Facile synthesis of silylated 4,5-disubstituted phthalates via inverse electron-demand cycloaddition of 2-pyrone-4,5-dicarboxylate with silylacetylenes

Article abstract of DOI:10.1246/cl.170820

A facile and efficient synthesis of silylated 4,5-disubstituted phthalates through the inverse electron-demand [4+2] cycloaddition of 2-pyrone-4,5-dicarboxylate with various silylacety-lenes has been developed. The reaction was promoted by 4A molecular sieves (MS 4A) to afford the corresponding polysubstituted arenes with functionalizable silyl groups in good to high yield, thus providing versatile access to a wide variety of functionalized phthalates that represent promising intermediates for the synthesis of fine chemicals, particularly photochemically active compounds.

Full text of DOI:10.1246/cl.170820

Received: August 29, 2017 | Accepted: September 16, 2017 | Web Released: September 23, 2017
CL-170820
Facile Synthesis of Silylated 4,5-Disubstituted Phthalates via Inverse Electron-demand
Cycloaddition of 2-Pyrone-4,5-dicarboxylate with Silylacetylenes
Yujiro Hoshino,* Yoshitaka Ikeda, Yota Nakai, and Kiyoshi Honda*
Graduate School of Environment and Information Sciences, Yokohama National University,
79-7 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501
(
E-mail: hoshino-yujiro-hy@ynu.ac.jp)
A facile and efficient synthesis of silylated 4,5-disubstituted
phthalates through the inverse electron-demand [4+2] cyclo-
addition of 2-pyrone-4,5-dicarboxylate with various silylacety-
lenes has been developed. The reaction was promoted by 4A
molecular sieves (MS 4A) to afford the corresponding
polysubstituted arenes with functionalizable silyl groups in
good to high yield, thus providing versatile access to a wide
variety of functionalized phthalates that represent promising
intermediates for the synthesis of fine chemicals, particularly
photochemically active compounds.
Keywords: Silylated phthalates |
Inverse electron-demand cycloaddition
-Pyrone-4,5-dicarboxylate
|
2
Phthalic acid and its derivatives are important compounds in
1
pharmaceutical and materials chemistry. Recently, functional-
ized phthalic acid derivatives have garnered much attention for
2
their photochemical applications such as triboluminescence,
3
4
5
chemiluminescence, fluorescence, and photochromism, as well
as their application in supramolecular chemistry (Figure 1a). In
6
this context, synthetic strategies for polysubstituted phthalates,
which are promising intermediates to access these phthalic acid
derivatives, have been developed (Figure 1b). These approaches
7
include the oxidation of suitable aromatic compounds, 6π-
electrocyclization of conjugated trienes,8 transition-metal-
Figure 1. a) Representative phthalate derivatives; b) synthetic
strategies toward phthalates.
9
catalyzed [2+2+2] cycloaddition of alkynes, enyne metathesis
1
0
followed by Diels­Alder and aromatization reactions, and
cycloaromatization through tandem cycloaddition/extrusion of a
small molecule, e.g., CO, SO , and CO , between acetylenedi-
2
2
carboxylates and appropriate cyclic dienes, such as cyclopenta-
,4-dien-1-ones, thiophene 1,1-dioxides, furans, and 2-py-
2
11
rones. In green chemistry, the latter method is more attractive
because it avoids the use of transition metals and produces only
gaseous emissions as waste. However, to prepare polysubstituted
phthalates, the method requires tedious routes to access the diene
Scheme 1. Inverse electron-demand Diels­Alder reaction for
the synthesis of substituted phthalates.
11a,12
starting materials.
Alternatively, inverse electron-demand
[
4+2] cycloadditions of electron-deficient 2-pyrones with
phthalic acid derivatives, because arylsilanes can be transformed
1
4
dienophiles represent a promising approach for the synthesis
of polysubstituted phthalates (Scheme 1). To the best of our
knowledge, only one preliminary report has been published
concerning the inverse electron-demand [4+2] cycloaddition
of pyridazine-4,5-dicarboxylate,13 but there has been no report
on the cycloaddition of 2-pyrone-4,5-dicarboxylates with
dienophiles. Herein, we report the first successful synthesis of
silylated 4,5-disubstituted phthalates through the inverse elec-
tron-demand [4+2] cycloaddition of diethyl 2-pyrone-4,5-
dicarboxylate with various silylacetylenes in the presence of
into a variety of functionalized aromatic conpounds. In
addition, arylsilanes have also drawn great attention as func-
tional materials that are applicable in optoelectronic devices
1
5
owing to the presence of σ*­π* conjugation.
Diethyl 2-pyrone-4,5-dicarboxylate (1) is a known com-
pound that is readily available from triethyl O-acetylcitrate (2) in
three steps according to a slight modification of the procedure
1
6
reported in the literature (Scheme 2). The elimination of acetic
acid from O-acetylcitrate 2, and the subsequent TiCl4/N-
methylmorpholine-mediated condensation with ethyl formate
afforded conjugated diene ester 3, which was treated with formic
acid at reflux to give 2-pyrone 1. The product 1 is a stable pale
4
A molecular sieves (MS 4A). The products, silyl-substituted
phthalates, can serve as useful precursors of polyfunctionalized
Chem. Lett. 2017, 46, 1743–1746 | doi:10.1246/cl.170820
© 2017 The Chemical Society of Japan | 1743

Table 2. The scope of substrate of the reactiona
Entry
4
Sib
Ar
5
Yield/%
1
2
3
4
5
6
7
8
9
4b
4c
4d
4e
4f
4g
4h
4i
DMS
TES
Ph
Ph
Ph
Ph
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
68
52
50
10
91
77
77
64
73
68
57
29
73
61
53
67
Scheme 2. Synthesis of 2-pyrone 1 from triethyl O-acetylci-
trate: a) TiCl4 (4 equiv), ethyl formate (4 equiv), N-methylmor-
pholine (8 equiv), CCl4, THF, 0 °C to rt, 20 h; b) formic acid,
TBDMS
TIPS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
100 °C, 1 h.
C6H4-4-NMe2
C6H4-4-OMe
C6H4-4-Me
C6H4-3-Me
C6H4-2-Me
C6H4-4-Cl
C6H4-4-CO2Et
C6H4-4-NO2
1-naphthyl
2-naphthyl
2-thenyl
Table 1. Optimization of reaction conditionsa
4j
4k
4l
1
0
1
1
12
13
14
15
16
4m TMS
4n
4o
4p
4q
TMS
TMS
TMS
TMS
Ratio of 1
to 4a
Entry
Conditions
Time/h Yield/%
1
2
3
4
5
6
7
8
9
a
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1.6:1
1.6:1
1.6:1
1.6:1
xylene, reflux
xylene, reflux
xylene, reflux
xylene, 200 °C
neat, 200 °C
xylene, 200 °C
MS 3A, xylene, 200 °C
MS 4A, xylene, 200 °C
citric acid, xylene, 200 °C 24
12
24
48
24
24
24
24
24
26
32
50
64
69
72
77
quant.
91
2-benzothiazolyl
aConditions: 2-pyrone 1 (0.8 mmol), 4 (0.5 mmol), MS 4A
(0.5 g), and xylene (2 mL) at 200 °C in a sealed tube for 24 h.
DMS: dimethylsilyl, TES: triethylsilyl, TBDMS: tert-butyldi-
b
b
b
b
methylsilyl, TIPS: triisopropylsilyl, TMS: trimethylsilyl.
b,c
b,c
b,d
we propose that the molecular sieves act as a mild acid and
activate the carbonyl group of 2-pyrone 1 toward cycloaddition
by lowering LUMO energy. Citric acid also improves the yield
to the same level achieved with MS 4A (Entry 9), showing
evidence to support this working hypothesis.
1
9
Conditions: 2-pyrone 1 (0.5 mmol), 4a (0.75 mmol), and xylene
2
0
b
c
(
2 mL). The reaction was performed in a sealed tube. MS
¹
1
d
(
10 mg mg of 1) was used. Citric acid (1 equiv) was added.
With the optimized conditions in hand, the substrate scope
2
1
was subsequently explored (Table 2). Various arylsilylacety-
lenes were subjected to the optimal conditions. It was found
that the steric hindrance of the silyl groups affected the yield of
the phthalates (Entries 1­4). Dimethylsilyl (DMS), triethylsilyl
(TES), and tert-butyldimethylsilyl (TBDMS) groups gave the
desired products 5b­5d in good yields (50­68%), while the
more sterically demanding triisopropylsilyl (TIPS) group af-
forded the corresponding phthalate 5e in low yield (10%).
Trimethyl(phenylethynyl)silanes with electron-donating groups
(e.g., NMe2, OMe, and Me) at the para position generally
produced better yields than the substrate having an electron-
withdrawing group (e.g., CO2Et and NO2) (Entries 5­12). These
results strongly suggest that the present cycloaddition reaction
follows an inverse electron-demand process. Notably, a methyl
group at the meta position slightly reduced the yield of phthalate
5i, mainly due to a lower resonance effect compared to those
having the substituent at the ortho and para positions (Entries 7­
9). Fused aromatic rings, such as naphthalene and benzothiazole,
and heteroaromatic systems also gave the products 5n­5q in
good yields (Entries 13­16).
yellow solid that easily turns into a liquid at ambient temperature
and could be prepared on more than a 10 g scale.
During the course of our recent studies on the inverse
electron-demand Diels­Alder reaction,17 we have demonstrated
that silylacetylenes are good dienophiles in the [4+2] cyclo-
addition of in situ generated o-quinonemethides, thus affording
novel silylated 2H-1-benzopyrans.18 Based on these findings,
trimethyl(phenylethynyl)silane (4a) was chosen as a model sub-
strate and was subjected to preliminary cycloaddition conditions
using 2-pyrone-4,5-dicarboxylate (1, 1.5 equiv) (Table 1). When
the reaction was performed in refluxing xylene under atmos-
pheric conditions for 12 h, the desired phthalate 5a was obtained
in 26% yield along with the recovery of acetylene 4a (52%)
(Entry 1). The yield of phthalate 5a gradually increased to 50%
by extending the reaction time (Entries 1­3). To increase the
yield of the product as predicted by the Le Chatelier principle,
experiments under high pressure in a sealed tube (200 °C) were
perfomed; this resulted in an improved yield of ca. 20% when
compared to the atmospheric conditions (Entries 4 and 5 vs. 3).
When the quantity of 2-pyrone was increased (1.6 equiv to
acetylene), a slight improvement in the yield was observed
After the success demonstrated with various arylsilylacety-
lenes, we turned our attention to the substitution of other
acetylenes (Table 3). While the cycloaddition with symmetric
internal alkynes having alkyl, aryl, and ester groups proceeded
sluggishly to afford the corresponding phthalates in low yields
(
Entries 4 and 6). Finally, several additives were examined; the
highest yield was obtained in the presence of powdered MS 4A
Entries 6­8). Although the peculiar role of MS 4A is not clear,
(
1744 | Chem. Lett. 2017, 46, 1743–1746 | doi:10.1246/cl.170820
© 2017 The Chemical Society of Japan

Table 3. Cycloaddtion of 2-pyrone 1 with acetylenesa
Entry
4
R1
R2
5
Yield/%
1
2
3
4
5
6
4r
4s
4t
4u
4v
4w
n-Bu
Ph
CO2Me
TMS
H
n-Bu
Ph
CO2Me
TMS
Ph
5r
5s
5t
5u
5v
5w
14
24
0
quant.
68
87
H
C8H17
aConditions: 2-pyrone 1 (0.8 mmol), 4 (0.5 mmol), MS 4A
0.5 g), and xylene (2 mL) at 200 °C in a sealed tube for 24 h.
(
Scheme 4. Derivatization of silylphthalates 5a and 5e.
5
e using di-tert-butyl peroxide (DTBP) proceeded efficiently to
2
9
afford 9-silafluorene 11 in good yield (46%).
In conclusion, we have demonstrated for the first thime
a facile and efficient synthesis of silylated 4,5-disubstituted
phthalates through an inverse electron-demand [4+2] cyclo-
addition of 2-pyrone-4,5-dicarboxylate with various silylacety-
lenes. The reaction was conducted at 200 °C in a sealed tube and
was promoted by MS 4A to afford the corresponding 4-aryl-5-
silylphthalates in good to high yield. In addition, some trans-
formations of the silyl groups in phthalates were illustrated, thus
indicating the efficacy of the present method as a versatile access
to a wide variety of functionalized phthalates that would be
promising intermediates for the synthesis of fine chemicals,
particularly photochemically active compounds.
Scheme 3. Cycloadditon of 2-pyrone 1 with olefins.
(
4
Entries 1­3),22 bis(trimethylsilyl)acetylene (4u) afforded diethyl
,5-bis(trimethylsilyl)phthalate (5u) as a sole product in quanti-
tative yield (Entry 4). It is noteworthy that the present method
gives 4,5-disubstituted phthalates as a sole isomer without the
isomerization of the silyl groups, although the acid-catalyzed
isomerization of 1,2-bis(trimethylsilyl)benzenes, which leads to
a mixture of regioisomers, is reported in the literature.23 It seems
likely that a substantial elimination of the acidic impurities
derived from the synthesis of 2-pyrone 1 would be achieved in
our case by neutralization with sodium bicarbonate in workup
and purification by column chromatography. Interestingly,
terminal alkynes are also good substrates for this cycloaddition
to afford 4-monosubstituted phthalates 5v and 5w in good yields
The authors thank Mr. Shinji Ishihara (Instrumental Analysis
Center, Yokohama National University) and Mr. Naoya Ohtsuka
for HRMS analyses. We would like to thank Enago (www.
enago.jp) for the English language review.
Supporting Information is available on http://dx.doi.org/
10.1246/cl.170820.
Dedicated to the late Professor Yoshihiko Ito on the
occasion of the 10th anniversary of his sudden death.
(Entries 5 and 6). In addition, the reactions with two alkenes,
References and Notes
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6
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1
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© 2017 The Chemical Society of Japan