Exploration of the Role of Double Schiff Bases as Catalytic Intermediates in the Knoevenagel Reaction of Furanic Aldehydes: Mechanistic Considerations

Article abstract of DOI:10.1055/s-0037-1610235

This paper presents mechanistic considerations on an efficient, green, and solvent-free Knoevenagel procedure for the chemical transformation of furanic aldehydes into their corresponding α,β-unsaturated compounds. In the proposed mechanism furanic aldehydes react with ammonia, released from ammonium salts, to form a catalytically active double Schiff base. The catalytic intermediates involved in the condensation step are characterized.

Full text of DOI:10.1055/s-0037-1610235

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J. van Schijndel et al.
Letter
Synlett
Exploration of the Role of Double Schiff Bases as Catalytic Inter-
mediates in the Knoevenagel Reaction of Furanic Aldehydes:
Mechanistic Considerations
Jack van Schijndel*a,b
Luiz Alberto Canallea
Dennis Molendijka
Jan Meuldijkb
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a Research Group Biopolymers/Green Chemistry, Centre of Ex-
pertise BioBased Economy, Avans University of Applied Sci-
ence, Lovensdijkstraat 61, 4818 AJ Breda, The Netherlands
jam.vanschijndel@avans.nl
b Department of Chemical Engineering and Chemistry, Lab of
Chemical Reactor Engineering/Polymer Reaction Engineering,
Eindhoven University of Technology, Den Dolech 2, 5600 MB
Eindhoven, The Netherlands
Received: 12.04.2018
Accepted after revision: 17.07.2018
Published online: 13.08.2018
value group of chemicals derived from biomass and are
identified as key chemicals produced in the lignocellulosic
biorefinery.11,12 An example of a furanic aldehyde is furfural
(1a), which is currently used predominately as a selective
solvent.13 5-Methylfurfural (1b) is another example and
serves as a versatile solvent and a useful intermediate for
the production of, e.g., pharmaceuticals, chemicals for agri-
culture, and perfumes.14–16 5-Hydroxymethylfurfural (5-
HMF, 1c) has received a lot of attention as it can be pro-
duced on a large scale by acid-catalyzed dehydration of
fructose. 5-HMF is an intermediate for many products, in-
cluding pharmaceutical products,17,18 flavor enhancers in
the food industry,19 polymers,10 and alkane biofuels.20
The Knoevenagel condensation is a useful reaction for
producing the above-mentioned ,-unsaturated com-
pounds from an aldehyde and an activated methylene com-
pound.21–23 In this paper, we report the use of various am-
monium salts in the solvent-free Knoevenagel condensa-
tion of furanic aldehydes (Scheme 1) and use this case to
gain more mechanistic insight into this reaction.24
DOI: 10.1055/s-0037-1610235; Art ID: st-2018-b0227-l
Abstract This paper presents mechanistic considerations on an effi-
cient, green, and solvent-free Knoevenagel procedure for the chemical
transformation of furanic aldehydes into their corresponding ,-unsat-
urated compounds. In the proposed mechanism furanic aldehydes react
with ammonia, released from ammonium salts, to form a catalytically
active double Schiff base. The catalytic intermediates involved in the
condensation step are characterized.
Key words furfural, 5-HMF, green Knoevenagel, catalytic intermedi-
ates, double Schiff base
,-Unsaturated compounds have drawn interest from
diverse areas like medicine, biochemistry, and polymer
chemistry.1–3 These ,-unsaturated compounds are essen-
tial units in various substances of natural origin like phero-
mones, insecticides, pesticides, etc.4 Introduction of hetero-
cyclic moieties into these ,-unsaturated compounds has
become important in synthetic chemistry for the prepara-
tion of highly complex molecules. Hence, there is always a
need to synthesize ,-unsaturated compounds by efficient
and novel methods.5 In recent years, synthetic organic
chemistry has furthermore focused on environmentally
friendly catalysts and the use of renewable feedstocks.6–9
Furans are heterocyclic aromatic compounds that can be
prepared from aliphatic sugars and thereby provide inter-
esting platform molecules for the bio-based process indus-
try.10 Furans have been emphasized as one of the top-added
H
O
O
O
OH
O
O
ammonium salts
–H2O
O
OH
R
+
H
R
HO
O
HO
1
2
3
1a furfural
R = H
1b 5-methylfurfural
1c 5-HMF
R = CH3
R = CH2OH
Scheme 1 Knoevenagel condensation of furanic aldehydes 1 with ma-
lonic acid 2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
J. van Schijndel et al.
Letter
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To extend the application of the Knoevenagel condensa-
tion on aromatic aldehydes, the condensation with malonic
acid was performed on furfural (1a) using the previously
reported catalyst ammonium bicarbonate under solvent-
free conditions.24 In line with the results with benzalde-
hyde, the conversion of furfural to its corresponding furanic
dicarboxylic acid 3a was completed at 50 °C within 1 hour
with high isolated yields. This green Knoevenagel conden-
sation also performed well under the same conditions using
5-methylfurfural (1b) or 5-HMF (1c) as shown in Table 1.
R
O
O
O
H
ammonium salts
R
O
O
R
N
N
R
1
4
1a furfural
1b 5-methylfurfural
1c 5-HMF
R = H
R = CH3
R = CH2OH
Scheme 2 Formation of the catalytically active double Schiff base hy-
drofuramide 4 (isolated yields >95%) with different ammonium salts.
Reagents and conditions: furanic aldehydes 1, 0.67 equiv of either NH4HCO3,
(NH4)2CO3, or NH4H2NCO2 for 2 h at 50 °C.
Table 1 Knoevenagel Condensation of Different Furanic Aldehydes 1
with Malonic Acida
O
H
O
O
O
NH4H2NCO2 worked just as well and all above-mentioned
hydrofuramides were isolated in high yields (>95%) using all
three salts. We assume that ammonia is easily released
from these ammonium salts and is thereby the key reactive
component in the formation of the hydrofuramides.
OH
O
NH4HCO3 cat.
–H2O
O
O
OH
+
R
H
R
HO
HO
1
2
3
To demonstrate that the hydrofuramides are not just
storage for the furanic aldehydes and ammonia but a ‘cata-
lytic’ intermediate, various amounts of hydrofuramide 4a
were added to a mixture of furfural and malonic acid at 50
°C (Figure 1). The reported mol percentages of hydrofura-
mide were calculated relative to malonic acid, and the total
amount of furfural (free and incorporated in 4a) was kept
equal to malonic acid. Figure 1 clearly shows that hydrofur-
amide accelerates the conversion of furfural into its corre-
sponding furanic dicarboxylic acid (3a). Using 10 mol%, hy-
drofuramide full conversion towards furanic dicarboxylic
acid was reached within 1 hour. Using 1.25 mol% of hydro-
furamide, complete conversion was reached within 2 hours.
Entry
R
Conversion (%) Product Yield (%) of 3 Yield (%) of 3
of 1 (HPLC)
(HPLC)
(isolated)
1
2
3
H
100
100
100
3a
3b
3c
100
100
98
94
95
93
CH3
CH2OH
a Reaction conditions: furanic aldehyde 1, 1.0 equiv malonic acid, and 0.1
equiv NH4HCO3 for 1 h at 50 °C. Reported conversions and yields are based
on the ratio of peaks of the HPLC chromatogram measured with an UV de-
tector operating at 300 nm.25
In order to gain more insight into the catalytic interme-
diates of this Knoevenagel condensation, it was attempted
to isolate the catalytically active compounds. In order to do
so, increasing amounts of ammonium bicarbonate were
added to furfural at 50 °C in the absence of malonic acid.
Under these conditions, a yellow-white solid with a decom-
position temperature around 110 °C was isolated. At a ratio
of 0.67 equivalents of ammonium bicarbonate to furfural, a
100% conversion of furfural was achieved. Analysis with
NMR spectroscopy and MS showed the product to be hy-
drofuramide (N,N′-difurfurylidene-2-furanethane-diamine
(4a), Scheme 2).26 For 5-methyl furfural and 5-hy-
droxymethyl furfural the corresponding hydrofuramides 4b
and 4c could also be isolated and characterized with NMR
spectroscopy and MS. To the best of our knowledge this is
the first time the compounds hydro 5-methyl furamide (4b)
and hydro HMF furamide (4c) are reported (see Supporting
Information).
Figure 1 Concentration–time profile of furanic dicarboxylic acid 3a
formed using various amounts of hydrofuramide 4a in a mixture with
an equal total amount of furfural and malonic acid at 50 ° C (+ = 0 mol%,
✱ = 1.25 mol%, X = 2.5 mol%, O = 5 mol%, ▽ = 10 mol%, △ = 20 mol%,
□ = 33 mol%). Reported furanic dicarboxylic acid HPLC yields are based
on the ratio of peaks of the HPLC chromatogram measured with an UV
detector operating at 300 nm.
These double Schiff bases were not stable and returned
quickly to their corresponding furanic aldehydes in the
presence of an acid. The instability of the hydrofuramides
in an acidic environment explains why they were not ob-
served previously during the Knoevenagel condensation us-
ing malonic acid. Formation of the different hydrofura-
mides was not limited to ammonium bicarbonate; ammo-
nium carbonate (NH4)2CO3 and ammonium carbamate
Note that without the addition of hydrofuramide 4a, the
product furanic dicarboxylic acid 3a was also formed. This
is because the carboxylic acids of malonic acid also have
catalytic activity in the condensation reaction.27 In order to
block the effect of the carboxylic acid groups of malonic
acid and to obtain an accurate picture of the catalytic activ-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
J. van Schijndel et al.
Letter
Synlett
ity of hydrofuramide, the same set of experiments was per-
formed using diethyl malonate (5a, Figure 2) instead of ma-
lonic acid.
Scheme 3 proposes a complete reaction scheme for the
condensation step of the Knoevenagel between furfural 1a
and diethyl malonate 5a. On the right hand of the figure,
the build-up of the isolated catalytic intermediate hydrofu-
ramide 4a is shown: ammonia, formed after decomposition
of NH4HCO3, reacts with furfural and results in furfuryl
imine I. This intermediate could not be detected, due to its
highly reactive nature.29,30 Two molecules of furfuryl imine I
can subsequently combine into molecule II which has been
identified in the reaction mixture using MS. Finally, a third
furfural is incorporated into molecule II, resulting in the
production of hydrofuramide 4a, which forms the basis of
the catalytic cycle marked by the green cycle at the bottom
of Scheme 3. This catalytically active double Schiff base can
couple diethyl malonate 5a to one of its furanic units, re-
sulting in the desired end product 6a. Molecule II is formed
as another catalytic intermediate of this reaction and can
regenerate hydrofuramide 4a, closing the catalytic cycle.
After all furanic starting material has been transformed
into the product, hydrofuramide is consumed in subse-
quent steps, each generating product 6a as shown on the
left hand of Scheme 3.
Scheme 4 expands on a possible mechanism for the cat-
alytic cycle from Scheme 3. First, a hydrogen atom from the
-carbon of diethyl malonate 5a is transferred to an imine
nitrogen in hydrofuramide 4a (step i). The ion pair created
reacts to form a carbon–carbon bond (step ii). After this re-
action, a second hydrogen atom from the -carbon of the
diethyl malonate moiety is removed by the former imine
nitrogen atom (step iii) and the desired ,-unsaturated
product 6a is formed after a final electron flow (step iv).
Molecule II is formed as an accompanying product and re-
generates hydrofuramide after coupling with furfural (step
v). To determine the order of the reaction, both the concen-
tration of furfural and diethyl malonate were varied. With
higher concentrations of furfural, the conversion rate to
product 6a remained constant. With a higher diethyl
malonate concentration, the conversion rate to product 6a
increased. This shows that diethyl malonate is involved in
the rate-determining step.
Figure 2 Concentration–time profile of diethyl 2-furylmalonate 6a
formed using various amounts of hydrofuramide 4a in a mixture with
an equal total amount of furfural and diethyl malonate acid at 90 °C
(+ = 0 mol%, ✱ = 1.25 mol%, X = 2.5 mol%, O = 5 mol%, ▽ = 10 mol%,
△ = 20 mol%, □ = 33 mol%). Reported furanic dicarboxylic ethyl ester
HPLC yields are based on the ratio of peaks of the HPLC chromatogram
measured with an UV detector operating at 300 nm.
Upon addition of 33 mol% of hydrofuramide 4a, all fur-
fural is incorporated in the catalytically active double Schiff
base. Once in contact with diethyl malonate, the final prod-
uct diethyl 2-furylmalonate 6a was produced very fast.
There was still a proper conversion of furfural to diethyl 2-
furylmalonate using relatively small amounts of hydrofura-
mide, i.e., using 2.5 mol% hydrofuramide relative to diethyl
malonate resulted in 50% conversion of furfural in 2 hours.
Contrary to the experiments with malonic acid, the desired
product was only formed after addition of the catalytic in-
termediate hydrofuramide.
As demonstrated by the results collected in Table 2, the
Knoevenagel condensation of furanic aldehydes with dieth-
yl malonate using ammonium bicarbonate also performed
well using 5-methylfurfural (1b) or 5-HMF (1c) with near
quantitative HPLC yields and high isolated yields above 80%.
Table 2 Knoevenagel Condensation of Different Furanic Aldehydes 1
with Diethyl Malonatea
O
H
O
O
In addition to diethyl malonate, other -keto com-
pounds were tested as reaction partners for furfural. To get
a good picture of the varying reactivity of the -keto com-
pounds, a temperature of 60 °C was chosen (Table 3). The
acidity of the -hydrogen in the -keto compounds appears
to play a major role in the interaction between the -keto
compound and the double Schiff base 4a. More acidic -hy-
drogens31,32 corresponded with higher conversion to the
,-unsaturated products after 1 hour. These observations
seem to underline the importance of the hydrogen transfer
between the -carbon of diethyl malonate and the imine
nitrogen of hydrofuramide 4a in the catalytic mechanism.
O
NH4HCO3 cat.
–H2O
OC2H5
OC2H5
5a
O
OC2H5
OC2H5
R
H
+
R
O
O
1
6
Entry
R
Conversion (%) Product Yield (%) 6
Yield (%) 6
(isolated)
1 (HPLC)
(HPLC)
1
2
3
H
100
100
100
6a
6b
6c
100
100
95
80
84
86
CH3
CH2OH
a Reaction conditions: furanic aldehyde 1, 1.0 equiv diethyl malonate, and
0.1 equiv NH4HCO3 for 1 h at 90 °C. Reported conversions and yields are
based on the ratio of peaks of the HPLC chromatogram measured with an
UV detector operating at 300 nm.28
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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J. van Schijndel et al.
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O
O
O
O
+
NH3
O
O
O
H
1a
6a
O
NH3
H2O
O
–NH3
NH3
O
O
O
O
5a
H
H
HN
H
H2N
NH2
O
O
I
III
O
O
O
6a
O
HN
H
O
I
O
O
O
O
O
N
5a
H
H
NH2
O
O
O
O
II
O
O
H
1a
6a
O
O
O
H2O
O
O
H
H
5a
O
O
O
N
N
4a
Scheme 3 Proposed mechanism of the overall green Knoevenagel condensation of furfural 1a with diethyl malonate 5a, the intermediate III between
square brackets could not be characterized or isolated. Intermediates I and II were characterized by MS, and hydrofuramide 4a was isolated.
Table 3 Knoevenagel Condensation of Furfural 1a with Various -Keto Compounds 5 towards ,-Unsaturated Compounds 6
O
H
O
O
hydrofuramide (5 mol%)
–H2O
O
R1
R1
O
H
+
R2
O
R2
O
1a
5
6
Entry
5
Name
R1
R2
pKa (DMSO) (Bordwell)
Yield (%, HPLC)
1
2
3
4
5
5a
5b
5c
5d
5e
diethyl malonate
dimethyl malonate
dibenzyl malonate
ethyl acetoacetate
acetylacetone
OC2H5
OCH3
OC2H5
OCH3
OCH2C6H5
CH3
16.40
15.87
6a
6b
6c
6d
6e
1
12
50
65
95
OCH2C6H5
OC2H5
CH3
14.20
13.30
CH3
In the literature, a lot of different ammonium salts such
as ammonium acetate NH4CH3COO,33 diammonium hydro-
gen phosphate (NH4)2HPO4,34 ammonium formate
NH4HCOO,35 ammonium carbonate (NH4)2CO3,36 and am-
monium carbamate NH4H2NCO2 are reported as catalysts
in Knoevenagel-like reactions of aromatic aldehydes. Some-
37
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

E
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O
O
N
N
O
O
O
O
O
O
H
H
O
O
O
6a
iv
iii
O
O
O
N
O
N
O
O
N
O
O
H
N
O
H
H
H
II
O
ii
O
v
O
O
N
O
N
1a
4a
–H2O
N
H
i
N
O
O
O
O
O
O
H
H
H
O
O
O
O
O
O
5a
Scheme 4 Proposed mechanism of the reaction between furfural 1a and diethyl malonate 5a towards diethyl 2-furylmalonate 6a catalyzed by hydro-
furamide 4a
times these reactions proceed in a biphasic system with
water but most of the time in solvent-free conditions. Our
idea is that all these different reactions proceed via the
same, above-mentioned mechanism. This is reinforced by
the fact that when we revisited the original Knoevenagel re-
action using different ammonium salts as catalyst (in line
with the conditions reported in Tables 1 and 2), hydrofura-
mide 4a and intermediate II were always found in the reac-
tion mixture using MS analysis.
To the best of our knowledge, this is the first time this
kind of catalytic activity of hydrofuramides is reported in
Knoevenagel-like reactions. Further research needs to be
done on aspects of solubility, stability, and catalytic activity
of these double Schiff bases in the Knoevenagel condensa-
tion.
In conclusion, it has been shown that the green Knoeve-
nagel condensation is very suitable for making ,-unsatu-
rated compounds from furanic aldehydes. A mechanism is
proposed in which the furanic aldehydes react with ammo-
nia, released from ammonium salts to form a catalytically
active double Schiff base. A closed catalytic cycle has been
proposed where the -keto compound is involved in the
rate-determining step, but the furanic aldehyde is not. This
mechanism explains why many different ammonium salts,
including ammonium bicarbonate, have been correctively
reported as catalysts in Knoevenagel-like reactions.
Funding Information
The authors are grateful for the financial support from Netherlands
Organization for Scientific Research (NWO) (grant 023.007.020
awarded to Jack van Schijndel).
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Acknowledgment
We further thank Edward Knaven, Avans University of Applied Sci-
ence, for expert help with the LC/MS measurements and Sebastian
van Schijndel for his help on the graphical abstract and his helpful in-
sights.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610235.
S
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p
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ortiInfogrmoaitn
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References and Notes
mL 30% (m/m) ammonia and subsequently removing the
solvent by filtration.
(1) Romani, F.; Corrieri, R.; Braga, V.; Ciardelli, F. Polymer 2002, 43,
1115.
(2) Ju, Y.; Varma, R. S. J. Org. Chem. 2006, 71, 135.
(3) Ansari, A.; Ali, A.; Asif, M. New J. Chem. 2016, 41, 16.
(4) Eftekhari-Sis, B.; Zirak, M.; Akbari, A. Chem. Rev. 2013, 113,
2958.
(5) Chiriac, C. I.; Tanasa, F.; Onciu, M. Molecules 2005, 10, 481.
(6) Jessop, P. G. Green Chem. 2016, 18, 2577.
Hydrofuramide (4a)
Brown solid, decomposes at 117 °C. 1H NMR (400 MHz, DMSO):
 = 8.44 (s, 2 H), 7.91 (s, 2 H), 7.65 (d, J = 0.4 Hz, 1 H), 7.11 (d,
J = 3.4 Hz, 2 H), 6.70–6.62 (m, 2 H), 6.46 (dd, J = 3.1, 1.9 Hz, 1 H),
6.38 (d, J = 3.2 Hz, 1 H), 6.11 (s, 1 H). 13C NMR (101 MHz, CDCl3):
 = 152.81, 151.41, 150.61, 145.33, 142.52, 115.85, 111.90,
110.42, 107.78, 84.16. MS (ESI): m/z calcd: 268.27 g/mol; found
[M + H]+: 269.
(7) Sheldon, R. A. Green Chem. 2017, 19, 18.
(8) Sheldon, R. A. Green Chem. 2016, 18, 3180.
(9) Sneddon, H. F. Green Chem. 2016, 18, 582.
Hydro 5-Methylfuramide (4b)
Light brown solid, decomposes at 84 °C. 1H NMR (400 MHz,
DMSO):  = 8.29 (s, 2 H), 6.95 (d, J = 3.1 Hz, 2 H), 6.27 (d, J = 2.6
Hz, 2 H), 6.20 (d, J = 2.9 Hz, 1 H), 6.02 (d, J = 1.8 Hz, 1 H), 5.92 (s,
1 H), 2.34 (s, 6 H), 2.23 (s, 3 H).13C NMR (101 MHz, DMSO):  =
155.94, 152.73, 151.72, 150.35, 150.34, 118.45, 109.08, 108.04,
106.87, 84.80, 13.93, 13.75. MS (ESI): m/z calcd: 310.35 g/mol;
found [M + H]+: 311.
(10) van Putten, R.-J.; van der Waal, J. C.; de Jong, E.; Rasrendra, C. B.;
Heeres, H. J.; de Vries, J. G. Chem. Rev. 2013, 113, 1499.
(11) Binder, J. B.; Raines, R. T. J. Am. Chem. Soc. 2009, 131, 1979.
(12) Bhaumik, P.; Dhepe, P. L. Catal. Rev. 2016, 58, 36.
(13) Mariscal, R.; Maireles-Torres, P.; Ojeda, M.; Sádaba, I.; López
Granados, M. Energy Environ. Sci. 2016, 9, 1144.
(14) Tradtrantip, L.; Sonawane, N. D.; Namkung, W.; Verkman, A.
J. Med. Chem. 2009, 52, 6447.
(15) Jung, M. E.; Im, G. J. J. Org. Chem. 2009, 74, 8739.
(16) Michail, K.; Matzi, V.; Maier, A.; Herwig, R.; Greilberger, J.; Juan,
H.; Kunert, O.; Wintersteiger, R. Anal. Bioanal. Chem. 2007, 387,
2801.
(17) Sriwilaijaroen, N.; Kadowaki, A.; Onishi, Y.; Gato, N.; Ujike, M.;
Odagiri, T.; Tashiro, M.; Suzuki, Y. Food Chem. 2011, 127, 1.
(18) Chuda, Y.; Ono, H.; Ohnishi-Kameyama, M.; Matsumoto, K.;
Nagata, T.; Kikuchi, Y. J. Agric. Food Chem. 1999, 47, 828.
(19) Villard, R.; Robert, F.; Blank, I.; Bernardinelli, G.; Soldo, T.;
Hofmann, T. J. Agric. Food Chem. 2003, 51, 4040.
(20) Rosatella, A. A.; Simeonov, S. P.; Frade, R. F. M.; Afonso, C. A. M.
Green Chem. 2011, 13, 754.
(21) Knoevenagel, E. Ber. Dtsch. Chem. Ges. 1898, 31, 2596.
(22) van Schijndel, J.; Canalle, L. A.; Smid, J.; Meuldijk, J. Open J. Phys.
Chem. 2016, 6, 101.
Hydro 5-HMF Furamide (4c)
Brown solid, decomposes at 125 °C. 1H NMR (400 MHz, DMSO):
 = 8.36 (d, J = 0.7 Hz, 2 H), 7.02 (d, J = 3.3 Hz, 2 H), 6.48 (d, J = 3.3
Hz, 2 H), 6.27 (dd, J = 12.5, 3.1 Hz, 2 H), 6.01 (s, J = 8.0 Hz, 1 H),
4.48 (s, 4 H), 4.37 (s, 2 H).13C NMR (101 MHz, DMSO):  =
178.42, 162.63, 159.26, 155.71, 153.52, 152.19, 150.85, 150.80,
124.91, 118.05, 110.15, 109.62, 108.16, 107.96, 84.65, 56.40,
56.28, 56.11. MS (ESI): m/z calcd: 358.35 g/mol, found [M + H2O
+ H]+: 377.
(27) Dalessandro, E. V.; Collin, H. P.; Guimaraes, L. G. L.; Valle, M. S.;
Pliego, J. R. Jr. J. Phys. Chem. B 2017, 121, 5300.
(28) Typical Protocol for the Green Knoevenagel Condensation
towards 6a with 10 mol% ammonium bicarbonate:
Diethyl malonate (5a, 1.6 g, 10 mmol) was mixed with furfural
(1a, 0.96 g, 10 mmol) and ammonium bicarbonate (79 mg, 1.0
mmol) was subsequently added. The reaction mixture was
stirred and kept for 1 hour at 90 °C for complete conversion of
furfural.
(23) List, B. Angew. Chem. Int. Ed. 2010, 49, 1730.
(24) van Schijndel, J.; Canalle, L. A.; Molendijk, D.; Meuldijk, J. Green
Chem. Lett. Rev. 2017, 10, 404.
The product 6a was obtained by adding 5 mL saturated brine
solution to the oily product and this aqueous layer was
extracted three times with ethyl acetate (3 x 5 mL). After drying
the combined organic layers over MgSO4 ethyl acetate was
removed under reduced pressure and the product was dried at
60 °C in a vacuum oven.
(25) Typical Protocol for the Green Knoevenagel Condensation
towards 3a with 10 mol% Ammonium Bicarbonate:
Malonic acid (1.0 g, 10 mmol) was dissolved in furfural (1a, 0.96
g, 10 mmol), and ammonium bicarbonate (79 mg, 1.0 mmol)
was subsequently added. The reaction mixture was stirred and
kept for 1 h at 50 °C for complete conversion of furfural. In a
total workup, the reaction mixture was dissolved in 10 mL satu-
rated NaHCO3 solution and subsequently acidified to a pH of 2
using an aqueous 6 M HCl solution. The aqueous layer was
extracted with ethyl acetate (3 × 5 mL). After drying the com-
bined organic layers over MgSO4 the solvent was removed
under reduced pressure, and the solid product was subse-
quently dried at 60 °C in a vacuum oven.
(29) Chatterjee, M.; Ishizaka, T.; Kawanami, H. Green Chem. 2016, 18,
487.
(30) Huang, J.; Zhang, J.; Dong, Y.; Gong, W. J. Org. Chem. 2011, 76,
3511.
(31) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(32) Perez, G. V.; Perez, A. L. J. Chem. Educ. 2000, 77, 910.
(33) Balalaie, S.; Nemati, N. Synth. Commun. 2000, 30, 869.
(34) Balalaie, S.; Bararjanian, M.; Hekmat, S.; Salehi, P. Synth.
Commun. 2006, 36, 2549.
(35) Saha, M.; Roy, S.; Kumar Chaudhuri, S.; Bhar, S. Green Chem. Lett.
Rev. 2008, 1, 113.
(36) Sonar, J. P.; Shisodia, S. U.; Pardeshi, S. D.; Dokhe, S. A.; Zine, A.
M.; Pawar, S. N.; Thore, S. N. Eur. Chem. Bull. 2017, 69.
(37) Mase, N.; Horibe, T. Org. Lett. 2013, 15, 1854.
(26) Optimized Protocol for the Synthesis of Hydrofuramide (4a)
A mixture of furfural (1a, 1.44 g, 15 mmol) and ammonium
bicarbonate (0.79 g, 10 mmol) was brought to a temperature of
50 °C, resulting in a solid yellow-white substance in 2h. The
solid was purified by suspending the obtained precipitate in 10
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F