Pyrone Synthesis from Renewable Sources: Easy Preparation of 3-Acetoxy-2-oxo-2H-pyran-6-carboxylic Salts and their Derivatives as 3-Hydroxy-2H-pyran-2-one from C6 Aldaric Acids

Article abstract of DOI:10.1002/ejoc.201901427

2-Pyrones are compounds present in several natural products and represent interesting building blocks for the preparation of intermediates in organic syntheses. For these reasons, many different preparation protocols have been developed for the synthesis of pyrone moieties. In this work, a green approach toward the synthesis of those compounds starting from C6 aldaric acids has been investigated. These products are an interesting and versatile class of poly functional C6 units coming from renewable sources. In this paper, we report a green procedure based on a reaction with acetic anhydride under different pH conditions to convert mucic acid and glucaric acid salts into the 3-acetoxy-2-oxo-2H-pyran-6-carboxylic acid salts and their derivatives. The salts, in the presence of hydrochloric acid, are quantitatively converted into the corresponding 3-hydroxy-2-oxo-2H-pyran-6-carboxylic acid, which afforded 3-hydroxy-2H-pyran-2-one in very high yield by further thermal decarboxylation. Crystal structure of the five membered ring lactone intermediate is reported.

Full text of DOI:10.1002/ejoc.201901427

A Journal of
Accepted Article
Title: Pyrones Synthesis from Renewable Sources: Easy Preparation
of 3-Acetoxy-2-oxo-2H-pyran-6-carboxylic Salts and their
Derivatives as 3-Hydroxy-2H-pyran-2-one from C6 Aldaric Acids
Authors: Gabriella Leonardi, Jiemong Li, Grazia Isa Carla Righetti, Ada
M. Truscello, Cristian Gambarotti, Giancarlo Terraneo, Attilio
Citterio, and Roberto Sebastiano
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901427
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901427
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
FULL PAPER
Pyrones Synthesis from Renewable Sources: Easy Preparation of
3-Acetoxy-2-oxo-2H-pyran-6-carboxylic Salts and their
Derivatives as 3-Hydroxy-2H-pyran-2-one from C6 Aldaric Acids
Gabriella Leonardi,[a] Jiemong Li,[a] Grazia Isa C. Righetti,[a] Ada M. Truscello,[a] Cristian Gambarotti,[a]
Giancarlo Terraneo,[a] Attilio Citterio,[a] and Roberto Sebastiano*[a]
Abstract: 2-Pyrones are compounds present in several natural
products and represent interesting building blocks for the preparation
of intermediates in organic syntheses. For these reasons, many
different preparation protocols have been developed for the syntheses
of pyrone moieties. In this work, a green approach toward the
synthesis of those compounds starting from C6 aldaric acids has been
investigated. These products are an interesting and versatile class of
poly functional C6 units coming from renewable sources. In this paper,
we report a green procedure based on a reaction with acetic
anhydride under different pH conditions to convert mucic acid and
glucaric acid salts into the 3-acetoxy-2-oxo-2H-pyran-6-carboxylic
acid salts and their derivatives. The salts, in the presence of
hydrochloric acid, are quantitatively converted to the corresponding 3-
hydroxy-2-oxo-2H-pyran-6-carboxylic acid, which afforded 3-hydroxy-
2H-pyran-2-one in very high yield by further thermal decarboxylation.
Crystal structure of the five membered ring lactone intermediate is
reported.
Among the large variety of carbohydrate derivatives, in the
last decades, aldaric acids have aroused great interest in the
industry as precursor of several derivatives starting from natural
feedstock. As hydroxyl acids, these compounds show
a
significant tendency, also in aqueous media, to give the
corresponding lactones and dilactones[3] depending on the
stereochemistry of the carbon atoms bearing the hydroxyl groups.
They undergo dehydration reactions resulting in the
corresponding unsaturated derivatives; therefore, these
compounds are good candidates for the syntheses of 2-pyrones
starting from natural sources. In particular, hexaric acids should
be a suitable platform for substituted pyrones. Based on this, we
report an easy preparation of 3-acetoxy-2-oxo-2H-pyran-6-
carboxylic acid salts and their derivatives. In particular, the 3-
hydroxy-2-oxo-2H-pyran-6-carboxylic acid, recently patented as
precursor of terephthalic acid,[4] was prepared in very low yields
starting from ethyl succinate and oxalate (Figure 1A).[5] In general,
2-pyrones are a class of six-membered unsaturated lactones
present in several natural products[6] such as pheromones,
solanopyrones, α-chymotrypsin. These compounds exhibit
pharmacological activity as antifungal, antibiotic, neuro-, cyto-
and phyto-toxic, HIV protease and selective COX-2 inhibitors.[7]
Due to their peculiar structure in which conjugated diene and
lactone functions are present, and at the same time aromatic like[8]
character, they are important building blocks in organic,
medicinal[9] and polymer chemistry.[10,11] As dienes they are widely
utilized in cycloaddition reactions to obtain functionalized
intermediates.[10,12] In the last decades, many synthetic
procedures have been developed for the synthesis of pyrone
scaffolds,[9a,13] including biosynthetic methods[7a] and protocols
based on renewable resources.[10,11,14]
In this context, procedures for the synthesis of substituted
2-pyrones from aldo-derivatives as glucosaminic acid,
gluconolactone and rhamnonolactone have been proposed.[15]
However, to the best of our knowledge, only few examples on the
use of C6 aldaric acids as precursor of 2-pyrones are reported.
In 1956, a 2H-pyrone derivative was prepared from mucic acid
diethyl ester; the authors claimed to have probably obtained 4-
acetoxy-6-(ethoxycarbonyl)-2H-2-pyrone.[16] 3-Hydroxy-2-pyrone,
synthesized in 1927 from arabinose,[17] is actually prepared from
pyrolysis of mucic acid[18] with a loss of one carbon atom in low
yield in the presence of potassium hydrogen sulfate or potassium
dihydrogen phosphate at high temperature (Figure 1B).
Introduction
Nowadays, in the quest for more sustainable chemical
processes, as well as to reduce the fossil-based feedstock, the
global community is moving towards the development of a green
and sustainable economy based on natural and renewable
resources. At the same time, the continuous population growth
forces institutions and industries towards the valorisation of
agrofood residues and waste.[1] In this context, the transformation
of biomass into valuable building blocks has a key role in the
sustainable bio-based green economy.[2] The major fraction of
biomass is based on C5 and C6 sugars building blocks and
structural polysaccharides, containing repeating units of D-
glucose, D-galactose, D-mannose, D-xylose, D-arabinose, etc.,
that are economically suitable for using as chemical raw materials.
[a]
Dr. G. Leonardi, Dr.J. Li, M.Sc. G. I. C. Righetti, Dr. A. M. Truscello,
Prof. Dr. C. Gambarotti, Prof. Dr. G. Terraneo, Prof. A. Citterio and
Prof. Dr. R. Sebastiano.
Department of Chemistry, Materials and Chemical Engineering
“Giulio Natta”
Politecnico di Milano
Piazza Leonardo da Vinci 32, I-20133 Milano - Italy
E-mail: roberto.sebastiano@polimi.it
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
A
O
COOEt
HO
to10%
up
NaOEt
HCl
+
O
1)
2)
2
(COOEt)2
The direct dehydration reaction of the aldaric acids is not a
simple process: the most effective reaction is in fact based on
COOEt
COOH
B
oxorhenium-catalyzed
deoxydehydration
in
alcohols,[19]
O
OH
OH
O
O
,
°
>
300
C
HO
KHSO4
T
,
O
performed under harsh conditions and limited to substrates where
vicinal syn hydroxyl groups are present. Looking for a sustainable
process, we investigated the dehydration reactions of the mucic
acid, as representative model of the C6 aldaric acids, following an
approach based on cheap and safe reactants potentially
applicable to these classes of compounds. Then, we verified the
possibility to extend the method starting from galactaric calcium
and potassium salts, with comparable results.
O
HO
-
11 40%
,
°
or
KH2PO4
P
400
2O5 C
OH
OH
OH
OH
art
prior
C
O
O
OH
OH
HO
up
HO
O
O
O
HO
>90%
OH
OH
COOH
to 73%
work
this
Dehydration of alcohols is a reaction typically performed in the
presence of a strong acid as catalyst but, in the case of aldaric
acids, these reaction conditions lead to a complex mixture where
also furane derivatives and their polymers are formed.[20] To
minimize the formation of polymers derivatives we investigated
mucic acid reactivity in the system acetic anhydride/ methane
sulfonic acid (Ac2O/MSA): Scheme 1 summarizes investigated
reactions in acid medium.
Figure 1. Prior syntheses of target 3-hydroxy-2-pyrones.
Our aim was therefore to find an efficient and low cost 2H-
pyrone-6-carboxylic acid derivatives synthetic protocol, which
would allow to preserve all the six carbon atoms present in the
starting hexaric acid and to focus our attention on the overall
mechanism and on the reaction intermediates as well. At the
same time an easy procedure to obtain the corresponding
decarboxylated 3-hydroxypyrone in high yield has been
developed (Figure 1C).
OH
O
HO
AcO
OAc
O
O
HO
AcO
O
OH
Ac
2O,
H+
OH
OAc
O
Ac
2O
O
O
R2
R3
OH
OAc
reflux
literature
OAc
HO
HO
OH
AcO
5 (>
1
6a
90%)
R4
R1
R5
Ac
∆
MSA
2O,
Ac
2O
Ac
2O
MSA
reflux
MSA
reflux
AcO
O
O
O
O
AcO
AcO
O
O
OH
+
+
COOH
HO
OAc
4
2b
3
Scheme 1. Investigated reactions in acid medium. Lactone 5, was obtained as racemic mixtures.
As indicated in R1 (Scheme 1), the main products obtained
were the pyrones 2b and 3, and the diacetoxy muconic acid 4.
Target pyrone 2b was fully characterized; product 4 was isolated
in a very small amount, whereas structure of 3 was assigned on
the basis of its 1H NMR spectrum.
Table 1 summarizes the most significant data collected while
performing the reactions in acetic anhydride under different
conditions, in terms of molar ratio MSA/mucic acid, temperature
and reaction time. The molar ratio Ac2O/mucic acid used was 8.
As expected, the products distribution depends mainly on the
molar ratio MSA/mucic acid although temperature and reaction
time have a role too: in fact, a higher molar ratio between MSA
and mucic acid favours the formation of the open chain di-
eliminated derivative 4 (entries 1-3); while high initial temperature
(entry 1) or longer reaction time at 128 °C (entries 5, 8 and 9),
lead to lower mass balance. In this temperature range
decarboxylation of 2b to give the pyrone 3 always occurs, and the
ratio 3/2b is substantially constant. In almost all the experiments,
various acetylated derivatives of mucic acid and its lactone were
found (entries 2-9). The best result was obtained when performing
the reaction with a low ratio MSA/mucic acid and long reaction
time (Table 1, entry 5). In any case, the isolation and the
purification of 2b from the crude reaction mixture was laborious
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
FULL PAPER
and time consuming mainly because of the presence of several
by-products, which interfered in the isolation process steps.
These results, combined with the work-up difficulties
showed that the acid promoted reaction of acetylated mucic
acid derivatives does not seem to be a convenient process for
the synthesis of pyrones.
Table 1. Reactivity of mucic acid 1 in the system Ac2O/MSA [R1] at reflux
AcO
O
HO
O
O
O
HO
Table 2. Reaction of 5 and 6a in the system Ac2O/MSA (R4 and R5) at reflux
for 5 hours. Molar ratio of MSA/reagent = 2 and Ac2O/reagent = 3
HO
AcO
O
O
Ac
2O,
MSA
OH
O
O
OH
+
+
OH
∆
COOH
HO
OAc
HO
OH
OH
O
1
2b
3
4
O
OAc
O
Entrya
MSA
[Mr]b
Tic
[°C]
t
[h]
2b
3
4
OAc
AcO
OAc
O
AcO
[Ya%]d
[Ya%]d
[Ya%]d
O
O
5
AcO
AcO
Ac
MSA
O
O
OH
2O,
O
+
+
or
+
5
reflux
COOH
1
2
3
4
5
6
7
8
9
3
3
140
120
120
120
128
128
128
128
128
4
9
4
8
9
9
9
9
9
53
56
43
46
52
66
54
60
33
12
15
10
11
16
14
17
12
8
15
15
15
4
HO
AcO
O
2b
3
4
AcO
O
OH
OAc
HO
OAc
6a
3
1e
Entry
Reag.
5
Conv.
%
2b
3
4
5
[Reaction]
[Ya%]a
[Ya%]a
[Ya%]a
[Ya%]a
1
8
1
98
99
68
13
16
2
0.8
0.8e
0.6
0.4
4
[R4]
4
2
6a
46
10
13
30
[R5]
3
[a] Ya= analytical yield.
<1
[a] Reaction reported as R1 in the experimental part. [b] Mr= molar ratio. [c]
Ti= initial temperature of the reaction. [d] Ya= analytical yield. [e] MSA was
added over 5 hours.
As a consequence, the reactivity of the C6 aldaric acids in
buffered acido-base media was investigated.
As known, mucic acid presents a very low solubility in almost
all solvents and shows marked propensity to cyclize, in several
media, including water, to give a more soluble five membered
lactone.[22]The latter can be a convenient substitute of mucic acid
to perform such chemical reactions. Surprisingly, there are no
methods described in literature where this derivative has been
isolated as a pure solid and also our attempts to make it have
failed. For this reason, the structural attribution of this lactone has
been assigned only by NMR analysis. On the contrary, the
corresponding pyridinium salt 7 can be easily synthetized and
isolated by boiling mucic acid in pyridine (Scheme 2 [R6]). The
single crystal structure analysis of the corresponding DABCO salt
7’ has definitely confirmed the structure of this lactone (Figure 2).
Furthermore, the two main side products 3 and 4 were
unavoidable under these conditions. In particular, pyrone 2b
underwent decarboxylation at 90-100 °C in acidic medium
giving pyrone 3.
It is known that in the presence of a catalytic amount of
strong acids, mucic acid reacts in acetic anhydride at 60-85 °C,
achieving the corresponding tetra-acetylated derivative 6a.[21]
We found that in the presence of sulfuric acid at solvent reflux
temperature, the carboxylic pyrone 2b and the corresponding
decarboxylated 3 were formed together with a small amount of
diacetoxy muconic acid 4. On the other hand, by refluxing
mucic acid in acetic anhydride only the corresponding lactone
5 is formed in high yield.
However, even reactions of lactone 5 and mucic acid
tetracetate 6a in the Ac2O/MSA system resulted in the same
mixture made of 2b, 3 and 4. The results of the two reactions
R4 and R5 are listed in Table 2. The presence of products 3
and 4 denotes how, even though the final products are
identical, the pyrone synthesis from mucic acid can follow
different paths in which 6a and 5 can be considered as reaction
intermediates.
The data show that formation of 2b is faster starting from five
membered ring lactone 5 than from the open chain O-
peracetylated derivative 6a, although significant amounts of
the by-products 3 and 4 are still present. This different
reactivity can be related to the fact that 6a converts to 5.
Figure 2. Crystallographic representation (ellipsoid 50% of probability) of
compound 7’. Colour code: C, grey; O, red; N, blue; H, white.
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
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However, attempts to perform the direct dehydrating reactions
in moderate acid buffered media (AcOH/AcO-Na+ at reflux) on this
substrate failed (Scheme 2 [R7]).
of the pyrone derivatives (Scheme 3). Lower yields were obtained
using other bases such as NaOH, AcONa and 1,4-
diazabicyclo[2.2.2]octane (DABCO).
O
O
HPy+
OH
OH
OH
O
OH
O
-Na+
OH
OH
O
O
Py
AcOH, AcO
reflux
O
O
R6
R7
O
O
AcOH,
OAc
OAc
HO
reflux
O
O
AcO-Et3NH+
OH
OH
OH
HO
OAc
7
(93%)
1
week
AcO
RT, 1
AcO
5
8
(34%)
racemic
mixture
racemic
mixture
racemic
mixture
Scheme 2. Synthesis of mucic acid 1,4-lactone pyridiniun salt (7) [R6] and its
reactivity in moderate acid buffered medium [R7] .
Scheme 3. Synthesis of lactone 8 [R8]
At the light of this result, mucic acid was reacted with acetic
anhydride in the presence of a base (NaOH, pyridine or NaOAc)
This result can be ascribed to the too weak acidity of the
HOC˗H bonds present in the molecule: therefore, we tested the
reactivity of the per-acetylated lactone 5 in moderate acidic buffer
AcOH/AcO-Et3NH+; in this case the mono-eliminated five-
membered ring lactone 8 was isolated (24% yield) without traces
(R9, R9’ or R9’’). Scheme
investigated in buffered medium.
4 summarizes the reactions
HO
O
HO
O
OH
OH
HPy+
OH
HO
O-
OH
OH
OH
1
O
O
O
O
OAc
R9
R
R ''
9',
9
,
O
O
OAc
Ac
2O
HO
AcO
'
7
R10
2O
R10
NaOH/Py/ NaOAc
90°C
5
Ac
2O
AcONa
Ac
90°C
90°C
O
AcO
O
COOX
Ac
2O
Ac
=
=
2O
2a
2b
Na 2 AcOH
H)
-
AcO
OAc
O
(X
(X
)
AcONa/Py
90°C
Py
AcO
60°C
OH
O
O
HO
OH
68% 90%
'
R12
R
12
,
R11
OAc
O
OAc
O
6a
8
AcO
Scheme 4. Investigated reactions in buffered medium. Lactones 5 and 8 were obtained as racemic mixtures
In these conditions the pyrone 2b (or its sodium salt 2a) was
obtained in good yields (69-78%). The reaction can be performed
with a stoichiometric (Table 3, entry 1 [R9] and entry 2 [R9’]) or
catalytic amount (entry 3 [R9’’]) of base. When NaOH was used
in stoichiometric quantity, the product crystalized directly from the
crude mixture as sodium salt•2 AcOH while, when using pyridine
or AcONa in catalytic amount the acid form of the pyrone 2c could
be advantageously isolated by treatment with hydrochloric acid.
As expected, when following the reactions through the time,
the per-acetylated five membered ring lactone 5 was observed as
intermediate. To better understand the mechanism of the
reactions R9, R9’ and R9’’, lactone 5 was reacted in an
Ac2O/AcONa system (Table 3, entry 4 [R10]): the pyrone 2b was
obtained in short time and high yield (94%). This result clearly
indicates that the lactone 5 is a key reaction intermediate. Thus,
the conversion of the per-acetylated five membered ring lactone
5 to the six membered ring pyrone 2b requires an open chain
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
FULL PAPER
intermediate. When following the reaction R10’ (Table 3, entry 5)
by 1H-NMR analysis through time species 4 and 8 were identified.
In order to reduce the amount of acetic anhydride and, at the
same time, use a cheaper base, we found that it was possible to
obtain 2a in good yield using NaOH in an equimolar amount in
respect to mucic acid in the minimum amount of anhydride
needed to have a stirrable mixture (Table 3, entry 1). This
experiment was performed on 50 g scale obtaining the direct
crystallization of the desired product 2a in a 61% yield and
another 8% of 2a after work-up of the remaining solution.
We also investigated the reactivity of the mucic acid
tetracetate 6a in the system B-, B:/Ac2O (Table 3, entry 7 [R12]
with AcONa as base and entry 8 [R12’] with Pyridine as base):
also in those cases the pyrone 2a (or 2b) was formed fast and in
high yield.
pyridine to convert mucic acid to the mixture of 2b and 2c and
then HCl to complete the hydrolysis. [R13’]. In addition, the pyrone
2c can be easily decarboxylated to the 3-hydroxypyrone (9) in
very high yield (97%) by heating under vacuum (170 °C and 0.3
mmHg) (Scheme 5 [R14]).
O
O
2 CH3COOH
COO-Na+
O
HO
HCl 36%
O
O
R13
O
RT, 48 h
COOH
2c
(91%)
2a
HO
O
O
HO
HO
reaction
Telescoped
Acetic
O
O
OH
R13'
1)
OH
90°C, 3h
anhydride, Py,
COOH
2c
(74%)
HO
OH
solvent elimination
HCl 36%, RT, 48 h
2)
3)
1
O
O
O
HO
HO
Table 3. Synthesis of Pyrones 2a, 2b, 2c, 2d and 2e
O
∆
R14
COOH
Entry
[Reaction]
Ra
Ac2O
[Mr]b
Base
[Mr]b
T
[°C]
t
[h]
P
2c
9
(97%)
[Ya%]c
[Yi%]d
Scheme 5. Synthesis of 2c from 2a (R13) or from 1 (R14) and 9 from 2c
[R14].
1
[R9]
1
1
1
5
13
22
53
20
NaOH
1.04
90
90
4
3
2a
69
As anticipated we also verified the reactivity of two glucaric
acid salts. This C6 aldaric acid is a glucose derivative, the
cheapest and the most abundant renewable feedstock. As
expected, these salts showed a comparable reactivity in respect
to mucic acid: the difference is mainly related to their different
solubility in the reaction media. We tested calcium glucarate 10,
a cheap and commercially available derivative, very insoluble in
the reaction conditions, as well as the corresponding pyrone
calcium salt (Table 3, entry 9, Scheme 6 [R15]). The process
allows to recover the reaction product 2d by filtration. The co-
2
[R9’]
Py
1.00
2b + 2c
54 + 21
3
AcONa
0.15
100
90
18
15
2b
78
[R9’’]
4
AcONa
0.28
2b
94
74
[R10]
5
7
21
-
90
60
3
2b + 2c
64+30 =94
36+26 =62
[R10’]
precipitated product
(5%) is compatible with 2.5-
diacetoxymuconic salt in the unfavourable trans-trans
conformation to cyclize to the pyrone derivative.
6
8
151
34
71
39
13
Py
0.23
2
4
3
9
1
2b
78
[R11]
O
7
6a
6a
10
11
AcONa
1.13
reflu
x
2a
78
HO
O
HO
AcO
[R12]
O
O
Ac
2O
°
OX
100 C
OH
8
Py
2.28
100
100
110
2b + 2c
94+3
COOX
XO
OH
calcium
: mono
[R12’]
:
salt
potassium
:
2d
calcium
salt
salt
10
11
salt
:
2e
potassium
9
-
-
2d
45e
[R15]
Scheme 6. Synthesis of 2d and 2e from D-glucaric acid calcium salt (10)
[R15] and glucarate mono potassium salt (11) [R16] respectively.
10
[R15’]
2e
90
53
We tested also a more soluble (and much more expensive)
potassium glucarate mono acid 11: in this case the reaction is
faster and proceeded without significant formation of by-products
to give the corresponding pyrone potassium salt 2e in high yield
and purity (Table 3, entry 10 [R15’]).
It is worth mentioning that in both cases the reaction runs in acetic
anhydride without catalysts, because the carboxylate anions
(glucarate and acetate generated in situ) are able to promote the
reaction themselves.
[a] R = Reagent. [b] Mr = molar ratio. [c] Y = analytical yield. [d] Yi = isolated
yield. [e] Precipitate from the reaction mixture.
Notice that 2a and 2b represent an easy access to 3-hydroxy-
2-oxo-2H-pyran-6-carboxylic acid (2c). In fact, by stirring 2a or 2b
in concentrated hydrochloric acid at room temperature for 48
hours, 2c was obtained in high yield. Hydrolysis of 2a, performed
on 35 g scale afforded 91% yield. [R13]. We found also that 2c
can be obtained in high yield in a telescoped reaction using
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
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Reaction mechanism
first step: this hypothesis is supported by the reaction R8 (Scheme
3). In that case, in fact, by working in moderate acidic buffered
conditions (AcO-/AcOH) only the unsaturated five membered ring
lactone 8 is formed: this result indicates that the most acidic
hydrogen present in the molecule is Ha (Scheme 7).
Scheme 7 reports the mechanism proposed for the reactions
R10 and R10’ (Scheme 4). Although the lactone 5 has four C-H
bonds, all in principle susceptible of deprotonation, the
mechanism suggested involves the loss of the proton Ha as the
Hb
Hb
OAc
Hb
OAc
Hb
-
-
XOOC
OAc
H
OAc
H
HOOC
HOOC
OAc
H
HOOC
HOOC
O
XOOC
OAc
H
H
O
OAc
OAc
OAc
B:
B:
O
O
O
O
O
O
-
-
-AcO-
-
BH
+
+
-
BH
Ha
OAc
OAc
OAc
OAc
O
OAc
-AcO-
O
O
O
AcO
5
8
XOOC
AcO
COOX
H
OAc
H
COOX
COOX
-
COOX
-
AcO
O
AcO
O
-AcO-
-O
-O
O
O
=
X
CH CO
3
H,
O
O
O
O
OAc
OAc
OAc
OAc
OAc
4'
2
Scheme 7. Suggested mechanism for the reactions R10 and R10’
It is remarkable how it is possible to control the C-H
deprotonation of the saturated lactone 5 in different solvents by
modulating the strength of the base AcO-: in acetic acid it is
possible to stop the reaction to the mono eliminated derivative 8
converted to the pyrone 2. A possible mechanism could involve
the loss of Hb as proton from unsaturated lactone 8 giving the
open chain derivative 4’ which evolves to the six membered
pyrone 2 (Scheme 7). As anticipated, the synthesis of the pyrone
while using acetic anhydride (Table 3, entry 4 [R10], entry 5 [R10’], can be also promoted by a typical organic Lewis’s base like
entry 6 [R11]), also a second deprotonation occurs leading to
dieliminated derivatives. The unsaturated lactone 8 is a second
intermediate in the pyrone synthesis starting from mucic acid (the
first intermediate is the lactone triacetate 5). This hypothesis was
confirmed by the reaction R11 where the unsaturated lactone 8,
in presence of AcO-/Ac2O (instead of AcO-/AcOH) was easily
pyridine. Indeed, in reaction R10’ (Table 3, entry 5) the pyridinium
salt of the mucic acid lactone 7 is converted in situ to the
corresponding per-acetylated lactone 5, which is then
deacetylated to the pyrone in high yields without addition of an
external base thanks to the basic species present in solution:
pyridine and RCOO-.
O
-
H
COOH
OAc
COOH
H
COOH
H
C
O
H
O
AcO
AcO
AcO
AcO
AcO
AcO
AcO
AcO
B:
-BH+
B:
-BH+
-AcOH
BH+
Ac
OAc
OAc
H
OAc
H
-OOC
OAc
HOOC
HOOC
HOOC
II
II'
6
I
H
H
O
C
O
COOH
H
COOH
H
COOH
COOH
O
Ac
-O
AcO
O
H
O
AcO
AcO
AcO
Ac
O
O
-
O
-AcOH
BH+
B:
-BH+
H
O
B:
-BH+
-AcOH
Path 1
AcO
HO
-
H
O
H
OAc
2b
OAc
OAc
H
O
H
OAc
OAc
HOOC
HOOC
OAc
O
4'
II
H
H
O
O
O
O
COOH
H
O
COOH
COOH
-
COOH
Ac
-O
C
O
AcO
AcO
Ac
O
O
-AcO-
B:
-BH+
-
-AcO-
BH+
O
O
O
Path 2
O
O
O
H
OAc
OAc
OAc
OAc
O
OAc
-OOC
II'
H
AcO
OAc
OAc
OAc
OAc
III
2b
Scheme 8. Suggested mechanism for the reactions R12 and R12’
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
FULL PAPER
We also investigated the reactivity of mucic acid tetracetate
6a: in the moderate buffered media AcO-/AcOH, in analogy with
reaction R8, this substrate did not react. This result is coherent
with the supposed acidic difference of Ha and Hb observed in the
per-acetatylated lactone 5 by the reaction R8: in fact, in the open
chain derivative 6a, the reactive Ha is not present and, as already
observed, Hb hydrogen does not react in that media. On the other
hand, as expected, the derivative 6a reacts well in the system B-,
B:/Ac2O (Table 3, entry 7 [R12] and entry 8 [R12’]): in these cases
the pyrone 2a (or 2b) was formed faster and in higher yield if
compared with the analogue reaction R10. Clearly now, in
principle, the formation of the five membered ring lactone is not
possible, and a different mechanism has to be taken into account
(Scheme 8).
The first step of the process is compulsory: it is the deprotonation
of the hydrogen in α to the carboxylic group to give the
intermediate I in Scheme 8. It is worth noting that the next step of
deacetylation is kinetically assisted by the hydrogen bond traced
in the structure in square brackets. This deduction is supported
by the experimental observation that the corresponding diethyl
ester 6c or the diacetyl mixed anhydride of mucic acid tetracetate
6d, prepared by literature procedure,[21] did not react under the
same reaction conditions (Scheme 9).
work was to use an oxidized pectine-based and polysaccharides-
based feedstock, such as mucic and glucaric acid, to obtain
pyrones by an easy synthesis of 3-acetoxy-2-oxo-2H-pyran-6-
carboxylic acid salts and their derivatives in good yields. This
approach preserves all the six carbon atoms present in the
starting C6 aldaric acids, and allows a green isolation procedure
of the products. 3-Acetoxy-2-oxo-2H-pyran-6-carboxylic acid
sodium salt can be seen as a protected form of 3-hydroxy-2-oxo-
2H-pyran-6-carboxylic acid which is obtainable in very high yield
by a simple hydrolysis reaction. These syntheses have been
performed on several grams scale, and the good results achieved
suggest the possibility of an easy further scale-up. At the same
time,
a
simple procedure to obtain the corresponding
decarboxylated 3-hydroxypyrone in high yield has been reported;
in this case, the synthesis was performed only on a gram scale
due to the limitation of the sublimation apparatus utilized. A
complete characterization of the two most important pyrones here
synthesized is provided by crystallographic studies.
A reaction mechanism has been proposed on the base of
the identified intermediates, starting from mucic 1,4-lactone salt
isolated for the first time during this work. A second reaction
mechanism has been proposed starting from the open chain
mucic acid tetracetate.
As underlined in the introduction, pyrones are interesting
intermediates for the synthesis of several classes of compounds
including polymers. The synthesis here reported represents a
convenient green method for the production of these derivatives
from removable sources and can favour a further development of
compounds and materials based on them.
AcO
O
AcO
Ac2O
O
OX
OAc
or
AcONa B:
XO
OAc
100 °C
=
6c
6d
Et)
(X
(X
(
(
)
)
=
COMe)
Experimental Section
Scheme 9. 6c and 6d in moderate acid buffered medium.
Reagents and solvents, commercially available, were purchased from
Sigma-Aldrich except acetic anhydride (Carlo Erba), mucic and
methanesulfonic acid (Acros, Organics) and were used as received.
1H NMR (400 MHz) and 13C NMR (100.5 MHz) spectra were recorded at
302 K on a Bruker Avance 400 instrument. Chemical shifts were reported
in ppm respect to the solvent residual peak as internal standard (DMSO-
d6: δH= 2.50 ppm, CDCl3: δH= 7.26 ppm, Acetone-d6: δH= 2.05 ppm).
Analytical yields were calculated using terephtalic acid as standard.
Infrared spectra were recorded with FTIR Varian 640 instrument acquired
in KBr disks. Mass spectra were recorded by using Electrospray Ionization
(ESI) with a Bruker Esquire 3000 plus ion-trap mass spectrometer
instrument equipped with an ESI Ion Trap LC/MSn System. Melting points
were determined by using a Büchi 535 apparatus and were not corrected.
Direct phase silica gel TLC plates were used for thin layer chromatography.
Single crystals X-ray diffraction data were collected on a Bruker KAPPA-
APEX II CCD diffractometer using Mo-Kα radiation (λ = 0.71073 Å), see
Supporting information for specific crystallographic details (Table S1 and
Figure S1-S6).
The reactions starting from the substrate 6a present less by-
products if compared with the ones starting from the lactone
derivatives and no intermediates were detected by 1H NMR in the
crude mixtures. In particular no trace of the compound 4’ (or its
configurational isomers), key intermediate of the Path 1, was
observed in the analysed crude mixtures. On the contrary, this
product was detected when starting from five membered ring
lactones (lactone 5, Table 3, entry 4 (R10) and lactone 8 entry 6
(R11)). This means that Path 2 should be the favourite one. The
preference for this path is also supported by relative abundance
of species II’ compared with the species II due to the favourable
acido-base equilibrium between them. Moreover, the species II,
requires a C-H deprotonation step to evolve, which is not needed
for the intermediate II’.
Synthesis of 3-acetoxy-2-oxo-2H-pyran-6-carboxylic acid (2b) from 1
with methanesulfonic acid [R1]. Mucic acid (1) (5.0 g, 24 mmol), acetic
anhydride (18.0 mL, 190 mmol) and methanesulfonic acid (1.24 mL, 19.0
mmol) were loaded in a round bottom flask. The reaction was refluxed
under stirring for 9 hours; after this time the mixture was cooled to room
temperature. A sample was withdrawn and analysed by 1H NMR to
calculate the analytical yields of 2b (66%), 3 (14%) and 4 (4%) in the
presence of an internal standard. The reaction mixture was then cooled
down and kept overnight at 4 °C. The solid was filtered and washed with 6
Conclusions
The more the valorization of renewable biomass will
progress toward not only production of fuel but also toward
production of useful chemicals, the more lignocellulosic biomass
or bio-waste could really replace oil. The main challenge of our
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
FULL PAPER
mL of a mixture of acetic acid-acetic anhydride 5:1 obtaining 2b as a beige
m/z 619 (10) [(3·M - H) + 2·Na]‾, 405 (11) [2(M - H) + Na]‾, 383 (76) [2(M
- H) + H]‾,191 (100) [M - H]‾.
solid (1.1 g, purity 91%, 5.0 mmol, yield 21%,); Rf: 0.3 (5% acetic acid in
1
ethyl acetate); H NMR (DMSO-d6,): δ 7.47 (d, 1H, J = 7.2 Hz), 7.02 (d,
Synthesis of mucic acid 1,4-lactone DABCO salt (7’) [R6’]. Pyridinium
mucic acid 1,4-lactone salt (7) (1.0 g, purity 93%, 3.4 mmol) and ethanol
(25 mL) were charged in a two-neck round bottom flask equipped with a
condenser. The mixture was refluxed under stirring until the mixture turned
homogeneous. Then, DABCO (0.82 mg, 7.2 mmol) was added to the hot
solution obtaining initially a sticky solid which in 20 minutes turned into a
fine powder. The reaction mixture was then cooled to room temperature
and filtered obtaining 7’ as a white solid (907 mg, purity 99%, 2.94 mmol,
yield 87%); m.p.: 203-212 °C ; 1H NMR (DMSO-d6, ppm): δ 4.24 (d, J =9.1
Hz, 1H), 4.21 (dd, J =2.7, J =8.3 Hz, 1H), 4.07 (t, J =8.8 Hz, 1H), 3.79 (d,
J =2.7 Hz, 1H), 2.96 (s, 12H) ; 13C NMR (DMSO-d6): δ 175.0, 174.2, 81.5,
74.1, 73.9, 68.9.
Synthesis of 2b from 5 with methanesulfonic acid [R4]. Mucic acid
tetraacetate (6a) (1.13 g, 88% purity, 2.63 mmol), acetic anhydride (750
μL, 7.92 mmol) and methanesulfonic acid (507 mg, 5.28 mmol) were
charged in a round bottom flask equipped with a condenser. The mixture
was refluxed under stirring for 5 hours and then cooled to room
temperature. A sample was withdrawn and analysed by 1H NMR to
calculate the analytical yields of 2b (46%), 3 (10%), 4 (13%) and 5 (30%)
in the presence of an internal standard.
1H, J = 7.2 Hz), 2.26 (s, 3H); 13C NMR (DMSO-d6): δ 168.1, 160.2, 156.4,
147.2, 140.1, 131.6, 110.6, 20.6; FT-IR (( νmax max, cm-1): 3560, 3444, 3141,
3102, 3065, 2893, 2831, 2763, 2598, 2654, 2598, 2511, 2485, 2189, 1978,
1950, 1781, 1735, 1708, 1644, 1619, 1438, 1377, 1268, 1232, 1194, 1141,
1121, 1070, 1007, 980, 902, 877, 796, 774, 759, 671, 597, 529, 458; -
MS/MS (ESI): m/z 197 (14) [M - H]‾, 153 (100) [M - H - CO2]‾, 111(86) [153
- CH2CO]‾, 81 (3). 2,5-Diacetoxymuconic acid (4) 1H NMR (400 MHz,
DMSO-d6): δ 6.99 (s, 2H), 2.28 (s, 6H); FT-IR (νmax, cm-1): 3466, 3082,
2991, 2866, 2674, 2592, 2530, 1779, 1713, 1695, 1614, 1431, 1376, 1319,
1261, 1182, 1107, 1048, 1007, 921, 896, 833, 767, 665, 657, 585. +MS
(ESI) (methanol):m/z 281 [M + Na]+, 539 [2·M + Na]+, 561 [2M – H + 2·Na]+.
3-Acetoxy-2H-pyran-2-one (3): 1H NMR (400 MHz, DMSO-d6): δ 7.69
(dd, 1H, J = 1.8 Hz; J = 5.1 Hz), 7.38 (dd, 1H, J = 1.8 Hz; J = 7.1 Hz), 6.43
(dd, 1H, J = 5.1 Hz; J = 7.1 Hz), 2.24 (s, 3H).
Synthesis of 2-acetoxy-2-(-3,4-diacetoxy-5-oxotetrahydrofuran-2-
yl)acetic acid (5) (mucic acid 1,4-lactone triacetate) [R2]. Mucic acid (1)
(5.0 g, 23.8 mmol) and acetic anhydride (22.5 mL, 214 mmol) were
charged in a three-neck bottom flask equipped with a thermometer and a
condenser. The reaction mixture was refluxed under stirring for 6 hours. A
sample was withdrawn and analysed by 1H NMR to calculate the analytical
yield of 5 (94%) in the presence of an internal standard. The solvent and
the formed acetic acid were removed in vacuo at 60 °C and a green/brown
oil was obtained. The oil was stirred with 250 mL of diethyl ether overnight
to give 5 as a white precipitate (4.85 g, purity 97%, 14.79 mmol, yield
62%,); 1H NMR (DMSO) δ: 5.89 (d, 1H, J = 7.7 Hz), 5.49 (dd, 1H, J = 7.7
Hz, J = 7.3 Hz), 5.26 (d, 1H, J’ = 2.8 Hz), 5.01 (dd, 1H, J = 2.8 Hz, J = 7.3
Hz), 2.14 (s, 3H), 2.13 (s, 3H), 2.07 (s, 3H); 13C NMR (DMSO-d6): δ 170.4,
169.8, 169.7, 168.7, 167.9, 77.5, 72.4, 72.0, 70.0 , 20.9, 20.7, 20.6; FT-IR
(νmax, cm-1): 3487, 2947, 1852, 1817, 1758, 1645, 1432, 1375, 1323, 1226,
1171, 1118, 1047, 959, 926, 894, 782, 741, 708, 605; -MS (ESI) (CH3CN):
m/z 634 (100) [2·M - H]‾, 575 (4) [2·M – CH3COOH – H]‾, 317 (7) [M - H]‾.
Synthesis of (2R,3S,4R,5S)-2,3,4,5-tetraacetoxyhexanedioic acid (6a)
(mucic acid tetracetate) [R3]. Mucic acid (1) (10.0 g, 47.6 mmol), acetic
anhydride (45.0 mL, 476 mmol) and trifluoroacetic acid (20.0 mL, 260
mmol) were charged in this order in a round bottom flask equipped with a
condenser. The mixture was heated and stirred at 80 °C for 9 hours; then
the heterogeneous reaction mixture was cooled to room temperature. The
solid was filtered, washed twice 4 mL of ethyl acetate and filtered to give
6a as a white solid (12.5 g, purity 88%, 29.1 mmol, yield 61%); m.p.: 243-
Synthesis of 2b from 6a with methanesulfonic acid [R5]. Mucic acid
1,4-lactone triacetate (5) (0.26 g, 97% purity, 0.79 mmol), acetic anhydride
(225 μL, 2.37 mmol) and methanesulfonic acid (151 mg, 1.57 mmol) were
charged in a round bottom flask equipped with a condenser. The mixture
was refluxed under stirring for 5 hours and then cooled to room
temperature. A sample was withdrawn and analysed by 1H NMR to
calculate the analytical yields of 2b (68%), 3 (13%), 4 (16%) and 5 (2%) in
the presence of an internal standard.
Synthesis
of
2-acetoxy-2-(-4-acetoxy-5-oxo-2,5-dihydrofuran-2-
yl)acetic acid (8) from 5 [R8]. Mucic acid 1,4-lactone triacetate (5) (0.23
g, purity 97%, 0.70 mmol), acetic acid (4.30 mL, 45.5 mmol) and
triethylamine (30 μL, 0.22 mmol) were loaded in a round bottom flask. The
reaction was stirred at room temperature for one week. After this time, a
sample was withdrawn and analysed by 1H NMR to calculate the analytical
yields of 8 (34%). The solvent was removed in vacuo at 60 °C and product
8 was recovered by flash chromatography (eluent 1.25% of CH3COOH in
AcOEt) as a white solid (41 mg, 24% yield); 1H NMR (DMSO-d6): δ 7.37
(d, 1H, J =2.0 Hz); 5.69 (dd, 1H, J = 2.0 Hz, J =3.2 Hz); 5.19 (d, 1H, J =3.2
Hz); 2.28 (s, 3H); 2.00 (s, 3H); 13C NMR (DMSO-d6): δ 169.8, 167.8, 167.6,
166.7, 137.8, 134.3, 79.1, 71.4, 20.9, 20.8; IR (νmax, cm-1): 3528.9, 3467.3,
3272.2, 3148.7, 2951.4, 1782.9, 1739.9, 1642.9, 1562.7, 1433.5, 1376.7,
1347.5, 1303.1, 1237.9, 1187.7,1120.9, 1073.3, 1016.0, 922.6, 867.0,
828.2, 793.4,760.3,704.3, 682.6, 640.6, 609.7, 567.1, 512.9, 444.9;
+MS(ESI) m/z: 303 [M - H + 2·Na]+.
Synthesis of sodium 3-acetoxy-2-oxo-2H-pyran-6-carboxylate (2a)
from 1 with sodium hydroxide [R9]. Mucic acid (1) (50.0 g, 0.24 mol) and
acetic anhydride (300.0 mL, 3.17 mol) were placed in a round bottom flask
equipped with a condenser, stirred and heated at 90 °C. To this
suspension, sodium hydroxide (10.0 g, 0.25 mol) was added over a period
of 2 hours keeping the temperature between 90-95 °C and then mixture
was left at this temperature for other 2 hours. The reaction was cooled to
room temperature turning in a viscous brown solution. After one night the
formed precipitate was filtered, washed twice with 10 mL of a mixture of
5% acetic anhydride in acetic acid and dried under vacuum, giving 2a as
a light brown solid (48.0 g, purity 98%, 13.8 mmol, yield 58%). The filtered
solution was concentrated down to 100 mL at reduced pressure heating at
45 °C. At room temperature a solid was formed, then it was filtered,
washed twice with the same mixture of acetic anhydride/ acetic acid and
dried under vacuum obtaining another crop of 2a (11.1 g, purity 81%, 2.70
mmol, yield 11%, impurity consists of sodium acetate and acetic acid).
Overall yields of 2a 69% ; 1H NMR (DMSO-d6): δ 7.44 (d, 1H, J = 7.2 Hz),
6.87 (d, 1H, J = 7.2 Hz), 2.27 (s, 3H), 1.91 (s, 6H); 13C NMR (DMSO-d6):
δ 173.4, 168.4, 161.9, 157.9, 155.8, 137.3, 132.9, 105.9; 22.2, 20.6; FT-
1
248 °C; H NMR (acetone-d6): δ 5.75 (s, 2H), 5.17 (s, 2H), 2.13 (s, 6H),
2.05 (s, 6H); 1H NMR (DMSO-d6): δ 5.57 (s, 2H), 5.03 (s, 2H), 2.10 (s, 6H),
2.01 (s, 6H); 13C NMR (DMSO-d6): δ 170.0, 169.2, 168.3, 69.9, 68.3, 21.5,
20.7; FT-IR (νmax, cm-1): 3406, 3058, 2916, 1757, 1737, 1420, 1376, 1328,
1230, 1107, 1058, 948, 898, 846, 769, 675, 634, 593, 561; -MS/MS (ESI)
(methanol):m/z 377 (100) [M - H]‾, 317 (57) [M - H - CH3COOH]‾, 273 (40)
[M - H - CH3COOH - CO2]‾, 213 (14), 171 (11), 141 (11). Spectroscopic
data in accordance with what stated in literature.[21]
Synthesis of mucic acid 1,4-lactone pyridinium salt (7) [R6]. Mucic acid
(1) (5.0 g, 2.4 mmol) and pyridine (50 mL, 0.62 mol) were charged in a
round bottom flask equipped with a condenser. The mixture was refluxed
under stirring for 4 hours. The solvent of the reaction mixture was removed
in vacuo at 60 °C to obtain a sticky solid. The solid was dispersed in 30
mL of CH3CN and stirred overnight; then was filtered to give 7 as a light-
yellow solid (6.0 g, purity 93%, 2.1 mmol, yield 88%); m.p.: 123-132 °C;
(DMSO-d6): δ 8.58 (m, 2H), 7.79 (m, 1H), 7.39 (m, 2H), 4.34 (dd, J =1.7,
J =9.1 Hz, 1H), 4.32 (d, J =9.1 Hz, 1H), 4.21 (d, J =1.8 Hz, 1H), 4.17 (7, J
=8.7, 1H); 13C NMR (DMSO-d6): 174.5, 173.43, 150.0, 136.7, 124.4, 80.9,
74.0, 72.3, 67.4; FT-IR (KBr, νmax, cm-1): 3423, 3364, 3137, 3103, 2946,
2922, 2883, 2697, 2520, 2168, 2041, 1785, 1760, 1638, 1596, 1546, 1487,
1384, 1328, 1286, 1225, 1204, 1172, 1149, 1133, 1105, 1016, 990, 956,
921, 879, 830, 762, 734, 686, 642, 599, 517, 479; – MS (ESI) (methanol):
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
FULL PAPER
IR (νmax, cm-1): 3416, 3104, 3076, 3022, 2941, 2900, 2840, 2774, 2667,
2607, 2539, 2365, 2165, 1772, 1727, 1651, 1619, 1412, 1372, 1332, 1289,
1200, 1135, 1100, 1062, 1007, 972, 150 , 887, 855, 811, 784, 747, 675,
654, 599, 577, 565, 529, 468, 429, 408; -MS/MS (ESI) (methanol): m/z 197
(6) [M - H]‾, 153 (29) [M - H - CO2]‾, 111 (100) [153 - CH2CO]‾, 81 (3).
Synthesis of 3-acetoxy-2-oxo-2H-pyran-6-carboxylic acid (2b) from 1
with pyridine [R9’]. Mucic acid (1) (5.00 g, 23.8 mmol), pyridine (1.90 mL,
23.6 mmol) and acetic anhydride (50.0 mL, 529 mmol) were mixed
together in a three-neck round bottom flask, equipped with a thermometer
and a condenser, stirred and heated at 90 °C for 3 hours. After this time,
the hot mixture was filtered to remove the small amount of mucic acid still
present. The solution was concentrated to half of its volume obtaining a
(15.0 mL, 159 mmol) were charged in a round bottom flask equipped with
a condenser. The mixture was stirred and heated. When the reaction
turned homogeneus (about 110 °C), sodium acetate (AcONa·3H2O, 719
mg, 5.28 mmol) was added to the hot solution. The heterogeneous
reaction mixture was refluxed for 4 hours until it became a yellow solution.
The solution was then cooled to room temperature, concentrated to half of
its volume obtaining the formation of 2a as a white solid (0.60 g, %, purity:
98%, 1.73 mmol, yield: 37%). The mother liquors were concentrated to
obtain a brown solid (2a, 0.69 g, purity 93%, 1.89 mmol, yield: 41%).
Overall yield of 2a (78).
Synthesis of 2b starting from 6a with pyridine [R12’]. Mucic acid
tetraacetate (6a) (255 mg, 88% purity, 0.59 mmol), pyridine (107 mg, 1.35
mmol) and acetic anhydride (4.0 mL, 42 mmol) were charged in a round
bottom flask equipped with a condenser. The mixture was heated at 100 °C
and stirred for 3 hours. After this time, a sample was withdrawn,
concentrated and analysed by 1H NMR to calculate the analytical yield of
2b (94%) and 2c (3%) in the presence of an internal standard.
Synthesis of 3-hydroxy-2-oxo-2H-pyran-6-carboxylic acid 2c from 2a
[R13]. In a 50 mL round bottom flask, 33 mL of HCl 37% were placed and
then sodium 3-acetoxy-2-oxo-2H-pyran-6-carboxylate (2a) (35.1 g, purity
98%, 101 mmol) was added. The heterogeneous mixture was stirred for
48 hours at room temperature. After this time, the solid was filtered,
suspended in water (50 mL) and stirred at room temperature for 12 hours
to remove NaCl. After this time the solid was filtered obtaining 2c as a
white solid (15.3 g, purity 94%, 92.2 mmol, yield 91%); m.p.: 209-212 °C
with decomposition); 1H NMR (DMSO-d6): δ 7.12 (d, 1H, J = 7.4 Hz); 6.69
(d, 1H, J = 7.4 Hz); 13C NMR (DMSO-d6): δ 161.1, 158.8, 147.7, 141.2,
115.0, 113.8; IR (KBr, νmax, cm-1): 3308, 3116, 3080, 2921, 2781, 2643,
2589, 2486, 2898, 1715, 1659, 1554, 1437, 1350, 1267, 1227, 1161, 1074,
972, 868, 756, 705, 634, 600, 535, 466; - MS((-)-ESI): m/z 155 (33) [M -
1
light violet solid (4.1 g). The solid was filtered and analysed by H NMR
revealing to be composed by 2b (54%), 2c (21%), acetic acid and pyridine
in the presence of an internal standard.
Synthesis of 3-acetoxy-2-oxo-2H-pyran-6-carboxylic acid (2b) from 1
with sodium acetate [R9’’]. Mucic acid (1) (5.00 g, 23.8 mmol), sodium
acetate (500 mg, 3.67 mmol) and acetic anhydride (120 mL, 1.27 mol)
were mixed together in a two-neck round bottom flask, equipped with a
thermometer and a condenser, and were stirred and heated at 100 °C for
18 hours. After this time, the reaction was cooled down to 0 °C, 1 mL of
HCl 36% was added and the mixture was stirred for two hours at room
temperature. The solution was concentrated until a white solid precipitated
(5.78 g). The solid was dispersed in 15 mL of acetic acid and the resulting
suspension was refluxed obtaining a solution. This latter was then cooled
to room temperature obtaining 2b as white crystals (3.70 g, purity 85%
yield 67%, the impurity consists of sodium acetate and acetic acid). From
the filtered solution a second crop of 2b was recovered as a white solid
(800 mg, purity 67%, yield 11%, the impurity consists of sodium acetate
and acetic acid).Overall yield of 2b 78%.
Synthesis of 2b from 5 with sodium acetate [R10]. Mucic acid-1,4-
lactone-triacetate (5) (520 mg, 97% purity, 1.59 mmol) and acetic
anhydride (3.0 mL, 32 mmol) were charged in a round bottom flask
equipped with a condenser. Sodium acetate (AcONa·3H2O 60 mg, 0.44
mmol) was added and, then, the system was heated and stirred at 90 °C
for 15 hours. A sample was withdrawn and analysed by 1H NMR to
calculate the analytical yield of 2b (97%) in the presence of an internal
standard. The solvent was removed under reduced pressure, and the
resulting brown viscous oil was dissolved in acetic anhydride (4.0 mL). To
this solution, 0.5 mL of HCl 37% were added and the formed precipitate
was filtered off obtaining a homogeneous solution. The solvent was
removed under reduced pressure to obtain 324 mg of a sticky solid. The
solid was dispersed in 3.0 mL of THF, stirred overnight and then filtered
obtaining 2b as a beige solid (250 mg, purity 93% 1.17 mmol, yield 74%,).
Synthesis of 2b + 2c from 7 [R10’]. Mucic acid 1,4-lactone pyridinium salt
(7) (200 mg, purity 98%, 0.71 mmol) and acetic anhydride (1.4 mL, 15
mmol) were charged in a three-neck round bottom flask, equipped with a
condenser. The mixture was stirred and heated at 90 °C for 3 hours and
then cooled to room temperature obtaining a viscous brown liquid. A
sample was withdrawn and analysed by 1H NMR to calculate the analytical
yield of 2b (64%) and 2c (30%) (overall yield 94%, molar ratio 2c/2b =
0.47).in the presence of an internal standard. To the crude, 10 mL of
CH3CN were added and the mixture was stirred overnight at room
temperature giving a precipitate. The solid was filtered, washed twice with
CH3CN and dried under vacuum obtaining 107 mg of a mixture of 2b + 2c
(overall yield 62%, molar ratio 2c/2b = 0.42).
H]‾, 127 (36) [M - CHO] ‾, 111 (100) [M - H - CO2]‾, 83 (11) [M - CO2 -
CHO]‾. Spectroscopic data are consistent with those reported in
literature.[5]
Synthesis of 3-hydroxy-2-oxo-2H-pyran-6-carboxylic acid 2c from
mucic acid 1. Mucic acid (1) (5.00 g, 23.8 mmol), pyridine (1.90 mL, 23.6
mmol) and acetic anhydride (50.0 mL, 529 mmol) were mixed together in
a three-neck round bottom flask equipped with a thermometer and a
condenser. The reaction was stirred and heated at 90 °C for 3 hours. Then,
the hot mixture was filtered to remove the residual solid and the solution
was evaporated to obtain 5.25 g of a brown solid. The solid was dispersed
in 6 mL of HCl 37% and the resulting suspension was stirred for 48 hours
at room temperature. The solid was filtered and washed with 3 x 1 mL of
water recovering 2c as a beige solid (3.14 g, purity 87%, 17.5 mmol yield
73.5%).
Synthesis of 3-hydroxy-2H-pyran-2-one (9) by decarboxylation of 2c
[R14]. Pyrone 2c (1.10 g, purity 94%, 6.62 mmol) was introduced in a
sublimation apparatus and this latter was placed in an oil bath at 170 °C.
At 140 °C and 0.3 torr the sublimation took place and the product started
to deposit on the surface of the cold finger cooled by circulating tap water.
At the end of the reaction, 3-hydroxy-2H-pyran-2-one (9) was recovered
as a white solid (730 mg, purity 99%, 6.52 mmol, yield 98%); m.p.: 90-
91 °C (sublimation);[23] 1H NMR (CDCl3, ppm): δ 7.09 (dd, 1H, J = 1.7 Hz,
J = 5.2 Hz); 6.61 (dd, 1H, J = 1.7 Hz, J = 7.1 Hz); 6.14 (dd, 1H, J = 5.2 Hz,
J = 7.1 Hz); 13C NMR (CDCl3): δ 161.6, 142.4, 142.2, 114.5, 107.1.
Spectroscopic data are consistent with those reported in literature.[24]
Synthesis of 3-hydroxy-2-oxo-2H-pyran-6-carboxylic acid (2c) from
calcium D-glucarate (10) [R15]. Calcium D-glucarate tetrahydrate (10)
(5.60 g, 17.5 mmol) and acetic anhydride (65.0 mL, 688 mmol) were mixed
together in a three-neck round bottom flask, equipped with a thermometer
and a condenser. The resulting mixture was stirred and heated at 100 °C
for 9 hours. Then, the brown heterogeneous mixture was cooled to room
temperature and filtered. The solid was washed twice with 3.0 mL of a
mixture of 5% acetic anhydride in acetic acid and dried under vacuum
obtaining a light brown solid (4.18 g). The 1H NMR analysis in D2O
(trioxane as internal standard) revealed the presence of a product
Synthesis of 2b from 8 with pyridine [R11]. 2-acetoxy-2-(-4-acetoxy-5-
oxo-2,5-dihydrofuran-2-yl)acetic acid (8) (23.3 mg , purity 77%, 0.07 mmol),
1.00 mL (151 mmol) of acetic anhydride and pyridine (13 µL, 16 μmol) in
were loaded in a round bottom flask. The reaction was stirred and heated
at 60 °C for 2 hours. After this time, a sample was withdrawn and analysed
by 1H NMR to calculate conversion of 8 (100%) and analytical yields of 2b
(78%) in the presence of an internal standard.
Synthesis of 2a starting from 6a with sodium acetate [R12]. Mucic acid
tetraacetate (6a) (2.00 g, 88% purity, 4.66 mmol) and acetic anhydride
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10.1002/ejoc.201901427
European Journal of Organic Chemistry
FULL PAPER
compatible with 3-acetoxy-2-oxo-2H-pyran-6-carboxylic acid calcium salt
2d (analytical yield 45%) and a secondary product compatible with 2,5-
diacetoxymuconic calcium salt (analytical yield 4.5%). 1H NMR (D2O),
signals ascribed to pyrone 2d: δ 7.55 (d, 1H, J = 7.4 Hz), 7.14 (d, 1H, J =
7.4 Hz), and 2.37 (s, 3H); signals ascribed to 2,5-diacetoxymuconic
calcium salt: δ 6.93 (s, 2H) and 2.35 (s, 6H). In a round bottom flask, the
light brown solid (4.0 g) was added to 6 mL of HCl 37% and the
heterogeneous mixture was stirred for 48 hours at room temperature. Then,
the solid was filtered, washed with water recovering 1.10 g of 2c (purity
90%, 6.35 mmol, yield 80 % based on 2d. The impurity mainly consists of
product 4).
Synthesis of potassium 3-acetoxy-2-oxo-2H-pyran-6-carboxylate (2e)
from D-glucaric acid potassium salt (11) [R15’]. D-glucaric acid
potassium salt (11) (0.41 g, 1.63 mmol) and acetic anhydride (2.0 mL, 21
mmol) were mixed together in a three-neck bottom round flask, equipped
with a thermometer and condenser. The resulting mixture was stirred and
heated at 110 °C. After 1 hour the mixture turned homogeneous and a
sample was withdrawn and analysed by 1H NMR to calculate the analytical
yield of 2e (90%) in the presence of an internal standard. The reaction
mixture was cooled to room temperature, 5 mL of ethyl acetate were added
obtaining the formation of a grey solid. The mixture was filtered and the
solid was washed with 5 mL of ethyl acetate obtaining 2e (0.22 g, purity:
>95%, 0.89 mmol, yield: 55%); 1H NMR (DMSO-d6): δ 7.41 (d, 1H, J = 7.2
Hz), 6.11 (d, 1H, J = 7.2 Hz), and 2.26 (s, 3H); 13C NMR (DMSO-d6): δ
168.5, 160.7, 158.1, 157.3, 136.7, 133.1, 105.1, 20.7.
Synthesis of diethyl 2,3,4,5-tetraacetoxyhexanedioate (6c) from
diethylmucate (6b). Diethylmucate, prepared according to a reported
method[25] (1.00 g, purity 94%, 3.53 mmol) was dispersed in 10 mL of
acetic anhydride. H2SO4 (0.7 mL, 13.1 mmol) was added dropwise into the
mixture at room temperature under stirring. After few minutes the mixture
turned homogenous and within one hour 6c precipitated as a white solid
that was recovered by filtration (1.30 g, purity 90%, 2.69 mmol, yield 76%,);
1H NMR (DMSO-d6): δ 5.55 (d, 2H, J = 0.9 Hz), 5.17 (d, 2H, J = 0.9 Hz),
4.11 (dd, 4H, d, 2H, J = 7,1 Hz), 2.12 (s, 3H), 2.02 (s, 3H), 1.17 (t, 6H, J =
7,1 Hz); 13C NMR (DMSO-d6): δ 170.0, 169.3, 166.8, 69.8, 67.9, 62.2, 20.6,
20.6, 14.2.
[10] a) G. A. Kraus, G. R. Pollok III, C. L. Beck, K. Palmer, A. H. Winter, RSC
Advances 2013, 3, 12721-12726; b) J. J. Lee, G. A. Kraus, Green Chem.
2014, 16, 2111-2116.
[11] a) T. Michinobu, M. Bito, Y. Yamada, M. Tanimura, Y. Katayama, E.
Masai, M. Nakamura, Y. Otsuka, S. Ohara, K. Shigehara, Polym. J. 2009,
41, 1111-1116; b) H. Furrer, H. Steppan, G. Lohaus, US Patent 1976
3,969,323; c) M. Tang, A. J. P. White, M. M. Stevens, C. K. Williams,
Chem Commun. 2009, 941-943.
[12] K. Afarinkia, V. Vinader, T. D. Nelson, G. H. Posner, Tetrahedron 1992,
48, 9111-9171; b) Y. Wang, H. Li, Y.-Q. Wang, Y. Liu, B. M. Foxman, L.
Deng, J. Am. Chem. Soc. 2007, 129, 6364-6365; c) R. P. Singh, K.
Bartelson, Y. Wang, H. Su, X. Lu, L. Deng, J. Am. Chem. Soc. 2008, 130,
2422-2423; d) G. A. Kraus, S. Riley, T. Cordes, Green Chem. 2011, 13,
2734-2736; e) J. J. Lee, G. R. Pollock III, D. Mitchell, L. Kasuga, G. A.
Kraus, RSC Advances 2014, 4, 45657-45664; f) M.-Q. Zhou, J.-Q. Zhao,
Y. You, X.-Y. Xu, X.-M. Zhang, W.-C. Yuan, Tetrahedron 2015, 71, 3903-
3908; g) L.-M. Shi, W.-W. Dong, H.-Y. Tao, X.-Q. Dong, C.-J. Wang, Org.
Lett. 2017, 19, 4532-4535.
[13] J. D. Hepworth in Comprehensive Heterocyclic Chemistry: Pyrans and
Fused Pyrans: (iii) Synthesis and Applications Vol. 3 (Eds.: A. R.
Katritzky, C. W. Rees), Pergamon Press, Oxford, UK, 1984; pp. 737-
883.
[14] a) A. M. Medway, J. Sperry, Green Chem. 2014, 16, 2084-2101; b) D.
Dobler, O. Reiser, J. Org Chem. 2016, 81, 10357-10365.
[15] a) C. Neuberg, Ber. 1902, 35, 4014; b) M. Bergmann, L. Zervas, E.
Silberkweit, Ber. 1931, 64, 2428-2436; c) C.R. Nelson, J. S. Gratzl,
Carbohydr. Res. 1978, 60, 267-273; d) O. J. Varela, A. F. Cirelli, R. M.
De Lederkremer, Carbohydr. Res. 1980, 79, 219-224.
[16] J. W. Morgan, M. L. Wolfrom, J. Am. Chem. Soc. 1956, 78, 1897-1899.
[17] V. Hasenfratz, C. R. Hebd. Seances Acad. Sci. 1927, 184, 210-213.
[18] a) J. A. Profitt, T. Jones, D. S. Watt, Synth. Commun. 1975, 5, 457-460;
b) F. Frebault. M. T. Oliveira, E. Wostefeld, N. Maulide, J. Org. Chem.
2010, 75, 7962-7965; c) T. Suzuki, S. Watanabe, S. Kobayashi, K.
Tanino, Org. Lett. 2017, 19, 922-925; d) R. H. Wiley, C. H. Jarboe, J. Am.
Chem. Soc. 1956, 78, 2398-2401; e) F. E. Jacobsen, J. A. Lewis, K. J.
Heroux, S. M. Cohen, Inorg. Chim. Acta 2007, 360, 264-272; f) C. E.
Blunt, C. Torcuk, Y. Liu, W. Lewis, D. Siegel, D. Ross, C. J. Moody,
Angew. Chem. Int. Ed. 2015, 54, 8740-8745; g) J. D. Warren, V. J. Lee,
R. B. Angier, J. Heterocyclic Chem. 1979, 16, 1617-1624; h) E. J. Corey,
A. P. Kozikowski, Tetrahedron Lett. 1975, 16, 2389-2392.
Keywords: 2-pyrones • mucic acid • aldaric acids • mucic acid
lactone • renewable biomass
[19] a) Y. Zhang, X. Li, PCT Int. Appl., 2016032403; b) X. Li, D. Wu, T. Lu, G.
Yi, H. Su, Y. Zhang, Angew. Chem. Int. 2014, 53, 4200-4204; c) M.
Shiramizu, F. D. Toste; Angew Chem Int. 2013, 52, 12905-12909; d) B.
Hočevar, M. Grilc, B. Likozar, Catalysts 2019, 9, 286-305.
[1]
C. S. K. Lin, L. A. Pfaltzgraff, L. Herrero-Davila, E. B. Mubofu, S.
Abderrahim, J. H. Clark, A. A. Koutinas, N. Kopsahelis, K. Stamatelatou,
F. Dickson, S. Thankappan, Z. Mohamed, R. Brocklesby, R. Luque,
Energy Environ. Sci. 2013, 6, 426-464.
[20] a) J. Lewkowski, Polish Journal of Chemistry 2001, 75(12), 1943-1946;
b) G. Bratulescu, Revue Roumaine de Chimie 2001, 45(9), 883-885; c)
A. S. Amarasekara, A. Razzaq, P Bonham, ISRN Polymer Science 2013,
645169/1-645169/5; d) N. Guo, Neng Patent WO 2017083297; e) J.
M.Longmire, S. Herrmann, E. L. Dias, O. Den Ouden, J. C. Henricus, S.
Torssell, R. Shrestha, G. M. Diamond, Patent WO 2019014393.
[21] a) T. Mehtiö, L. Nurmi, V. Rämö , H. Mikkonen, A. Harlin, Carbohydr. Res.
2015, 402, 102-110; b) S B. van Witteloostuijn, K. Mannerstedt, P.
Wismann, E M. Bech, M. B. Thygesen, N. Vrang, J. Jelsing, K. J. Jensen,
S L. Pedersen; Mol. Pharmaceutics 2017, 14, 193−205.
[2]
[3]
J. J. Bozell, G. R. Petersen, Green Chem. 2010, 12, 539-554.
T. Mehtiӧ, M. Toivari, M. G. Wiebe, A. Harlin, M. Penttila, A. Koivula, Crit.
Rev. Biotechnol. 2016, 36, 904-916.
[4]
[5]
K. Albizati, C. Tracewell, Patent WO2012/075053A2.
a) D. Wiedeman, A. Grohmann, Z. Naturfosh 2009, 64b, 1276-1288; b)
W. N. Haworthe, E. L. Hirst, J. K. N. Jones, J. Chem. Soc. 1938, 710-
714.
[6]
[7]
a) G. P. McGlacken, I. J. S. Fairlamb, Nat. Prod. Rep. 2005, 22, 369-385;
b) A. Goel, V. J. Ram, Tetrahedron 2009, 65, 7865-7913.
a) T. F. Schäberle, Beilstein J. Org. Chem. 2016, 12, 571-588; b) J. M.
Dickinson, Nat. Prod. Rep. 1993, 10, 71-98.
[22] a) C. Niemann, K. P. Link, J. Biol. Chem. 1932, 95, 203-211; b) E. Fisher,
Ber. 1891, 24, 2136; c) L. W. Mapson, F. A. Isherwood, Biochem. J. 1956,
64 (1), 13-22.
[8]
[9]
C. W. Bird, Tetrahedron 1986, 42, 89-92.
a) J. S. Lee, Mar. Drugs 2015, 13, 1581-1620; b) P.-P. Yeh, D. S. B.
Daniels, D. B. Cordes, A. M. Z. Slawin, A. D. Smith, Org. Lett. 2014, 16,
964-967.
[23] R. H. Wiley and C. H. Jarboe, J. Am. Chem. Soc. 1956, 78, 2398-2401.
[24] F. E. Jacobsen, J. A. Lewis, K. J. Heroux, S. M. Cohen, Inorg. Chim. Acta
2007, 360 (1), 264-272.
[25] a) R. S. Tipson, M. A. Clapp, J. Org. Chem. 1953, 18, 952-963; b) G.
Prömpers, H. Keul, H. Höcker, Green Chem. 2006, 8, 467-478.
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10.1002/ejoc.201901427
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Entry for the Table of Contents
FULL PAPER
A green approach to the synthesis of
3-acetoxy-2-oxo-2H-pyran-6-
O
Gabriella Leonardi, Jiemong Li, Grazia
Isa C. Righetti, Ada M. Truscello,
HO
O
carboxylated derivatives from bio-
derived C6 aldaric acids has been
investigated. All the six carbon atoms
present in the aldaric acid are
preserved. For the first time mucic
acid lactone salt has been isolated
and fully characterized.
Cristian Gambarotti, Giancarlo Terraneo,
Attilio Citterio, Roberto Sebastiano*
COOH
O
OH OH
O
HO
Page No. – Page No.
OH
OH OH
Pyrones Synthesis from Renewable
Sources: Easy Preparation of 3-
Acetoxy-2-oxo-2H-pyran-6-
carboxylic Salts and their Derivatives
as 3-Hydroxy-2H-pyran-2-one from C6
Aldaric Acids
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