Construction of 4-Isochromanones through Cu(OTf)2-Catalysed Sequential C=O and C–O Bond Formation

Article abstract of DOI:10.1002/ejoc.201701808

A new strategy for the facile and efficient synthesis of 4-isochromanones has been developed. The reaction involves a Cu(OTf)₂-catalysed sequential reaction of epoxides carrying electron-deficient alkenes using the solvent DMSO as the oxidant.

Full text of DOI:10.1002/ejoc.201701808

A Journal of
Accepted Article
Title: Construction of 4-Isochromanones via Cu(OTf)2-Catalyzed
Sequential C=O and C-O Bond Formations
Authors: Siyang Xing, Nan Gu, Jiajing Qin, Hong Cui, Yan Li, Kui
Wang, Dawei Tian, Bo Chen, and Guo Yu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701808
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European Journal of Organic Chemistry
10.1002/ejoc.201701808
FULL PAPER
Construction of 4-Isochromanones via Cu(OTf) -Catalyzed
2
Sequential C=O and C-O Bond Formations
Siyang Xing,* Nan Gu, Jiajing Qin, Hong Cui, Yan Li, Kui Wang,* Dawei Tian,* Bo Chen and Guo Yu
[
5]
Abstract: A new strategy for the facile and efficient synthesis of 4-
isochromanones has been developed via a Cu(OTf) -catalyzed
compounds containing the isochroman moieties . Considering
their synthetic utility and application in pharmaceuticals, a
variety of synthetic methods have been developed for the
synthesis of 4-isochromanones. Conventionally, these
compounds were prepared by cyclization reactions including
2
sequential reaction of epoxides carrying electron-deficient alkenes
using the solvent DMSO as the oxidant. The single-step process
involves a sequential oxidative ring opening of epoxides and oxa-
Michael addition where one new C=O bond and one new C-O bond
were created. The advantages of this methodology include high
bonding efficiency, a broad substrate scope and mild conditions.
[
6]
[7]
Dieckmann condensation , Friedel-Crafts reaction , lithium-
[
8]
[9]
acylation reaction and thiol-catalysed acyl radical addition .
However, most of these methods have significant limitations
such as limited substrate scope, harsh reaction conditions or
inferior bonding efficiency. Efficient and general approaches
allowing more diversified syntheses of 4-isochromanones were
few.
was recognized as an efficient and
environmentally friendly strategy for the construction of
complicated target molecules from readily available materials.
Recently, Zhang et al. reported an elegant Yb(OTf) -catalyzed
3
sequential epoxide ring opening/Friedel-Crafts cyclization for the
construction of 4-isochromanones (Scheme 2, eq 1). Prasad
et al. achieved another efficient synthesis of 4-isochromanones
Introduction
[
10]
Sequential reaction
The structural motif of 4-isochromanones is widely occurring in
many natural products and synthetic bioactive molecules
[
1]
(
Scheme 1). For example, terreinol was isolated as a novel
metabolite in an effort to screen enzymatic activity in malt
extracts from cultures of Brazilian strains of A. terreus.
[11]
[
2]
Eleganketal
A ,
possessing
a
highly
oxygenated
dibenzospiroketal ring system, was obtained from the fungus
3
via an AuCl -catalyzed cascade triggered by an internal
[
3]
Spicaria elegans KLA03. Hongconin was isolated from the
rhizome of Eleutherine americana Merr et Heyne (Iridaceae) and
displayed cardioprotective activity against angina pectoris in
[12]
nucleophile (Scheme 2, eq 2). Encouraged by these notable
advances, we hoped to further develop efficient and general
ways to construct the 4-isochromanones from readily available
starting materials.
[
4]
preliminary clinical trials. XJP and its analogues were shown to
exhibit large variety of biological activities including
antioxidative, antiinflammatory, antihypertensive and
a
cardioprotective. Moreover, 4-isochromanones were also
employed as key building blocks for the synthesis of complex
Scheme
2
Previous sequential reactions for the synthesis of 4-
isochromanones
[
13]
[14]
Epoxides
and electron-deficient alkenes , as two kinds
of useful synthetic intermediates, were readily to react with
nucleophiles to afford the corresponding ring-opened products
and addition products, respectively. However, few tandem
reactions simultaneously involving ring opening of epoxides and
Michael addition of electron-deficient alkenes have been
Scheme 1 Representative natural products
[
15]
reported. As
a
part of our ongoing research
on the
[
a]
Tianjin Key Laboratory of Structure and Performance for Functional
Molecules; Key Laboratory of Inorganic-Organic Hybrid Functional
Material Chemistry (Tianjin Normal University), Ministry of
Education; College of Chemistry, Tianjin Norma University, Tianjin
development of highly selective strategies for heterocyclic
compounds with complicated structure, we designed and
synthesized a new type of substrates carrying both epoxides
and electron-deficient alkenes. When we treated them with
DMSO in the presence of Lewis acids, sequential oxidative ring
opening of epoxides and oxa-Michael addition took place to
furnish a series of 4-isochromanones in moderate to good yields
by the formation of one C=O bond and one C-O bond (Scheme
300387, People’s Republic of China.
E-mail:hxxyxsy@tjnu.edu.cn (S. Xing);
hxxywk@tjnu.edu.cn (K. Wang);
hxxytdw@tjnu.edu.cn (D, Tian)
[
16]
[17]
[b]
Supporting information for this article is given via a link at the end of
the document.
3). Herein, we would report the detailed results of the new
sequential reaction.
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European Journal of Organic Chemistry
10.1002/ejoc.201701808
FULL PAPER
O
O
O
S
O
Me
Me
LA
LA
CO2Me
O
OH
-
Me2S
Oxa-Michael
addition
CO2Me oxidative ring
opening of epoxidesMeO2C
CO2Me
MeO2C
CO2Me
Scheme 3 Sequential reaction for the construction of 4-isochromanones
Scheme 4 Preparation of epoxide 2a
Results and Discussion
[
a]
Epoxide 2a could be prepared starting from commercial 2-
Table 1 Optimization of conditions for the sequential reaction
bromobenzaldehyde in a three-step sequence (Scheme 4). 2-
[
15a]
bromobenzaldehyde underwent Stille coupling reaction
Knoevenagel reaction
and
to provide the desired alkene 1a. Then
selective epoxidation of alkene 1a afforded the requisite epoxide
a (Scheme 4). With the target compound in hand, we started
[
15a]
2
optimizing the conditions of the sequential reaction for the
synthesis of 4-isochromanone 3a (Table 1). Initially, in the open
air, the sequential reaction of epoxide 2a was carried out using
o
[b]
Entry
Catalyst
-
Solvent
T ( C)
70
70
70
70
70
70
70
70
90
70
70
70
70
70
70
70
70
t (h)
12
10
10
10
10
10
10
10
4
Yield (%)
o
DMSO as the solvent at 70 C for 12 h (Entry 1). To our delight,
1
2
3
4
5
6
7
8
9
2
Me SO
33
60
69
73
53
24
-
product 3a was successfully obtained in 33% yield. To improve
the yield of the sequential reaction, several different Lewis acids
were screened. We found that a series of metal triflates
AgOTf
Me
2
Me
2
Me
2
Me
2
SO
SO
SO
SO
Yb(OTf)
3
including AgOTf, Yb(OTf)
obviously promote the sequential reaction (Entries 2~5). When
Cu(OTf) was used, the best result was obtained and product 3a
was isolated in 73% yield. BF OEt and SnCl were not good
3 2 3
, Cu(OTf) and In(OTf) were able to
Cu(OTf)
2
2
In(OTf)
3
3
2
4
catalysts for the sequential reaction and only poor yields were
observed (Entries 6~7). It should be noted that HOTf, as a
proton acid, also successfully promoted the sequential reaction
to afford product 3a in 45% yield (Entry 8). Then we attempted
3
BF OEt
2
Me SO
2
SnCl
4
Me
2
Me
2
Me
2
Me
2
SO
SO
SO
SO
HOTf
45
46
55
55
0
o
to raise the reaction temperature to 90 C, product 3a was
afforded in 46% yield (Entry 9). When the sequential reaction
was run using degassed DMSO in Ar, product 3a was afforded
in 55% yield (Entry 10). We guessed that keeping the by-product
Cu(OTf)
Cu(OTf)
2
[
[
c]
1
0
2
10
10
10
10
10
10
10
10
c,d]
Me
2
S in the closed reaction system had a slight bad influence on
11
Cu(OTf)2
2
Me SO
the generation of product 3a. Therefore, we run the sequential
reaction by passing Ar through the reaction mixture to drive the
1
2
3
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
2
DCE
by-product Me
obtained in 55% yield (Entry 11). In the previous literature
Tsuji reported an oxidative ring opening of epoxides with DMSO
via a free-radical mechanism in the presence of O . We
supposed that the lower yield of product 3a was attributed to the
absence of O in the reaction system. So the open-air condition
2
S. It was found that product 3a remained to be
1
DMF
DCE
DMF
DCE
DCE
0
[
16h]
,
[
[
[
[
e]
e]
f]
14
26
0
2
15
2
16
Cu(OTf)2
Cu(OTf)
0
of was critical to afford sequential product 3a in a satisfactory
yield. Moreover, using DCE or DMF as the solvent instead of
DMSO, no desired product 3a was obtained (Entry 12 and 13).
At last, the sequential reactions were run employing excessive
DMSO, Ph SO and Bn SO (Entries 14~17). It was found that the
2 2
reaction employing excessive DMSO in DCE gave rise to
product 3a in a low yield. Excessive DMSO in DMF failed to
2 2
provide the sequential product 3a. Ph SO and Bn SO are not
appropriate oxidants and no product 3a was observed.
g]
17
2
0
[
a] Reaction conditions: 2a (1 equiv., 0.05 mmol), the catalyst (20 mol %), the
1
solvent (1 mL), in the open air. [b] Determined by H NMR using 1-chloro-2,4-
dinitrobenzene as the internal standard. [c] The reaction was run using
degassed DMSO in Ar. [d] The reaction was run by passing Ar through the
reaction mixture. [e] Me
equiv., 1 mmol) was added. [g] Bn
,2-dichloroethane.
2
SO (20 equiv., 1 mmol) was added. [f] Ph
2
SO (20
2
SO (20 equiv., 1 mmol) was added. DCE=
1
With the optimized conditions in hand, several epoxides 2 with
different substituent groups on the aromatic ring were tested for
exploring the sequential reaction scope. The results were
summarized in Table 2. In general, various electron-donating and
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European Journal of Organic Chemistry
10.1002/ejoc.201701808
FULL PAPER
[
a]
Table 2 Investigating substituent effect on the aromatic ring
1
2
3
4
[b]
Entry
2 R /R /R /R
2a H/H/H/H
2b F/H/H/H
t (h)
10
12
16
10
10
10
10
16
16
10
10
10
16
8
3
Yield (%)
73
1
2
3a
3b
3c
3d
3e
3f
40
c
3
2c Me/H/H/H
2d H/F/H/H
26
Figure 1 ORTEP drawing for the product 3e
4
5
6
7
8
9
61
2e H/Cl/H/H
2f H/Me/H/H
2g H/t-Bu/H/H
2h H/Ph/H/H
2i H/OMe/H/H
2j H/H/F/H
63
found that a series of substituents including F, Cl, Me, Ph and 4-
OMeC were tolerated well, generating the corresponding
69
6 4
H
products 3j~3n in 33%~66% yields.
3g
3h
3i
74
Having investigated the substituent effect on the aromatic ring;
next, we moved on to study the scope and limitation of the
substituents on the electron-deficient alkenes and epoxides. The
results were summarized in Table 3. Changing the bulkiness of
the ester group from methyl to ethyl, isopropyl, normal-butyl, tert-
butyl and benzyl were tolerated and provided the corresponding
65
72
10
11
12
13
14
15
3j
47
2k H/H/Cl/H
2l H/H/Me/H
2m H/H/Ph/H
2n H/H/4-OMeC
2o H/H/H/F
3k
3l
66
Table 3 Investigating substituent effect on epoxides and electron-deficient
[
a]
alkenes
42
3m
3n
3o
50
6
4
H /H
33
10
62
1
2
[b]
Entry
2 R /R
t (h)
10
10
16
16
10
10
3
Yield (%)
[
4
2
a] Reaction conditions: 2 (1 equiv., 0.2 mmol), Cu(OTf) (20 mol%, 0.04 mmol),
o
1
2
3
4
5
6
2p Et/H
2q iPr/H
2r nBu/H
2s tBu/H
2t Bn/H
3p
3q
3r
3s
3t
66
68
68
84
89
0
mL DMSO, 70 C, in the open air. [b] Isolated yields.
electron-accepting substituents residing at different positions on
the aromatic ring were well tolerated to give the products with
1
acceptable yields. First, the substrates 2b and 2c possessing R
substituents at the ortho-position of the epoxide were subjected
into the sequential reactions (Entries 2 and 3). It seemed that
the steric hinderence from ortho-substituents had a negative
influence on the oxidative ring opening of epoxides. The
corresponding sequential products 3b and 3c were only obtained
in 40% and 26% yields, respectively. Then the sequential
O
O
2
4
reactions of several substrates 2 with R and R substituents at on
the meta-position of the epoxide ring were carried out under the
optimized conditions. It was found that the substrates 2d~2i with
CO2Me
3u
[
d]
7
2v Me/Me
2
2w Me/CO Me
10
10
10
3v
3v
75
2
the R substituents led to the corresponding products 3d~3i in
[
c]
8
0
good yields (Entries
unambiguously confirmed by X-ray crystal structure analysis
Figure 1). Compared with the substrates with electron-accepting
4
~8). The structure of 3e was
[
18]
O
9
0
(
substituents, the substrates with electron-donating substituents
provided the corresponding sequential products in higher yield.
When the substrate 2o with the R substituent was used as the
MeO2C
CO2Me
2x
4
substrate, the desired product 3o was afforded in 62% yield (Entry [a] Reaction conditions: 2 (1 equiv., 0.2 mmol), Cu(OTf) (20 mol%, 0.04 mmol),
2
o
1
5). At last, the sequential reactions of the substrates 2j~2n with 4 mL DMSO, 70 C, in the open air. [b] Isolated yields. [c] The reaction was run
different R substituents on the para-position of the epoxide were
also run under the optimized conditions (Entries 9~14). It was
o
3
at 90 C. [d] dr=1:1.
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European Journal of Organic Chemistry
10.1002/ejoc.201701808
FULL PAPER
products 3p~3t in good yields (Entries 1~5). However, the 4-isochromanone 3a. Alkylation reactions of 3a were performed
monoester substrate 2u failed to furnish the corresponding using methyl iodide and allyl bromide under basic conditions,
product 3u due to low reactivity of its own Michael acceptor (Entry furnishing the corresponding products 6a and 6b in 85% and 75%
6). Then the epoxide 2v bearing methyl group on the epoxide ring yields, respectively.
was employed as the substrate of the sequential reaction (Entry
7). It was found that the corresponding product 3v was provided in
75% yield, but along with a poor diastereoselectivity. The result
indicated that the sequential reaction had potential application for
the synthesis of the natural product examples in Scheme 1 such
as Hongconin and XJP in the future. Next, the sequential reaction
of the epoxide 2w with methoxycarbonyl group on the epoxide
ring was carried out under the optimized reaction conditions
(
Entry 8). Unluckily, no desired product 3w was obtained along
with the recovered substrate even though the reaction
o
temperature was raised to 90 C. In the case of alkyl substituted
epoxide 2w, strong decomposition of the epoxide ring was
observed and no cyclization product 3x was found in the reaction
system (Entry 9).
A possible mechanism for the sequential reaction was then
proposed (Scheme 5). Initially, the attack of the oxygen atom of
[
16e,f]
DMSO on the epoxide ring
Cu(OTf) to generate ring-opening intermediate A. Then the
dissociative triflate anion from Cu(OTf) captured the benzylic
hydrogen of intermediate A, initiating the removal of methyl sulfide
to afford intermediate B. Next, Cu(OTf) was regenerated by the
hydrogen exchange between intermediate B and HOTf. At last,
2
the generated intermediate underwent further Cu(OTf) -
took place in the presence of
2
2
Scheme 6 Derivatization of 3a
2
C
catalyzed intramolecular oxa-Michael addition to furnish the
desired product 3a.
Conclusions
2
We have accomplished a general and efficient Cu(OTf) -
catalyzed sequential reaction involving oxidative ring opening of
epoxides and oxa-Michael addition. The present strategy allows
the synthesis of a series of 4-isochromanones in moderate to
good yields by the formation of one new C=O bond and one new
C-O bond. Features of the reaction include broad substrate
scope, high bonding efficiency and mild conditions. Further
investigations on the sequential reaction involving epoxides and
electron-deficient alkenes are currently under study in our group.
Scheme 5 a possible mechanism for the sequential reaction
Experimental Section
Further chemical transformations of the 4-isochromanone
products are carried out to explore the application of this method
General Procedure for the sequential reaction:
(
Scheme 6). We noted that keto carbonyl group is a potential
Cu(OTf)
2
(0.04 mmol, 20% cat.) was added to a solution of epoxide 2a
reactivity center in 4-isochromanone 3a. It was found that Oxime
4
was reported to display remarkable antimalarial activity
(
0.2 mmol) in dimethyl sulfoxide (4 mL) at room temperature. The
[
19]
o
a was potential medicine for treating hypertension . Alkene 5a reaction mixture was stirred at 70 C for 10 h. Then the reaction mixture
[
20]
.
was cooled to room temperature and poured into water (20 mL) and
Considering these applications in the field of medicine, the extracted with ethyl acetate (5 × 10 mL). The combined organic extract
2 4
was washed with brine (20 mL), dried over Na SO and evaporated
conversions from 4-isochromanone 3a to oxime 4b and alkene 5b
were first tested. We ran the reaction of 3a and hydroxylamine
hydrochloride in the presence of sodium acetate in ethanol,
affording the corresponding oxime 4b in 66% yield. When we
treated 3a with methyltriphenylphosphonium bromide and t-BuOK
in THF, the desired alkene 5b was obtained in 40% yield.
Besides, 1,3-diesters group is another potential reactivity center in
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate, 5:1~3:1,
gradient elution) to afford product 3a.
4
-Isochromanones product 3b~3t and 3v were synthesized according to
the above General Procedure. There are purified by flash column
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European Journal of Organic Chemistry
10.1002/ejoc.201701808
FULL PAPER
chromatography on silica gel (petroleum ether/ethyl acetate, 5:1~3:1,
gradient elution). These compounds were all new compounds, which has
been characterized well by H NMR, C NMR, HRMS and IR.
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European Journal of Organic Chemistry
10.1002/ejoc.201701808
FULL PAPER
[20] Y.
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European Journal of Organic Chemistry
10.1002/ejoc.201701808
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Sequential synthesis*
Me
Siyang Xing,* Nan Gu, Jiajing Qin, Hong
Cui, Yan Li, Kui Wang,* Dawei Tian,* Bo
Chen and Guo Yu
O
S
Me
R
O
O
Cu(OTf)2, 70 o
up to 89% yield
sequential synthesis RO2C
C
R
O
CO2R
RO2C
CO2R
21 examples of 4-isochromanones
Page No. – Page No.
A new Cu(OTf)
2
-Catalyzed sequential reaction involving oxidative ring opening of
Construction of 4-Isochromanones
via Cu(OTf)2-Catalyzed Sequential
C=O and C-O Bond Formations
epoxides by the solvent DMSO and oxa-Michael addition of electron-deficient alkenes
have been developed. In this transformation one new C=O bond and one new C-O bond
were created. The sequential reaction allowed for the rapid and efficient synthesis of 4-
isochromanones in moderate to good yields in mild conditions.
This article is protected by copyright. All rights reserved.