Efficient route for the construction of polycyclic systems from bioderived HMF

Article abstract of DOI:10.1039/c7gc02211e

The first synthesis of tricyclic compounds from biobased 5-hydroxymethylfurfural (HMF) is described. The Diels-Alder reaction was used to implement the transition from HMF to a non-planar framework, which possessed structural cores of naturally occurring biologically active compounds and building blocks of advanced materials. A one-pot, three-step sustainable synthesis in water was developed starting directly from HMF. The reduction of HMF led to 2,5-bis(hydroxymethyl)furan (BHMF), which could be readily involved in the Diels-Alder cycloaddition reaction with HMF-derived maleimide, followed by hydrogenation of the double bond. The described transformation was diastereoselective and proceeded with a good overall yield. The applicability of the chosen approach for the synthesis of analogous structures containing amine functionality on the side chain was demonstrated. To produce the target compounds, only platform chemicals were used with carbohydrate biomass as the single carbon source.

Full text of DOI:10.1039/c7gc02211e

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Efficient route for the construction of polycyclic systems from
bioderived HMF
F. A. Kucherov, K. I. Galkin, E. G. Gordeev and V. P. Ananikov*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first synthesis of tricyclic compounds from biobased 5-hydroxymethylfurfural (HMF) is described. The Diels-Alder
reaction was used to implement the transition from HMF to non-planar framework, which possessed the structural
cores of naturally occurring biologically active compounds and building blocks of advanced materials. A one-pot, three-
step sustainable synthesis in water was developed starting directly from HMF. The reduction of HMF led to 2,5-
bis(hydroxymethyl)furan (BHMF), which could be readily involved in the Diels-Alder cycloaddition reaction with HMF-
derived maleimide, followed by hydrogenation of the double bond. The described transformation was
diastereoselective and proceeded with a good overall yield. The applicability of the chosen approach for the synthesis of
analogous structures containing amine functionality on the side chain was demonstrated. To produce the target
compounds, only platform chemicals were used with carbohydrate biomass as the single carbon source.
provides more opportunities to "fine tune" chemical
properties.16-21 Indeed, the vast majority of natural bioactive
compounds possess evolved skeletal diversity.22,23 Smart and
Introduction
In recent decades, the development of renewable resources
processing for organic synthesis has obtained considerable
attention.1-8 Currently, one of the most important challenges
in the global chemical industry deals with the implementation
of sustainable processes with the full integration of plant
bioresources.9 5-(Hydroxymethyl)furfural (HMF) is a versatile
bioderived platform chemical with several applications.1-10 An
important advantage of such a useful compound is the
possibility for its synthesis directly from biomass without using
other (non-renewable) precursors.1-12 Accordingly, the
preparation of practically important compounds using only
platform chemicals as the single carbon source represents a
highly efficient and sustainable approach.
stimuli responsive materials represent additional fascinating
applications for chemical structures with diverse molecular
skeleton frameworks.
Diels-Alder
reaction
HMF
O
R
R
chemicals,
materials,
drugs
O
HO
O
O
O
N
H
this work:
HO
OH
Diels-Alder
reaction
O
BHMF
OH
HO
one-pot procedure
reaction in water
O
O
O
N
H
The outstanding platform potential of HMF for liquid
biofuels, bioplastics and chemicals production has been
platform for construction
of non-planar structures:
discussed.1-15
The well-established strategies of HMF chemistry
R
O
involve transformations of the side groups or
reduction/hydrolysis of the furanic core, which leads to two
dimensional molecular structures. Although HMF chemistry is
very well developed currently, access to only a limited carbon
skeleton diversity imposes severe limitations. Particularly, the
preparation of compounds with non-planar 3D molecular
framework is required to obtain bioactive products, as it
R
O
X
endo
O
Scheme 1 Sustainable production of tricyclic non-planar compounds from HMF via
the Diels-Alder reaction (norcantharimide core is shown in blue).
The construction of three-dimensional polycyclic
frameworks from HMF is a challenging task. The Diels-Alder
reaction is a powerful synthetic tool for the creation of non-
planar heterocyclic systems.24,25 It is known that furans readily
undergo the Diels-Alder reaction to form oxabicyclic
systems.26-31 However, HMF is an exception and does not
directly participate in the cycloaddition reaction in contrast to
† Electronic Supplementary Information (ESI) available. CCDC 1557878 and CCDC
1557879.
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2,5-dimethylfuran.32 As a result, the synthesis of oxabicyclic
derivatives from HMF is not possible (Scheme 1).33
Results and discussion
The high reactivity of furan and dimethylfuran in the Diels-
Alder reaction has been shown experimentally and
theoretically.32 However, the reactivity of HMF and the
possibility to tune the bioderived core for Diels-Alder
chemistry remains unknown. To evaluate the possibility of
performing the Diels-Alder reaction with HMF and BHMF, we
carried out theoretical calculations at the DFT level
(Scheme 2).
From an application point of view, the product of the
cycloaddition to HMF with a 7-oxabicyclo[2.2.1]heptane core is
a structural component of the naturally occurring anticancer
drugs cantharidin and norcantharimide, and such compounds
possess considerable practical potential.34-38 Materials science
is another area of application for this functionalized tricyclic
product, which can be used as a monomer for controlled
polymerization either involving two OH groups or via a ring-
opening process.
In this work, we report the selective synthesis of non-
planar tricyclic molecular structures starting from HMF by a
one-pot Diels-Alder reaction in water (Scheme 1). The reagents
were chosen based on the concept of a sustainable process:
only platform chemicals (HMF and bioethanol) were used as a
carbon source.39-41 HMF can serve as the starting material for
both the diene (BHMF) and dienophile (maleimide). An
additional approach to functionalized amines, ethers and
esters by the Diels-Alder reaction was also explored in the
present study.
Quantum chemical calculations were performed at the
PBE1PBE/6-311++G(d,p) level with dispersion interaction
corrections by Grimme D3 with Becke-Johnson damping and
with the consideration of solvent effects at the SCRF(SMD,
water) level. A comparative computational study showed that,
for BHMF, the reaction with maleimide is energetically much
more favorable compared with that for HMF (Scheme 2). The
low reactivity of HMF is reflected by the considerably higher
activation energies for this molecule in the Diels-Alder
reaction: ΔG‡
= 22.0 kcal/mol (endo) and ΔG‡
= 23.5
I→IV-TS
I→II-TS
kcal/mol (exo) compared to BHMF (ΔG‡
= 16.9 kcal/mol
VI→VII-TS
To the best of our knowledge, there have not been any
published examples of the Diels-Alder reaction of
unsubstituted BHMF with alkenes. Only few examples of
cycloaddition reactions of substituted polyesters and peptide
macrocycles have been reported.42-46
(endo) and ΔG‡
= 19.2 kcal/mol (exo)). In the case of
VI→IX-TS
HMF, the calculated energy change shows
a nearly
thermoneutral transformation with ΔGI→III = -1.3 kcal/mol
(endo) and ΔGI→V = -1.8 kcal/mol (exo).
Scheme 2 Schemes of the cycloaddition reactions for HMF and BHMF and representations of the frontier molecular orbitals for the reagents. Gibbs activation energies
(ΔG‡, kcal/mol) and Gibbs reaction energies (ΔG, kcal/mol) are shown; theory level: PBE1PBE/6-311++G(d,p), GD3BJ and SCRF(SMD,water).
2 | Green Chem., 2017, 00, 1-3
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one-pot
(i), (ii),(iii)
water
In the case of BHMF, the process is much more exothermic
with ΔGVI→VIII = -9.0 kcal/mol (endo) and ΔGVI→X = -8.8 kcal/mol
(exo). Thus, in the case of BHMF, both kinetic and
thermodynamic factors are more preferable for the Diels-Alder
reaction. Concerning the product geometry, the energetic
factors are more favorable for the endo form of product.
The different reactivities of the HMF and BHMF molecules
in the reaction with maleimide acting as a dienophile were also
confirmed by analyzing the electronic structures of the
reacting molecules (Scheme 2). The HOMO energy of the
BHMF molecule is higher than the HOMO energy of the HMF
molecule by 0.25 eV, which reflects the greater favorability of
BHMF to interact with the dienophile in the cycloaddition
reaction (interaction of the diene HOMO with the dienophile
LUMO). The maleimide molecule is characterized by the lowest
HOMO energy (-8.25 eV) and lowest LUMO energy (-2.76 eV).
Consequently, the maleimide molecule will act as an electron
acceptor from the sides of the dienes (-6.91 eV HOMO and -
1.95 eV LUMO for HMF; -6.66 eV HOMO and -0.42 eV LUMO
for BHMF). Thus, the calculations clearly show that BHMF
should be more reactive in the Diels-Alder cycloaddition
process than HMF.
HO
OH
HMF
O
O
HO
O
73%
O
O
N
H
1
4
(i)
99% in water
(iii) 87% in water
BHMF
HO
OH
O
(ii)
HO
OH
O
83% in EtOAc
67% in water)
(
O
O
N
2
H
3
Overall yields:
Stepwise (water, EtOAc)
Stepwise (water)
One-pot (water)
71%
58%
73%
X-raystructureof 4
Scheme 3 Synthesis of bis-(hydroxymethyl)norcantharimide
water; (ii) maleimide, water; (iii) H2, 1 atm, 10% Pd/C or Ni/Ra, water. Single-
To verify the computational modeling, the following
4
in water. (i) NaBH4,
sequence of steps was performed: HMF
BHMF in aqueous solution (Scheme 3). BHMF was subjected
to the cycloaddition reaction with maleimide, and the
corresponding tricyclic product was successfully formed.
1 was reduced to
crystal X-ray structure of bis-(hydroxymethyl)norcantharimide 4.
2
3
Carrying out the reaction in water and avoiding organic
solvents would be an important improvement. Preliminary
It is known that Diels-Alder coupling products are capable
of undergoing a reverse transformation. Conducting the
reaction in ethyl acetate allows for the isolation of cycloadduct
experiments showed that the step-by-step synthesis of
aqueous media is possible, but it is less efficient. The reductive
transformations of HMF → BHMF and proceeded
selectively with high yields (99% and 87%, respectively).
However, the second stage, BHMF → , in water was quite
problematic. In this case, the isolation of was complicated
4 in
3
in a pure form, as the Diels-Alder product was removed from
the reaction media as a precipitate (Scheme 3). In ethyl
acetate compound was obtained in high yield (83%). To
exclude the possibility of the reverse process, unsaturated
product was reduced to bis-(hydroxymethyl)norcantharimide
in an atmosphere of gaseous hydrogen in the presence of a
3
→ 4
3
3
3
3
due to the high solubility of target compound in water.
Moreover, the reaction sequence of retro-DA makes it difficult
4
metal catalyst (10% Pd/C or Ni/Ra).
to obtain the substance in pure form. Thus, derivative
3 was
There are two possible routes of attacking the dienophile,
which lead to the corresponding exo- and endo-cycloaddition
products. The key stage involves BHMF interacting with
maleimide diastereoselectively to form the endo product with
de = 96%, in full accordance with the theoretical calculations.
prepared from BHMF in water in a 67% yield, thus resulting in
much lower overall yield: 58% vs. 71% (Scheme 3). This
problem was solved by the introduction of a one-pot protocol
in water. The total yield of bis-(hydroxymethyl)-
norcantharimide
4 in the one-pot, three-step synthesis in
An even higher purity of final compound
simple recrystallization from ethanol. The structure of the
obtained bis-(hydroxymethyl)norcantharimide was
4 was achieved by a
water proved to be more efficient with a yield of 73%, while
for the three consecutive steps in water, the yield was
considerably lower at 58% (Scheme 3).
4
unambiguously determined by single-crystal X-ray diffraction
(Scheme 3).
To assess the scope of the developed synthetic approach,
several substituted derivatives were tested in the
cycloaddition/reduction sequence. BHMF was transformed
into 2,5-bis(ethoxymethyl)furan
6
in ethanol in the presence of
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a catalytic amount of acid (TsOH) in an 81% yield (Scheme 4).
The resulting compound was subjected to the one-pot
cycloaddition-reduction sequence, which resulted in a 62%
yield of tricycle
2,5-Bis(acetoxymethyl)furan
acylation of BHMF with acetyl chloride in pyridine in 98% yield.
The one-pot reaction of compound with maleimide followed
by hydrogenation by molecular hydrogen led to product in
permethylated compound 15 was determined by single-crystal
6
X-ray diffraction (Scheme 5). Thus, it can be concluded that the
endo configuration of starting compound
4 was not affected
8.
during alkylation even under strongly basic conditions. A
7
was obtained through the
comparison of the chemical shifts of the MeO-CH2 and EtO-CH2
1
characteristic protons in the H NMR spectra of homologous
7
compounds 15 and
8 revealed a difference of only 0.01 ppm
9
(3.73 and 3.74 ppm, respectively). Considering the endo
configuration of 15 and based on the similarity of the chemical
76% yield. These transformations also proceeded
diastereoselectivity with de >97%, leading to the
corresponding endo products.
shifts of 15 and
bis(ethoxymethyl)furan
selective manner.
8
,
most likely, the studied 2,5-
6
reacted with maleimide in an endo-
alkylation
or
acylation
R'O
OR'
O
(iv), (v)
OH
HO
OR'
R' = Et, 81%
R'O
O
O
O
O
2, BHMF, 99%
N
H
6
7 R' = Ac, 98%
8
R' = Et, 62%
9 R' = Ac, 76%
(ii)
O
HO
O
O
1, HMF
(i)
R2N
NR2
O
(iv), (v)
(iii)
NR2
R2N
O
O
O
O
O
N
H
5, DFF, 95%
10
R = Et, 80%
12 R = Et, 51%
11 R =
, 98%
O
13
O
, 42%
R =
*
*
Scheme 4 Synthesis of the norcantharimide derivatives. (i) [Pip*(O)][BF4],
[BMIm][Cl]; (ii) NaBH4, water; (iii) HNEt2 or morpholine, STAB; (iv) maleimide; (v)
H2, 1 atm, 10 % Pd/C.
Scheme 5 Possible modifications by alkylation and acylation: (i) AcCl, Py; (ii) MeI,
NaH, DMF; (iii) MeI, K2CO3, DMF. Single-crystal X-ray structure of N-methyl-bis-
(methoxymethyl)norcantharimide 15
.
The developed synthesis strategy can be applied not only
to alcohols but also to amines. An dialkylaminomethyl moiety
can be introduced into the molecule through reductive
amination. For this purpose, HMF was oxidized to 2,5-
diformylfuran (DFF, 5) by recyclable system containing 4-
acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoro-
borate ([Pip*(O)][BF4]) in ionic liquid media in 95% yield.47 The
Bis-(hydroxymethyl)norcantharimide
chloride in pyridine to form di-O-acetyl derivative
yield. Considering the proven endo structure of starting
compound (Scheme 3), an endo configuration can also be
assigned to reaction product . Diacetyl derivative was also
4
reacted with acetyl
9
in 81%
4
9
9
reaction of dialdehyde
or morpholine, followed by treatment with sodium
triacetoxyborohydride as reducing agent, led to the
5 with two equivalents of diethylamine
obtained through an alternative synthetic route by Diels-Alder
cycloaddition (Scheme 4). A comparison of the chemical shifts
in the 1H NMR spectra showed the full equivalence of both
a
corresponding tertiary amine 10 or 11, respectively, in high
yield (80% or 98%). Derivatives 10 and 11 interacted in a
similar way with maleimide, followed by hydrogenation of the
cycloadducts. This reaction led to compounds 12 and 13
containing two dialkylaminomethyl groups at the head of the
1,4-epoxycyclohexane bridge. Somewhat lower yields of 51%
and 42% are associated with more bulky substituents on the
side chain.
products obtained by the counter syntheses
This confirms the endo-selective nature of the Diels-Alder
reaction of substituted derivative with maleimide.
Independent confirmation of the structure assignment was
also performed by carrying out nuclear Overhauser effect
spectroscopy (NOESY) and analysis of the obtained NOE data
(see the Supplementary Information).
Such reactivity clearly shows the possibility to vary the
order of modification of the functional groups and gain access
to wide range of compounds.
7 → 9 and 4 → 9.
7
To assess the synthetic potential of the obtained
heterocyclic system, it was important to probe the reactivity of
its functional groups. For this, compound 4 was subjected to
acylation and alkylation reactions (Scheme 5).
The imide moiety was readily methylated by methyl iodide
with potassium carbonate in DMF. In the presence of a weak
base, none of hydroxyl groups were affected, but one alkyl
group was introduced into the molecule with the selective
formation of the N-Me derivative 14 in 78% yield. When
Conclusions
Computational modeling showed that unsubstituted 2,5-
bis(hydroxymethyl)furan (BHMF) is a more reactive compound
in the Diels-Alder reaction with maleimide compared to 5-
(hydroxymethyl)furfural (HMF). Following the theoretical
predictions, reduction of HMF to BHMF was used to raise the
reactivity of the platform-chemical-derived molecule. An
sodium hydride was used in the reaction of
4 with methyl
iodide in dry DMF, complete alkylation took place with the
formation of derivative 15 in 72% yield. The structure of
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efficient three-step, one-pot procedure in water was
A solution of 2,5-diformylfuran 47 5 (0.5 g, 4 mmol) and the
implemented, and the first example of the Diels-Alder reaction corresponding amine (8.4 mmol) in chloroform (15 mL) was
of unsubstituted BHMF with maleimide was carried out in stirred at 24 °C for 20 min, and then, sodium
water with high diastereoselectivity. The developed synthetic triacetoxyborohydride
approach was extended to functionalized amines, ethers and portionwise. The reaction mixture was stirred overnight, then
esters with a furanic core. poured into a saturated sodium bicarbonate solution and
(3.4 g,
16 mmol)
was
added
The present study developed an approach to solve the extracted with chloroform (3 × 7 mL). The combined organic
synthetic problem of preparing tricyclic non-planar derivatives phases were washed with water, dried with sodium sulfate,
from HMF. The implementation of this protocol opens new evaporated and dried under high vacuum. The target
opportunities for the synthesis of demanded functional compounds were obtained as slightly yellow oils.
derivatives.
2,5-Bis(N,N-diethylaminomethyl)furan 10, yield 80%.
2,5-Bis(morpholinomethyl)furan 11, yield 98%.
Experimental section
2,5-Bis(hydroxymethyl)furan (BHMF),
HMF (5 g, 40 mmol) was dissolved in distilled water
(70 mL), and solution of sodium borohydride (1.5 g,
2
1
General
a
NMR spectra were recorded on Bruker DRX500 NMR
spectrometer using residual solvent peaks as internal
standards. The NMR spectra were processed using ACDLabs
SpecManager 6.0. Mass spectra were measured on a high-
resolution time-of-flight Bruker maXis instrument using
electrospray ionization (ESI-MS). Measurements were
performed in positive ion mode, with an interface capillary
voltage of 4.5 kV, at an effective scan range of m/z 100 - 1200,
with external calibration (0.016 М sodium formate in a 1:1
mixture of MeCN-water or ESI-L Low Concentration Tuning
Mix, Agilent Technologies), with a direct syringe injection at a
flow rate of 3 μL/min, with nitrogen as a dry gas (4 L/min), and
at an interface temperature of 180 °C. The spectra were
processed using the Bruker Data Analysis 4.0 software
package. Chromatographic separations were performed on
silica gel (Merck Kieselgel 230–400 mesh) with analytical grade
solvents. Analytical TLC was performed on Merck silica gel
plates with a QF-254 indicator. Visualization was accomplished
with a UV light and/or p-anisaldehyde-MeOH-H2SO4 and/or an
acidic solution of KMnO4.
40 mmol) in water (15 mL) was added dropwise while
vigorously stirring. The reaction mixture was stirred for 1 h at
24 °C, then extracted with ethyl acetate (4 × 20 mL). The
combined organic phases were dried with sodium sulfate,
evaporated and dried under high vacuum. 2,5-
Bis(hydroxymethyl)furan
99% (5 g).
2 was obtained as a white solid, yield
2,5-Bis(ethoxymethyl)furan,
6
A solution of BHMF 2 (1 g, 7.8 mmol) and TsOH (20 mg) in
absolute ethanol (30 mL) was heated at 60 °C for 3 h and then
evaporated at reduced pressure. The residue was purified by
flash chromatography (ethyl acetate/petroleum ether, 1:8).
2,5-Bis(ethoxymethyl)furan
yield 81% (1.16 g).
6
was obtained as a yellow oil,
2,5-Bis(acetoxymethyl)furan,
To a solution of BHMF
7
2
(1 g, 7.8 mmol) in dry pyridine (15
mL), acetic anhydride (1.85 mL, 19.6 mmol, 2.5 eq) was added
dropwise. The reaction mixture was stirred at 24 °C for 6 h, the
volatiles were evaporated under reduced pressure, 1 M HCl
(15 mL) was added to the residue, and the product was
extracted with chloroform (3 × 8 mL). The combined organic
phases were washed with water, dried with sodium sulfate,
evaporated and dried under high vacuum. 2,5-
One-pot
hexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione,
5-(Hydroxymethyl)furfural 11
(0.15 g, 1.2 mmol) was
dissolved in water (2.5 mL), and solution of sodium
synthesis
of
endo-4,7-bis(hydroxymethyl)
4
1
a
borohydride (45 mg, 1.2 mmol) in water (0.7 mL) was added
dropwise. The reaction was stirred at 24 °C for 2 h and at 60 °C
for 1 h. Then, the solution was cooled to 24 °C, and maleimide
(0.23 g, 2.4 mmol, 2 eq) was added. Solution was stirred for
16 h. 10% Pd/C (20 mg) or Raney nickel (30 mg) was added,
and the reaction mixture was placed under a hydrogen
atmosphere for 12 h at 24 °C. The catalyst was filtered off and
washed thoroughly with water (3 × 1 mL), and the filtrate was
evaporated under reduced pressure. The residue was washed
with diethyl ether (3 × 2 mL) to remove succinimide, then
washed with acetone (3 × 4 mL) to separate the target
compound. The acetone filtrate was evaporated under
reduced pressure, and the residue was recrystallized from
Bis(acetoxymethyl)furan
solid, yield 98% (1.62 g).
7 was obtained as a slightly yellow
Endo-4,7-bis(hydroxymethyl)-3a,4,7,7a-tetrahydro-1H-4,7-
epoxyisoindole-1,3(2H)-dione,
BHMF (0.2 g, 1.56 mmol) was dissolved in ethyl acetate
3
2
(1.5 mL), maleimide (0.3 g, 3.1 mmol) was added, and the
reaction was stirred at 24 °C for 16 h. The precipitate was
filtered off, washed with ethyl acetate (2 × 1 mL), and dried on
a filter. Target compound
83% (0.29 g).
3 was obtained as a white solid, yield
Endo-1,3-dioxohexahydro-1H-4,7-epoxyisoindole-4,7-
diyl)bis(methylene) diacetate, (Method A)
Diacetate (0.2 g, 0.94 mmol) was dissolved in ethyl
ethanol. Target compound
yield 73% (0.2 g).
4 was obtained as a white solid,
9
7
acetate, and maleimide (0.18 g, 1.9 mmol, 2 eq) was added.
General procedure for the amination of 2,5-diformylfuran
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The reaction mixture was stirred for 24 h at 24 °C; 10% Pd/C evaporated under reduced pressure. The residue was purified
was added (20 mg), and the reaction mixture was placed under by flash chromatography (ethyl acetate). Target compound 13
a hydrogen atmosphere for 8 h at 24 °C. The catalyst was was obtained as a slightly yellow oil, yield 42% (98 mg).
filtered off and washed thoroughly with hot ethyl acetate
(3 × 4 mL). The filtrate was evaporated under reduced
Endo-4,7-bis(hydroxymethyl)-2-methylhexahydro-1H-4,7-
pressure. The residue was washed with diethyl ether (3 × 3 mL) epoxyisoindole-1,3(2H)-dione, 14
to remove succinimide. Target compound
white solid, yield 76% (0.22 mg).
9
was obtained as a
Compound 4 (28 mg, 0.12 mmol) was dissolved in dry DMF
(1 mL), methyl iodide (10 µL, 0.16 mmol) and potassium
carbonate (34 mg, 0.24 mmol) were added successively. The
reaction was stirred for 16 h at 24 °C, the volatiles were
evaporated under reduced pressure. Residue was washed with
Endo-1,3-dioxohexahydro-1H-4,7-epoxyisoindole-4,7-
diyl)bis(methylene) diacetate, (Method B)
Compound
9
4
(64 mg, 0.28 mmol) was dissolved in dry ethyl acetate (3 × 1 mL). The filtrate was evaporated and dried
pyridine (2 mL), acetyl chloride (120 µL, 1.68 mmol) was added in high vacuum. Target compound 14 was obtained as a white
dropwise, and the reaction was stirred for 24 h at 24 °C. The solid, yield 78% (23 mg).
volatiles were evaporated under reduced pressure, and the
residue was poured into 1 M HCl and extracted with ethyl
acetate (4 × 2 mL). The combined organic phases were dried epoxyisoindole-1,3(2H)-dione, 15
with sodium sulfate, evaporated and dried under high vacuum. Compound (55 mg, 0.24 mmol) was dissolved in dry DMF
Endo-4,7-bis(methoxymethyl)-2-methylhexahydro-1H-4,7-
4
Target compound
(71 mg).
9
was obtained as a white solid, yield 81% (2 mL), sodium hydride (60% dispersion in mineral oil, 32 mg,
0.79 mmol) was added and the mixture was stirred for 1 h at
24 °C. The solution of methyl iodide (91 µL, 1.44 mmol) in DMF
Endo-4,7-bis(ethoxymethyl)hexahydro-1H-4,7-epoxyisoin-
dole-1,3(2H)-dione,
2,5-Bis(ethoxymethyl)furan
(1 mL) was added dropwise, and the reaction was stirred for
24 h at 24 °C. Volatiles were evaporated under reduced
8
6
(0.17 g, 0.92 mmol) was pressure, residue was poured into 1M HCl and extracted with
dissolved in ethyl acetate (2 mL), and maleimide (0.18 g, ethyl acetate (4 × 2 mL). Combined organic phases were dried
1.9 mmol, 2 eq) was added. The reaction mixture was stirred with sodium sulfate, evaporated and dried in high vacuum.
for 24 h at 24 °C; 10% Pd/C was added (20 mg), and the Target compound 15 was obtained as a white solid, yield 72%
reaction mixture was placed under a hydrogen atmosphere for (51 mg).
8 h at 24 °C. The catalyst was filtered off and washed
thoroughly with hot ethyl acetate (3 × 4 mL). The filtrate was
Acknowledgements
evaporated under reduced pressure. The residue was purified
by flash chromatography (hexane-ethyl acetate, 4:1). Target
This study was supported by Russian Science Foundation
(Grant RSF 17-13-01176).
compound 8 was obtained as a white solid, yield 62% (0.16 g).
Endo-4,7-bis((diethylamino)methyl)hexahydro-1H-4,7-epo-
xyisoindole-1,3(2H)-dione, 12
2,5-Bis(N,N-diethylaminomethyl)furan
10
(0.14 g,
Notes and references
0.59 mmol) was dissolved in ethyl acetate (2 mL), and
maleimide (0.12 g, 1.2 mmol, 2 eq) was added. The reaction
mixture was stirred for 24 h at 24 °C; 10% Pd/C was added
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Green Chemistry
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DOI: 10.1039/C7GC02211E
TOC Entry
Efficient one-pot synthesis of tricyclic compounds from biobased 5-hydroxymethylfurfural (HMF) is described using
[4+2] cycloaddition reaction.