Using light and a molecular switch to 'lock' and 'unlock' the Diels-Alder reaction

Article abstract of DOI:10.1039/c2ob06908c

Light is used to 'gate' the Diels-Alder reaction using a photoresponsive dithienylfuran backbone and turn the reversibility of the Diels-Alder reaction 'off' and 'on' at 100 °C. These features make the reported system an excellent candidate for developing the next generation of self-healing polymers and photothermal drug delivery vehicles.

Full text of DOI:10.1039/c2ob06908c

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PAPER
Using light and a molecular switch to ‘lock’ and ‘unlock’ the Diels–Alder
reaction†
Zach Erno,‡ Amir Mahmoud Asadirad,‡ Vincent Lemieux and Neil R. Branda*
Received 11th November 2011, Accepted 31st January 2012
DOI: 10.1039/c2ob06908c
Light is used to ‘gate’ the Diels–Alder reaction using a photoresponsive dithienylfuran backbone and turn
the reversibility of the Diels–Alder reaction ‘off’ and ‘on’ at 100 °C. These features make the reported
system an excellent candidate for developing the next generation of self-healing polymers and
photothermal drug delivery vehicles.
and offer the end-user the control to turn ‘off’ and ‘on’ the
bond-forming and cleaving reactions ‘on-command’.
Introduction
The reversibility of the Diels–Alder reaction and its sensitivity to
temperature make it an attractive motif to develop technologies
that benefit from molecular assembly through covalent bonds at
one set of conditions (low to moderate temperatures) and frag-
mentation of the components at another (high temperatures).1,2
One example is in dynamic combinatorial chemistry, where
its reversibility facilitates rapid exchange of diene–dienophile
partners to generate chemical libraries that can be screened in
real time for host–guest binding interactions.3 New functional
materials based on the retro-Diels–Alder reaction have also
grown rapidly in number and this versatile reaction has been
used to cleave dendrimers4,5 and surfactants,6 help remendable
polymers spontaneously heal damaged regions at the molecular
level,7–9 and release payloads from nanoparticle-based vehicles
for potential drug delivery applications.10
We recently published a system that illustrates the concept of
using light to ‘lock’ the Diels–Alder reaction based on the photo-
reactions of the well-known dithienylethene molecular architec-
ture (Scheme 1).11 It involves two reversible reactions, the first
requiring two types of light as the stimuli. Because the ring-
closed polycycles of dithienylethenes have linearly conjugated
π-electron backbones, they undergo photochemical bond-break-
ing reactions when exposed to visible light (these compounds
are highly coloured)12,13 and produce their ring-open counter-
parts, which owing to the lack of linear conjugation between
their two ‘arms’ are colourless. Exposing the ring-open poly-
cycles to ultraviolet light activates the hexatrienes, triggers the
reverse reactions and regenerates the ring-closed versions.
However, the true usefulness of these control strategies is
limited by shortcomings inherent in the nature of the thermally
regulated Diels–Alder equilibrium. Exposure of molecules or
materials to elevated temperatures may be difficult to avoid or
even essential in certain working environments, causing prema-
ture thermolysis of the molecular components, cleavage of syn-
thetic tethers or loss of mechanical strength and integrity in
remendable polymers. Dynamic combinatorial libraries can also
undergo significant changes in composition as the temperature is
varied, making it difficult or even impossible to isolate and
characterize desired target molecules at ambient conditions. A
second stimulus that would selectively ‘gate’ the reversibility of
the thermal Diels–Alder reaction would overcome this limitation
4D LABS, Department of Chemistry, Simon Fraser University, 8888
University Drive, Burnaby, B.C., Canada. E-mail: nbranda@sfu.ca;
Fax: +1 778 7823765; Tel: +1 778 7828061
†Electronic supplementary information (ESI) available: Spectroscopy of
new and key compounds and thermal release studies. See DOI: 10.1039/
c2ob06908c
Scheme 1 Conceptual scheme of photo-locking the Diels–Alder reac-
tion using the dithienylethene molecular system. Only after ring-opening
the ring-closed isomer can the reverse Diels–Alder reaction take place.
‡Authors made equal contributions.
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Scheme 3 Synthesis of the dithienylfurans used in the studies
described in this report.
Scheme 2 Three variations of the dithienylfuran diene can react with
three different dienophiles to produce nine bicyclic dithienylethene ring-
open isomers.
contributions to the Diels–Alder reaction equilibria and may also
affect the temperature dependency. In this report, we describe the
syntheses of the three dithienylfuran dienes, their reactivities
with three the dienophiles, the reversible photochemical ring-
closing reactions of their Diels–Alder products when exposed to
UV and visible light, and their ability to ‘gate’ the reversible
cycloaddition reaction.
In general, we noticed that the reactivities of all the dithienyl-
furan compounds towards all the dienophiles are greatly dimin-
ished relative to that of the previously studied fulvene (in most
cases, the Diels–Alder equilibrium does not favour the products
at all).13 Of the two successful Diels–Alder partners, we high-
light one (1c + maleimide → 2c) that can be used to ‘lock’ the
reaction (it is resistant to spontaneous ring-opening even at elev-
ated temperatures over extended periods of time) and facilitate
‘on’-or-‘off’ control by undergoing repeated bidirectional photo-
isomerization with minimal photofatigue.
The important differentiating structural feature of the two
polycycles (ring-closed vs. ring-open) is the absence or presence
of the cyclohexene ring shown in bold in the scheme. While the
ring-open isomer has the cyclohexene necessary for the reverse
Diels–Alder reaction to proceed, its ring-closed counterpart does
not. It is, therefore, effectively ‘locked’ and visible light is
required to ‘unlock’ it. Our observations are that the ring-open
polycycle is highly unstable and spontaneously breaks into its
Diels–Alder fragments, fulvene (labeled ‘diene’ in the scheme)
and diethyl dicyanofumarate. This constitutes the second revers-
ible reaction of the system. Depending on the reaction conditions
(concentration, temperature, stoichiometry), the Diels–Alder
equilibrium favours the starting material or products.14
The ‘lockable’ feature of our published system makes it attrac-
tive for applications that benefit from spontaneous thermolysis
at ambient temperatures upon exposing the ring-closed isomer
to visible light. However, other environments of use may require
systems whose equilibria favour bond formation at ambient
temperatures. This need demands the design of molecular
switching systems capable of regulating the Diels–Alder equili-
brium over a wider temperature range than is currently possible.
In this report, we describe the effects of different dienes, dieno-
philes and thiophene substituents on ‘gating’ the Diels–Alder
equilibria using light and demonstrate that the concept can be
applied to reactions that occur only at elevated temperatures.
We chose to base our molecular design on the dithienylfuran
architecture (Scheme 2) knowing that furan-based Diels–Alder
dienes tend to undergo thermolysis at higher temperatures15–17
than those based on fulvenes.18,19 We selected three representa-
tive dienophiles representing a range of chemical reactivities due
to their varying electron-deficiencies. N-Ethylmaleimide was
chosen as the least reactive,4–6,10,14,20,21 diethyl dicyanofumarate
as having intermediate reactivity3,11 and tetracyanoethylene as
the most reactive dienophile.22,23 The last variable we included
were the specific functional groups decorated onto the two thio-
phene rings. Phenyl (1a), chloro (1b) and ethoxycarbonyl (1c)
groups impart different combinations of steric and electronic
Results and discussion
We synthesized dithienylfuran derivatives 1a and 1b using a
two-fold Suzuki cross-coupling reaction between 3,4-dibromo-
furan and the corresponding thiopheneboronic acids (Scheme 3).
The former heterocycle was prepared by the oxidative cyclocon-
densation of (E)-2,3-dibromo-2-butene-1,4-diol in chromic acid
following a literature procedure.24 The latter two heterocycles
were prepared from the known bromothiophenes 5a25 and 5b26
by lithium–halogen exchange, boronylation and hydrolysis of
the resulting boronate esters in a three-step, one-pot procedure.27
The two-fold Suzuki cross-coupling reaction occurred in moder-
ately poor yields, with the dominant side products formed from
reductive dehalogenation of the mono-coupled intermediate.28
The dithienylfuran dicarboxylic acid was prepared from the
dichloro derivative (1b) by a two-step, one-pot procedure invol-
ving lithium–halogen exchange followed by carboxylation with
gaseous CO2 and acidification. The poor solubility of the result-
ing diacid in nonpolar organic solvents encouraged us to convert
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Scheme 4 Synthesis of Diels–Alder products 2b and 2c and their
photochemical ring-closing and ring-opening reactions.
Fig. 1 UV-vis absorbance spectra of CHCl3 solutions of 1a, diethyl
dicyanofumarate and tetracyanoethylene (left) and mixtures of 1a with
diethyl dicyanofumarate and tetracyanoethylene (right). All solutions
were 30 mM with respect to the chromophores and measured at 20 °C.
the diacid into its corresponding diester (1c), which was done
under Fisher esterification conditions with ethanol.29
To our surprise, dithienylfuran dienes 1a and 1c did not react
with diethyl dicyanofumarate or tetracyanoethylene despite their
being the most reactive dienophiles. No attempts were made to
carry out similar reactions using dithienylfuran 1b due to its ten-
dency to undergo rapid photodegradation during photochemical
ring-closing as will be shown later in this manuscript. A more
accurate statement would be that no cycloaddition products
could be observed under various conditions (different reactant
stoichiometries, solvents, and temperatures: see Table S1 in the
ESI† for details). This could imply that the reaction does, in fact,
occur but the equilibrium lies so dominantly to favour the start-
ing materials that even trace amounts of product cannot be
observed by 1H NMR spectroscopy. Given our goals were to
develop high-temperature reactions, we did not pursue these
studies any further but concentrated our efforts on the other
derivatives. The diphenyl derivative (1a) did undergo formation
of charge transfer complexes with these dienophiles as suggested
by the appearance of a distinct colour (the two starting materials
are colourless) as shown in Fig. 1.
We also did not observe any products when the phenyl deriva-
tive of the dithienylfuran (1a) was treated with N-ethylmale-
imide. Dienes 1b and 1c did, however, produce bicyclic
compounds 2b and 2c, respectively under appropriate conditions.
When equimolar quantities of 1b and the dienophile were
reacted in CDCl3, the reaction appeared to proceed sluggishly at
room temperature according to 1H NMR spectroscopy, with little
to no observable product being formed after 24 h. Increasing the
temperature of the reaction to 60 °C had little effect even after
19 h. A temperature of 70 °C seems to be the activation
threshold and the Diels–Alder product 2b was observed after just
4 h at this temperature. The product was identified to consist
exclusively in its isomeric exo form.7,30 After allowing the reac-
tion to continue at 70 °C for another 20 h, the bicyclic product
(2b) could be isolated in 79% yield by column chromatography.
The cycloaddition reaction of diester 1c with N-ethylmaleimide
was carried out under identical conditions. No detectable
product was formed after 24 h at room temperature or at 60 °C
for 20 h. Once again, heating the reaction at 70 °C for 38 h pro-
duced the exo product (2c) in 65% isolated yield (Scheme 4).
The photoinduced ring-closing of Diels–Alder products 2b
(in CD2Cl2) and 2c (in CD3CN) was monitored by UV-vis
Fig. 2 Changes in UV-vis absorbance spectra when solutions of (a) 2b
in CD2Cl2 (10−6 M) and (b) 2c in CD3CN (10−6 M) are irradiated with
313 nm light every 5 s for a total of 70 s. The inset plots show the
changes in the absorbances corresponding to the (◯) ring-open
(247 nm for 2b and 258 nm for 2c) and (◆) ring-closed isomers
(434 nm for 2b(c) and 521 nm for 2c(c)) upon alternate irradiation with
313 nm light (un-shaded) and >450 nm light (shaded). All measure-
ments were acquired at 20 °C.
absorbance and 1H NMR spectroscopy, with spectra acquired
intermittently after irradiation with 313 nm light for 5 and 120
second intervals, respectively. In both cases, the changes in the
UV-vis absorption spectra are typical for dithienylethene deriva-
tives (Fig. 2). Exposing the solutions to UV light produced an
immediate decrease in the intensity of the high-energy absor-
bance bands (centered at 247 nm for 2b and 258 nm for 2c) and
the appearance of new broad absorbance bands in the visible
region of the spectra (centered at 434 nm for 2b and 521 nm for
2c), which can be attributed to ring-closed isomers (2b(c) and 2c
(c)). These spectral changes account for the changes in colour of
the solutions from colourless to yellow in the case of 2b and red
in the case of 2c. When these coloured solutions are irradiated
with light of wavelengths longer than 450 nm, the colours disap-
pear and the original spectra are generated as ring-opening is
induced, confirming that photoisomerization of these species is
bidirectional.
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to the ring-open isomer were the only ones to reduce in intensity
shows that the reverse Diels–Alder reaction only occurs using
this isomer as the starting material. The peaks for the ring-closed
isomer did not change in intensity, revealing its thermal stability
under these conditions. This observation is supported by a calcu-
lation of the mole fraction of each component based on peak
integrals, which reveals that the amount of 2c present in the
mixture has decreased in proportion to the amounts of N-ethyl-
maleimide and 1c generated, whereas the amount of 2c(c)
remains unchanged.
Conclusions
We have developed 3,4-dithienylfuran systems that can undergo
the Diels–Alder reaction with suitable dienophiles to provide
molecular photoswitches. These species can then be made to
undergo bidirectional ring-closing and ring-opening isomeriza-
tion reactions in response to irradiation with UV and visible
light, respectively. We have also established that the changes in
molecular structure accompanying ring-closure turn off the
reversibility of the Diels–Alder reaction. Irradiation with visible
light regenerates the ring-open isomer as well as its ability to
undergo the reverse Diels–Alder reaction. These systems are sig-
nificant in their potential to address the limitations of numerous
beneficial technologies in synthetic chemistry and materials
science, and our future studies will evaluate dithienylfuran-based
molecular switches in those contexts.
1
Fig. 3 Partial H NMR spectra of a DMSO-d6 solution of (a) N-ethyl-
maleimide, (b) diene 1c, (c) a 1 : 1 mixture of 2c and 2c(c) generated by
reacting 1c with N-ethylmaleimide, isolating the Diels–Alder product
and irradiating with 313 nm light until the appropriate ratio was reached,
and (d) the same 1 : 1 mixture after heating at 100 °C for 24 h.32
The distinguishing difference between the two isomers is the
dichloro derivative’s exhibiting limited photochromic behaviour.
UV irradiation generates a photostationary state that contains
only a small amount of the ring-closed isomer (36%) and
induces significant decomposition as evident from 1H NMR
spectroscopy. This degradation is consistent with the lack of an
isosbestic point in the UV-vis absorption spectra and the
reduction in the amounts of both isomers as the system is cycled
between its states using both types of light (inset to Fig. 2a).
Both the low photoconversion and degradation are typical
among dithienylethenes bearing chloro substituents.31 The
diester derivative 2c, on the other hand, showed much better
photochromic behaviour and reached a photostationary state con-
sisting of 87% of the ring-closed isomer (2c(c)) with insignifi-
Experimental
General methods
All solvents and reagents used for synthesis, chromatography,
UV-vis spectroscopy measurements and photolysis studies were
purchased from Aldrich or Fisher and used as received, unless
otherwise noted. Solvents for NMR analysis were purchased
from Cambridge Isotope Laboratories and used as received.
Column chromatography was performed using silica gel 60
(230–400 mesh) Silicycle Inc.
1H NMR and 13C NMR characterizations of all synthesis pre-
cursors to compounds 2a–2c were performed on Bruker
AVANCE 400 BBOF plus direct probe working at 400.13 MHz
1
cant amounts of side-products being formed as monitored by H
NMR spectroscopy. Also, a clear isosbestic point can be
observed in the UV-vis absorption spectra as the system is
induced to undergo ring-closing and by the minimal reduction in
the absorbances corresponding to either isomer as the system is
cycled between its two forms (inset to Fig. 2b).
The concept of a ‘light-gated’ Diels–Alder reaction was
demonstrated only for compound 2c given the poor behaviour of
the chloro derivative. We achieved this using a DMSO-d6 sol-
ution containing equal amounts of the ring-open isomer (2c) and
its ring-closed counterpart (2c(c)), which was produced by
periodically irradiating a solution of the pure ring-open isomer
with 313 nm light until the desired concentration of its corre-
1
1
for H and 100.62 MHz for 13C NMR spectra. The H NMR
photoisomerization studies of adducts 2b (in CD2Cl2) and 2c
(in CD3CN) were performed using a Bruker AVANCE 500 TXI
inverse H/13C/19F probe working at 500.19 MHz for 1H and
1
125.78 MHz for 13C NMR spectra. Chemical shifts (δ) are
reported in parts per millions (ppm) relative to tetramethylsilane
(TMS) using the residual solvent peak as a reference standard.
Coupling constants (J) are reported in hertz. UV-vis absorption
spectroscopy was performed using a Varian Cary 300 Bio
Spectrometer.
1
sponding photoisomer was observed by H NMR spectroscopy
Photochemistry
(Fig. 3c). When this solution was heated at 100 °C for 24 h, a
composite spectrum in which N-ethylmaleimide and dithienyl-
furan 1c was observed, indicating that the reverse Diels–Alder
reaction had taken place. The fact that the peaks corresponding
All ring-closing reactions were carried out using light source
from a lamp used for visualizing TLC plates at 313 nm (Spectro-
line ENF-260C, 3.5 mW cm−2). The ring-opening reactions
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were performed using the light of a 300 W halogen photo optic
source passed through a 450 nm cutoff filter to eliminate higher
energy light.
and the reaction mixture was allowed to warm to room tempera-
ture. After 1 h, the mixture was treated with aqueous HCl
(10 mL, 10%) causing any precipitate to dissolve. The mixture
was washed with water (25 mL) and the organic layer was
removed and the aqueous layer further extracted with Et2O (2 ×
20 mL). The combined organic layers were extracted with
aqueous NaOH (2.5 M, 2 × 100 mL). The combined aqueous
layers were treated with concentrated HCl until the pH reached
below 1, resulting in the formation of white precipitate, which
was collected by vacuum filtration and washed with water.
Purification using chromatography on silica gel (9 : 1 : 0.01
CH2Cl2 : MeOH : acetic acid) afforded 88 mg (62%) of 4,4′-
(furan-3,4-diyl)bis(5-methylthiophene-2-carboxylic acid) as a
white solid. M.p. decomposed at 250 °C. IR (KBr): ν˜ =
1667 cm−1 (CvO). 1H NMR (MeOH-d4, 400 MHz): δ 7.63
(s, 2H), 7.25 (s, 2H), 2.18 (s, 6H). 13C NMR (MeOH-d4,
400 MHz): δ 225.6, 182.1, 163.8, 161.8, 155.2, 150.0, 140.1,
33.7. HRMS (ESI+) m/z calculated for C16H13O5S2 (M + H+)
349.0199, found 349.0199.
3,4-Bis(2-methyl-5-phenylthiophen-3-yl)furan (1a). A solu-
tion of (2-methyl-5-phenylthiophen-3-yl)boronic acid (6a)
(0.7 g, 3.1 mmol) in THF (25 mL) was treated with 3,4-dibromo-
furan (0.34 g, 1.57 mmol) and a saturated aqueous solution of
Na2CO3·H2O (20 mL). The resulting suspension was deoxy-
genated with a stream of N2 and treated with a catalytic amount
of Pd(PPh3)4. The mixture was heated to reflux while stirring
magnetically for 3 days, at which time the heating source was
removed and the reaction was allowed to cool to room tempera-
ture. Et2O (50 mL) was added to the mixture and the layers were
separated. The aqueous layer was extracted with Et2O (3 ×
20 mL). The combined ether layers were washed with brine
(50 mL), dried over MgSO4, filtered and evaporated under
reduced pressure. Purification by column chromatography using
silica gel (neat hexanes) afforded 200 mg (31%) of white solid.
1
M.p. = 43–45 °C. H NMR (CDCl3, 500 MHz): δ 7.56 (dd, J =
8.4, 1.3 Hz, 4H), 7.36 (tt, J = 1.5, 7.4 Hz, 4H), 7.25 (tt, J = 1.2,
7.4 Hz, 2H), 7.12 (s, 1H), 7.11 (s, 1H), 6.74 (dd, J = 1.2, 2.3
Hz, 1H), 6.73 (dd, J = 1.2, 2.3 Hz, 1H), 2.52 (s, 3H), 2.53
(s, 3H). 13C NMR (CDCl3, 500 MHz): δ 142.1, 139.6, 134.8,
128.9, 127.1, 126.3, 125.6, 123.0, 15.5. UV-vis (acetonitrile):
λmax nm (log ε) 293 (4.64).
Diethyl 4,4′-(furan-3,4-diyl)bis(5-methylthiophene-2-carboxy-
late) (1c). A solution of 4,4′-(furan-3,4-diyl)bis(5-methylthio-
phene-2-carboxylic acid) (57.0 mg, 0.16 mmol) in anhydrous
EtOH (25 mL) was treated with 5 drops of concentrated H2SO4.
The reaction mixture was heated to reflux and stirred magneti-
cally for 17 h under N2 and then it was cooled to room tempera-
ture. Water (50 mL) was added to the mixture and it was
extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were dried over MgSO4, filtered and evaporated under
reduced pressure. Purification by column chromatography using
CH2Cl2 as the eluent afforded 46 mg (70%) of the product as
white crystals. IR (NaCl): ν˜ = 1716 cm−1 (CvO). 1H NMR
(CDCl3, 400 MHz): δ 7.50 (s, 2H), 7.38 (s, 2H), 4.28 (q, J = 7.1
Hz, 4H), 2.19 (s, 6H), 1.33 (t, J = 7.0 Hz, 6H). 13C NMR
(CDCl3, 400 MHz): δ 161.1, 143.6, 140.9, 135.0, 129.8, 129.5,
120.2, 60.9, 29.6, 14.4, 14.2. HRMS (CI) m/z calculated for
3,4-Bis(5-chloro-2-methylthiophen-3-yl)furan (1b). A solution
of compound (5-chloro-2-methylthiophen-3-yl)boronic acid (6b)
(1.18 g, 6.70 mmol) in DMF (25 mL) was treated with 3,4-
dibromofuran (608 mg, 3.00 mmol) and Na2CO3·H2O (2.0 g,
16.0 mmol). The resulting suspension was purged for 1.5 h with
a stream of N2 and treated with Pd(PPh3)4 (93 mg, 80 μmol).
The mixture was heated at 110 °C and stirred magnetically for
52 h using an oil bath, at which time the heating source was
removed and the reaction was allowed to cool to room tempera-
ture. Water (100 mL) was added and the mixture was extracted
with Et2O (3 × 50 mL). The combined organic layers were dried
over MgSO4, filtered and solvent was evaporated using a rotary
evaporator. Purification of the product by column chromato-
graphy (silica gel, neat hexanes) afforded colourless crystals that
rapidly developed a yellow/brown colour upon exposure to
oxygen and light at ambient temperatures. Recrystallization from
CH2Cl2 and hexanes under reduced pressure yielded colourless
crystals once more, which were stored under N2 at −20 °C in
the dark (451 mg, 46%). M.p. 81–83 °C. 1H NMR (CDCl3,
400 MHz): δ 7.43 (s, 2H), 6.49 (s, 2H), 2.14 (s, 6H). 13C NMR
(CDCl3, 400 MHz): δ 147.9, 140.9, 134.4, 127.7, 125.7, 120.2,
13.8. HRMS (CI) m/z calculated for C14H11Cl2OS2 (M + H+)
328.9, found 329.2.
+
C20H24NO5S2 (M + NH4 ) 422.1090, found 422.1107.
(3aR,4R,7S,7aS)-5,6-Bis(5-chloro-2-methylthiophen-3-yl)-2-ethyl-
3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione (2b). A
solution of 3,4-bis(5-chloro-2-methylthiophen-3-yl)furan (1b)
(18 mg, 55 μmol) in CHCl3 (0.6 mL) was treated with N-ethyl-
maleimide (7.0 mg, 55 μmol) and the mixture was transferred to
an NMR tube. The NMR tube was protected from light as it was
heated at 70 °C for 73 h in an oil bath. Purification of the
product by column chromatography (silica gel, CH2Cl2) in the
darkness afforded 20 mg (79%) of white crystals. M.p. =
166–167 °C. IR (KBr): ν˜ = 1694 cm−1 (CvO). 1H NMR
(CDCl3, 500 MHz): δ 6.67 (s, 2H), 5.35 (s, 2H), 3.55 (q, J = 7.2
Hz, 2H), 3.06 (s, 2H), 1.95 (s, 6H), 1.17 (t, J = 7.2 Hz, 3H). 13
C
NMR (CD2Cl2, 600 MHz): δ 176.0 ppm, 138.9, 136.9, 129.4,
127.4, 126.2, 85.6, 48.9, 34.4, 30.2, 14.8, 13.2. HRMS (CI) m/z
calculated for C20H18Cl2NO3S2 (M + H+) 454.0100, found
454.0110.
4,4′-(Furan-3,4-diyl)bis(5-methylthiophene-2-carboxylic acid).
A stirred solution of 3,4-bis(5-chloro-2-methylthiophen-3-yl)
furan (1b) (135 mg, 0.41 mmol) in anhydrous Et2O (10 mL) was
treated with t-BuLi (1.00 mL of 1.5 M solution in pentane,
1.64 mmol) dropwise over 5 min under nitrogen at −78 °C.
After 1.5 h of stirring at this temperature, gaseous CO2 (sublimed
from solid CO2 and passed through a drying tube filled with
Drierite) was bubbled under the surface of the reaction mixture
for 3 h at −78 °C. After this time, the cooling bath was removed
Diethyl 4,4′-((3aR,4R,7S,7aS)-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-
hexahydro-1H-4,7-epoxyisoindole-5,6-diyl)bis(5-methylthiophene-
2-carboxylate) (2c). To a solution of diethyl 4,4′-(furan-3,4-diyl)
bis(5-methylthiophene-2-carboxylate) (1c) (20 mg, 49 μmol)
in CDCl3 (0.6 mL), N-ethylmaleimide (6.2 mg, 49 μmol) was
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added and the mixture was transferred to a 600 MHz NMR tube.
The NMR tube was protected from light and it was heated up to
70 °C using an oil bath. Monitoring the reaction by NMR spec-
troscopy showed the completion of reaction after 38 h. Purifi-
cation by column chromatography on silica gel (5% EtOAc in
CH2Cl2) in the dark afforded the product as white crystals
(17 mg, 65%). M.p. = 78–81 °C. IR (KBr): ν˜ = 1698 cm−1
(CvO). 1H NMR (CD3CN, 500 MHz): δ 7.56 ppm (s, 2H), 6.38
(s, 2H), 4.28 (q, J = 7.1 Hz, 4H), 3.47 (q, J = 7.2 Hz, 2H), 3.23
(s, 2H), 2.01 (s, 6H), 1.31 (t, J = 7.0 Hz, 6H), 1.10 (t, J = 7.1
Hz, 3H). 13C NMR (CD3CN, 600 MHz): δ 177.2, 162.8, 146.4,
140.3, 134.3, 132.3, 132.1, 86.3, 62.5, 49.5, 34.8, 15.6, 14.9,
13.6. HRMS (ESI+) m/z calculated for C26H28NO7S2 (M + H+)
530.1302, found 530.1338.
Acknowledgements
We are grateful for the financial support from the Natural
Sciences and Engineering Research Council (NSERC) of
Canada, the Canada Research Chairs Program and Simon Fraser
University (SFU) through the Community Trust Endowment
Fund.
Notes and references
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1
oil bath. The reaction was monitored by H NMR spectroscopy
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1.7 × 10−4 M−1
.
32 See ESI† for details.
2792 | Org. Biomol. Chem., 2012, 10, 2787–2792
This journal is © The Royal Society of Chemistry 2012