), 7.60ꢀ7.59 (m, 1H), 7.43ꢀ7.38 (m,
2H), 7.12ꢀ7.10 (m, 1H), 7.06ꢀ7.00 (m, 2H), 6.95ꢀ6.89 (m, 1H), 6.29ꢀ6.23 (m, 2H), 2.70 (d,
J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.8 (d, 1JCꢀF = 246.8 Hz), 160.9, 134.1,
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4
3
133.8, 133.1, 132.8, 131.6 (d, JCꢀF = 3.1 Hz), 128.6 (d, JCꢀF = 8.3 Hz), 127.8, 122.9 (d,
2
5JCꢀF = 2.3 Hz), 115.6 (d, JCꢀF = 22.0 Hz), 79.0, 75.9, 64.6. IR (neat): 3295, 3106, 3045,
2124, 1706, 1601, 1222, 1069, 747 cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C16H11O2SF
286.0464; Found 286.0470.
(E)-1-(4-(Trifluoromethyl)phenyl)pent-1-en-4-yn-3-yl thiophene-2-carboxylate (1j).
Method B was used. 2 mmol scale. Column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate = 20:1) afforded 1j in 73% yield (491.8 mg) as a light
yellow amorphous solid. M.p. 73ꢀ75 oC. 1H NMR (400 MHz, CDCl3) δ 7.88ꢀ7.87 (m, 1H),
7.60ꢀ7.57 (m, 3H), 7.51 (d, J = 8.4 Hz, 2H), 7.11 (dd, J = 4.4 Hz, 4.0 Hz, 1H), 6.99 (d, J =
16.0 Hz, 1H), 6.43 (dd, J = 15.8 Hz, 6.4 Hz, 1H), 6.29 (d, J = 6.0 Hz, 1H), 2.74 (d, J = 2.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.8, 138.9, 134.2, 133.3, 133.2, 132.7, 130.1 (q,
2JCꢀF = 33.2 Hz), 127.9, 127.1, 125.8, 125.5 (q, 3JCꢀF = 3.8 Hz), 124.0 (q, 1JCꢀF = 270.4 Hz),
78.6, 76.2, 64.2. IR (neat): 3287, 3098, 2920, 2124, 1708, 1610, 1156, 1071, 757 cmꢀ1.
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HRMS (EIꢀTOF) m/z: M+ calcd for C17H11O2F3S 336.0432; Found 336.0431.
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(E)-1-(p-Tolyl)pent-1-en-4-yn-3-yl thiophene-2-carboxylate (1k). Method B was used.
1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 3.8 Hz, 1.2 Hz, 1H), 7.57 (dd, J = 5.0 Hz, 0.8
Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.09 (dd, J = 4.8 Hz, 4.0 Hz,
1H), 6.92 (d, J = 14.8 Hz, 1H), 6.31ꢀ6.24 (m, 2H), 2.69 (d, J = 1.6 Hz, 1H), 2.33 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 160.9, 138.5, 135.0, 134.0, 133.0, 132.6, 129.3, 127.8,
126.9, 122.0, 79.2, 75.7, 64.8, 21.2. IR(neat): 3266, 3112, 2920, 2118, 1710, 1244, 1066,
748 cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C17H14O2S 282.0715; Found 282.0718.
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(E)-1-(3,4,5-Trimethoxyphenyl)pent-1-en-4-yn-3-yl thiophene-2-carboxylate (1l).
Method B was used. 2 mmol scale. Column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate = 5:1) afforded 1l in 62% yield (446.1 mg) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 3.6 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.11 (t, J
= 4.4 Hz, 1H), 6.91ꢀ6.86 (m, 1H), 6.67 (s, 2H), 6.29ꢀ6.23 (m, 2H), 3.88 (s, 6H), 3.85 (s,
3H), 2.73 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 160.9, 153.2, 138.5, 135.1, 134.0, 133.0,
132.9, 131.1, 127.8, 122.5, 104.0, 79.0, 75.8, 64.6, 60.8, 56.0. IR (neat): 3287, 3095, 2838,
2118, 1707, 1582, 1246, 1069, 747 cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C19H18O5S
358.0875; Found 358.0869.
(E)-1-(2-Fluorophenyl)pent-1-en-4-yn-3-yl thiophene-2-carboxylate (1m). Method B
was used. 3 mmol scale. Column chromatography on silica gel (eluent: petroleum ether:
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ethyl acetate = 20:1) afforded the title product in 82% yield (701.3 mg) as a white
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amorphous solid. H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 3.8 Hz, 1.2 Hz, 1H), 7.59
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(dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.49ꢀ7.45 (m, 1H), 7.28ꢀ7.22 (m, 1H), 7.13ꢀ7.07 (m, 3H),
7.05ꢀ7.02 (m, 1H), 6.44 (dd, J = 16.0 Hz, 6.4 Hz, 1H), 6.28ꢀ6.26 (m, 1H), 2.72 (d, J = 2.4
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Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.8, 160.5 (d, JCꢀF = 249.7 Hz), 134.1, 133.1,
132.8, 129.9 (d, 3JCꢀF = 9.1 Hz), 128.0 (d, 3JCꢀF = 3.8 Hz), 127.8, 127.5 (d, 4JCꢀF = 3.0 Hz),
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125.6 (d, JCꢀF = 5.3 Hz), 124.1 (d, JCꢀF = 3.8 Hz), 123.3 (d, JCꢀF = 12.1 Hz), 115.8 (d,
2JCꢀF = 21.2 Hz), 78.8, 76.0, 64.7. IR (neat): 3260, 3095, 2920, 2121, 1716, 1219, 1066,
745 cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C16H11O2FS 286.0464; Found 286.0467.
(E)-1-(3-Chlorophenyl)pent-1-en-4-yn-3-yl thiophene-2-carboxylate (1n). Method B
was used. 3 mmol scale. Column chromatography on silica gel (eluent: petroleum ether:
ethyl acetate = 20:1) afforded the title product in 52% yield (468.5 mg) as a white solid.
M.p. 64ꢀ65 oC. 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 3.8 Hz, 1.2 Hz, 1H), 7.57 (dd,
J = 5.0 Hz, 1.2 Hz, 1H), 7.39 (s, 1H), 7.28ꢀ7.22 (m, 3H), 7.09 (dd, J = 4.8 Hz, 4.0 Hz, 1H),
6.88 (d, J = 15.6 Hz, 1H), 6.33 (dd, J = 15.6 Hz, 6.4 Hz, 1H), 6.27ꢀ6.25 (m, 1H), 2.73 (d, J
= 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.7, 137.2, 134.4, 134.1, 133.4, 133.1,
132.6, 129.8, 128.3, 127.8, 126.7, 125.1, 124.5, 78.7, 76.1, 64.3. IR (neat): 3291, 3109,
2909, 2121, 1707, 1247, 1066, 746 cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C16H11O2SCl
302.0168; Found 302.0164.
(E)-1-(4-((4-Methoxyphenyl)ethynyl)phenyl)pent-1-en-4-yn-3-yl-thiophene-2-carboxyl
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ate (1o). Method A was used. 1 mmol scale, 1.5 equiv thiopheneꢀ2ꢀcarbonyl chloride, 2.0
equiv Et3N and 10 mol% DMAP were used. Column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate = 20:1) afforded the title product in 68% yield (271.7 mg) as
a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.87ꢀ7.86 (m, 1H), 7.58 (d, J = 4.8 Hz,
1H), 7.47 (t, J = 5.6 Hz, 4H), 7.40 (d, J = 7.6 Hz, 2H), 7.11ꢀ7.09 (m, 1H), 6.94 (d, J = 15.6
Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 6.35 (dd, J = 15.6 Hz, 6.4 Hz, 1H), 6.27 (d, J = 6.4 Hz,
1H), 3.81 (s, 3H), 2.71 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 160.9, 159.6, 135.0, 134.4,
134.1, 133.1, 133.0, 132.9, 131.6, 127.8, 126.9, 123.8, 123.7, 115.1, 114.0, 90.6, 88.0, 79.0,
75.9, 64.6, 55.2. IR (neat): 3276, 3004, 2915, 2840, 2212, 1711, 1606, 1265, 1066, 756
cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C25H19O3S 399.1049; Found 399.1048.
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(E)-1-(Naphthalen-2-yl)pent-1-en-4-yn-3-yl thiophene-2-carboxylate (1p). Method B
was used. 1 mmol scale. Column chromatography on silica gel (eluent: petroleum ether:
1
ethyl acetate = 20:1) afforded 1p in 94% yield (298.2 mg) as a light yellow oil. H NMR
(400 MHz, CDCl3) δ 7.87 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 7.79ꢀ7.75 (m, 4H), 7.59ꢀ7.57 (m,
1H), 7.55ꢀ7.53 (m, 1H), 7.47ꢀ7.41 (m, 2H), 7.11ꢀ7.05 (m, 2H), 6.44 (dd, J = 15.4 Hz, 6.0
Hz, 1H), 6.32ꢀ6.30 (m, 1H), 2.72 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.9,
135.1, 134.1, 133.3, 133.1, 132.9, 132.8, 128.3, 128.1, 127.8, 127.6, 127.5, 126.3, 126.3,
123.4, 123.3, 79.1, 75.9, 64.7. IR (neat): 3279, 3109, 2948, 2121, 1682, 1269, 1091, 745
cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C20H14O2S 318.0715; Found 318.0718.
(E)-2-Methyl-1-phenylpent-1-en-4-yn-3-yl thiophene-2-carboxylate (1q). Method A
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was used. 3 mmol scale. Column chromatography on silica gel (eluent: petroleum ether:
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ethyl acetate = 20:1) afforded the title product in 79% yield (667 mg) as a white solid. H
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NMR (400 MHz, CDCl3) δ 7.86 (d, J = 3.6 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.36ꢀ7.30 (m,
4H), 7.24 (t, J = 7.2 Hz, 1H), 7.09 (dd, J = 4.4 Hz, 4.2 Hz, 1H), 6.84 (s, 1H), 6.16 (d, J =
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0.8 Hz, 1H), 2.65 (d, J = 2.0 Hz, 1H), 2.06 (s, 3H); C NMR (100 MHz, CDCl3) δ 160.8,
136.3, 134.0, 133.0, 132.4, 130.1, 129.0, 128.1, 127.8, 127.1, 79.3, 75.4, 69.6, 14.2. IR
(neat): 3290, 3020, 2915, 2124, 1708, 1249, 1070, 745 cmꢀ1. HRMS (EIꢀTOF) m/z: M+
calcd for C17H14O2S 282.0715; Found 282.0728.
(E)-4-Benzylidenedec-1-yn-3-yl thiophene-2-carboxylate (1r). Method B was used. 3
mmol scale. Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate =
1
20:1) afforded the title product in 69% yield (725.0 mg) as a colorless oil. H NMR (400
MHz, CDCl3) δ 7.85 (dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.52ꢀ7.51 (m, 1H), 7.34ꢀ7.24 (m, 4H),
7.22ꢀ7.21 (m, 1H), 7.06ꢀ7.04 (m, 1H), 6.92 (s, 1H), 6.27ꢀ6.26 (m, 1H), 2.68 (d, J = 2.4 Hz,
1H), 2.52ꢀ2.37 (m, 2H), 1.70ꢀ1.52 (m, 2H), 1.34ꢀ1.19 (m, 6H), 0.84 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.7, 136.8, 136.4, 133.8, 132.9, 130.4, 128.5, 128.1, 127.7,
127.0, 79.4, 75.7, 68.1, 31.2, 29.2, 28.3, 28.3, 22.3, 13.9. IR (neat): 3292, 3020, 2954, 2927,
2124, 1712, 1249, 1085, 746 cmꢀ1. HRMS (EIꢀTOF) m/z: M+ calcd for C22H24O2S
352.1497; Found 352.1501.
(E)-Hex-4-en-1-yn-3-yl thiophene-2-carboxylate (1s). Method A was used. 10 mmol
scale, 1.5 equiv thiopheneꢀ2ꢀcarbonyl chloride, 2.0 equiv Et3N and 10 mol% DMAP were
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used. Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15:1)
afforded the title product in 67% yield (1.39 g) as a yellow oil. 1H NMR (400 MHz, CDCl3)
δ 7.833ꢀ7.826 (m, 1H), 7.57 (d, J = 4.8 Hz, 1H), 7.10ꢀ7.08 (m, 1H), 6.14ꢀ6.06 (m, 1H),
6.03 (d, J = 6.4 Hz, 1H), 5.67 (dd, J = 15.2 Hz, 6.4 Hz, 1H), 2.63 (s, 1H), 1.77 (d, J = 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 133.8, 133.1, 132.8, 132.1, 127.7, 125.5,
79.5, 75.1, 64.6, 17.5. IR (neat): 3292, 3103, 2918, 2124, 1706, 1250, 1070, 747 cmꢀ1.
HRMS (EIꢀTOF) m/z: M+ calcd for C11H10O2S 206.0402; Found 206.0401.
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(E)-1-(4-Bromophenyl)pent-1-en-4-yn-3-yl acetate (1t). Method A was used. 2 mmol
scale, 2.0 equiv acetic anhydride, 3.0 equiv Et3N and 10 mol% DMAP were used. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10:1) afforded the
1
title product in 67% yield (371.8 mg) as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.44
(d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 16.0 Hz, 1H), 6.22 (dd, J = 15.6
Hz, 6.4 Hz, 1H), 6.03 (d, J = 6.4 Hz, 1H), 2.68 (d, J = 2.0 Hz, 1H), 2.12 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 169. 4, 134.3, 133.4, 131.6, 128.3, 123.9, 122.3, 79.0, 75.5, 63.6, 20.9.
IR (neat): 3293, 3034, 2931, 2125, 1736, 1219, 1008, 801 cmꢀ1. HRMS (EIꢀTOF) m/z: M+
calcd for C13H11O2Br 277.9942; Found 277.9948.
Synthesis of Bicyclo[3.2.1]octa-3,6-dienes 3.
Typical
procedure
for
the
synthesis
of
(1R*,2S*,5R*,8R*)-8-phenyl-2-((E)-styryl)bicyclo[3.2.1]octa-3,6-diene-3,6-diyl
dibenzoate 3a.
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To a solution of (E)ꢀ1ꢀphenylpentꢀ1ꢀenꢀ4ꢀynꢀ3ꢀyl benzoate 1a (78.7 mg, 0.3 mmol) in
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toluene (3 mL) was added BuXphosAu(MeCN)SbF6 (5.4 mg, 0.006 mmol). The resulting
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solution was stirred at room temperature for 1 h. Then the mixture was filtered through a
pad of silica gel. The solvent was evaporated under the reduced pressure and the residue
was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl
acetate = 100:1 to 20:1) to afford the product 3a in 70% yield (54.9 mg) as a white solid.
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(1R*,2S*,5R*,8R*)-8-Phenyl-2-((E)-styryl)bicyclo[3.2.1]octa-3,6-diene-3,6-diyl
dibenzoate (3a). M.p. 122ꢀ124 oC. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.6 Hz, 2H),
8.00 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.51ꢀ7.44 (m, 3H), 7.37ꢀ7.16 (m, 12H),
6.56 (d, J = 16.0 Hz, 1H), 6.48 (d, J = 6.4 Hz, 1H), 6.20 (dd, J = 15.8 Hz, 9.6 Hz, 1H), 5.67
(d, J = 2.8 Hz, 1H), 3.99 (dd, J = 9.2 Hz, 4.0 Hz, 1H), 3.70 (s, 1H), 3.35ꢀ3.34 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 165.3, 163.6, 159.7, 148.8, 141.8, 137.0, 133.5, 133.3, 133.2,
130.0, 129.8, 129.6, 129.3, 128.5, 128.40, 128.36, 128.1, 127.6, 127.3, 126.6, 126.30,
126.25, 121.7, 107.3, 56.3, 49.1, 47.1, 44.5. IR (neat): 3056, 3023, 2942, 1740, 1717, 1175,
1056, 743 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M+NH4]+ calcd for C36H32NO4 542.2326; Found
542.2324.
(1R*,2S*,5R*,8R*)-8-Phenyl-2-((E)-styryl)bicyclo[3.2.1]octa-3,6-diene-3,6-diyl
bis(4-methoxybenzoate) (3b). 0.3 mmol scale, 1b (87.7 mg, 0.3 mmol), toluene (3 mL),
tBuXphosAu(MeCN)SbF6 (5.4 mg, 0.006 mmol) were used. Purification of the crude
product by preparative TLC on silica gel (eluent: petroleum ether: DCM = 1:1) afforded
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the title product in 60% yield (52.3 mg) as a light yellow oil. 1H NMR (400 MHz, CDCl3)
δ 8.05 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.38ꢀ7.18 (m, 10H), 6.94 (d, J = 8.4 Hz,
2H), 6.84 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 16.0 Hz, 1H), 6.44 (d, J = 6.8 Hz, 1H), 6.20 (dd,
J = 15.6 Hz, 9.6 Hz, 1H), 5.62 (d, J = 2.4 Hz, 1H), 3.97 (dd, J = 9.2 Hz, 5.2 Hz, 1H), 3.87
(s, 3H), 3.81 (s, 3H), 3.69 (s, 1H), 3.33ꢀ3.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.0,
163.8, 163.5, 163.4, 159.8, 148.7, 142.0, 137. 1, 133.1, 132.2, 131.9, 128.4, 128.1, 127.7,
127.2, 126.8, 126.3, 121.9, 121.6, 121.6, 113.7, 113.6, 106.8, 56.2, 55.5, 55.4, 49.1, 47.2,
44.6. IR (neat): 3059, 3023, 2937, 2843, 1728, 1603, 1252, 1045, 763 cmꢀ1. HRMS
(ESIꢀTOF) m/z: [M+NH4]+ calcd for C38H36NO6 602.2537; Found 602.2534.
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(1R*,2S*,5R*,8R*)-8-Phenyl-2-((E)-styryl)bicyclo[3.2.1]octa-3,6-diene-3,6-diyl
bis(4-(trifluoromethyl)benzoate) (3c). 0.3 mmol scale, 1c (99.1 mg, 0.3 mmol), toluene
t
(3 mL), BuXphosAu(MeCN)SbF6 (5.4 mg, 0.006 mmol) were used. Purification of the
crude product by preparative TLC on silica gel (eluent: petroleum ether: DCM = 5:1)
afforded the title product in 69% yield (68.7 mg) as a light yellow oil. 1H NMR (400 MHz,
CDCl3) δ 8.21 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.62
(d, J = 8.0 Hz, 2H), 7.37ꢀ7.18 (m, 10H), 6.57 (d, J = 15.6 Hz, 1H), 6.52 (d, J = 6.8 Hz, 1H),
6.19 (dd, J = 15.8 Hz, 9.2 Hz, 1H), 5.72 (d, J = 2.0 Hz, 1H), 4.00 (dd, J = 9.2 Hz, 4.8 Hz,
1H), 3.71 (s, 1H), 3.38ꢀ3.36 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 164.0, 162.4, 159.4,
2
2
148.7, 141.5, 136.8, 134.9 (q, JCꢀF = 32.7 Hz), 134.7 (q, JCꢀF = 32.7 Hz), 133.6, 132.8,
3
132.5, 130.4, 130.2, 128.5, 128.2, 127.59, 127.55, 126.47, 126.2, 126.1, 125.5 (q, JCꢀF
=
3
1
3.8 Hz), 125.4 (q, JCꢀF = 3.8 Hz), 123.5 (q, JCꢀF = 270.9 Hz), 121.9, 108.1, 56.3, 48.8,
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47.1, 44.6. IR (neat): 3067, 3026, 2945, 1737, 1264, 1067, 732 cmꢀ1. HRMS (ESIꢀTOF)
m/z: [M+NH4]+ calcd for C38H30F6NO4 678.2074; Found 678.2067.
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(1R*,2S*,5R*,8R*)-8-phenyl-2-((E)-styryl)bicyclo[3.2.1]octa-3,6-diene-3,6-diyl
bis(furan-2-carboxylate) (3d). 0.3 mmol scale, 1d (75.7 mg, 0.3 mmol), toluene (3 mL),
tBuXphosAu(MeCN)SbF6 (5.4 mg, 0.006 mmol) were used. Purification of the crude
product by preparative TLC on silica gel (eluent: petroleum ether: DCM = 1:2) afforded
the title product in 47% yield (35.6 mg) as a light yellow oil. 1H NMR (400 MHz, CDCl3)
δ 7.63 (s, 1H), 7.54 (s, 1H), 7.35ꢀ7.20 (m, 11H), 7.13 (d, J = 2.8 Hz, 1H), 6.57 (d, J = 15.6
Hz, 2H), 6.45 (d, J = 7.2 Hz, 2H), 6.16 (dd, J = 15.6 Hz, 9.6 Hz, 1H), 5.63 (s, 1H), 3.98
(dd, J = 8.2 Hz, 4.4 Hz, 1H), 3.65 (s, 1H), 3.32ꢀ3.31 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 158.9, 156.8, 155.4, 148.3, 147.1, 146.8, 143.8, 143.6, 141.6, 137.0, 133.4, 128.4, 128.1,
127.6, 127.4, 126.33, 126.28, 126.22, 121.8, 119.4, 118.9, 112.2, 112.0, 107.6, 56.0, 49.1,
47.1, 44.4. IR (neat): 3140, 3026, 2931, 1732, 1575, 1288, 1068, 750 cmꢀ1. HRMS
(ESIꢀTOF) m/z: [M+NH4]+ calcd for C32H28NO6 522.1911; Found 522.1907.
(1R*,2S*,5R*,8R*)-8-Phenyl-2-((E)-styryl)bicyclo[3.2.1]octa-3,6-diene-3,6-diyl
bis(thiophene-2-carboxylate) (3e). 0.3 mmol scale, 1e (80.5 mg, 0.3 mmol), toluene (3
mL), tBuXphosAu(MeCN)SbF6 (5.4 mg, 0.006 mmol) were used. Purification of the crude
product by preparative TLC on silica gel (eluent: petroleum ether: DCM = 1:1) afforded
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the title product in 81% yield (65.3 mg) as a colorless oil. H NMR (400 MHz, CDCl3) δ
7.87 (d, J = 3.6 Hz, 1H), 7.77 (d, J = 3.6 Hz, 1H), 7.61 (d, J = 4.8 Hz, 1H), 7.49 (d, J = 4.8
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Hz, 1H), 7.35ꢀ7.17 (m, 10H), 7.12 (t, J = 4.4 Hz, 1H), 7.02 (t, J = 4.0 Hz, 1H), 6.57 (d, J =
16.0 Hz, 1H), 6.47 (d, J = 6.8 Hz, 1H), 6.17 (dd, J = 16.0 Hz, 9.2 Hz, 1H), 5.62 (d, J = 2.0
Hz, 1H), 3.95 (dd, J = 8.8 Hz, 4.8 Hz, 1H), 3.65 (s, 1H), 3.33ꢀ3.31 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 160.6, 159.3, 159.1, 148.4, 141.7, 137.0, 134.5, 134.2, 133.6, 133.4, 133.1,
132.8, 132.6, 128.4, 128.1, 128.0, 127.8, 127.6, 127.3, 126.3, 126.31, 126.26, 121.8, 107.3,
56.1, 48.9, 47.1, 44.4. IR (neat): 3106, 3023, 2934, 1719, 1246, 1053, 736 cmꢀ1. HRMS
(ESIꢀTOF) m/z: [M+NH4]+ calcd for C32H28NO4S2 554.1454; Found 554.1453.
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(1R*,2S*,5R*,8R*)-8-Phenyl-2-((E)-styryl)bicyclo[3.2.1]octa-3,6-diene-3,6-diyl
diacetate (3f). 0.3 mmol scale, 1f (60.1 mg, 0.3 mmol), toluene (3 mL),
tBuXphosAu(MeCN)SbF6 (5.4 mg, 0.006 mmol) were used. Purification of the crude
product by preparative TLC on silica gel (eluent: petroleum ether: ethyl acetate = 5:1)
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afforded the title product in 63% yield (37.8 mg) as a colorless oil. H NMR (400 MHz,
CDCl3) δ 7.36 (d, J = 7.2 Hz, 2H), 7.32ꢀ7.19 (m, 8H), 6.53 (d, J = 15.6 Hz, 1H), 6.22 (dd,
J = 7.0 Hz, 2.0 Hz, 1H), 6.07 (dd, J = 15.8 Hz, 9.6 Hz, 1H), 5.44 (d, J = 2.8 Hz, 1H), 3.83
(dd, J = 9.0 Hz, 3.6 Hz, 1H), 3.52 (s, 1H), 3.22ꢀ3.21 (m, 1H), 3.10 (d, J = 6.8 Hz, 1H), 2.15
(s, 3H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.50, 167.73, 159.45, 148.54,
141.78, 136.95, 133.05, 128.52, 128.06, 127.55, 127.46, 126.64, 126.27, 126.25, 121.19,
106.66, 55.92, 48.89, 46.99, 44.29, 21.23, 20.81. IR (neat): 3059, 3023, 2937, 1756, 1192,
1006, 733 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M+NH4]+ calcd for C26H28NO4 418.2013; Found
418.2008.
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