Transition-Metal-Free Valorization of Biomass-derived Levulinic Acid Derivatives: Synthesis of Curcumene and Xanthorrhizol

Article abstract of DOI:10.1002/cssc.202002167

Levulinic acid (LA) is acknowledged one of the most promising biomass-derived platform molecules and can be transformed into various value-added chemicals. Here, we report a new reaction process for the valorization of LA derivatives under transition-meta

Full text of DOI:10.1002/cssc.202002167

Chemistry–Sustainability–Energy–Materials
Accepted Article
Title: Transition-Metal-Free Valorization of Biomass-derived Levulinic
Acid Derivatives: Synthesis of Curcumene and Xanthorrhizol
Authors: Wen-Yan Xu, Kai-Feng Zhuo, Tian-Jun Gong, and Yao Fu
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To be cited as: ChemSusChem 10.1002/cssc.202002167
Link to VoR: https://doi.org/10.1002/cssc.202002167
01/2020

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Transition-Metal-Free Valorization of Biomass-derived Levulinic
Acid Derivatives: Synthesis of Curcumene and Xanthorrhizol
Wen-Yan Xu,+ Kai-Feng Zhuo,+ Tian-Jun Gong,* and Yao Fu*
Abstract: Levulinic acid (LA) is acknowledged one of the most
promising biomass-derived platform molecules, and can be
transformed into various value-added chemicals. Here, we report a
new reaction process for the valorization of levulinic acid derivatives
under transition-metal-free condition. The protocol combined with
the conversion of the levulinate to tosylhydrazone and base
promoted arylation, acylation, and etherification cross-coupling.
Moreover, our method was applied to synthesize three biologically
active molecules, rac-curcumene, rac-xanthorrhizol and rac-4,7-
dimethyl-l-tetralone. This reaction discloses a new avenue for the
high-value utilization of platform molecules.
esters to synthesize new types of LA-derived compounds.
Based on the structure of levulinic esters, we envisaged that
one of the route to valorization of levulinic esters is the
difunctionalization of carbonyl and carboxyl for synthesis of 1,4-
disubstituted frameworks, which possesses delicate structure
for applications as key intermediates for the synthesis of
biologically active molecules (Scheme 1b).[13] Herein, we report
a new method of arylation, acylation and etherification based on
levulinate derived tosylhydrazones under transition-metal-free
condition. This strategy can realize the diversified utilization of
biomass platform compounds levulinic acid, furfural and
phenols. Moreover, the obtained products can be transformed
into natural aromatic sesquiterpene rac-curcumene, rac-
xanthorrhizol and rac-4,7-dimethyl-l-tetralone via simple
manipulations (Scheme 1c).
Introduction
The development of methods to conversion of renewable
biomass-derived platform compounds into high-value chemicals
have drawn much attention in the past decades.[1] Levulinic acid,
which is produced from hemicellulose or cellulose with multiple
catalytic reactions, are promising renewable platform chemicals
as it is a vital “C5” resource with enormous synthetic potential.[2-
3]
Numerous of efforts have been devoted to the conversion of
levulinic acid and its esters into highly valuable chemicals under
homogeneous or heterogeneous catalytic system (Scheme
1a).[4-11] For examples, hydrogenation to produce γ-
valerolactone,[4] 1,4-pentanediol,[5] valerate esters,[6] 2-
methyltetrahydrofuran (2-MeTHF), n-alkanes depending on
the hydrogenation conditions, and reductive
amination/cyclization converted into pyrrolidinone or
[7]
[8]
pyrrolidines[9]. Selectivity oxidation for synthesis of maleic
anhydride, succinic acid, and 3-hydroxypropanoic acid.[10]
Condensation with furfural, α-angelica lactone or dimerization
to generate precursors for renewable fuels and polymer
monomers.[11] Moreover, Levulinic acid and its esters can also
be used to react with phenylhydrazine for the synthesis of drug
molecule, Indomethacin.[12] Although a lot of research has been
conducted on the conversions of LA, it is still a high desirable to
seek more innovative routes to leverage levulinic acid and its
[a]
W.-Y. Xu, K.-F. Zhuo, Dr. T.-J. Gong, Prof. Y, Fu
Hefei National Laboratory for Physical Sciences at the Microscale,
CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province
Key Laboratory of Biomass Clean Energy, iChEM, University of
Science and Technology of China, Hefei, 230026, (China)
E-mail: gongtj@ustc.edu.cn
fuyao@ustc.edu.cn
[b]
Dr. T.-J. Gong
Hefei Institute of Energy, Hefei (China)
[+] These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1. a) Typical appilication of levulinic acid derivatives as “C5” building block, b) Some bioactive molecules containing 1,4-disubstituted frameworks, c) Our
design for conversion of levulinic acid derivatives.
Results and Discussion
Tosylhydrazone compounds, which can easily obtained
from carbonyl group (ketones or aldehydes) and TsNHNH2 (4-
methylbenzenesulfonhydrazide), are very excellent reaction
intermediates in organic transformation to forge various C-C
and C-hetero bond under metal or non-metal catalytic
condition[14-17]. In 2009, Barluenga and Valdés pioneered the
reductive cross-coupling of tosylhydrazone and boronic acid to
form C(sp3)-C bonds under matal-free condition[15a]
.
Subsequently, diverse of C-C[15-16], C-O[17a-b], C-N[17c] and C-B[17f]
Scheme 2. Gram-scale preparation of levulinate derived tosylhydrazones.
bonds were successfully constructed using tosylhydrazone as
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should be noticed that, bio-based solvent 2-MeTHF (which can
be prepared by hydrogenation of levulinic acid [7]) can promote
the reaction afford acceptable yield (entry 13, 14). This result
indicates that 2-MeTHF can be used as an alternative green
solvent for the valorization of biomass.[18]
“hub molecule”. These series of studies have proved that using
tosylhydrazone as the "hub molecule" is an effective way to
build C-C or C-X bonds based on carbonyl group.
Coincidentally, biomass-derived levulinic acid and its esters
contain a carbonyl structure, the use of tosylhydrazone as a
“hub molecule” is expected to be a new route to accomplish
high-value utilization. We started our studies by condensation
of methyl levulinate with TsNHNH2 in methanol solvent at 80℃
for 30 mins to obtain a white solid 1a (87%). The bench-stable
white solid 1a was identified to be a 10:1 E/Z mixture by 1H
NMR spectroscopy (Scheme 2, see SI for details). Ethyl
levulinate can also afford the corresponding tosylhydrazone
compound by a similar method (EtOH as solvent). Then, we
chose 1a and 4-tolylboronic acid (2a) as model substrates for
C-C cross-coupling reaction, various parameters on the
outcome of the reaction were conducted (table 1). Types of
bases was tested,
Table 1. Optimization of the reaction conditions.a
Entry base (1.5 eq)
solvent
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
THF
T oC
110
110
110
110
110
110
90
Yield%b
8
1
2
Na2CO3
K2CO3
25
72
14
5
3
Cs2CO3
CsF
4
5
K3PO4
6
NBu4F
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
3
7
20
30
75
66
42
63
62
69
8
100
120
130
110
110
110
120
9
10
11
12
13
14
2-MeTHF
2-MeTHF
[a] All the reactions were carried out with 0.5 mmol of 1a and 0.75 mmol of 2a
in 2 mL solvent for 4h. [b] Isolated yield. Ts=4-Toluolsulfonyl; Dioxane=1,4-
Dioxacyclohexane; THF=Tetrahydrofuran; 2-MeTHF=2-methyltetrahydrofuran.
we were delighted to found that Cs2CO3 can achieve 72% yield
of 3a, and the reaction efficiency of Na2CO3, K2CO3, CsF,
K3PO4 and NBu4F were poor. Then, different reaction
temperatures were examined, it was found that higher yields
can be obtained under 120℃. Lowering the temperature to
90℃ or 100℃ (entry 7-8), the conversion of starting materials
were not complete. Increasing the temperature to 130℃ leads
to condensation of the product under alkaline condition.
Moreover, the influence of different solvents was examined in
the transformation, it was found that ether solvents can promote
the reaction afford the target product in moderate yields. It
Scheme 3. Substrate scope. 1 (0.5 mmol), arylboronic acids 2 (0.75 mmol),
Cs2CO3 (0.75 mmol), dioxane (2 mL), 120 ℃, 4 h under Ar atmosphere.
Isolated yield.
With the optimized reaction conditions in hand, we
examined the substituent effect of the arylboronic acids
(Scheme 3). Types of arylboronic acids were tested, both
electron-donating and withdrawing arylboronic acids exhibited
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good reactivities. Naphthyl-substituted boronic acid and 4-
biphenylboronic acid could be well compatible in this reaction.
For electron-withdrawing arylboronic acids, 4-Ac and 4-COOEt
substituted boronic acids could be employed in this reaction to
afford corresponding products in moderate yields (3c, 3f). It
was noteworthy that, alkenylboronic acid was also compatible
in this reaction and afford the mixed products, which was in
consist with previous result.[15b]
noticed that rac-4,7-dimethyl-l-tetralone 7 was aslo very
important intermediate for biologically active compounds.[20]
Similarly, The rac-xanthorrizol precursor 8 was synthesized via
arylation, hydrogenation and alkenylation sequences.
Encouraged by the successful conversion of the arylation
reaction, we tried to tested other types of conversion to further
expand the application of biomass-derived levulinic esters. As
we all know, lignocellulose were consist by cellulose,
hemicellulose and lignin, where cellulose or hemicellulose can
be transformed into furan compounds by hydrolysis, and lignin
can be converted into phenolic compounds. The development
of the upgrading reaction using two biomass-derived
components is appealing for the utilization of biomass
resources. We first tried the reaction of 1a with furfural, by
using cesium carbonate as the base, and react at 110℃ for 6
hours. It was delighted to found that product 10a can be
obtained in 57% yield. Furfural can also react with 1b afford
product 10b in 54%. Moreover, the cellulose-derived 5-
methylfurfural and methyl 5-formylfuran-2-carboxylate can also
participate in the reaction afford the target products 10c-10f in
moderate yields (Figure 2). Compared with the previous
literature, this reaction provides a new strategy for C-C coupling
Considering the simplicity and efficiency of the sequential
process of condensation and arylation, we tried to prepare 3a
through a "one-pot, two-step" procedure (Scheme 4, see SI for
details). First,
3 mmol of methyl levulinate and sulfonyl
hydrazide were reacted in dioxane at 80℃ for 2 hours, then 4.5
mmol of 4-tolylboronic acid and 4.5 mmol of Cs2CO3 were
added, the mixture were heated at 120℃ for 4 hours. After
separation and purification, the product 3a can be obtained in a
total yield of 51%. This operation can shorten the reaction time
and save more solvent.
b]
of biomass-derived levulinic esters and furfural.[11a, Both the
arylation and acylation reactions mentioned above have
achieved the construction of C-C bonds, the development of
other types of C-hetero bond cross-coupling was also valuable
in promoting the high-value utilization of biomass. Then, we
tried the reaction of 1a with phenol under base condition at
120℃ for 24 hours, 49% yield of etherification product 11a was
obtained. This method provides an approach to synthesize
different structural compound compounds, which is an
important supplementary to previous reaction of levulinic acid
with phenol to prepare diphenolic acid.[21] By using vanillin as a
starting material, product 11b and 11c can be obtained in 53%
and 57% yields, respectively.
Scheme 4. “One-pot two steps” procedure for synthesis of 3a.
The above results motivated us to further explore the
application of this transformation (Figure 1). First, scaled-up
experiment was conducted afford 3a in 74% (10 mmol scale).
The product 3a can be converted to aldehyde (4) through the
hydrogenation using diisobutylaluminum hydride. Rac-
curcumene (5), an natural aromatic sesquiterpene,
[13a-d]
was
obtained by the subsequent Wittig reaction. Moreover, the
product 3a can also be readily converted to trinorsesquiterpene
[19]
7
by means of hydrolysis and Friedel-Crafts acylation. It was
Figure 1. Synthesis of bioactive compounds. a) DIBAL, CH2Cl2, -40 ℃; b) iso-propyltriphenylphosphonium iodide, n-BuLi, THF, -10 ºC to 0 ℃; c) LiOH,
THF:MeOH:H2O, 50 ℃; d) TFAA, TFA, 0 ℃.
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Figure 2. Valorization of methyl levulinate with bio-based aldehydes and phenols.
stirred at 80 ℃ until the solid was dissolved. The methyl (or ethyl) levulinate
(50 mmol) was added slowly, and the mixture was heated in an oil bath at
80°C for 30 min, the mixture was then cooled to 0 ℃, white solid precipitated
and the product was collected on a BFchner funnel, washed with cold methol
or ethanol (5 mL) and petroleum ether, and then dried in vacuo to afford the
corresponding N-tosylhydrazones.
Conclusion
We reported an unprecedented example of transition-
metal-free arylation, acylation, and etherification reactions of
levulinic acid derivatives. Types of arylboronic acids can be
applied in this transformation to afford γ-aryl valerates. Using
methyl levulinate ester as a starting material, the condensation
and arylation reaction can be achieved smoothly through a
“one-pot, two-step” process without isolation of the
tosylhydrazone intermediate. Moreover, the arylated products
can be used for further transformation to obtain three biologically
active molecules, rac-urcumene, rac-xanthorrhizol, and rac-4,7-
dimethyl-l-tetralone. In addition to the cross-coupling reaction
with boronic acid, the metal-free reductive cross-coupling can
also undergo acylation and etherification with lignocellulose
derivatives (aldehydes and phenols) to prepare more types of
products. Therefore, the strategy reported here is an important
supplement to the high-value utilization of levulinic acid and its
esters, and it also provides a new idea for the high-value
utilization of other biomass platform molecules.
Reaction of 1 with boronic acid: A 10 mL Schlenk tube equipped with a
magnetic stirrer was charged with tosylhydrazone 1a or 1b (0.5 mmol),
Cs2CO3 (1.5 equiv., 0.75 mmol), and arylboronic or alkenylboronic acids (1.5
equiv., 0.75 mmol). The tube was evacuated and backfilled with argon for
three times, and then dioxane (2 mL) was added by syringe under argon. The
reaction mixture was stirred at 120 ℃ for 4 h. Then EtOAc and water were
added and the layers were separated. The aqueous phase was extracted
with EtOAc (3 mL x 2) and the combined organic layers were dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash column
chromatography on silica gel with petroleum ether/ethyl acetate as the eluent
to give the corresponding products.
General procedure for synthesis of rac-crucumene:
A 250 mL Schlenk tube equipped with a magnetic stirrer was charged
with tosylhydrazone 1a (10 mmol), Cs2CO3 (1.5 equiv., 15 mmol), and 4-
tolylboronic acid (1.5 equiv., 15 mmol). The tube was evacuated and
backfilled with argon for three times, and then dioxane (40 mL) was added by
syringe under argon. The reaction mixture was stirred at 120 ℃ for 4 h. Then
EtOAc and water were added and the layers were separated. The aqueous
phase was extracted with EtOAc (20 mL x 2) and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. The residue was
Experimental Section
Preparation of tosylhydrazone derivatives 1: A 500 mL round bottom flask
equipped with a magnetic stirrer was charged with TsNHNH2 (50 mmol), then
100 mL of dry methanol or ethanol was added. The reaction mixture was
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Foundation (BJ2060190102). We also thank the Hefei Leaf Biotech Co.,
Ltd for free samples (methyl levulinate and ethyl levulinate) benefited
our ability to conduct this study.
purified by flash column chromatography on silica gel with petroleum
ether/ethyl acetate as the eluent to give the products 3a (74%).
At -40 ℃, under nitrogen atmosphere, DIBAL (1.0 M in PhMe, 8.2 ml,
8.2 mmol) was added dropwise to a solution of 3a (7.4 mmol) in CH2Cl2 (15
mL). The reaction mixture was stirred at -40 ℃ for 1h. After quenching the
reaction with MeOH (5 mL) at -40 ℃, saturated potassium sodium tartrate (20
mL) was added. The solution was stirred until it turned clear. Then Et2O (30
mL) and water were added and the layers were separated. The aqueous
phase was extracted with Et2O (20 mL × 3 ) and the combined organic layers
were dried over Na2SO4, filtered, and concentrated. The residue was purified
by flash column chromatography on silica gel with petroleum ether/ethyl
acetate as the eluent to afford the aldehyde 4 (91% yield) as a colorless oil.
Keywords: biomass conversion • levulinic acid derivatives •
tosylhydrazone • rac-curcumene • rac-xanthorrhizol
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Reaction of 1a with aldehydes: A 10 mL Schlenk tube equipped with a
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Reaction of 1a with phenols: A 10 mL Schlenk tube equipped with a
magnetic stirrer was charged with 1a (0.5 mmol), Cs2CO3 (3.5 equiv., 1.75
mmol). The tube was evacuated and backfilled with argon for three times,
and then phenol or vanillin (2 equiv., 1 mmol) in dioxane (2 mL) was added
by syringe under argon. The reaction mixture was stirred at 120 ℃ for 24 h.
Then EtOAc and water were added and the layers were separated. The
aqueous phase was extracted with EtOAc (3 mL x 2) and the combined
organic layers were dried over Na2SO4, filtered, and concentrated. The
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We acknowledge the support from National Key R&D Program of China
(2018YFB1501600), the National Natural Science Foundation of China
(21732006, 51821006, 51961135104 and 22071228) Strategic Priority
Research Program of CAS (XDA21060101) and the Major Program of
Development Foundation of Hefei Centre for Physical Science and
Technology (WK3530000007). Anhui Provincial Natural Science
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10.1002/cssc.202002167
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Wen-Yan Xu, Kai-Feng Zhuo, Tian-Jun
Gong*, and Yao Fu*
Metal-free
reductive
cross-
coupling arylation, acylation, and
etherification reactions of biomass-
derived levulinic esters were reported
herein. Three biologically active
Page No. – Page No.
Transition-Metal-Free Valorization of
Biomass-derived
molecules,
rac-curcumene,
rac-
Levulinic
Acid
xanthorrhizol, and rac-4,7-dimethyl-l-
tetralone were accomplished by this
method. This reaction provides a new
route for the high-value utilization of
biomass platform molecules.
Derivatives: Synthesis of Curcumene
and Xanthorrhizol
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Title
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