One-pot synthesis of 2-hydroxymethyl-5-methylpyrazine from renewable 1,3-dihydroxyacetone

Article abstract of DOI:10.1039/c7gc00578d

An efficient and green method for the synthesis of 2-hydroxymethyl-5-methylpyrazine was achieved from biomass derived 1,3-dihydroxyacetone and diammonium phosphate via a one-pot reaction. The product yield was as high as 72% under optimized conditions of pH = 8.0-9.1 at 90 °C for 1 hour in a dioxane and water mixture as a solvent. A possible reaction mechanism was proposed according to the reaction kinetics, NMR and in situ ATR-IR characterization studies.

Full text of DOI:10.1039/c7gc00578d

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One-pot synthesis of 2-hydroxymethyl-5-methylpyrazine from
renewable 1,3-dihydroxyacetone
Received 00th January 20xx,
Accepted 00th January 20xx
Lei Song,a,b Mingyuan Zheng,*b Jifeng Pang,b Joby Sebastian,b Wentao Wang, Minjie Qu,*a Jian
Zhaoa, Xinhong Wanga, and Tao Zhangb
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient and green method for the synthesis of 2- Currently, pyrazine compounds are synthesized through three
hydroxymethyl-5-methylpyrazine was achieved from biomass routes: (1) Maillard reaction using monosaccharides and amino
derived 1,3-dihydroxyacetone and diammonium phosphate via acids as reactants; (2) intramolecular cyclization reaction between
one-pot reaction. The product yield was as high as 72% under hydroxypropyl ethylenediamine; (3) intermolecular dehydration
optimized conditions of pH=8.0-9.1 at 90 oC for 1 hour in a dioxane and dehydrogenation reaction using ethylenediamine and 1,2-
and water mixture as solvent. A possible reaction mechanism was propanediol.14-16 Unfortunately, these routes suffer from problems
proposed according to the reaction kinetic, NMR and in situ ATR- of low product selectivity and environmentally unfriendly operation
IR characterization studies.
conditions, especially for the synthesis of functionalized pyrazines
with specific groups. Many expensive and corrosive chemicals such
as 2,5-dimethylpyrazine, N-chlorosuccinimide, benzoyl peroxide,
H2O2 and acetic anhydride are used in the HMMP synthesis process.
As reported in literatures, 2,5-dimethylpyrazine was oxygenated to
pyrazine-mono-N-oxides with H2O2 at 84% yield17 and further
treated with acetic anhydride to give 2-acetoxymethyl-5-
methylpyrazine at 33% yield.18 After hydrolysis with aqueous alkali,
HMMP was obtained at a very low overall yield.18 In another
improved method, 2,5-dimethylpyrazine was first chlorinated with
N-chlorosuccinimide in presence of benzoyl peroxide to form 2-
chloromethyl-5-methylpyrazine, which was further hydrolysed to
HMMP.19 Evidently, the reaction efficiency and product selectivity
in HMMP synthesis need to be improved.
The ever increasing concern on the depleting fossil resource and
global warming has stimulated great research interest in using
renewable biomass for the synthesis of fuels and chemicals.1,2
Owing to the abundant hydroxyl groups, biomass derived chemicals
are regarded as ideal intermediates for synthesizing oxygen or
hydroxyl groups containing fine chemicals such as some specific
polyols, acids and esters.3-5 Additionally, biomass derived chemicals
may possess unique functional groups for introducing
heteroatoms,6 which are difficult to be obtained from traditional
fossil chemical industry. Hence, it is highly attractive to synthesize
such value-added chemicals from biomass through simple
processes.
Nitrogen-containing compounds are important fundamental
chemicals for synthesis of polymers, pharmaceuticals,
agrochemicals and etc.7,8 In particular, pyrazine and its derivatives
containing two para N atoms in the six-membered ring are key
feedstocks for producing many pharmaceuticals.9-11 For instance, 2-
Some researchers dedicated to improve the reaction efficiency
and product selectivity in synthesis of N-containing compounds.
Beller and Behr’s groups synthesized primary ammines from
aldehyde and ammonia with soluble transition metal complex
catalysts.20,21 Liang et al. prepared a spectrum of primary amines in
good yields using biomass derived aldehydes or ketones and
hydroxymethyl-5-methylpyrazine (HMMP) can be used as
a
aqueous ammonia in the presence of
a
Ru/ZrO2 catalyst.22
precursor for synthesis of commercial medicines, like Glipizide and
Acipimox which are used in therapy of diabetes and hyperlipemia.
Nevertheless, it is still a challenge to obtain these pyrazine
compounds in simple and environmentally benign ways.12,13
Shibamoto et al. used various sugars or sugar derived chemicals to
synthesize pyrazine compounds. They found that 1,3-
dihydroxyacetone (DHA) reacted with ammonium hydroxide to
form 2-methyl-pyrazine. However, the total yield of pyrazines was
merely 1.2%.23 Hence, it is highly desirable to develop an effective,
cheap, and environmentally benign method for preparing the
hydroxymethyl pyrazine. In the present study, we prepared HMMP
from biomass-derived C3 hydroxyl aldehydes through a one-pot
reaction, and got a high yield up to 72% under mild conditions. This
is a simple and efficient process without using expensive or toxic
chemicals, and would give inspirations for the synthesis of pyrazine
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compounds containing functional groups from renewable feedstock acetone reactants are inactive in the presence of DAP under the
in environmentally benign ways.
present reaction conditions. According to literature, the rate of
reaction between aldehydes and ammonia has a close relationship
with the solution pH,24 which is also demonstrated in the present
study.
Table 1 Results of reaction between C2-C3 alcohols, aldehydes, ketones and
DAPa
Considering that the two N atoms in a pyrazine ring could be
introduced by a reaction involving ammonium ions and a reactant
bearing two hydroxyl or carbonyl groups such as polyols or hydroxyl
aldehydes or acetones, we tested more polyols and small sugar
reactants. As shown in Entries 4 and 5, the polyols of ethylene
glycol and glycerol did not show activity in the reaction, indicating
that the hydroxyl groups in polyols are chemically stable. Differently,
glycolaldehyde is very active with a conversion up to 96.5% (Entry
6). However, no pyrazine compounds were detected. In the case of
acetol, the conversion was 26.5% with 27.3 selectivity for 2,5-
dimethyl pyrazine (Entry 7). Correlating to the conversions of
glyoxal and methyl glyoxal (containing two carbonyl groups) that
did not form pyrazines (Entries 8 and 9), the molecular structure of
α-hydroxyl acetone seems to be pivotal for pyrazine ring formation
via reaction with ammonium cations. This is consistent with the
report that acetoin can react with ammonium ion to form
tetramethylpyrazine.12,25 When using di-hydroxyl carbonyl reactants,
i.e., DHA or glyceraldehyde, the pyrazine yield was greatly increased
to 53.5%. More importantly, one hydroxyl group was retained in the
product (Fig. S1, ESI†), endowing the pyrazine compound with high
versatility for synthesis of pharmaceutical and high-value added
chemicals. DHA and glyceraldehyde are platform chemicals derived
from cellulose via retro-aldol condensation26 or glycerol selective
oxidation over Pt-Bi catalysts.27,28 Therefore, they could be the
readily available feedstocks for the HMMP production. Additionally,
DHA and glyceraldehyde can be transformed mutually under base
conditions via isomerization reaction, i.e., Lobry de Bruyn−van
Ekenstein transformation.29 The NMR analysis for the reaction at
different time found that glyceraldehyde was formed when using
DHA as a feedstock. (Fig. S2, ESI†) This may accounts for their
similar reaction performance in HMMP formation. It should be
mentioned that the mass balance of the reaction was less than
100%, probably due to the undetectable reaction intermediates or
some by-products. We used a HPLC (high performance liquid
chromatography) equipped with a UV detector to analyse the
reacꢀon products at different reacꢀon ꢀme (Fig. S3, ESI†). At least
eight products were found in the reaction solution, and the product
distribution changed with the reaction time. There should be
several possible reasons. For instance, DHA can polymerize or can
undergo aldol reaction to form C6 compounds.30 Maillard reaction
Conv
./%
Entry
Reactant
Main product Sel./%
Acetaldehy
de
1
2
3
25.3
unknownb
17.5
Propanal
Acetone
1.0
1.2
0.8
0.5
96.5
-
-
-
-
Ethylene
glycol
4
5
6
7
-
-
-
-
Glycerol
-
Glycolaldeh
yde
-
Acetol
26.5
62.5
100
27.3
8
9
Glyoxal
8.4
9.2
Methyl
glyoxal
unknownb
Glyceralde
hyde
10
97.6
96.1
34.5
55.6
Dihydroxya
cetone
11
a
Reaction conditions: 0.1 mol/L reactant, 0.1 mol/L diammonium
phosphate, 15 mL deionized water, 100 oC, 1 h, protection gas: 0.1 MPa N2.
The selectivity of the unknown product is calculated by area
b
normalization method on a gas chromatograph.
Initially, a series of biomass-based reactants, i.e., C2-C3 alcohols,
aldehydes, and ketones, were screened in the reaction with
diammonium phosphate (DAP), and the results are shown in Table 1.
The conversion of acetaldehyde was 25.3% (Entry 1), but the main
product was not the target product, which could not be identified
by a Gas Chromatograph-Mass Spectrometer (GC-MS). When using
propanal and acetone as feedstocks, the conversions were lower
than 2% (Entries 2 and 3), indicating that the mono-aldehyde or
Fig. 1 Conversion of DHA and yield of HMMP at different pH (a), DAP: DHA mole ratio (b), temperature (c) and time (d). Reaction conditions: the
reaction was typically conducted with 1.5 mmol of feedstock and 3.0 mmol of DAP in 15 mL of deionized water under magnetic stirring, at 90oC, 60
min; one condition was varied with other factors intact in each case.
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did not give obvious enhancement toward HMMP. In contrast,
ethanol-water and dioxane-water mixtures gave the most notable
enhanced yield of HMMP. At the dioxane content of 50 v/v%, the
HMMP yield reached the highest value of 72%. Several possible
explanations might account for the solvent effect, such as the
solubility of DAP in the mixed solution and alternated strength of
hydrogen bonding to the reactants and/or reaction intermediates.33
In addition, the dehydration reaction was involved in the process of
HMMP formation. The relatively low content of water in the
mixture may benefit this step and enhance the pyrazine formation.
may occur to generate browning products and polymeric
compounds.31 In addition, the reaction intermediate, i.e., 2-imino-
1,3-propanediol (intermediate 1, Scheme 1) was observed in liquid
products by NMR analysis (Fig. S2, ESI†; Fig. S4, ESI†), but could not
be detected by GC due to its high boiling point (363 oC).
The influence of reaction conditions on the product selectivity
was studied. Besides (NH4)2HPO4, several other types of ammonium
salts were tested in the reaction and the results are shown in Fig. S5.
The anions showed influence on the reaction. In the presence of
-
strong acid ions (SO42-, NO3 , and Cl-), the DHA conversion was
significantly depressed to ca. 40%. (NH4)2CO3 also showed lightly
lower DHA conversion as compared to (NH4)2HPO4. With respect to
the reaction selectivity, NH4Cl and (NH4)2HPO4 gave the best results
(ca. 60%). In view of the comprehensive performance, we focused
on diammonium phosphate as the suitable reactant in this study. As
shown in Fig. 1 (a), the activity and selectivity showed close
relationship with the pH of reactant solution. In basic solutions
(pH=8.0-9.1), the DHA conversion levelled off at 95-98% with ca. 56%
yield of HMMP. Further increasing the pH to 10.2 led to a notable
decrease in the reaction selectivity. Differently, in acidic
environments, the reaction was depressed significantly but the
selectivity was comparable to that under the optimal pH conditions.
Hence, the pH of the solution was optimized to 8.0-9.1.
100
80
60
40
20
0
100
80
60
40
20
0
a
b
Con. /%
Yield /%
Con. /%
Yield /%
0%
30%
50%
70%
100%
0%
30%
50%
70%
100%
Percent of ethanol in water (v/v)
Percent of ethylene glycol in water (v/v)
100
80
60
40
20
0
100
80
60
40
20
0
d
c
Con. /%
Yield /%
Con. /%
Yield /%
The influence of DAP: DHA mole ratio on the reaction is shown in
Fig. 1 (b). The theoretical mole ratio of DAP: DHA to form one
molecule of HMMP is 0.5. At this ratio, however, the DHA
conversion was as low as 62% with 33% selectivity for HMMP.
Increasing the mole ratio improved reaction results. The DHA
conversion and reaction selectivity reached 100% and ca. 60%,
respectively, at DAP: DHA mole ratio larger than 2 to 10. The
excessive amount of ammonium ions is beneficial to the HMMP
formation due to the shift of chemical equilibrium. In addition, the
effect of reactant concentration was tested and results are shown
in Fig. S6. When the concentrations of two reactants were
concurrently increased by 2 and 4 times, the DHA conversion
levelled off at ca. 97% but the HMMP yield decreased to 25.4%. This
is possibly related to the side reaction which is enhanced under
high concentrations of reactants. Designing novel reaction systems
might be helpful for resolving this problem.32
0%
30%
50%
70%
100%
0%
30%
50%
70%
100%
Percent of dioxane in water (v/v)
Percent of tetrahydrofuran in water (v/v)
Fig. 2 Conversion of DHA and yield of HMMP in various solvent mixtures at
different ratios: (a) ethanol/water (b) ethylene glycol/water (c)
tetrahydrofuran/water (d) dioxane/water.
669
1394
1406
648
40.5 min
682
1375
36.0 min
31.5 min
1559
1520
1541
1507
40.5 min
36.0 min
31.5 min
27.0 min
22.5 min
27.0 min
22.5 min
18.0 min
13.5 min
18.0 min
13.5 min
9.0 min
4.5 min
We further optimized the reaction temperature and time, and
the results are shown in Fig. 1 (c) and (d) respectively. In terms of
the reaction selectivity and activity, 90 oC is the optimal reaction
temperature, which activated the reactants without causing
undesirable side reactions. The HMMP reached the maximum yield
of 53.5% after 1 hour reaction and decreased gradually at longer
reaction times, demonstrating the product is reasonably stable
under the reaction conditions. Evidently, the reaction efficiency in
this study is much higher than that of the previous results in
literature.17,19,23
9.0 min
4.5 min
0 min
0 min
DHA
DHA
750
700
650
600
1600
1500
1400
1300
1200
Fig. 3 On site attenuated total reflection infrared (ATR-IR) spectra during
Reaction solvents often have significant effects on the products DHA and DAP reaction at 90oC in a mixture of water-ethylene glycol as
selectivity and reaction efficiency.33-35 According to the physical
solvent. The ATR-IR spectroscopy was continuously collected in the mid IR
range (4000–400 cm− 1) on a BRUKER Equinox 55 spectrometer equipped
properties of reactants and reaction conditions, we screened
with liquids retainer and volatiles cover.
several oxygen-containing organic solvents mixed with different
ratios of water. As shown in Fig. 2, compared to the solvent of pure
water, ethylene glycol-water and tetrahydrofuran-water systems
To gain insight into the reaction mechanism, in situ ATR-IR was
used to monitor the reaction progress. As shown in Fig. 3, bands at
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1500-1560 cm-1 were present at the beginning of the reaction and indicates that the first reaction involving one DHA molecule is a fast
their intensity gradually increased as prolonging the reaction time. step in the whole reaction, which is consistent with the result of
These bands are associated with the C=N bond, which can be ATR-IR experiment. In addition, the apparent activation energy is
ascribed to intermediate 1 (Scheme 1) and the pyrazine product of 56.4 kJ/mol (Fig. S12, ESI†), which can account for the mild reaction
HMMP. In combination with the reaction results (Fig. 1 (d)), we can conditions.
conclude that intermediate 1 containing C=N bond was rapidly
In conclusion, we have described herein an efficient and
formed and then gradually transformed into HMMP. The bands at environmentally benign method for pyrazine compound HMMP
1370-1410 cm-1 are associated with the C-N bond, which belongs to synthesis. Biomass derived DHA was found to be the most active
intermediate 2 and HMMP. It should be noted that the bands feedstock for HMMP production among a variety of C2-C3 hydroxyl-
ascribed to C-N were present later than that of C=N. This strongly aldehydes or ketones. The HMMP yield reached 72% under the
suggests that intermediate 1 was first formed from C=O and optimized reaction conditions of pH=8.0-9.1, DAP: DHA ratio of 2,
ammonium ion, and further underwent cyclization to form 90 oC for 1 h in a solvent mixture of 50% v/v dioxane in water.
intermediate 2 and HMMP. Three characteristic bands near 650 - Moreover, through the in situ ATR-IR characterization and kinetic
690 cm-1 belonging to the pyrazine ring increased their intensity studies, a three-step reaction mechanism was proposed, which
with reaction time, further confirming the gradual formation of involves ketimine condensation, cyclization, and dehydration
pyrazine ring. In the NMR analysis of products (Fig. S2, ESI†; Fig. S4, reactions. The conversion of DHA follows pseudo-first order kinetics
ESI†), intermediate 1 was also detected. This suggests that with an apparent activation energy of 56.4 kJ/mol.
intermediate 1 is relatively stable under reaction conditions and
ensures the high selectivity for the subsequent cyclization step. We
Acknowledgment:
further tried to separate the various products and reaction
This work was supported by the National Natural Science
Foundation of China (21376239, 21306191, 21690081), the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB17020100), and the Department of Science and
Technology of Liaoning province under contract of 2015020086-101.
intermediates 1 and 2 by using thin-layer chromatography (Fig. S7-
9). From Fig. S7, it can be found that seven components were
separated by this method. The HMMP product was successfully
isolated and identified by the NMR analysis (Fig. S8, product B, and
Fig. S9). However, the other six isolated components cannot be
1
identified due to the limited information in the HNMR spectra and
the too weak 13CNMR signals. Also, the reaction intermediates 1
and 2 were not found in the isolated products. According to the
literatures, the imines like the intermediates 1 and 2 would be
unstable in water, they are very readily to hydrolyze at pH below 8
and hardly isolatable.36-37 According to all the analysis and ATR-IR
results, the reaction mechanism was proposed and is shown in
Scheme 1. Three reaction steps are involved, i.e., ketimine
condensation, cyclization, and dehydration reactions, and the
cyclization reaction is the rate-determining step. In addition, as
mentioned above, DHA isomerization to glyceraldehyde occurred
during the reaction. This suggests that glyceraldehyde is also a
suitable feedstock for this reaction.
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An
efficient
and
environmentally
benign
method
for
the
synthesis
of
2-hydroxymethyl-5-methylpyrazine (HMMP) from biomass derived 1,3-dihydroxyacetone was
developed.