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One-step synthesis of 2,5-diformylfuran from monosaccharides by lanthanum(III) triflate, View Article Online
DOI: 10.1039/D0CC05582D
sulfur, and DMSO

Quynh Nhu Ba Nguyen,a,b Hao Anh Nguyen Le,a,b Phat Duc Ly,a,b Ha Bich Phan,a,b,c Phuong Hoang
Tran a,b*

Affiliations

aDepartment of Organic Chemistry, Faculty of Chemistry, University of Science, Ho Chi Minh City,
721337, Viet Nam.

ChemComm Accepted Manuscript

bVietnam National University-Ho Chi Minh City (VNU-HCM), 721337, Viet Nam.

cInstitute of Public Health, Ho Chi Minh City, 700000, Viet Nam.

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Journal Name DOI: 10.1039/D0CC05582D

COMMUNICATION

One-step synthesis of 2,5-diformylfuran from monosaccharides by

lanthanum(III) triflate, sulfur, and DMSO
Received 00th January 20xx,
Accepted 00th January 20xx Quynh Nhu Ba Nguyen,a,b Hao Anh Nguyen Le,a,b Phat Duc Ly,a,b Ha Bich Phan,a,b,c Phuong Hoang

ChemComm Accepted Manuscript

Tran a,b*
DOI: 10.1039/x0xx00000x

www.rsc.org/
Published on 18 September 2020. Downloaded on 9/21/2020 3:49:50 AM.

two steps, dehydration of monosaccharide (e.g., fructose or

A combination of lanthanum(III) triflate, sulfur, and dimethyl glucose) and oxidation of the intermediate HMF.17-21
sulfoxide prompted a facile, direct preparation of 2,5- Cheap and readily available sulfur is an attractive element
diformylfuran from glucose and fructose. The one-step for reactivity as its smaller congener oxygen, acting as
dehydration/oxidation of fructose afforded 2,5-diformylfuran in oxidant and promoting the oxidative reactions.22, 23 In
excellent yield with high selectivity. A proposed mechanism, large- contrast to oxygen, sulfur remains in a solid state at room
scale synthesis, and product separation were presented. This temperature; sulfur is a stable, non-volatile, and therefore
approach represents a straightforward and eco-friendly pathway,
easy to work with.24, 25 The melting point of sulfur is lower
which can be applied in large-scale production of 2,5-
(115.2 oC), and it can act as reaction media in the molten
diformylfuran from fructose.
state.26, 27

Efficient and sustainable synthesis of fuels, polymers, and

chemicals from inexpensive and inexhaustible resources of Previous work 12, 17, 18, 20, 28-30
carbohydrates has received increasing attention.1-3 5-
Hydroxymethylfurfural (HMF), generated through O O
HO selective oxidation O
dehydration of fructose, is known to be a critical precursor Fructose dehydration O O

and platform chemical to link biomass resources with HMF DFF

sustainable energy and chemical industry.4, 5 HMF This work
possesses hydroxyl and aldehyde functional groups, which O
La(OTf)3 (2.5 mol%), 150 oC O O
can easily be oxidized or reduced to provide a wide range Fructose
S (3.0 mmol), DMSO (2.0 mL)
of chemicals for applications in the synthesis of biofuel, DFF (up to >99% yield by HPLC)
polymers, and pharmaceuticals.3, 6 2,5-Diformylfuran (DFF), Scheme 1. Synthesis DFF from fructose.
which can be achieved from HMF via oxidation, has
potential applications in the preparation of
In current work, we report that the mixture of
pharmaceuticals, organic conductors, polymers,
lanthanum(III) triflate, sulfur, and DMSO is an efficient,
heterocyclic ligands, and luminophores.7-11 The
practical, and straightforward reaction medium in the
straightforward conversion of carbohydrates to DFF is
direct preparation of DFF from monosaccharides including
highly attractive due to available and cheap starting
fructose and even more challenging glucose substrate.
materials.12-16 The one-pot preparation of DFF from
Notably, DFF was produced with a yield of almost 100% in a
carbohydrates involves a tandem reaction using an acid
one-step process. Metal triflates have recently attracted
catalyst and an oxidative reagent. The procedure comprises
considerable attention because their Lewis acidity is higher
than metal halides.31, 32 Moreover, metal triflates work well
not only in organic solvents but also in aqueous media.33, 34
aDepartment of Organic Chemistry, Faculty of Chemistry, University of Science, Ho Chi Recently, there have been numerous reports describing
Minh City, 721337, Viet Nam.
bVietnam National University-Ho Chi Minh City (VNU-HCM), 721337, Viet Nam. various useful methods for the direct derivatization of
cInstitute of Public Health, Ho Chi Minh City, 700000, Viet Nam. fructose to DFF assisted by either homogeneous or
All authors contributed equally.
heterogeneous catalysts.7, 18-20, 30, 35, 36 However, these
Corresponding author: [email protected]
Electronic Supplementary Information (ESI) available: [details of any processes involved two steps as follows: Brønsted acid-
supplementary information available should be included here]. See promoted dehydration of fructose into HMF, and formation
DOI: 10.1039/x0xx00000x

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 1

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of DFF through the metal-assisted oxidation of HMF. Up to 10 H2SO4 DMSO 150 6.4 44.3
View Article Online
now, the use of metal triflate combined with S/DMSO in 11 H3PO4 DMSO 150
DOI: 0
10.1039/D0CC05582D 0
one-step preparation of DFF from fructose has not been 12 - DMSO 150 0 0
reported in the literature. The preparation of DFF from a Reaction conditions: Catalyst (2.5 mol%), fructose (1 mmol), S (6
fructose using La(OTf)3 and sulfur in DMSO was reported mmol), solvent (2 mL), 18 h. DFF and HMF yields were quantified by
herein as a novel “one-pot, one-step” procedure. The high the use of HPLC with an external standard.
temperature plays a vital role in the dehydration of
fructose in DMSO.13, 37 Thus, in a preliminary experiment, Under the optimized conditions, the reaction time effect on
fructose (1.0 mmol), La(OTf)3 (2.5 mol%), sulfur (6.0 mmol), the reaction yield was investigated. The reaction mixture
and DMSO (2.0 mL) were heated at 150 °C for 18 h, and was heated at 150 oC in various periods of time. As plotted
subsequent analysis showed that DFF yield was obtained in in Figure 1, the DFF yields slowly increased at 0-4 h, rapidly
82.8%. Next, the control experiments were carried out in increased at 9-18 h, and obtained 100% DFF yield at 24 h.
DMSO (2.0 mL) at 150 °C for 18 h without La(OTf)3 or sulfur. The yield variations of HMF and DFF at various periods of
In both cases, no DFF was detected by HPLC analysis. reaction time indicated that the oxidation hardly

ChemComm Accepted Manuscript

Interestingly, a significant improvement of the DFF yield proceeded in short reaction time. Next, the amount of
was achieved in the same condition with the use of both sulfur was tested, and the results were presented in Figure
La(OTf)3 and sulfur, rationalized by the synergistic effects of 2. DFF yield increased gradually with the further addition of
combined La(OTf)3 and sulfur (Table 1, entry 4). The sulfur. The best yield of DFF was observed by using 10
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reaction hardly occurred at lower reaction temperatures mmol of sulfur at 12 h and then kept constant. The results
(Table 1, entries 1-3). No reaction was observed at room demonstrate that the current method was affected by the
temperature, at which both oxidation and dehydration are sulfur loading level.
disfavored, while the progressive formation of HMF was
noted at low temperature. DFF yield was increased by
raising reaction temperature to 150 oC. Thus, the selectivity
to HMF or DFF could be easily tuned by governing the
reaction temperature. The solvent demonstrated a vital
effect on the DFF yields in previous reports.5, 13 Among the
evaluated solvents, DMSO is the best solvent for the
current method (Table 1, entries 5-7). Besides, the yields of
the DFF also decreased when other metal triflates such as
Bi(OTf)3 and Ho(OTf)3 were employed (Table 1, entries 8-9).
The synthesis of DFF was also carried out with Brønsted
acids, including H2SO4 and H3PO4 (Table 1, entry 10-11). We
observed that the reaction using H2SO4 as a catalyst
proceeded with difficulty, affording only 44.3% yield of DFF.
However, the desired product was not detected in the
presence of a catalyst with lower acidity (H3PO4). Fig. 1 The effect of reaction time in the presence La(OTf)3 (2.5
mol%), fructose (1 mmol), S (6 mmol), DMSO (2 mL), 150 oC.
Table 1. Optimization of the reaction condition.a

HO OH
O O O
HO Catalyst O O
HO + O
HO OH S/DMSO
Fructose HMF DFF

Entry Catalyst Solvent Temp. HMF DFF

(oC) yield yield
1 La(OTf)3 DMSO rt 0 0
2 La(OTf)3 DMSO 80 30.3 0
3 La(OTf)3 DMSO 120 64.5 5.3
4 La(OTf)3 DMSO 150 0 82.8
5 La(OTf)3 DMF 150 0 0
6 La(OTf)3 Nitrobenzene 150 1.8 1.4
7 La(OTf)3 Dioxane 150 0 0
8 Bi(OTf)3 DMSO 150 0 36.5 Fig. 2 The effect of sulfur loading in the presence La(OTf)3
9 Ho(OTf)3 DMSO 150 42.7 55.8 (2.5 mol%), fructose (1 mmol), DMSO (2 mL), 150 oC.

2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

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Journal Name COMMUNICATION

O S
View Article Online
La(OTf)3
H DOI:HO
10.1039/D0CC05582D
H
HO HO La(OTf)2
OH O O
To probe the mechanism, a control experiment was carried out O
OH
O
OH OH
- TfO - La(OTf)2OH
in the absence of sulfur resulting in 0% yield of DFF; HMF was HO OH HO OH
HO OH

the major product (51.6% yield) (Supporting information, Fig. D-Fructose

HO
La(OTf)2OH + OTf La(OTf)3 + OH
HO
S1-b). The use of a substoichiometric amount of sulfur gave rise O
OH
tautomerization
O
O
La(OTf)3 -
to the generation of DFF yet in poor yield (Fig. S1-e). These HO OH HO OH
OTf

results verified the key role of elemental sulfur as a co-oxidant O S

HO H HO HO
in the reaction. Based on these experiments (Fig. S1) and the O
La(OTf)2
O
O
La(OTf)2
O
O
La(OTf)2
O
previous literature,13, 30, 38 a plausible mechanism is presented in HO HO O H HO O H OTf
OH H O S
Scheme 2. The two-step mechanism, including dehydration and HO
O S
H
HO
oxidation, took place due to the presence of lanthanum O
O
O HO H
O
HO
O
O
triflate/S/DMSO. The Lewis acid site of lanthanum triflate - La(OTf)3 - OTf - La(OTf)2OH

ChemComm Accepted Manuscript

O O
HO
- H 2O La(OTf)3
H O
HO HMF
coordinates with the hydroxyl group (most basic) attached to La(OTf)2

the anomeric carbon of fructose (the occurrence of this complex S

S
S S
S S S H
S S S
S S S S O
(m/z 616.8819) was affirmed by HRMS-ESI). Then, we S
O S S
O S
O CHO
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speculated that the second step would be DMSO-assisted

S
deprotonation on the active methylene group to form enol O
S
O S
O
OHC H OHC O
intermediate.39 Next, the enol form tautomerizes to its more O
H
- H 3C
S
CH3
OHC
O CHO

stable keto form, followed by the loss of another water DFF

O S
molecule to generate the carbocation, and finally produced
HMF, which was detected by HRMS-ESI (m/z 127.0379). Albeit Scheme 2. Proposed mechanism for the one-pot synthesis of DFF from fructose
using La(OTf)3/S/DMSO.
the dehydration of fructose with metal triflate and DMSO is not
clear at the moment, the detection of HMF by HPLC gave the
visible evidence for the synergistic catalysis of these
compounds. Recently, S/DMSO was found to be an excellent
oxidant system in organic synthesis.40-42 Thus, we suggested
that elemental sulfur via ring-opening could trigger the
activation of DMSO oxidant by binding to its oxygen atom.
Accordingly, DMSO was reduced to Me2S, while HMF was
oxidized to DFF. Me2S with a strong and unpleasant odor was
produced during the oxidation step. This outgoing gas was
bubbled into a cold mixture of methanol and diethyl ether and
was characterized by HRMS-ESI (m/z 61.9881). The high
selectivity of S/DMSO oxidant system is a prominent feature of
this method, giving the desired DFF product in excellent yield
Fig. 3 The direct synthesis of DFF from glucose. Condition:
without the formation of 2,5-furandicarboxylic acid.
glucose (1 mmol), La(OTf)3 (2.5 mol%), sulfur (3 mmol), DMSO (2
mL), 150 oC.
Next, glucose was tested as another carbohydrate feedstock.
The reaction was known to be challenging, which also agreed Moreover, we also investigated the applicability of the
with our initial studies herein. Under the standard condition present method in scale-up production wherein the product
described above, 13% yield of DFF accompanied with 12% yield could be isolated by phase extraction. The gram-scale
experiment was carried out with the same procedure with a
of HMF was obtained after 6 h. Prolonging the reaction time up small-scale reaction. In 100 mL round-bottomed flask, a
to 12 h and 24 h gave slightly better yields of DFF at 13% and mixture of fructose (10 mmol), La(OTf)3 (0.25 mmol),
20%, respectively, but HMF was absent (Figure 3). We supposed DMSO (20 mL), S (30 mmol) was heated at 150 oC for 24 h,
that the amount of lanthanum triflate was too small to achieve and DFF yield was obtained in 94%. Next, we tried to
separate DFF from the resulting reaction mixture by liquid-
a complete tautomerization of glucose to fructose, hence
liquid extraction. DFF is a less polar compound and
providing the desired product in low yields. However, the DFF insoluble in water, which can be separated from the reaction
yield did not increase with the use of 30 mol% La(OTf)3. solutions efficiently by organic solvent (Supporting
Information Fig. S2). Upon completion, the resulting
reaction mixture was diluted with 50 mL of cold water; the
sulfur residue was removed. The mixture was then extracted

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with 50 mL of ethyl acetate and diethyl ether 17. G. A. Halliday, R. J. Young and V. V. Grushin, Org. Lett.,
View Article Online
with a volume ratio of 2/23 (10 x 5 mL). The upper layer 2003, 5, 2003-2005. DOI: 10.1039/D0CC05582D
was separated from the lower aqueous/DMSO layer by a 18. J. Zhao, A. Jayakumar and J.-M. Lee, ACS Sus. Chem.
funnel. The combined organic extracts were then washed Eng., 2018, 6, 2976-2982.
with cold water (2 x 30 mL). Residual water was removed 19. Q. Wang, W. Hou, T. Meng, Q. Hou, Y. Zhou and J.
by anhydrous Na2SO4, and the solvent was recovered under Wang, Catal. Today, 2019, 319, 57-65.
reduced pressure. DFF was isolated in 81% yield from the 20. B. Sarmah and R. Srivastava, Mol. Catal., 2019, 462, 92-
crude reaction mixture by liquid-liquid extraction without 103.
the presence of DMSO in the organic extraction (Supporting 21. Z.-Z. Yang, J. Deng, T. Pan, Q.-X. Guo and Y. Fu, Green
information, Fig. S3 and S4). Chem., 2012, 14, 2986-2989.
22. T. B. Nguyen and P. Retailleau, Org. Lett., 2017, 19,
In conclusion, we have successfully developed an effective 3887-3890.
campaign for a direct dehydration/oxidation of fructose to 23. T. B. Nguyen, L. Ermolenko and A. Al-Mourabit, Green
DFF. It is shown that a synergetic effect of La(OTf)3, Chem., 2013, 15, 2713-2717.
DMSO, and elemental sulfur could give rise to the 24. L. A. Nguyen, Q. A. Ngo, P. Retailleau and T. B. Nguyen,

ChemComm Accepted Manuscript

formation of DFF in one-pot fashion. The straightforward Green Chem., 2017, 19, 4289-4293.
synthesis of DFF from fructose is more favorable than the 25. T. B. Nguyen and P. Retailleau, Org. Lett., 2017, 19,
two-step procedure in terms of eliminating the isolation and 4858-4860.
purification of HMF and saving time, energy, and chemical. 26. T. B. Nguyen and P. Retailleau, Adv. Synth. Catal., 2017,
Moreover, DFF has easily separated from the reaction
Published on 18 September 2020. Downloaded on 9/21/2020 3:49:50 AM.

359, 3843-3847.
mixture by a commercially available mixture of organic 27. P. H. Pham, K. X. Nguyen, H. T. B. Pham, T. T. Nguyen
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30. B. Sarmah, B. Satpati and R. Srivastava, Catal. Sci.
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View Article Online
DOI: 10.1039/D0CC05582D

Graphical abstract

La(OTf)3 (2.5 mol%), 150 oC O

Fructose O O
(1 mmol) S (3.0 mmol), DMSO (2.0 mL)
DFF (up to >90% yield by HPLC)
one-step procedure

ChemComm Accepted Manuscript

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