Furoic acid and derivatives as atypical dienes in Diels-Alder reactions

Article abstract of DOI:10.1039/d1gc01535d

The furan Diels-Alder (DA) cycloaddition reaction has become an important tool in green chemistry, being central to the sustainable synthesis of many chemical building blocks. The restriction to electron-rich furans is a significant limitation of the scope of suitable dienes, in particular hampering the use of the furans most readily obtained from biomass, furfurals and their oxidized variants, furoic acids. Herein, it is shown that despite their electron-withdrawing substituents, 2-furoic acids and derivatives (esters, amides) are in fact reactive dienes in Diels-Alder couplings with maleimide dienophiles. The reactions benefit from a substantial rate-enhancement when water is used as solvent, and from activation of the 2-furoic acids by conversion to the corresponding carboxylate salts. This approach enables Diels-Alder reactions to be performed under very mild conditions, even with highly unreactive dienes such as 2,5-furandicarboxylic acid. The obtained DA adducts of furoic acids are shown to be versatile synthons in the conversion to various saturated and aromatic carbocyclic products.

Full text of DOI:10.1039/d1gc01535d

Volume 23
Number 15
7
August 2021
Pages 5233-5740
Green
Chemistry
Cutting-edge research for a greener sustainable future
rsc.li/greenchem
ISSN 1463-9262
PAPER
Pieter C. A. Bruijnincx et al.
Furoic acid and derivatives as atypical dienes in Diels–Alder
reactions

Green Chemistry
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Furoic acid and derivatives as atypical dienes in
Diels–Alder reactions†
Cite this: Green Chem., 2021, 23,
503
5
a
a
b
b
Răzvan C. Cioc, Tom J. Smak, Marc Crockatt, Jan C. van der Waal
and
a
Pieter C. A. Bruijnincx
*
The furan Diels–Alder (DA) cycloaddition reaction has become an important tool in green chemistry,
being central to the sustainable synthesis of many chemical building blocks. The restriction to electron-
rich furans is a significant limitation of the scope of suitable dienes, in particular hampering the use of the
furans most readily obtained from biomass, furfurals and their oxidized variants, furoic acids. Herein, it is
shown that despite their electron-withdrawing substituents, 2-furoic acids and derivatives (esters, amides)
are in fact reactive dienes in Diels–Alder couplings with maleimide dienophiles. The reactions benefit
from a substantial rate-enhancement when water is used as solvent, and from activation of the 2-furoic
acids by conversion to the corresponding carboxylate salts. This approach enables Diels–Alder reactions
to be performed under very mild conditions, even with highly unreactive dienes such as 2,5-furandicar-
boxylic acid. The obtained DA adducts of furoic acids are shown to be versatile synthons in the conversion
to various saturated and aromatic carbocyclic products.
Received 1st May 2021,
Accepted 23rd June 2021
DOI: 10.1039/d1gc01535d
rsc.li/greenchem
highly oxygenated furanics cannot be readily used in DA-based
synthesis strategies is a missed opportunity. Furoic acids are
Introduction
1
Since its discovery in 1929, the furan Diels–Alder (DA) reac- readily available via renewable platform molecules such as fur-
2
2
tion has been extensively applied in organic chemistry, with fural and 5-hydroxymethyl furfural (5-HMF). Furoic acids
the resulting 7-oxabicyclo[2.2.1]hept-2-enes being exploited in also offer the advantage of being stable renewable platform
natural product synthesis, drug discovery, bioconjugation, as molecules, this in contrast to, for instance, 5-HMF and its
2
–7
well as in polymer and materials science applications.
hydrogenated derivatives (2,5-dimethyl furan, 2,5-bishydroxy-
2
3
Indeed, furan DA reactions allow versatile synthons of con- methyl furan) which can readily degrade and/or polymerize.
siderable molecular complexity to be generated in an atom-
economical fashion, making it a highly attractive strategy for
8
green chemical synthesis of cyclic compounds. The reactivity
of furan derivatives as dienes has been the subject of numer-
ous theoretical and experimental studies. The general consen-
sus is that good kinetics requires electron-rich furanic rings,
as found in the parent furan and derivatives decorated with
electron-donating substituents (e.g. alkyl-, alkoxyalkyl-, acetals
9
–13
etc., Scheme 1A)
and accordingly most applications employ
such dienes.
Conversely, Diels–Alder reactions involving electron-poor
derivatives such as furoic acids (furans substituted with a
1
4–21
COOH group) are very much underexplored.
That such
a
Organic Chemistry and Catalysis, Debye Institute for Nanomaterials Science,
Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The
Netherlands. E-mail: p.c.a.bruijnincx@uu.nl
b
Department of Sustainable Process and Energy Systems, TNO, Leeghwaterstraat 44,
2628 CA Delft, The Netherlands
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1gc01535d
Scheme 1 Diels–Alder reactions with 2-furoic acid-derived dienes.
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Together, this makes them attractive building blocks for the 3-furoic acid with maleimides are actually favoured both kine-
3
2
atom- and redox-efficient synthesis of a large number of renew- tically and thermodynamically; on the other hand, the more
able value-added carboxylic acid- or ester-containing chemical readily available 2-regioisomer was found to be much less reac-
products, including biobased aromatics.
tive, with the coupling also being strongly entropically dis-
Unfortunately, only a handful of recent reports describe favoured. Interestingly, the authors note that reactivity could
attempts to capitalize on these advantages. Instead, the vast be tuned by solvent effects: rate and equilibrium conversions
majority of chemistry developed in this area relies on the well- were significantly higher in water compared to reactions in
established use of electron-rich furan dienes. While this conven- dimethyl formamide.
tional approach may be efficient for the individual DA step, it is
Encouraged by this precedent and following our interest in
often redox uneconomical overall, as exemplified for instance by the development of synthetic applications based on the Diels–
the cycloaddition between 2,5-dimethyl furan and ethylene tar- Alder chemistry of readily available oxygenated bio-based
24–27
33,34
geting renewable terephthalic acid (Scheme 1A).
This route furans,
we decided to investigate 2-furoic acids as underex-
is, in essence, the conversion of a highly oxygenated bio-derived plored class of dienes.
resource (e.g. 5-HMF) to an oxygen-rich product (terephthalic
acid) via a non-oxygenated hydrocarbon intermediate, p-xylene.
The non-productive use of redox reactions featured in this
Results and discussion
Reaction optimization
approach (the so-called “redox-detour”) greatly reduces the
incentive for scale-up of such routes.
In contrast, as solution to this problem, the groups of In line with the observations of Bowman et al., the reaction
15–17
18
19
20
Davis,
Clark and Jae and a patent by Avantium have dis- between furoic acid 1a and N-methyl maleimide 2a was slow in
closed new routes towards terephthalic acid starting from furan all common organic solvents. No obvious reactivity trend
carboxylic (di)acids or their esters and ethylene, but these diene/ (Table 1) could be discerned, although polar solvents seemed
dienophile combinations require very harsh conditions and the more beneficial for the reaction (MeOH, EtOH, DMSO, AcOH).
overall yields are low (Scheme 1B). Relatedly, Sibi et al. was suc- Hydrogen bonding interactions with the solvent might be
cessful in the valorisation of the dimethyl 2,5-furandicarboxylate important as only traces of product could be detected in
21
with benzyne as highly reactive dienophile (Scheme 1C). Finally, apolar aprotic solvents (CH Cl , CHCl ; toluene being a
2
2
3
the furoate ester/maleimide couple has on occasion been curious exception with 5% yield). Undoubtedly, the electron-
2
8–31
described in macromolecular applications,
even though the withdrawing effect of the COOH substituent on the furan ring
10
molecular version was deemed unfeasible by Boutevin et al.
translates into a lowered energy level for the HOMO of the
To the best of our knowledge, there is a single study diene and consequently a high activation barrier for the cyclo-
thoroughly investigating the reactivity of furoic acids in Diels– addition. We reasoned that the addition of a base would coun-
Alder chemistry. Bowman et al. showed that reactions of teract this effect, as neutralization to the carboxylate
Table 1 Solvent effects in the cycloaddition between 2-furoic acid 1a and maleimide 2a
Yields in neutral conditions
Yields with NEt
3
(1 equiv.)
endo-3, %
Entry
Solvent
exo-3, %
endo-3, %
Total, %
exo-3, %
Total, %
1
2
3
4
5
6
7
8
9
MeOH
EtOH
AcOH
DMSO
DMF
MeCN
AcOEt
THF
10
8
6
7
3
3
4
3
Trace
2
Trace
5
0
10
8
6
7
3
3
4
3
Trace
2
Trace
5
34
49
n.a.
35
25
28
28
27
27
50
41
38
83
6
1
n.a.
1
2
5
3
1
5
0
6
2
3
40
50
n.a.
36
27
33
31
28
32
50
47
40
86
Trace
0
Trace
0
0
0
Trace
Acetone
0
0
0
0
7
10
11
12
13
CHCl
CH Cl
Toluene
3
2
2
2
H O
56
63
General procedure: 2-Furoic acid 1a (0.5 mmol), (NEt
5
3
, 1 equiv.) and N-methyl maleimide 2a (1.5 equiv.) stirred in the respective solvent (1 M) at
0 °C for 6 h; yields determined from the H-NMR ratios of product isomers and starting material; conversion of 1a was clean; solvolysis of 2a
was detected as side reaction, in alcoholic solvents (in the presence of NEt ).
1
3
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diminishes the electron-withdrawing capability of the COOH
3
5
substituent:
indeed, in all solvents tested, the yields
increased substantially in the presence of 1 equiv. of triethyl-
amine. Adduct yields of nearly 50% (6 h reaction time, 50 °C)
were now observed in CH Cl , CHCl and EtOH. Correlating
2
2
3
reactivity with solvent properties is again not straightforward;
plausibly, the extent of proton transfer and charge separation
play a major role here.
Next, we turned our attention to water as solvent. The rate-
enhancement ability of water in Diels–Alder chemistry is well
known and many arguments have been proposed to explain
3
6,37
it.
In our system, the rate of reaction between 1a and 2a
(63% conversion in 6 h at 50 °C, Table 1, entry 13) is one order
of magnitude higher than in all organic solvents tested; in
fact, the reaction of the free acid in water even proved faster
than the best result obtained in an organic solvent in the pres-
ence of base (Table 1, entry 2 or entry 10).
The reaction also clearly benefited from the synergy of
using aqueous solvent and the base effect: nearly quantitative
yield of 1a was obtained when the cycloaddition was per-
formed in water in the presence of 1 equiv. of NaOH (Table 2,
entry 4). The reaction efficiency correlates with the base
strength (NaOH ≈ Na HPO > NEt3 > NaH PO ); clearly, the
2
4
2
4
effect of the base is not catalytic, as lowering the NaOH
loading (entries 7 and 8) produced results comparable to those
obtained when using the weaker base NaH PO . Finally, the
2
4
effect of temperature is typical for a reversible [4 + 2] cyclo-
addition: at lower temperatures (20 °C, entry 10), the reaction
is under kinetic control, with the major product being the
endo adduct, while at elevated temperatures (80 °C, entry 9),
the formation of exo-3a is nearly exclusive (see also Fig. 1,
bottom); noteworthy, the total yield diminishes with increas-
ing temperature due to the unfavourable entropy contribution.
The reaction profiles depicted in Fig. 1 illustrate the signifi-
Fig. 1 Kinetic traces for the cycloadditions between 2-furoic acid 1a
and maleimide 2a (1 : 1 ratio at 0.5 M) in water (top), with the addition of
cant enhancement of the rate of the cycloaddition in the pres- 1 equiv. NaOH (bottom); see ESI† for details; cf. Tables 2 and 3: reactions
ence of stoichiometric base: compared to the additive-free run at 1 : 1.5 ratio 1 : 2 and 1 M concentration.
Table 2 DA reaction between 2-furoic acid 1a and maleimide 2a in aqueous solution: effect of base
Entry
Additive
Amount, equiv.
Temp., °C
Time, h
exo-3, %
endo-3, %
Total, %
1
2
3
4
5
6
7
8
9
None
None
NaOH
NaOH
n/a
n/a
1
1
1
50
50
50
50
50
50
50
50
80
20
6
16
6
16
6
6
6
6
6
6
56
76
90
94
89
71
75
67
81
25
7
3
5
3
6
8
6
7
3
35
63
79
95
97
95
79
81
74
84
60
Na
NaH
2
HPO
PO
4
2
4
1
NaOH
NaOH
NaOH
NaOH
0.5
0.25
1
1
0
1
General procedure: 2-Furoic acid 1a (0.5 mmol), (additive) and N-methyl maleimide 2a (1.5 equiv.) stirred in aqueous solution (1 M) at the
1
indicated temperature for the indicated time; yields determined from the H-NMR ratios of product isomers and starting material.
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reaction (Fig. 1, top), the NaOH-mediated conversion is Table 3 Scope of DA reaction between 2-furoic acids and maleimides
in aqueous solution
approx. 5 times faster, in the first 30 min. In addition, the
system is nearly at equilibrium within 12 h, which is not the
case for the base-free experiment. Importantly, the conversion
of 1a was clean in both cases, with no side products originat-
ing from the diene detected. On the other hand, some hydro-
lysis of 2a (towards maleic acid) does occur, to a low extent,
and if the NaOH stoichiometry is increased beyond the 1 : 1
b
Isolated ,
%
1
2
a
ratio, the sodium salt of N-methyl maleamic acid is formed Entry
R
R
3
Conv. 1 exo-3, % endo-3, %
5
2
(
see also note ).
c
1
2
3
4
5
6
7
8
9
1
H
H
H
H
H
H
Me
CH
CH
Me 3a 98
3b 95
97
95
93
51
16
53
88
72
28
∼5
20
56
1
77(92)
H
Trace
3
Trace
2
3
5
19
Trace
Trace
0
68
72
21
n.d.
31
Reaction scope
n
Pr 3c 96
Ph 3d 51
Cy 3e 18
Cy 3e 56
Me 3f 93
d
The choice of water as reaction solvent allows the convenient
isolation of DA adducts 3 by precipitation. To maximize con-
version and simplify purification, we performed the title reac-
tion between 1a and 2a under more concentrated conditions
d
d,e
75
51
f
2
OH Me 3g 91
OH Ph 3h 28
d
2
11
(2 M) and with 1 : 1 stoichiometry; the precipitated product
g
0
CHO
COOH
COOH
Me 3i <10
Me 3j 20
Me 3j 56
n.d.
n.d.
n.d.
g
was isolated by filtration in a 63% yield. Unreacted starting 11
materials were recovered from the filtrate and reused without
g,h
12
0
loss of reaction efficiency (see ESI† for details). This example is General procedure: 2-Furoic acid, NaOH (1 equiv.) and maleimide (1.5
a
equiv.) stirred in water (1 M) at 50 °C for 16 h. Conversion deter-
an excellent showcase of the green chemistry principles:
1
mined from the H-NMR ratios of product isomers and starting
material in the crude mixture. Isolated yield after acidification.
40 mmol scale. Poor dissolution of 2. Methanol was used as cosol-
vent. After hydrogenation on Pd/C. Extensive hydrolysis of 2a to
renewable raw materials use, 100% atom-economy, eco-
friendly solvent, simple isolation, no additives and no waste.
In studying the reaction scope, we chose the conditions
shown in entry 4, Table 2 (with 1 equiv. NaOH), with the aim
of minimizing the amount of minor adduct endo-3 and simpli-
b
c
d
e
f
g
h
maleic acid. With 2 equiv. of NaOH.
fying the isolation of a pure product following a general proto- favourable cycloaddition and hence the highest adduct yield at
1
2
col. Thus, after reaction, the excess maleimide can be washed equilibrium. In the series R = H/Me/CH OH, the parent reac-
1
away (and recovered) with an organic solvent, while acidifica- tion (formation of 3a, R = H) was found to exhibit the highest
tion of the aqueous phase typically leads to the selective pre- equilibrium conversion (Table 3, entry 1 vs. 7 and 8; see also
cipitation of exo-3. This procedure allowed for the isolation of ESI† for further details) while the relative reactivity was Me > H
the exo-adducts 3a–c in good yields (Table 3, entries 1–3); the > CH OH. Despite the somewhat less favourable equilibrium,
2
1
performance of the reactions is only modestly influenced by adduct 3f (R = Me) could nonetheless be isolated in a good
the nature of the maleimide substituent in the series H/ yield (75%). Next, a high isolated yield was anticipated based
n
1
Me/ Pr. Higher homologues (N-Ph, N-Cy) proved problematic, on the analysis of the crude reaction mixture for adduct 3g (R
however, due to poor solubility of the dienophile in the = CH OH) but unfortunately this very polar molecule is highly
aqueous medium (entries 4 and 5); the addition of a cosolvent water soluble, which complicated its isolation. Nonetheless, a
MeOH) was beneficial in this case (entry 6) and although the yield of 51% of pure exo product was obtained after the
2
(
conversion levels were moderate, synthetically useful yields of sequential, one-pot conversion of 3g to a more stable deriva-
pure adducts 3d and 3e could be obtained without excessive tive, i.e. by hydrogenation over Pd/C, a method used before in
3
8–41
adjustment of the general procedure. Next, we proceeded with furan DA chemistry.
The less water-soluble Ph-analogue
the investigation of the furan diene scope, with the focus on could be obtained utilizing our standard protocol, albeit in a
easily accessible biomass-derived 5-substituted 2-furoic acids. low yield and purity (11%, entry 9). As expected, the presence
We found that both the kinetics and the thermodynamics of of a second electron-withdrawing substituent is highly detri-
the reaction are greatly influenced by the nature of the 5-sub- mental for the kinetics of the reaction (and likely also for the
9
,12,34
1
stituent. Expectedly, electron-donating groups (Me) increase thermodynamics
): adducts 3i and 3j (R is CHvO and
the reaction rate (entry 7, see ESI†) while electron-withdrawing COOH respectively) were formed in low amounts in the crude
groups (CHvO, COOH) showed the opposite effect, in line reaction mixtures. On the other hand, with 2 equiv. of NaOH,
with the generally-accepted Frontier Molecular Orbital theory- 2,5-furandicarboxylic acid (FDCA) gave a fast equilibration to
derived interpretation of kinetics in DA reactions. Substitution the exo-bis-Na salt of its adduct with 2a. In this case, isolation
at the furan 5-position, regardless of the nature of the substitu- after acidification was hampered by the highly polar nature, as
ent, not only influences kinetics but also the equilibrium posi- noted previously, and facile cycloreversion of the (neutral)
tion and likely destabilizes the DA adduct with respect to its adduct back to the addends. Noteworthy, all these reactions
addends, plausibly due to increased steric encumbrance in feature high stereoselectivity for the exo adduct, typically above
1
1
3
.
The implication is that the most reactive diene in a series 15 : 1 (with the exception of adduct 3g); the isolated products
does not necessarily lead to the most thermodynamically were single diastereoisomers.
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We then turned our attention to other furoic acid deriva- parent compound 3a under similar conditions (Table 2, entry
tives, such as esters and amides, anticipating that the elec- 2), whereas adduct precipitation likely pushed conversions
tronic properties of the furan diene would not be significantly above 90% for products 3q and 3s by favourably shifting the
different for the substituent series COOH/COOR/CONR
2
.
thermodynamic equilibrium. Thus, the ester and amide
However, the physical properties, water miscibility in particu- derivatives of 2-furoic acid also show good reactivity towards
lar, are certainly strongly modulated by the nature of the sub- maleimides and the aqueous protocol generally allows for a
stituent and this might impact the performance of the facile synthesis and isolation of the corresponding adducts.
aqueous Diels–Alder cycloaddition. This proved indeed to be Again, the reactions feature high stereoselectivity towards the
i
the case (Table 4). The 2-furoic acid esters tested (Me, Et, Pr, exo diastereoisomer (typically >12 : 1, with the exception of
t
Bu) are liquids with poor water miscibility; however, reactions adduct 3s).
still proceeded smoothly with so-called ‘on-water’
activation.
To the best of our knowledge, none of the adducts 3 have
been previously synthesized and characterized. In particular,
4
2,43
For ease of comparison, we employed reaction conditions while acknowledging the fact that the reactive diene is not
similar to those found in the optimization of the cycloaddi- FDCA itself but its Na salt, we would like to highlight the dis-
tions with 1a (1 mL water per mmol, 50 °C, 16 h). The reactiv- tinct nature of this adduct (Table 3) among the typical struc-
4
4,45
ity differences in the ester homologous series were marginal tures of furan DA adducts.
under these conditions. Product properties did vary, however,
as the adducts of the methyl ester turned out to be much more Follow-up chemistry
crystalline than the rest. Simple filtration of the resulting sus-
pensions was sufficient in this case to provide good yields of
pure (exo-) products 3k–m (43–52%). Moreover, the adduct 3l
could be obtained in a much-improved yield (82%), simply by
performing the reaction in more concentrated conditions (see
ESI† for details). Notably, the reactions are clean and the fil-
trate containing unreacted starting materials can readily be
recycled. Such crystallization from the crude reaction mixture
did not occur with higher homologous esters (entries 4–6),
necessitating chromatographic purification to isolate the
adducts. Most likely some cycloreversion occurs in the process,
leading to erosion of the final yield. Finally, 2-furamides were
included in the substrate scope and also proved to be surpris-
ingly reactive dienes (entries 7–9). The water soluble dimethyl-
amide adduct 3r was formed in a comparable yield to the
In addition to their facile preparation, Diels–Alder adducts 3
represent valuable synthons for further synthetic elaboration
(
Scheme 2). To complement the broad synthetic scope of our
2
methodology, diversification at the X- and R -positions in 3
Scheme 2) can also be readily achieved by straightforward
(
transformations of title adducts 3a and 3l: ethyl ester 3n can
be obtained by esterification of 3a in the presence of SOCl2
(
90% yield), whereas alkylation of 3l with benzyl bromide
afforded 3t in 88% yield. Aromatization of the 7-oxanorbor-
nene core by dehydration is a particularly interesting (and
45
extensively studied) transformation, as it provides access to
renewable aromatics based on the carbohydrate fraction of
lignocellulosic biomass. For the substrates studied here, the
presence of an electron-withdrawing substituent at the bridg-
head position in 3 is anticipated to hinder (typically) acid-
mediated dehydration. Nonetheless, preliminary experimen-
4
6
tation indicated that 33 wt% HBr in AcOH is a suitable acid
for the conversion of 3a to phthalimide derivative 4 (66% iso-
Table 4 Scope of DA reaction between 2-furoic acid derivatives (esters,
amides) and maleimides under aqueous conditions
2
a
b
Entry
X
R
3
Conv. 1 exo-3, % endo-3, % Isolated , %
1
2
3
4
5
6
7
8
9
OMe
OMe
OMe
OEt
Me 3k 70
3l 67
65
65
61
59
50
51
91
77
76
5
2
4
4
4
3
3
4
52(74)
43(64)/82
47(72)
29(46)
26(49)
25(46)
77(83)
41(51)
69(75)
c
H
Et 3m 65
Me 3n 63
Me 3o 54
Me 3p 54
Me 3q 94
Me 3r 81
i
O Pr
t
O Bu
NH
NMe
2
2
NHOH Me 3s 92
16
General procedure: 2-Furoic acid derivative and maleimide (1.5 equiv.)
a
Scheme 2 Follow-up chemistry starting with adduct 3. Reagents and
conditions: a. SOCl , EtOH, rt (from 3a); b. BnBr, K CO , DMF, rt (from
2 2 3
stirred in/on water (1 M) at 50 °C for 16 h. Conversion determined
1
from the H-NMR ratios of product isomers and starting material.
b
Isolated yield after (chromatographic) workup (in brackets, yield cor- 3l); c. 33 wt% HBr in AcOH, rt to 60 °C (from 3a); d. 35% HCl, 100 °C
c
rected on reacted starting material). 2 M initial concentration.
2
(from 4); e. H , Pd/C, rt (from 3a).
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lated yield). Acidic hydrolysis of 4 produces in high yield hemi- adduct (the more compact geometry). Both of these hallmarks
mellitic acid 5, an aromatic tricarboxylic acid with potential of the hydrophobic effect are consistently augmented with
4
7,48
application in the polymer and lubricant industry.
Finally, increasing additive concentration. Data in Table 5 summarizes
catalytic hydrogenation towards oxanorbornane derivative 6 the effect of additives on the rate of the cycloaddition between
was also facile.
1a and 2a (0.2 M). The observed yield and stereochemistry are
generally consistent with the expected trends, illustrating that
hydrophobic effect is a relevant influence in this system.
In addition, hydrogen bonding is likely to also play an
important role in our system, for instance by preferentially sta-
Mechanistic understanding
The above shows that furan carboxylic acid derivatives undergo
surprisingly efficient Diels–Alder couplings to maleimides in
aqueous solution. This result challenges the widely accepted
idea that the diene scope in furan Diels–Alder chemistry is
limited to electron-rich derivatives. While the nature of the
furan substituent impacts the cycloaddition kinetics in a rela-
tively predictable manner (the stronger the electron-withdraw-
ing effect, the slower the DA reaction), we would like to note
that moderate thermal activation can provide sufficient accel-
eration for seemingly unreactive inputs such as the 2-furoic
acid derivatives used here; this is particularly true when water
is used as solvent. The effect water has on the reaction can
have multiple causes and may differ for the furoic acids on the
one hand and the esters and amides on the other, depending
on their physical characteristics. The hydrophobic effect is
evidently relevant for the biphasic reactions, but may not play
a decisive role for the highly water-soluble 2-furoic acid sub-
strates. To probe the operation of the hydrophobic effect in
this case, we studied the title reaction between 1a and male-
imide 2a in the presence of salting-in and salting-out reagents
3
7
bilizing the transition state (and product) over the addends.
For example, the electron density around the oxygen atom in
the furan ring expectedly changes significantly during the reac-
tion since aromaticity is lost as the reaction proceeds; more-
over, in the product (and transition state), both oxygen lone
pairs can serve as hydrogen bond acceptors. In addition, the
engagement of the COOH group as H-bond donor in inter-
actions with surrounding water molecules increases the elec-
tron density around the furan ring and thus the rate of the DA
coupling. Indeed, the addition of base is the extreme case of
this, i.e. leading to complete proton transfer, as illustrated by
the observations that 2-furoate salts already react with malei-
mides at ambient temperatures and that the bis-Na salt of
FDCA is, counter to expectation, a reactive diene. It is impor-
tant to also note that in base-mediated reactions the thermo-
dynamics is favourably impacted as well: adduct 3a is roughly
4
9
4
times more acidic than the starting 2-furoic acid 1a (ΔpKa
approx. 0.6, see ESI†), which supplies an additional −3.6 kJ
mol to the ΔG °3 23 K, sufficient to render the reaction essen-
tially irreversible (>95% equilibrium conversion, see Table 2,
entry 4 vs. entry 2).
−1
(Table 5). The effect of salt additives on the rate of aqueous
5
0
Diels–Alder reactions has been extensively studied.
general, salting-out reagents (e.g. simple inorganic salts like
In
When 2-furoic acid esters are used as dienes, the system is
no longer homogeneous and the reactions proceed ‘on-water’.
Hydrophobic interactions and hydrogen bonding with water
molecules at the interface play an activating role here, together
with the high local concentration effect (in neat conditions for
example, the reaction also proceeds readily, but conversion is
hampered by the poor solubility of 2a in methyl furoate). In
addition, the yield of adduct formed, i.e. the ultimate
NaCl and CaCl ) lead to rate enhancements, whereas additives
2
that disturb hydrophobic interactions like guanidinium (Gn)
5
1
salts characteristically retard conversion.
In addition,
enhanced hydrophobic interactions are typically associated
with an increased preference for the endo configuration of the
Table 5 DA reaction between 2-furoic acid 1a and maleimide 2a in efficiency of the reaction, is definitely impacted by the crystalli-
aqueous solution: effect of additives
zation of the product; this improves kinetics by reducing the
rate of the back reaction and pushes the conversion beyond
the solution equilibrium. Indeed, in all examples where
product crystallization occurred, increased conversions were
obtained (e.g. Table 4, entries 1, 7 and 9).
Finally, furamides show comparable behaviour to the
parent furoic acids, as the aqueous reactions commence
exo-
endo-
Total, endo
homogeneously at 50 °C. In terms of kinetics, furamides are
likely somewhat more reactive than furoic acids, while the ten-
dency of the corresponding adducts to crystallize out of
aqueous solution is more pronounced. For instance, with
unsubstituted 2-furamide precipitation was observed within
minutes (at 50 °C), benefiting conversion. In the absence of
product crystallization (entry 8, Table 4, adduct 3r) the
efficiency of the reaction is lower and quite comparable to the
case of parent furoic acid 1a under similar conditions (entry 2,
Table 2).
Entry Additive Amount 3a, % 3a, %
%
selectivity, %
1
2
3
4
5
6
None
NaCl
NaCl
NaCl
n/a
39
42
43
43
50
37
5
5
7
9
9
4
44
47
50
52
59
41
13
12
16
22
18
11
1 M
2 M
4 M
2 M
2 M
CaCl
GnCl
2
a
General procedure: 2-Furoic acid 1a (0.5 mmol), (additive) and
N-methyl maleimide 2a (1.5 equiv.) stirred in H O (0.2 M) at 50 °C for
h; yields determined from the H-NMR ratios of product isomers and
2
1
6
a
starting material. GnCl = guanidinium chloride.
5508 | Green Chem., 2021, 23, 5503–5510
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Conflicts of interest
20 B. Wang, G. J. M. Gruter, M. A. Dam and R. M. Kriegel,
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There are no conflicts to declare.
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Acknowledgements
This work was supported by The Netherlands Organization for
Scientific Research (NWO LIFT grant 741.018.408).
Dr T. N. Ran and Dr J. T. B. H. Jastrzebski (Utrecht University)
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9
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5510 | Green Chem., 2021, 23, 5503–5510
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