Lewis Acid-Catalyzed Selective [2 + 2]-Cycloaddition and Dearomatizing Cascade Reaction of Aryl Alkynes with Acrylates

Article abstract of DOI:10.1021/jacs.7b07997

Combined Lewis acid, consisting of two or more Lewis acids, sometimes shows unique catalytic ability, and it may promote reactions which could not be catalyzed by any of the Lewis acids solely. On the other hand, the development of efficient methods for t

Full text of DOI:10.1021/jacs.7b07997

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Article
Lewis Acid-catalyzed Selective [2+2]-Cycloaddition and
Dearomatizing Cascade Reaction of Aryl Alkynes with Acrylates
Liang Shen, Kai Zhao, Kazuki Doitomi, Rakesh Ganguly,
Yongxin Li, Zhi-Liang Shen, Hajime Hirao, and Teck-Peng Loh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07997 • Publication Date (Web): 07 Sep 2017
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Lewis Acid-catalyzed Selective [2+2]-Cycloaddition and
Dearomatizing Cascade Reaction of Aryl Alkynes with Acry-
lates
Liang Shen,‡ Kai Zhao,†,‡ Kazuki Doitomi,♮ Rakesh Ganguly,‡ Yong-Xin Li,‡ Zhi-Liang Shen,*,†,‡
Hajime Hirao,‡,♮ and Teck-Peng Loh*,†,‡
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† Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation
Center for Advanced Materials, Nanjing Tech University, Nanjing, Jiangsu, P. R. China 210009.
‡ Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371
♮ Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China
Supporting Information Placeholder
bination of electron-rich alkynes and electron-deficient alkenes or
vice versa.7-10 For the former class of substrates, several elegant
and seminal works have been reported by Narasaka,8 Kozmin,9
Hsung10 and others; nonetheless, their applications are mainly
limited to more reactive alkynes bearing a heteroatom substituent,
reflecting the synthetic hurdle in using non-activated alkynes such
as aryl alkynes as substrates. Especially noteworthy is that cyclo-
butanes bearing aryl and ester functionalities are prevalent molec-
ular frameworks in a myriad of natural products as well as bio-
active intermediates (Fig. 1).3 In this regard, direct [2+2]-
cycloaddition of unactivated aryl alkynes with easily accessible
acrylates followed by hydrogenation will provide an easy entry to
above-mentioned cyclobutanes and to the best of our knowledge,
there is no precedent report on employment of a Lewis acid cata-
lyst system for this reaction.11
ABSTRACT: Combined Lewis acid, consisting of two or more
Lewis acids, sometimes shows unique catalytic ability and it may
promote reactions which could not be catalyzed by any of the
Lewis acid solely. On the other hand, the development of efficient
methods for the facile synthesis of cyclobutenes and densely
functionalized decalins are attractive targets for synthetic chemists
due to their versatile synthetic utilities and widespread occurrence
in natural products. Herein we wish to report an efficient method
for the assembly of cyclobutenes and densely functionalized
decalin skeletons through In(tfacac)3-TMSBr catalyzed selective
[2+2]-cycloaddition and dearomatizing cascade reaction of aryl
alkynes with acrylates with high chemo- and stereoselectivity.
The obtained cyclobutene could be easily converted into
cyclobutane as well as synthetically useful 1,4- and 1,5-diketones
with high chemo- and stereoselectivity. Based on mechanistic
studies, plausible reaction mechanisms were proposed for both of
the [2+2]-cycloaddition and the dearomatizing cascade reaction.
Finally, the computational studies of reaction mechanisms were
conducted and the results suggest that the combined Lewis acid
could efficiently promote both reactions.
O
O
O
O
iPr
O
MeO
MeO
iPr
O
O
O
O
H
MeO2C
H
HO2C
O
HO
OH
INTRODUCTION
MeO
Unnamed norlignan
CO2Me
OMe
SB-FI-26
Crotomembranafuran (+)-Bis(carvacrol)
The development of efficient methods which could rapidly in-
crease molecular complexity or assemble highly strained cyclic
ring systems is the continuing aim of organic chemists.1 In this
regard, cyclobutane and decalin rings are very attractive targets
mainly due to their widespread occurrence in terpenes, steroids,
and other natural products (Fig. 1).2-3
Figure 1. Representative compounds containing cyclobutane
moieties or functionalized decalin ring2-3
Dearomatization Diels-Alder Reaction of Styrene with Alkene.
Among the methods developed for the preparation of functional-
ized alicyclic compounds, the simple yet efficient strategies grant-
ed by dearomatization reaction of arenes are particularly attractive
in view of their prevalence, low cost, and susceptibility for syn-
thetic derivatizations.1,12 Considering the easy access of styrene
derivatives and the desire to develop atom-economic reactions,
the dearomatizing [4+2]-cycloaddition of a styrene with an olefin
has been considered as an ideal method for decalin formation.
However, there is no widely applicable method that has been de-
veloped in this area for two reasons: first, the associated loss of
Lewis Acid-catalyzed [2+2]-Cycloaddition of Aryl Alkyne with
Alkene. Synthetic strategies to assemble cyclobutene ring have
been intensively investigated because of the profound synthetic
values associated with their inherent ring strain.4-5 Among the
methods developed to access cyclobutenes, [2+2]-cycloaddition of
an alkyne with an alkene represents one of the most straightfor-
ward routes.6-12 The Lewis acid-catalyzed reactions usually re-
quire electronic imbalance between two coupling partners, a com-
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aromatic character requires either extremely reactive dienophiles
to attempt the reaction with a catalytic amount of InBr3 (20 mol%)
or harsh reaction conditions; second, the dearomatization product
(1:1 Diels-Alder adduct) is unstable so that it will decompose or
undergo further reaction to give the mixture of double Diels-Alder
adduct 1 as well as rearomatized products 2 and 3 (Scheme 1).13
Harman has reported an elegant Diels-Alder reaction of metal-
complex activated styrene with dienophiles with good selectivi-
ty.14 To date, there has been no catalytic system which can cata-
lyze the dearomatizing [4+2] reaction of styrene with common
dienophiles to give a stable dearomatization product under mild
conditions with good chemoselectivity.
in CH2Cl2 from 0 oC to room temperature (Table 1). However, no
reaction occurred under the above condition (entry 1). Increasing
the loading of InBr3 to 1 equiv or heating the reaction mixture to
80 oC did not effect the reaction, either (entries 2-3).11 Gratifying-
ly, the desired cyclobutene product 3ca could be obtained in 54%
yield when 3 equiv of TMSBr was added as additive (entry 4).
With this promising result in hand, optimization of the reaction
conditions was subsequently carried out. Among the different
indium catalysts studied (entries 6-10), In(tfacac)3 was also found
to exhibit the best catalytic activity to afford the desired product
3ca in 68% yield (entry 10). In sharp contrast, the similar catalyst
of indium(III) acetylacetonate [In(acac)3] could not catalyze the
reaction, providing no desired product 3ca (entry 9). Other com-
mon Lewis acid catalysts (e.g., AlBr3, ZnCl2, and TiCl4) were also
screened, which mostly resulted in no product formation or in
inferior yields (see Table SI-1 in Supporting Information for de-
tails). In addition, this reaction was found to work only in chlorin-
ated solvents such as CH2Cl2 or DCE, with the latter giving higher
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Scheme 1. Dearomatizing [4+2]-Cycloaddition of Styrene
with Alkene.
Table 1. Optimization of In(III)-TMSBr-catalyzed [2+2]-
Cycloaddition of 1c with 2aa
Combination of In(III) Salt and Trimethylsilyl Halide. Indi-
um(III) salts have found widespread applications as effective
Lewis acids in organic synthesis in recent decades.15 Given their
relatively weak strength as Lewis acid compared with other group
IIIA elements such as aluminum and boron, trimethylsilyl halide
is often employed together with indium salts as robust combined
Lewis acid catalyst. This combined Lewis acid system has been
utilized in various reactions developed by Baba,16 Lee,17 Corey,18
our group,19 and others.
entry
1
catalyst
InBr3
solvent
CH2Cl2
CH2Cl2
DCE
TMSX
-
yield (%)b
0
2
InBr3
-
0c
0d
54
0
Scheme 2. Selective Dearomatizing Cascade Reaction and
[2+2]-Cycloaddition of Aryl Alkyne with Acrylate
3
InBr3
-
4
InBr3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
TMSBr
TMSBr
TMSBr
TMSBr
TMSBr
TMSBr
TMSBr
TMSBr
TMSCl
TMSI
5
-
6
InF3
54
24
49
0
7
InCl3
8
InI3
9
In(acac)3
In(tfacac)3
In(tfacac)3
In(tfacac)3
In(tfacac)3
10
11
12
13
68
81
33
38
DCE
DCE
This work. In continuation of our research interest in the applica-
tion of indium in organic synthesis,19,20 herein we wish to report
the first example of In(III)-TMSBr catalyzed selective [2+2]-
cycloaddition and dearomatizing cascade reaction of aryl alkyne
with acrylate to access a series of densely functionalized decalin
derivatives and cyclobutenes bearing aryl and carbonyl substitu-
ents at room temperature with high chemo- and stereoselectivity
(Scheme 2). It is noteworthy that the obtained cyclobutene could
be easily converted into cyclobutane as well as 1,4- and 1,5-
diketones with high chemo- and stereoselectivity and the
dearomatizing cascade reaction involves the formation of a 1:1
Diels-Alder adduct as intermediate.
aUnless otherwise noted, all reactions were performed with 1c
(0.4 mmol), 2a (1.6 mmol), catalyst (20 mol%), TMSX (3 equiv),
o
b
c
0 C-rt, 2 h, N2. Isolated yields. 1.0 equiv of InBr3 was added.
dReaction temperature was 80 oC.
yield of 81% (entry 10 vs entry 11). In comparison, when TMSBr
was replaced by TMSCl or TMSI, the product yields were eroded
significantly to 33% and 38% (entries 12-13). An attempt to de-
crease the amount of TMSBr or methyl acrylate (2a) was ob-
served to have a detrimental impact on reaction efficiency (see
Table SI-1 in Supporting Information for details).
Substrate Scope of Aryl Alkynes for Indium(III)-TMSBr-
catalyzed [2+2]-Cycloaddition. With the optimized reaction
conditions in hand (Table 1, entry 11), we went on to probe the
generality of alkyne substrate scope of this [2+2]-cycloaddition
RESULTS AND DISCUSSION
Optimization of In(III)-TMSBr-catalyzed [2+2]-Cycloaddition
of Aryl Alkyne with Acrylate. At the outset, 1-phenyl-1-pentyne
(1c) and methyl acrylate (2a) were chosen as the model substrates
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with respect to 2a, and the results are summarized in Table 2a.
Substrate Scope of Acrylates for Indium(III)-TMSBr-
catalyzed [2+2]-Cycloaddition. Next, compatibility of different
acrylates 2 to the present reaction protocol was investigated using
1-phenyl-1-pentyne (1c) as standard coupling partner (Table 2b).
Reactions of acrylates containing longer O-alkyl substituents pro-
ceeded smoothly to give cyclobutenes 3cb-ce, albeit in relatively
low yields (13-61%) as compared to methyl acrylate (3ca). Acry-
lates tethered with other substituents aside from simple aliphatic
chain, such as chloroethyl, bromoethyl, phenyl, phenoxyethyl and
trifluoroethyl group, readily underwent the reaction to afford the
corresponding cyclobutenes 3cf-cj in moderate to good yields
(32-75%).
Both internal alkynes and terminal alkynes were proven to be
suitable substrates for this reaction protocol to produce respective
products 3aa-wa and 3xa-za in moderate to good yields.
Analogously, alkynes bearing linear alkyl substituents underwent
the transformation smoothly to afford 3aa-da in 73-85% isolated
yields. Presence of sterically more demanding substituents on
alkynes, for example, iso-butyl and tert-butyl groups, furnished
cyclobutenes 3ea and 3fa in reasonable yields. When halogen
substituents or phenyl group are present on phenyl ring, the
reactions worked equally well to deliver the corresponding
products 3ga-ja and 3qa in moderate to good yields, rendering
these products amenable for downstream chemical modifications.
Notably, alkynes possessing allyl or benzyl group are compatible
with the mild reaction conditions, leading to the anticipated
products 3sa and 3ta, respectively, both in 65% yield. The R1
substituent also could be ring motifs (eg., cyclopropyl, cyclohexyl,
and phenyl) and the corresponding tricylic cyclobutene products
3ua-wa were obtained in moderate yields. The obtained diphenyl
substituted cyclobutene 3wa possesses the main skeleton of the
unnamed norlignan shown in Fig. 1.3b
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Scheme 3. Functional Group Transformations of Cyclo-
butenes
Table 2. Substrate Scope for In(III)-TMSBr-catalyzed
[2+2]-Cycloadditiona,b
R
R
O
In(tfacac)3 (20 mol%)
TMSBr (3 equiv)
DCE, 0 oC-rt
O
R2
R2
O
O
+
R1
R1
1
2
3
(a) Substrate Scope of Aryl Alkynes
3aa, R1
3ba, R1
3ca, R1
3da, R1
=
=
=
=
Me, 73%
3ea, R1 = iBu, 65%
3fa, R1 = tBu, 63%
O
O
Et, 76%
nPr, 81%
nBu, 85%
O
O
O
R1
R1
Me
X
3ga, X = F, 51%
3ha, X = Cl, 62%
3ia, X = Br, 66%
3ja, X = Ph, 75%
O
Functional Group Transformation of Cyclobutenes. The exist-
ence of ester and alkene functionalities in the cyclobutene product
granted diversified chemical transformations of these products
(Scheme 3). The ester group could either be reduced by LiAlH4 to
afford the desired alcohol 3ca-1 or be hydrolyzed in the presence
of aqueous NaOH to deliver the corresponding carboxylic acid
3ca-2 (Scheme 3a). Moreover, the C-C double bond of 3ca could
be diastereoselectively hydrogenated by H2 in the presence of
Pd/C to give cyclobutane 3ca-3 and be oxidized by m-CPBA to
generate epoxide 3ca-4 as single diastereomers (Scheme 3b).21
Notably, 3ca-3 closely resembles the key cyclobutane skeleton
shown in Fig. 1.3 Encouragingly, the four-membered ring moiety
survived under these reaction conditions and remained intact dur-
ing the course of these transformations. The cyclobutene structure
was unambiguously confirmed by the X-ray diffraction analysis
of 3xa-1, which was prepared by the saponification of ester 3xa
followed by esterification with 6-Br-naphthol in the presence of
HATU and DMAP (Scheme 3c).22
3ka, 2-Me, 71%
3la, 3-Me, 58%
3ma, 4-Me, 74%
O
O
O
nBu
nBu
Br
O
O
O
O
O
O
O
O
O
R1
nBu
3qa, 65%
iBu
nBu
3na, R1 = tBu, 63%
3oa, R1 = iBu, 71%
3pa, 60%
3ra, 72%
O
O
Ph
O
O
O
O
Ph
3ta, 65%
3sa, 65%
3ua, 41%
3va, 35%
O
O
O
O
O
O
O
O
3xa, 56%
3ya, 64%
3za, 65%
3wa, 24%
(b) Substrate Scope of Acrylates
3cb, R2
3cc, R2
3cd, R2
3ce, R2
=
=
=
=
Et, 61%
nBu, 44%
O
O
O
R2
R
3cf, R = Cl, 75%
3cg, R = Br, 60%
Scheme 4. Acid and O2-mediated Selective Cleavage of C-
C/C=C Bond of 3ca
nHex, 35%
O
O
nC18H37, 13%
nPr
nPr
O
O
O
O
O
O
CF3
nPr
nPr
nPr
3ch, 67%
3ci, 40%
3cj, 32%
aUnless otherwise noted, all reactions were performed with 1 (0.4
mmol), 2 (1.6 mmol), In(tfacac)3 (20 mol%), TMSBr (3 equiv), 0
oC-rt, N2. bIsolated yields.
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rect cleavage of C=C bond using molecular oxygen instead of
ozone is rare; most of the existing methods were reported to work
only with acyclic alkenes and should proceed in the presence of
catalyst.24
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9
Substrate Scopes of Acid and O2-mediated Selective Cleav-
age of C-C/C=C Bond of Cyclobutene. Having recognized the
novelty and synthetic value of these C-C/C=C bond cleavage
reactions, we focused on examining the substrate scope felicitous
for these transformations, and the results are summarized in Table
3. It was found that both ring-opening reactions proceeded effi-
ciently under mild conditions to produce the desired 1,5- and 1,4-
dicarbonyl compounds in moderate to good yields in the presence
of InBr3-aq. HBr or atmospheric O2, respectively. It should be
noted that the effects of R1 substituent on both ring-opening reac-
tions are similar: as R1 chain was elongated from one to four car-
bons, the yields of 1,5-dicarbonyl compounds 4aa-da and 1,4-
dicarbonyl compounds 5aa-da decreased accordingly. In contrast,
when R2 alkyl chain length increased from methyl to n-hexyl
group, 4ca-cc were formed in decreased yield, while the for-
mation of 5ca-cd showed the opposite trend.
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Table 3. Acid and O2-mediated Selective Cleavage of C-C
Bond of Cyclobutene
Scheme 5. One-pot Synthesis of Pyrrole and Furan Deriva-
tives from 3caa,b
aReaction conditions: a: (1) 3ca (0.1 mmol), O2, rt, 72 h; (2)
NH4OAc (5 equiv), AcOH (0.3 mL), 90 oC, 24 h. b: 3ca (0.1
o
mmol), O2, rt, 72 h; (2) P2O5 (3 equiv), toluene, 100 C, 24 h.
bIsolated yield.
One-pot Synthesis of Pyrrole and Furan Derivatives from
3ca. Notably, 1,4-dicarbonyl compounds are difficult to prepare
by conventional methods but are useful building blocks towards
various carbocyclic and heterocyclic structural motifs.25 By em-
ploying this protocol, tri-substituted pyrrole 3ca-5 and furan 3ca-6
can be facilely synthesized in a one-pot manner by subjecting
cyclobutene 3ca to aforementioned oxygen-mediated cleavage
followed by ring-closure in the presence of NH4OAc/AcOH or
P2O5 (Scheme 5).25a
aUnless otherwise noted, all reactions were performed with 3 (0.1
mmol), InBr3 (1 equiv), 48% aq. HBr (1.5 equiv), DCM (1 mL),
c
36 h, rt, N2. bIsolated yield. Reaction time was 12 h. dUnless
otherwise noted, all reactions were performed with 3 (0.1 mmol),
O2 ballon, neat, rt, 72 h.
Preliminary Result of In(III)-TMSBr-catalyzed Dearomatiz-
ing Cascade Reaction. This dearomatizing cyclization reaction
was serendipitously discovered during our course of studying the
application of the combined Lewis acid system of InX3-TMSBr in
an attempted dearomatizing [4+2]-cycloaddition between α-aryl
vinyl bromide and acrylate under ambient conditions. Considering
the relative instability of α-aryl vinyl bromide, we speculated that
this Diels-Alder reaction could be realized in a one-pot manner by
in situ generation of α-aryl vinyl bromide c from aryl alkyne a in
Acid and O2-mediated Selective Cleavage of C-C/C=C
Bond of Cyclobutene 3ca. In addition to the above-mentioned
versatile functional group transformations, the existence of phenyl
and ester substituents might lead to some new reaction modes. It
is commonly known that cyclobutene could be easily transformed
to related diene under thermal conditions.4,5 However, when 3ca
was refluxed in toluene for 24 h, most of the starting material was
recovered and no diene product could be observed (Scheme 4a).
After many trials, we were pleased to find that cyclobutene 3ca
could be selectively converted into 1,5-dicarbonyl compound 4ca
or 1,4-dicarbonyl compound 5ca through selective cleavage of C-
C or C=C bond of 3ca in the presence of InBr3-aq. HBr or atmos-
pheric O2 at room temperature, respectively (Scheme 4b). It
should be noted that the present method for the synthesis of 1,5-
dicarbonyl compound is the first example of acid-mediated con-
version of cyclobutene to linear ketone.23 On the other hand, di-
the presence of
a a [4+2]
proton source,26 followed by
cycloaddition with Lewis acid-activated acrylate b to give 1:1
Diels-Alder product d that could presumably undergo further
reaction (Scheme 6a).
To test this hypothesis, a reaction using 4-ethynyltoluene (6a) and
methyl acrylate (2a) as model substrates was performed in the
presence of InBr3 (20 mol%), TMSBr (4 equiv; which could serve
as both additive and bromine source), H2O (1.0 equiv; which
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could serve as proton source) in CH2Cl2. When the reaction
o
mixture was stirred at 0 C to room temperature for 30 min, no
replaced by TMSCl, only a trace amount of the corresponding
product could be detected in the crude NMR spectrum (entry 11).
We also found that the amount of H2O critically affected the
product yield: decreased or increased the amount of H2O to 0.5 or
2.0 equiv hampered the yield significantly or even inhibited the
product formation (entries 12-13). Moreover, attempts to decrease
the amount of TMSBr, loading of methyl acrylate (2a) or that of
In(tfacac)3 were all observed to have a detrimental impact on
reaction efficiencies as well (see Table SI-2 in the Supporting
Information for details).
hypothesized 1:1 Diels-Alder product int-7aa was obtained. To
our surprise, a polycyclic ene 7aa was obtained in 37% yield
with >20:1 d.r., along with formation of 7aa-1 in 4% yield
(Scheme 6b). The structure of product 7aa was unequivocally
confirmed by single crystal X-ray diffraction analysis.22 After
meticulous structural examination of 7aa and 7aa-1, we
tentatively proposed that the initially postulated [4+2]-
cycloaddition could have occurred to give 1:1 Diels-Alder adduct
int-7aa as reaction intermediate. The expected high reactivity of
int-7aa could have allowed it to participate in tandem reactions
through interception by another molecule of aryl alkyne 6a to
generate 7aa or undergo rearomatization to give 7aa-1. To the
best of our knowledge, this is the first example of interception of
1:1 Diels-Alder adduct through a nucleophilic attack of alkyne.
While in another reported case, it was observed that the 1:1 Diels-
Alder adduct could react with another molecule of dienophile to
give either double-Diels-Alder product or Diels-Alder-ene
product (Scheme 1).13
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Table 4. Optimization of In(III)-catalyzed Dearomatizing
Cascade Reaction of 6a with 2aa
entry
1
catalyst
-
solvent
CH2Cl2
CH2Cl2
CH2Cl2
TMSX
TMSBr
TMSBr
-
yield (%)b
Scheme 6. Originally Proposed Dearomatizing [4+2]
Cycloaddtion of α-Aryl Vinyl Bromide with Acrylate
0
<5c
2
InBr3
3
InBr3
0
4
InBr3
CH2Cl2 TMSBr
37
33
12
35
31
66
31
<5
36d
<5e
5
InF3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
TMSBr
TMSBr
TMSBr
TMSBr
6
InCl3
7
InI3
8
In(OTf)3
In(tfacac)3
In(tfacac)3
In(tfacac)3
In(tfacac)3
In(tfacac)3
9
CH2Cl2 TMSBr
10
11
12
13
DCE
TMSBr
TMSCl
TMSBr
TMSBr
CH2Cl2
CH2Cl2
CH2Cl2
aUnless otherwise noted, all reactions were performed with 6a
(0.4 mmol), 2a (1.2 mmol), catalyst (20 mol%), TMSX (4 equiv),
o
b
c
d
0 C-rt, 2 h, N2. Isolated yields. H2O was not added. 0.5 equiv
of H2O was added. e2.0 equiv of H2O was added.
Optimization
of
In(III)-TMSBr-catalyzed
Cascade
Dearomatization Reaction of 6a with 2a. Intrigued by the
efficient and elegant construction of complex molecular
architectures from simple substrates under operationally simple
procedure, we commenced the optimization studies of this
reaction using 4-ethynyltoluene (6a) and methyl acrylate (2a) as
model substrates (Table 4). It was found that indium catalyst,
TMSBr and H2O were indispensable for product formation:
reactions performed in the absence of indium catalyst, H2O or
TMSBr resulted in almost negligible formation of the desired
product 7aa (entries 1-3). Among the different indium catalysts
evaluated (entries 4-9), indium(III) trifluoroacetylacetonate
[In(tfacac)3] was found to exhibit the best catalytic activity to
afford the desired product 7aa in 66% yield (entry 9). Common
Lewis acid catalysts (e.g., AlBr3, ZnCl2, and TiCl4) were also
screened, which mostly resulted in no product formation (see
Table SI-2 in the Supporting Information for details). In addition,
this reaction was found to be highly solvent-dependent and
worked only in chlorinated solvents such as CH2Cl2 or 1,2-
dichloroethane (DCE), albeit in relatively low yield with DCE
(entry 9 vs entry 10). On the other hand, when TMSBr was
Substrate Scope of In(III)-TMSBr-catalyzed Dearomatizing
Cascade Reaction. With the optimized reaction conditions in
hand (Table 4, entry 9), we sought to probe the generality of al-
kyne substrate scope of this reaction (Table 5). After extensive
studies, it was observed that para-substituted aryl acetylenes were
well suited to undergo present reaction in high stereocontrol
(>20:1 d.r.). Generally, when R1 chain gets longer from Me to nBu,
the yields of 7aa, 7ba and 7ea decreased accordingly. It is how-
n
ever interesting to find that when R1 is Pr, the highest yield of
product 7ca was achieved. Substrates bearing longer alkyl chain
including n-C5H11 or n-C6H13 moiety were also proven to be suit-
able candidates, capable of undergoing this transformation
smoothly to give the expected products 7ga and 7ha in moderate
yields. As R1 gets bulkier, a proportionate decrease of product
yield could be noted (7ca vs 7da and 7ea vs 7fa). When the R1
substituent is bulky 4-propyl-cyclohexyl, the reaction proceeded
with equal success to generate the corresponding product 7ia in
moderate yield. In addition, aryl alkynes possessing para-
substituent such as phenyl and fluorine were accommodated well
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for this reaction (7ja and 7ka). Aside from methyl acrylate, ethyl
In(III)-TMSBr-catalyzed Dearomatizing Cascade Reaction of
and n-butyl acrylates were also compatible substrates when inves-
tigated using 4-ethynyltoluene (6a) or 4-ethylphenylacetylene (6b)
as coupling partner. Their reactions proceeded smoothly to afford
6l/6m with 2a. On the other hand, when 4-chlorophenylacetylene
(6l) and 4-bromophenylacetylene (6m) were subjected to the reac-
tions with methyl acrylate (2a) under the standard conditions, the
double Diels-Alder products 7la-1 and 7ma-1 were formed, along
with formation of the aforementioned dearomatizing products 7la
and 7ma (Table 3). It should be noted that the complex tricyclic
compounds 7la-1 and 7ma-1 were assembled in a one-pot manner
synthesis from simple starting materials albeit the yield and selec-
tivity were only moderate. This tricyclic structure is also a com-
mon skeleton in naturally occurring compounds such as (+)-
Bis(carvacrol) (Fig. 1).2 The structures of 7la-1 and 7ma-1 were
unambiguously determined by single crystal X-ray diffraction
analysis.22 Formation of 7la-1 and 7ma-1 have also provided
mechanistic clues on this dearomatizing reaction.
Table 5. Substrate Scope of In(tfacac)3-TMSBr-catalyzed
Dearomatizing Cascade Reactiona,b
R1
H
CO2R
R1
In(tfacac)3
TMSBr
H2O
Br
H
Br
H
H
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
H
and/or
OR
+
CH2Cl2
0 oC-rt
R1
R1
CO2R
7-1
H
CO2R
6
2
7
(a) In(III)-TMSBr-catalyzed Dearomatizing Cascade Reaction
Et
nPr
Br
H
Br
H
Br
H
Functional Group Transformation of 7aa through Selective
Coupling Reactions. The existence of two different vinyl-Br
motifs in dearomatizing products granted chemical transfor-
mations by transition-metal catalyzed coupling reactions (Scheme
7). For example, in the presence of Pd catalyst, 7aa could undergo
selective Suzuki-Miyaura coupling to give 7aa-2 in 79% yield.
Moreover, 7aa also could undergo selective Sonogashira coupling
with two different terminal alkynes to produce the corresponding
products 7aa-3 and 7aa-4 in 75% and 71% yield, respectively.
Br
Br
Br
H
H
H
Et
nPr
H
H
H
CO2Me
CO2Me
CO2Me
7aa 66%
7ba, 61%
CCDC 1500386
tBu
7ca, 73%
nBu
nPen
iPr
Br
H
Br
H
Br
H
Br
H
Br
H
Br
Br
H
Br
H
H
nBu
tBu
nPen
iPr
Scheme 7. Functional Group Transformation of 7aa
H
H
H
H
CO2Me
CO2Me
7fa, 50%
CO2Me
CO2Me
7da, 70%
nHex
7ea, 60%
7ga, 56%
R
Ph
Br
H
Br
H
Br
H
Br
Br
H
Br
H
H
nPr
R =
nHex
R
Ph
H
H
H
CO2Me
CO2Me
CO2Me
7ha, 55%
7ia, 48%
7ja, 56%
F
Et
Experimental Studies of Activation of Acrylate by In(III)-
TMSBr. First, 29Si NMR studies of TMSBr in the presence of
additives were performed.16 Upon mixing with equimolar
amounts of In(tfacac)3 (0.2 M), the 29Si signal of TMSBr shifted
from 27.6 ppm to 7.4 ppm. On the other hand, when TMSBr was
mixed with AlBr3, the corresponding signal hardly changed (27.8
ppm) (see the Supporting Information for details). These results
indicate that TMSBr was activated by In(tfacac)3 by the formation
of a Lewis acid complex while this kind of activation did not oc-
cur when In(tfacac)3 was replaced by AlBr3. In addition, the
chemical shifts δ (13C) of carbonyl carbon of methyl acrylate in
the presence of In(tfacac)3 and/or TMSBr also were measured.16
When In(tfacac)3 was not used, almost no shift was observed.
When only In(tfacac)3 was added, this value changed from 166.4
ppm to 168.4 ppm. Finally, when both In(tfacac)3 and TMSBr
were added, the degree of low-field shift was enhanced (170.2
ppm) (see the Supporting Information for details). These results
show that the methyl acrylate was effectively activated by the
combined Lewis acid complex of In(tfacac)3 and TMSBr.
Br
H
Br
H
Br
H
Br
H
Br
H
Br
Br
H
Br
H
H
F
Et
H
H
H
H
CO2Et
CO2nBu
CO2Me
CO2Et
7ka, 50%
7ab, 55%
7bb, 52%
7ac, 37%
(b) In(III)-TMSBr-catalyzed Dearomatizing Reaction of 6l/6m with 2a
Cl
Br
MeO2C
MeO2C
H
H
Br
H
Br
H
Br
Br
Br
Br
H
H
+
+
Cl
Br
H
H
CO2Me
CO2Me
Cl
Br
H
H
CO2Me
7la (31%)
CO2Me
7ma (30%)
7ma-1 (32%)
7la-1 (29%)
7la-1
7ma-1
(CCDC 1500387)
(CCDC 1500388)
aUnless otherwise noted, all reactions were performed with 6 (0.4
mmol), 2 (1.2 mmol), In(tfacac)3 (20 mol%), TMSBr (4 equiv),
H2O (1.0 equiv), 0 oC-rt, N2. bIsolated yields.
Plausible Reaction Mechanism of In(tfacac)3-TMSBr-
catalyzed [2+2]-Cycloaddition. Base on the current experi-
mental results and literature reports,7-11 a possible reaction path-
way for the In(tfacac)3-TMSBr-catalyzed [2+2]-cycloaddition of
aryl alkyne and acrylate could be proposed as illustrated in
Scheme 8: first, In(tfacac)3 and TMSBr react to form the com-
bined Lewis acid complex with aggrandized acidity than either of
the anticipated products 7ab and 7ac, albeit in relatively low
yields (55% and 37%) as compared to that attainable with methyl
acrylate (7aa).
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them alone; second, the thus formed combined Lewis acid acti-
reflecting that α-aryl vinyl bromide should be a reaction interme-
diate and the Diels-Alder reaction should precede the attack of
aryl alkyne. In addition, both α-aryl vinyl bromides 6a-1 and 6l-1
were found to react with acrylate 2a to deliver bicyclic rings 7aa-
1 and 7la-1 respectively (eq. c); both of them should be generated
from the corresponding 1:1 Diels-Alder adducts. The result fur-
ther emphasized the role of 1:1 Diels-Alder adducts as the key
intermediate in these transformations. Through X-ray single crys-
tal diffraction analysis, the structure of 7aba was also confirmed
without ambiguity.22 The relatively low yields obtained in eq. b
and c might be attributed to the poor stability of the pre-prepared
α-aryl vinyl bromide. It is also worthwhile to note that in the ab-
sence of TMSBr, neither 7aba, 7aa-1 nor 7la-1 could be produced,
thus implying synergistic action of TMSBr with indium salt in the
catalysis of this reaction.
vates the acrylate through preferential coordination of silicon
center to the carbonyl group; third, aryl alkyne could act as nucle-
ophile and attacks the activated acrylate to give the enolate inter-
mediate int-1. An intramolecular nucleophilic attack then occurs
to furnish the cyclobutene product. Aryl alkynes bearing strong
electron-withdrawing groups (e.g., CF3, NO2 and CN) on phenyl
ring or triple bond were found unsuitable for this reaction because
the nucleophilic attack of alkyne to acrylate are difficult to take
place because of the electron deficiency of triple bond. Moreover,
the reactions employing alkyl-substituted alkynes, dimethyl male-
ate, methyl methacrylate, or methyl but-2-enoate as substrates
could not provide the desired cyclobutene products and only start-
ing materials could be recovered.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Plausible Reaction Mechanism of In(tfacac)3-
TMSBr-catalyzed [2+2]-Cycloaddition
Scheme 9. Mechanistic Studies of Dearomatizing Cascade
Reaction
Computational Studies of the Mechanisms of [2+2]-
Cycloaddition Catalyzed by In(III)-TMSBr. We performed a
density functional theory (DFT) study to find the most plausible
reaction pathway. All technical details are given in the Supporting
Information. To make our computational investigation easier,
InBr3, which also showed the catalytic activity in the experiment
(Table 1), was used instead of In(tfacac)3. In the most plausible
pathway (Figure 2), InBr3 initially abstracts a Br- ion from TMSBr
to form TMS+, which in turn coordinates to methyl acrylate to
lower the barrier for cycloaddition. Significantly, our calculations
show that the activated methyl acrylate reacts with phenyl acety-
lene in a stepwise manner to form a [2+2]-cycloaddition adduct.
The TMS+ moiety in the adduct then accepts a Br- ion from InBr4
-
Plausible Reaction Mechanism of In(tfacac)3-TMSBr-
catalyzed Dearomatizing Cascade Reaction. Based on the
above results, a plausible mechanistic pathway for this novel
dearomatic cascade reaction is proposed (Scheme 10). Initially, a
vinyl bromide 6-1 generated from aryl alkyne 6 would undergo a
Diels-Alder reaction with acrylate 2 catalyzed by the combined
Lewis acid system to give a 1:1 Diels-Alder adduct int-7. When
R1 is an electron-donating group, adduct int-7 is readily trapped
by a proton to generate a stabilized tertiary allylic carbocation int-
7-1. Next, the attack of the Br anion to alkyne and a concomitant
attack of the alkyne to the allylic carbocation from the less
hindered face of bicyclic ring occurs via a concerted SN2’-type
pathway (or via a stepwise pathway although no related by-
products could be detected), leading to desired product 7 bearing a
newly formed C-C double bond with E-geometry. On the other
hand, when R1 is Cl or Br, attack of alkyne to intermediate int-7
might not be so rapid, allowing a considerable amount of it to
undergo another Diels-Alder reaction with 2 from the sterically
less hindered side, furnishing the double-Diels-Alder adduct 7-1.
to regenerate TMSBr, thereby resulting in dissociation of the
TMS moiety from the carbonyl group and completion of the reac-
tion. We also examined a mechanism in which InBr3, in place of
TMS+, coordinates to methyl acrylate (see the Supporting Infor-
mation). However, DFT results suggest that this reaction is less
likely than the above-examined one, probably because of lower
Lewis acidity of InBr3. One may also wonder if both InBr3 and
TMSBr coordinate to methyl acrylate as separate Lewis acids to
facilitate the reaction. However, this pathway could not be found
by DFT calculations, leading us to rule out this reaction mode.
Mechanistic
Studies
of
In(tfacac)3-TMSBr-catalyzed
Dearomatizing Cascade Reaction. In order to gain in-depth
mechanistic insights into the present dearomatizing cascade reac-
tion, a series of experiments were carried out (Scheme 9). When
the reaction between 6a and 2a was conducted in D2O-saturated
CH2Cl2 with other parameters held constant, deuterated product
[D2]-7aa was obtained in 68% yield with ~80% D, indicating that
the two protons at positions 3 and 8 in the bicyclic ring should
have come from the D2O (eq. a). Moreover, the crossover reaction
of 6a-1 with 6b gave the corresponding crossover product 7aba in
32% yield and homo-coupling product 7ba in 14% yield (eq. b),
Discussion. According to the proposed pathway, some character-
istic properties of this dearomatizatiton reaction could be ex-
plained. First, existence of the electron-donating para-substituents
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on the phenyl ring is crucial for this cascade reaction because it
could accelerate the dearomatization/Diels-Alder reaction step as
well as stabilize int-7-1. For this reason, aryl alkynes bearing
strong electron-withdrawing group on phenyl ring were found
unsuitable for this reaction. Phenylacetylene, 2-ethynyltoluene
and 3-ethynyltoluene also could not give the desired product. The
existence of substituent on the triple bond or bulky substituents on
acrylates could result in difficulty in generating int-7. When the
linear alkyl substituent is elongated from methyl, ethyl, butyl to
hexyl, the corresponding decrease in product yield was obvious.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Zero-point energy (ZPE) corrected energy profile (in kcal/mol) for the most plausible reaction pathway, as determined at the
B3LYP(PCM,CH2Cl2)/[SDD(In),6-311+G**(others)]//B3LYP/[SDD(In),6-31G*(others)] level.
tionalized polycyclic compounds and cyclobutenes through selec-
tive dearomatizing cascade reaction and [2+2]-cycloaddition with
high chemo- and stereoselectivity was developed. The obtained
cyclobutenes were demonstrated to be versatile reaction interme-
diates which could undergo diversified functional group transfor-
mations (such as diastereoselective hydrogenation and epoxida-
tion) with the intactness of four-membered rings. It also could be
selectively converted into synthetically useful 1,5-dicarbonyl and
1,4-dicarbonyl compounds under ambient conditions. The
dearomatizing products also could be modified by selective cou-
pling reactions. Through 13C and 29Si NMR studies, it was found
that acrylate could be effectively activated by the combined Lewis
acid for further reactions. Based on the isotopic labelling experi-
ment, crossover experiment and controlled experiment, this
dearomatizing protocol is proposed to involve a tandem Diels-
Alder reaction of in situ generated α-aryl vinyl bromine with acry-
late followed by an interception of the thus-formed Diels-Alder
adduct by another molecule of aryl alkyne or acrylate. Finally,
computational studies of reaction mechanisms were conducted
and the results also suggest that the combined Lewis acid catalyst
could efficiently promote both reactions.
Scheme 10. Plausible Reaction Mechanism of In(III)-
TMSBr-catalyzed Dearomatizing Cascade Reaction
ASSOCIATED CONTENT
Supporting Information
CONCLUSION
Experiment procedures, compound characterization data, copies
1
In conclusion, a novel Lewis acid-catalyzed reaction of aryl al-
kynes with acrylates for the efficient assembly of densely func-
of H and 13C NMR spectra, and CIF files for 3xa-1, 7aa, 7ba,
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(11) Zhu and co-workers reported an In(III)-catalyzed cascade reaction
7la-1, 7ma-1, and 7aba. This material is available free of charge
via the Internet at http://pubs.acs.org.
involving [2+2] cycloaddition of aryl alkyne with an in situ generated
indenone from enynals and its condition could not afford the cyclobutene
product in our case: Liang R. X.; Jiang, H. F.; Zhu, S. F. Chem. Commun.
2015, 51, 5530.
AUTHOR INFORMATION
Corresponding Author
(12) For selected reviews on the dearomatization reaction, see: (a) Pape,
A. R.; Kaliappan, K. P.; Kündig, E. P. Chem. Rev. 2000, 100, 2917; (b)
López-Ortiz, F.; Iglesias, M. J.; Fernández, I.; Andújar Sánchez, C. M.;
Gómez, G. R. Chem. Rev. 2007, 107, 1580; (c) Pouységu, L.; Deffieux, D.;
Quideau, S. Tetrahedron 2010, 66, 2235; (d) Harrison, D. P.; Harman, W.
D. Aldrichimica Acta 2012, 45, 45; (e) Zhuo, C.-X.; Zhang, W.; You, S.-
L. Angew. Chem. Int. Ed. 2012, 51, 12662; (f) Ding, Q. P.; Zhou, X. L.;
Fan, R. H. Org. Biomol. Chem. 2014, 12, 4807; (g) Wu, W. T.; Zhang, L.-
M.; You, S.-L. Chem. Soc. Rev. 2016, 45, 1570; (h) Sun, W. S.; Li, G. F.;
Hong, L.; Wang, R. Org. Biomol. Chem. 2016, 14, 2164.
(13) (a) Williams, J. K.; Wiley, D. W.; McKusick, B. C. J. Am. Chem.
Soc. 1962, 84, 2210; (b) Ciganek, E. J. Org. Chem. 1969, 34, 1923; (c)
Nakahara, M.; Uosaki, Y.; Sasaki, M.; Osugi, J. Bull. Chem. Soc. Jpn.
1980, 53, 3395; (d) Brückner, R.; Huisgen, R.; Schmid, J. Tetrahedron
Lett. 1990, 31, 7129.
*ias_zlshen@njtech.edu.cn
*teckpeng@ntu.edu.sg
Notes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to Nanjing Tech University, SICAM Fellowship
from Jiangsu National Synergetic Innovation Center for Advanced
Materials, Nanyang Technological University, Singapore Ministry
of Education Academic Research Fund [Tier 1: MOE2015-T1-
001-070 (RG5/15) and MOE2014-T1-001-102 (RG9/14)], and
Singapore National Research Foundation (NRF2015NRF-
POC001-024) for generous financial support. H.H. thanks City
University of Hong Kong (7200534 and 9610369) for financial
support.
(14) Kolis, S. P.; Chordia, M. D.; Liu, R. G.; Kopach, M. E.; Harman, W.
D. J. Am. Chem. Soc. 1998, 120, 2218.
(15) For selected reviews on indium chemistry, see: (a) Li, C. J.; Chan, T.
H. Tetrahedron 1999, 55, 11149; (b) Babu, G.; Perumai, P. T. Aldrichim-
ica Acta 2000, 33, 16; (c) Lee, P. H. Bull. Korean Chem. Soc. 2007, 28, 17;
(d) Shen, Z.-L.; Wang, S.-Y.; Chok, Y.-K.; Xu, Y.-H.; Loh, T.-P. Chem.
Rev. 2013, 113, 271; (e) Zhao, K.; Shen, L.; Shen, Z.-L.; Loh, T.-P. Chem.
Soc. Rev. 2017, 46, 586.
(16) (a) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Tetrahedron 2002, 58,
8227; (b) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem.
2006, 71, 8516.
REFERENCES
(1) (a) Roche, S. P.; Porco, J. A. Jr. Angew. Chem. Int. Ed. 2011, 50, 4068;
(b) James, M. J.; O'Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Chem.
Eur. J. 2016, 22, 2856.
(2) Dhambri, S.; Mohammad, S.; Nguyen Van Buu, O.; Galvani, G.;
Meyer, Y.; Lannou, M.-I.; Sorin, G.; Ardisson, J. Nat. Prod. Rep. 2015, 32,
841.
(3) For selected examples of natural products and bio-active compounds
containing cyclobutane moieties with aryl and ester groups, see: (a)
Dembitsky, V. M. J. Nat. Med. 2008, 62, 1; (b) Li, Y.-Z.; Tong, A.-P.;
Huang, J. Chem. Biodivers. 2012, 9, 769; (c) Berger, W. T.; Ralph, B. P.;
Kaczocha, M.; Sun, J.; Balius, T. E.; Rizzo, R. C.; Haj-Dahmane, S.;
Ojima, I.; Deutsch, D. G. PLoS ONE 2012, 7, e50968.
(4) For selected reviews on the preparation and synthetic application of
cyclobutanes and cyclobutenes in organic synthesis, see: (a) Lee-Ruff, E.;
Mladenova, G. Chem. Rev. 2003, 103, 1449; (b) Namyslo, J. C.; Kauf-
mann, D. E. Chem. Rev. 2003, 103, 1485; (c) Xu, Y.; Conner, M. L.;
Brown, M. K. Angew. Chem. Int. Ed. 2015, 54, 11918; (d) Misale, A.;
Niyomchon, S.; Maulide, N. Acc. Chem. Res. 2016, 49, 2444.
(5) For selected examples on ring-opening of cyclobutenes, see: (a) Wang,
X.-N.; Krenske, E. H.; Johnston, R. C.; Houk, K. N.; Hsung, R. P. J. Am.
Chem. Soc. 2015, 137, 5596; (b) Frebault, F.; Luparia, M.; Oliveira, M. T.;
Goddard, R.; Maulide, N. Angew. Chem. Int. Ed. 2010, 49, 5672.
(6) For selected examples of transition metal-catalyzed [2+2]-
cycloaddition, see: (a) Treutwein, J.; Hilt, G. Angew. Chem. Int. Ed. 2008,
47, 6811; (b) Lopez-Carrillo, V.; Echavarren, A. M. J. Am. Chem. Soc.
2010, 132, 9292; (c) Schotes, C.; Mezzetti, A. Angew. Chem. Int. Ed. 2011,
50, 3072; (d) Nishimura, A.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc.
2012, 134, 15692; (e) Sakai, K.; Kochi, T.; Kakiuchi, F. Org. Lett. 2013,
15, 1024.
(7) (a) Snider, B. B.; Rodini, D. J.; Conn, R. S. E.; Sealfon, S. J. Am.
Chem. Soc. 1979, 101, 5283; (b) Inanaga, K.; Takasu, K.; Ihara, M. J. Am.
Chem. Soc. 2005, 127, 3668; (c) Ishihara, K.; Fushimi, M. J. Am. Chem.
Soc. 2008, 130, 7532; (d) Okamoto, K.; Shimbayashi, T.; Tamura, E.;
Ohe, K. Org. Lett. 2015, 17, 5843; (e) Kang, T. F.; Ge, S. L.; Lin, L. L.;
Lu, Y.; Liu, X. H.; Feng, X. M. Angew. Chem. Int. Ed. 2016, 55, 5541.
(8) (a) Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Niihata, S. J. Am. Chem.
Soc. 1992, 114, 8869; (b) Ito, H.; Takenaka, Y.; Kobayashi, T.; Iguchi, K.
J. Am. Chem. Soc. 2004, 126, 4520; (c) Takenaka, Y.; Ito, H.; Hasegawa,
M.; Iguchi, K. Tetrahedron 2006, 62, 3380.
(17) Lee, P. H.; Lee, K.; Sung, S.-Y.; Chang, S. J. Org. Chem. 2001, 66,
8646.
(18) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2014, 136, 10918.
(19) (a) Chan, K.-P.; Loh, T.-P. Org. Lett. 2005, 7, 4491; (b) Liu, F.; Loh,
T.-P. Org. Lett. 2007, 9, 2063; (c) Chan, K.-P.; Lin, H. Y.; Loh, T.-P.
Chem. Commun. 2007, 939; (d) Hu, X. H.; Liu, F.; Loh, T.-P. Org. Lett.
2009, 11, 1741.
(20) For selected typical examples of indium chemistry developed in our
group, see: (a) Zhao, Y.-J.; Loh, T.-P. J. Am. Chem. Soc. 2008, 130,
10024; (b) Shen, Z.-L.; Goh, K. K. K.; Cheong, H.-L.; Wong, C. H. A.;
Lai, Y.-C.; Yang, Y.-S.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 15852;
(c) Shen, Z.-L.; Goh, K. K. K.; Yang, Y.-S.; Lai, Y.-C.; Wong, C. H. A.;
Cheong, H.-L.; Loh, T.-P. Angew. Chem. Int. Ed. 2011, 50, 511; (d) Li.
B.; Lai, Y.-C.; Zhao, Y. J.; Wong, Y.-H.; Shen, Z. L.; Loh, T.-P. Angew.
Chem. Int. Ed. 2012, 51, 10619.
(21) The relative stereochemistry of the product 3ca-3 and 3ca-4 was
confirmed on the basis of 2D NMR spectra which is consistent with
reported data of a similar reaction and we believe that the hydrogenation
and epoxidation should proceed on the less hindered face of the
cyclobutene ring. For related examples, see: Mevellec, L.; Evers, M.;
Huet, F. Tetrahedron 1996, 52, 15103.
(22) The crystal data of 3xa-1 (CCDC 1480647), 7aa (CCDC 1500385),
7ba (CCDC 1500386), 7la-1 (CCDC 1500387), 7ma-1 (CCDC 1500388),
7aba (CCDC 1500389), can be obtained free of charge from The Cam-
bridge Crystallographic
www.ccdc.cam.ac.uk/data_request/cif.
Data
Centre
via
(23) An acid-mediated hydrolysis of amido-substituted cyclobutene to
ester was previously reported by Hsung (see reference 10).
(24) (a) Lin, R. Y.; Chen, F.; Jiao, N. Org. Lett. 2012, 14, 4158; (b) Gon-
zalez-de-Castro, A.; Xiao, J. L. J. Am. Chem. Soc. 2015, 137, 8206.
(25) (a) Xuan, J.; Feng, Z.-J.; Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J. Chem.
Eur. J. 2014, 20, 3045; (b) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 11546 and references cited therein.
(26) (a) Yu, W. S.; Jin, Z. D. J. Am. Chem. Soc. 2000, 122, 9840; (b)
Nishimoto, Y.; Moritoh, R.; Yasuda, M.; Baba, A. Angew. Chem. Int. Ed.
2009, 48, 4577.
(9) Sweis, R. F.; Schramm, M. P.; Kozmin, S. A. J. Am. Chem. Soc. 2004,
126, 7442.
(10) Li, H. Y.; Hsung, R. P.; Dekorver, K. A.; Wei, Y. G. Org. Lett. 2010,
12, 3780.
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