Reaction of N-heterocyclic carbaldehydes with furanones – An investigation of reactivity and regioselectivity

Article abstract of DOI:10.1016/j.tet.2017.06.012

The aldol reaction of N-heterocyclic carbaldehydes with furan-2-ones has been investigated. Very mild and metal-free reaction conditions have been applied. The substitution pattern of the product was found to be controlled by the aldehyde. A detailed inve

Full text of DOI:10.1016/j.tet.2017.06.012

Accepted Manuscript
Reaction of N-heterocyclic carbaldehydes with furanones – An investigation of
reactivity and regioselectivity
Fabian Uhrner, Felix Lederle, Jan C. Namyslo, Mimoza Gjikaj, Andreas Schmidt, Eike
G. Hübner
PII:
S0040-4020(17)30631-2
10.1016/j.tet.2017.06.012
TET 28777
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 April 2017
Revised Date: 2 June 2017
Accepted Date: 6 June 2017
Please cite this article as: Uhrner F, Lederle F, Namyslo JC, Gjikaj M, Schmidt A, Hübner EG, Reaction
of N-heterocyclic carbaldehydes with furanones – An investigation of reactivity and regioselectivity,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.06.012.
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ACCEPTED MANUSCRIPT
Reaction of N-heterocyclic carbaldehydes
Leave this area blank for abstract info.
with furanones – an investigation of
reactivity and regioselectivity
Fabian Uhrnera , Felix Lederlea , Jan C. Namysloa , Mimoza Gjikajb , Andreas Schmidta and Eike G. Hübnera,*
a Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstraße 6, DE-38678 Clausthal-
Zellerfeld, Germany
b Clausthal University of Technology, Institute of Inorganic and Analytical Chemistry, Paul-Ernst-Straße 4, DE-
38678 Clausthal-Zellerfeld, Germany

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Reaction of N-heterocyclic carbaldehydes with furanones – an investigation of
reactivity and regioselectivity
Fabian Uhrnera , Felix Lederlea , Jan C. Namysloa , Mimoza Gjikajb , Andreas Schmidta and Eike G.
Hübnera,*
a Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstraße 6, DE-38678 Clausthal-Zellerfeld, Germany
b Clausthal University of Technology, Institute of Inorganic and Analytical Chemistry, Paul-Ernst-Straße 4, DE-38678 Clausthal-Zellerfeld, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The aldol reaction of N-heterocyclic carbaldehydes with furan-2-ones has been
investigated. Very mild and metal-free reaction conditions have been applied. The
substitution pattern of the product was found to be controlled by the aldehyde. A
detailed investigation of the reactivity has been performed and the surprising regio-
and diastereoselectivity has been elucidated with the help of 2D-NMR techniques.
Here, we report on a convenient way to N-donor functionalized lactones, which had
scarcely been examined before.
Available online
Keywords:
Aldol reaction
Furanones
Lactones
N-Heterocyclic carbaldehydes
Regioselectivity
2009 Elsevier Ltd. All rights reserved.
1. Introduction
The aldol reaction of -angelica lactone (2) with aliphatic and
nitrogen-free aromatic aldehydes can be performed at milder
The base catalyzed aldol reaction of various aldehydes with 5-
membered ring lactones such as -butyrolactone (1), -angelica
lactone (2), and -crotonolactone (3) is a long known and
convenient way to - and -substituted butyrolactones. The
resulting structure motif is found in several bioactive compounds
such as losigamone as potential anticonvulsant,1 metabolites of
epicatechin2 and precursors for drugs such as physovenine
analogs3, protease inhibitors4 and several more5–7 (Figure 1).
conditions. In the presence of sodium acetate, several -
arylidene-5-methylfuran-2(3H)-ones have been isolated.15 In the
presence of amines such as HNEt2 or NEt3 as base, condensation
towards the -substituted derivates has been achieved.16–20 In the
additional presence of Bu2BOTf and at low temperatures, aldol
addition with aliphatic aldehydes towards the -(1-
hydroxyalkyl)-5-methylfuran-2(3H)-ones takes place.21 By
reaction with enals such as 1-pentenal and in presence of an
organocatalyst, vinylogous Michael aldol addition in -position
has been observed.22 In the case of -crotonolactone (3), the
lithiated butenolide has been reported to react with aliphatic
aldehydes towards a mixture of -(1-hydroxyalkyl)furan-2(5H)-
ones
and
-(1-hydroxyalkyl)furan-2(5H)-ones
at
low
temperatures.23,24 Aromatic aldehydes preferably form the -
adduct at the same reaction conditions.2,24 Applying milder
conditions at ambient temperature with secondary or tertiary
amines as base, aromatic non-N-heterocyclic aldehydes lead to
the -adduct, again. Condensation towards the -arylidene-furan-
2(5H)-ones is likely to happen subsequently.25–28 ,-Unsaturated
aldehydes lead to -Michael addition under comparable
conditions.29 In the presence of boron and tin compounds,
mixtures of - and -addition with a preference for the -position
have been obtained.30 Various (organo)catalysts featuring -
addition of nitrogen-free aromatic aldehydes providing additional
diastereo- and/or enantioselectivity of the resulting -(1-aryl-1-
hydroxymethyl)butenolides are known.31–35 Furthermore, -
addition may be forced by a synthetic pathway via aluminum
Fig 1. Losigamone (left) and one metabolite of epicatechin
(right).
The reaction of -butyrolactone (1) with aliphatic and nitrogen-
free aromatic aldehydes has been investigated in detail. Upon
deprotonation in -position (typically with sodium methoxide),
the aldol condensation products -arylidene/-alkylidene-
dihydrofurans are formed in good yields.3,8 At low temperatures,
the product of the aldol addition may be isolated. The choice of
the present metal ions (Li+ vs. additional Zn2+) allows controlling
syn/anti
configuration
of
the
resulting
-(aryl-
hydroxymethyl)dihydrofuranones.9 Various aldehydes and
variants of the reaction conditions, in some cases by activation of
-butyrolactone via reactive intermediates, have been applied.10–14

2
Tetrahedron
ACCEPTED MANUSCRIPT
enolates.36,37 Frequently, the butenolide is converted into a
protons in -position of the lactone ring. To compare the stability
2-trialkylsilyloxyfuran prior to aldol addition.38–40 In the presence
of dialkylzinc, aldol addition in -position takes place,
accompanied by reduction of the double bond.41,42 In a three-
component reaction, PhSLi and aryl aldehydes lead to -addition
of the aldehyde, accompanied by -addition of the thiolate.43 Due
to the large interest in the structure motif, additional pathways to
a large variety of -arylidenefuran-2(3H)-ones have been
investigated.44
of the anions, the deprotonation energies (Edep,rel) were
calculated on the LACVP**/PBE0 level of theory and are
discussed relative to the deprotonation energy of 1 in -position.
The reactivity of the aldehydes towards an attack of a nucleophile
was estimated by the global electrophilicity index °,55 and the
reactivity of the nucleophilic anions by the energy of the highest
occupied molecular orbital (HOMO).56 To compare the
nucleophilicity of the - and -position, additionally Fukui
indices57 (fk ) and plots of the Fukui f– function58 have been
–
Surprisingly, the reaction of N-heterocyclic aldehydes with the
aforementioned lactones has scarcely been investigated up to
now. Pyridinecarboxaldehydes have been reported to yield
unidentified tars upon reaction with -butyrolactone (1) in the
presence of NaOMe.8 One reference claims the reaction of
pyridinecarboxaldehydes with -angelica lactone (2) in the
presence of HNEt2 towards the ,-bis-substituted lactones,
probably by two consecutive aldol additions, to take place.45
calculated if appropriate. The anion of 1 shows an obvious
indication for enolization, visible by the calculated CO-C bond
length of 1.387 Å. Nevertheless, Cis still in posession of a
negative charge of -0.65 e (NBO charges) and is the most
nucleophilic position (fk– = 0.61). Interestingly, after formation of
-(hydroxy(phenyl)methyl)dihydrofuranone (1a) as isolable
intermediate9 the deprotonation of the remaining hydrogen in -
position is favoured by 60 kJ/mol compared to 1. In practice, no
indication for twofold addition is found. This is explained by the
strongly reduced nucleophilicity of the anion of 1a, indicated by
a lowering of the energy of the HOMO by 0.8 eV. Accordingly,
condensation towards the conjugated benzylidene 8 is favoured
instead of a second nucleophilic attack of 7. Performing the same
reaction with 4-pyridinecarboxaldehyde (4) instead of
benzaldehyde (7) did not lead to any well-defined reaction
products, even at low temperatures. This is in consistency with
literature.8 Chosing mild reaction conditions with diethylamine as
weak base did not lead to any reaction with 4 or 7 at all.
Benzofuran-2(3H)-one
substituted derivatives
yields
the
-pyridinylmethylene
treatment with
upon
pyridinecarboxaldehydes46 via aldol condensation in analogy to
the synthesis of marginalin from 2-coumaranone and p-
hydroxybenzaldehyde.47 -Crotonolactone (3) reacts in a two-step
conjugated addition-alkylation with lithiated dithianes and
pyridinecarboxaldehydes
to
the
-(1- hydroxy-1-
pyridinylmethyl)--(dithianyl)dihydrofuranones.48,49
Here, we present an investigation of the reactivity and
surprising
regioselectivity
of
the
reaction
of
4-
pyridinecarboxaldehyde (4), N-methylpyrazole-4-carboxaldehyde
(5), and N-methylimidazole-5-carboxaldehyde (6) with -
angelica lactone (2) and -crotonolactone (3) under very mild and
metal-free conditions. Our motivation is based on the prospective
use of the N-donor functionalized lactones as comonomers for
the ring-opening polymerization50,51 with lactide to yield metal
ion crosslinked and stabilized polylactides. These are of certain
interest as improved 3D-printing materials.52–54
Consequently, -angelica lactone (2) was chosen as substrate.
Delocalization stabilizes the anion of 2 by 76 kJ/mol (Scheme 2).
According to literature, the formation of the ,-bis(pyridinyl)-
substituted lactone should be expected upon treatment of 2 with 4
in presence of HNEt2.45 While the isolated product revealed a
mass peak of m/z = 313.0 matching the proposed structure, NMR
spectra revealed a mixture of isomers in the ratio of roughly 1:1.
With the help of reversed phase column chromatography, one
isomer could be purified and finally the structure was resolved as
the ,-bis-substituted derivative 3,5-bis(hydroxy(pyridin-4-
yl)methyl)-5-methylfuran-2(5H)-one (9). According to the NMR
data, both obtained diastereomers belong to the same type of
regioisomer. In both cases a clear set of cross signals of HMe with
7-Cand 7-H with CMe is observed in the Heteronuclear Multi
Bond Correlation (1H,13C-HMBC) NMR spectra. The formation
of this regioisomer may be described by a pathway given in
Scheme 2. The anion of 2 shows a rather strong localization of
the negative charge in -position (-0.57 e).
2. Results and Discussion
The well-known reaction of -butyrolactone (1) with
benzaldehyde (7) was chosen as starting point (Scheme 1).
According to literature, (E)-3-benzylidendihydrofuran-2-one (8)
is formed in good yields in the presence of NaOMe as base.
Basically, we followed a known literature procedure,14 but
performed the reaction at 0 °C to maintain exactly the same
temperature profile for all reactions discussed. The sole isolated
condensation product 8 was confirmed to have E-configuration
by a strong NOE visible in 1H,1H-Nuclear Overhauser Effect
Spectroscopy (NOESY) between the o-benzyl protons and the
Scheme 1. Reaction of benzaldehyde (7) with -butyrolactone (1).

3
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Scheme 2. Reaction of 4-pyridinecarboxaldehyde (4) with -angelica lactone (2) (top) and -crotonolactone (3) (bottom).
Nevertheless, the nucleophilicity of the - and -position is quite
similar according to their Fukui indices and even more with
regard to the more accurate Fukui f– function (Figure 2). The
reactivity of the anion is quite comparable to the reactivity of the
anion of -butyrolactone (1) according to the energy of the
HOMO. Upon reaction at the -position (which may be assumed,
since addition in -position would lead to an olefinic hydrogen in
-position which is unlikely to be deprotonated subsequently), 3-
(hydroxy(pyridin-4-yl)methyl)-5-methylfuran-2(3H)-one (2a) is
formed. The deprotonation of this intermediate is again favoured
by ~60 kJ/mol compared to 2 whereas the reactivity of the anion
is reduced. This is indicated by the lowering of the energy of the
HOMO of the anion of 2a by 1.0 eV. Nevertheless, a second
aldol addition can take place because the reactivity of 4-
pyridinecarboxaldehyde (° = 2.2 eV) is significantly increased
compared to benzaldehyde (° = 1.7 eV) according to their
global electrophilicity indices. This is in consistency with an
electron-poor 6-membered ring N-heterocyclic aromatic
carbaldehyde. The increased reactivity overcompensates the
decrease of nucleophilicity of the anion of 2a. Again, the second
nucleophilic attack may be induced from - or -position
according to the Fukui f– function (Figure 2). Reaction at -
position finally leads to regioisomer 9 as a mixture of two
diastereomers. Switching to -crotonolactone (3) as substrate for
the reaction with 4-pyridinecarboxaldehyde (4) leads to a
comparable reactivity (Scheme 2). The main mass peak at m/z =
406.2 indicated threefold aldol addition. The sole isolated
reaction product was identified as one main diastereomer of
3,5,5-tris(hydroxy(pyridin-4-yl)methyl)furan-2(5H)-one
(10).
Due to three rather similar pyridine moieties, the NMR data were
not straightforward to assign. The two hydroxymethylpyridine
residues in -position are either heterotopic (R*/S*) attached to
C as stereo centre or diastereotopic (R*/R*) with C as non-
stereogenic in this case, but leading to a unique set of signals in
the NMR spectra in any case. Identification of the spin systems
1
via Total Correlation Spectroscopy (TOCSY) and H,15N-HMBC
allowed to determine the regioisomer 10 unambiguously.
Significant proofs are two cross signals of HOC6A and HOC6B
with C and just one cross signal of 10-H with C=O in the
4
1H,13C-HMBC NMR spectra as well as the allylic JH,H coupling
of 10-H with H. The reaction sequence may be discussed in
analogy to the reactivity of -angelica lactone (2) (Scheme 2).
The Fukui f– function of the anion of 3 is closely related to the
electron density of the HOMO (see Fig. S2 and S3 of the
supplementary material) and features nucleophilicity in - and -
position. It should be noted, that for the reaction of the first
equivalent of 3 with 4 an alternative pathway according to
Baylis-Hillman leading to 3-(hydroxy(pyridin-4-yl)methyl)furan-
2(5H)-one (3b) may be followed. The reaction conditions applied
here are rather close to typical Baylis-Hillman conditions with

4
Tetrahedron
ACCEPTED MANUSCRIPT
a
b
c
d
Fig 2. Plot of the Fukui f– function of the anion of -angelica
lactone (2) (a), 3-(hydroxy(pyridin-4-yl)methyl)-5-methylfuran-
2(3H)-one (2a) (b), 3-(hydroxy(pyridin-4-yl)methyl)furan-2-one
(3a/b) (c), and 3,5-bis(hydroxy(pyridin-4-yl)methyl)furan-2(5H)-
one (3c) (d). Areas in red indicate large negative values and
correspond to nucleophilic centres.
Scheme 3. Reaction of N-methylpyrazole-4-carboxaldehyde (5)
with -angelica lactone (2).
first hydroxymethylpyridine moiety in -position. For the two
hydroxymethylpyridine residues in -position of 10, finally
(R*/R*) configuration has to be assumed to reduce the number of
possible diastereomers. From the NMR data, it is not possible to
determine wether the overall configuration of the
hydroxymethylpyridine units is (R*/R*/R*) or (S*/R*/R*).
The discussion of the stereochemical induction nicely matches
with the observation of two diastereomers for 9. Again, the
hydroxymethylpyridine moiety in -position of the anion of 2a
sterically demanding amines as base. Furan-2(5H)-one (3) has
been applied as substrate for Baylis-Hillman reactions with
benzaldehyde (7) in presence of more complex catalytic
systems.59,60 The Baylis-Hillman product 3b is more stable by 30
kJ/mol compared to the product of the aldol addition in -
position (3a) due to conjugation, but in either case deprotonation
of both 3-(hydroxy(pyridin-4-yl)methyl)furan-2-ones (3a/3b) is
favoured in comparison to 3 and the same anion is achieved. The
Fukui f– function indicates a comparable nucleophilicity of the -
and -position again (Figure 2). Since aldol addition in -position
would not allow for a subsequent third aldol addition, and in
analogy to the reaction of 2, 3,5-bis(hydroxy(pyridin-4-
yl)methyl)furan-2(5H)-one (3c) may be assumed to be formed as
intermediate. The reactivity of the corresponding anion is
reduced with each substitution step. For the anion of 3c, the
energy of the HOMO is lowered by 1.6 eV compared to the anion
of 3. Even this strong reduction of the nucleophilicity is
may
control
the
configuration
of
the
second
hydroxymethylpyridine unit introduced in -position by 1,5-
induction. Since C itself remains as a stereo centre in this case,
the number of possible stereoisomers is not reduced and the two
adjacent stereocentres lead to the two isolated diastereomers. The
overall configuration of 9 consequently is (R*/RC,*/R*) or
(S*/RC,*/R*) for one diastereomer and (R*/SC,*/R*) or
(S*/SC,*/R*) for the second diastereomer.
It should be noted, that a second explanation for the isolation
of just one diastereomer of 10 and two diastereomers of 9 may be
overcompensated
by
the
highly
reactive
4-
given
by
the
assumption
of
apparent-equivalent
pyridinecarboxaldehyde. The third nucleophilic attack may be
induced from - or -position according to the Fukui f– function
(Figure 2) and finally 10 is formed by aldol addition in -
position.
diastereoisomers.63 In these cases, isolated stereocentres of a set
of diastereomers lead to identical NMR spectra. Consequently, it
would not be possible to distinguish between (R*/R*/R*) and
(S*/R*/R*) configuration of 10. Since the minimum distance of
at least five carbon atoms between the stereogenic atoms has
been determined to achieve segregation of the stereoclusters,63
this seems rather unlikely in the case of 9 and 10 (bridge of three
carbon atoms).
Special attention is given to the striking fact, that only one
diastereomer of 10 is isolated in 87 % yield. Starting from the
beginning of the reaction sequence for the formation of 3a, some
syn/anti preference comparable to classic or Mukaiyama aldol
addition of cyclic enolates may be discussed (despite the absence
of chelating metal ions). In any case, the deprotonation of 3a
leads to an intermediate anion with just one remaining stereo
centre adjacent to the -position. To explain the overall
diastereoselectivity, an 1,5-induction for the subsequent second
aldol addition may be assumed. Consequently, the
stereochemistry of the second stereo centre attached to the -
position (3c) would be controlled by the -substituent. It is
noteworthy to point out the structural similarity of the system
with the well-known 1,5-asymmetric induction of aldol reactions
with boron enolates reported by Evans and Paterson.61,62 The
third aldol addition may be controlled by an 1,3-induction of the
The reactivity of N-methylpyrazole-4-carboxaldehyde (5) as
electron-rich 5-membered ring N-heterocyclic aromatic
carbaldehyde
significantly
differs
from
4-
pyridinecarboxaldehyde (4). For the reaction of 5 with -angelica
lactone (2), the Knoevenagel condensation product (E)-5-methyl-
3-((N-methylpyrazol-4-yl)methylene)furan-2(3H)-one (11) is
obtained in acceptable yields (Scheme 3). The reactivity is
explained rather straightforward keeping in mind the electronic
properties given in Scheme 2 as discussed before. After
deprotonation of 2, nucleophilic attack of 5 is induced from -
position. The deprotonation of the intermediate 5-methyl-3-
(hydroxy(N-methylpyrazol-4-yl)methyl)furan-2(3H)-one (2b) is
favoured again, but the reduced nucleophilicity of the anion of 2b

5
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Fig. 3. Molecular
structure
of
(E)-5-methyl-3-((N-
methylpyrazol-4-yl)methylene)furan-2(3H)-one (11); thermal
ellipsoids are drawn at the 50 % probability level. Selected bond
lengths [Å], angles [°] and dihedral angles [°]: d(C1–C) =
1.478(6), d(C–C) = 1.451(12), d(C–C) = 1.332(0), d(C–C8)
= 1.350(2), d(C1–O6) = 1.220(12), C,C,C) = 133.90(1),
Scheme 4. Reaction of N-methylimidazole-5-carboxaldehyde (6)
with -angelica lactone (2) (top) and -crotonolactone (3)
(bottom).
C,C8,C14)
= 128.80(2), (C,C,CC13) = 0.01(1),
(O6,C1,CC8) = -0.97(3), (C,C,C8C14) = 0.52(3).
(EHOMO is lowered by 0.6 eV compared to the anion of 2)
prohibits a second nucleophilic attack of 5. The reactivity of 5
The treatment of -crotonolactone (3) with 6 revealed a
comparable reactivity. The reaction proceeded slightly faster and
nucleophilic attack from the -position of the anion of 3 towards
6 led to 5-(hydroxy(N-methylimidazol-5-yl)methyl)furan-2(5H)-
one (13) in acceptable yields. The structure was readily
confirmed as the NMR data are in good agreement with 12. The
protons in - and -position show a rather interesting coupling
pattern as both are represented by a similar doublet of doublets at
(° = 1.3 eV)
is
remarkably
lower
than
of
4-
pyridinecarboxaldehyde (4). Consequently, the elimination of
water probably according to an E1cb-mechanism from the
stabilized anion of 2b towards the highly conjugated
condensation product 11 is favoured. A strong NOE of the
pyrazole protons with the -H of the lactone ring has been
observed by NOESY, and consequently E-configuration has been
assumed. Finally, a single-crystal X-ray structure determination
unambiguously revealed the regio- and stereochemistry of 11
(Figure 3). The dihedral angle C-C-C14-C13 = 0.01(1) °
demonstrates the perfect planarity of the molecule due to the
delocalized -electron system throughout the whole molecular
structure.
3
6.19 and 7.74 ppm. This is explained by a virtually identical JH,H
coupling constant (2.0 Hz) of H with H due to the Karplus
4
relation63 and JH,H coupling constant (1.7 Hz) of H with H. In
contrast to the reaction of aromatic aldehydes with 3 in presence
of piperidine reported in literature,27 the condensation product 5-
(N-methylimidazol-5-yl)methylene)furan-2(5H)-one was not
observed. This may be explained by the mild temperature profile
applied here. Additionally, and in contrast to 11, favourable
conjugation of the exocyclic double bond with the carbonyl
group would be missing in the condensation product. Overall,
although the deprotonation of 13 may proceed easily (Scheme 4),
neither E1cb elimination nor second aldol addition (explained by
the low reactivity of 6 and the anion of 13) nor rearrangement to
the unfavoured non-delocalized tautomer 13b is observed
(Scheme 4).
For the reaction of N-methylimidazole-5-carboxaldehyde (6)
with -angelica lactone (2) again a single aldol reaction step is
expected due to the low reactivity of 6 (° = 1.5 eV). Indeed, the
mass spectra revealed a peak at m/z = 209.1 indicating single
aldol addition. The 1H-NMR spectrum of the sole isolated
diastereomer showed a set of doublets at 6.08 and 7.80 ppm for
the olefinic protons in - and -position, respectively. This is
rather unique and in agreement with a series of -arylidene-furan-
2(5H)-ones.27 The -addition is unambiguously confirmed by a
cross signal of the methyl group in -position (HMe) with the
For the sole isolated diastereomer 13 the question of the
syn/anti configuration preferably formed is of certain interest.
For -hydroxycarbonyl compounds obtained by aldol addition,
the chemical shift of the HC(OH) proton is often used as
indication due to single bond anisotropy. Unfortunately, this can
not directly be transferred to the situation of 13. Straightforward
assignment is generally known to be rather prone to error.64
Furthermore, the NMR data given in literature for similar
compounds are contradictory, for example HC(OH) of 5-
(hydroxy(phenyl)methyl)furan-2(5H)-one is reported at 5.09 ppm
(syn), 4.70 ppm (anti)24 and vice versa (5.19 ppm (anti), 4.71
ppm (syn)39). Consequently, we applied the Murata method64–67
(J-based analysis) to elucidate the configuration of 13. Obtaining
good NMR data of 13 was rather challenging since good solvents
such as DMSO-d6 led to extremely broad peaks while the
1
carbon atom of the hydroxymethyl moiety (7-C) in the H,13C-
HMBC spectra. Obviously, the nucleophilic attack of the anion
of 2 (Scheme 2) towards 6 is induced from the -position in this
case. This is possible according to the Fukui f– function (Figure
2). The regioselectivity is in clear contrast to the formation of 11.
The aldol addition leads to 5-(hydroxy(N-methylimidazol-5-
yl)methyl)-5-methylfuran-2(5H)-one (12) which is free of
remaining acidic protons (Scheme 4). Additionally, the methyl
group in -position prevents condensation towards the
corresponding arylidene. It has to be noted, that the reaction is
very slow. The yield of 11 % was achieved after several days
while extremely slow product precipitation was still ongoing.

6
Tetrahedron
2
solubility in MeCN-d3 is poor. The NOESY spectra of 13
7A-H/7B-H and the corresponding JH,Hcouplingwhich allows
ACCEPTED MANUSCRIPT

already gave an indication for the presumable configuration,
because only the (R*/R*) isomer may satisfy all significant cross
signals of the NOESY data (H/6-H, MeImi/6-H, MeImi/H) while
at the same time a cross signal of MeImi and HImi with H and H
is absent at any mixing time (see Figure S1 of the supplementary
material for visualization). The resulting geometry is backed by a
2JC,H coupling constant of 6-H with C of 2 Hz measured by
Heteronuclear Single Quantum Multiple-Bond Correlation
to assign the structure of 14 unambiguously.
3. Conclusion
The aldol reaction of N-heterocyclic aldehydes with furan-2-
ones had scarcely been investigated before. Applying the same
reaction conditions for the aldol reaction of -angelica lactone
(2) and -crotonolactone (3) with 4-pyridinecarboxaldehyde (4),
N-methylpyrazole-4-carboxaldehyde (5) and N-methylimidazole-
5-carboxaldehyde (6) in the absence of chelating metal ions, an
interesting regioselectivity was resolved. The reactivity can be
explained in the context of quantum mechanical reactivity
indices. The isolated products were investigated by NMR
spectroscopy in detail and the resulting regioisomers have been
identified unequivocally. The regioselectivity of the aldol
addition has to be dominated by the aldehyde since the anions of
2 and 3 provide comparable nucleophilicity in - and -position.
The following observations were made:
2
(HSQMBC) as a key step of the J-based analysis. The JC,H
coupling constant follows a Karplus-like relation for the
orientation of the H-C-C-O dihedral angle.68 For the given
substitution pattern, the geometry assumed from the NOE data
with (H-C-C-O) roughly between ±135 ° and 180 ° matches the
3
observed coupling constant. Finally, the JH,H coupling constant
of 6-H with H (5.7 Hz) can be brought in agreement with the
structure as well (following the Karplus relation63 (H-C-C-O) =
147 ° is concluded). Overall, this may be seen as a coherent
indication for syn-configuration of (R*/R*)-13. Nevertheless, it
should be noted that free rotation may lead to wrong
interpretation of coupling constants (averaging) and the absence
of NOE is not a final proof. The preferred formation of the syn
diastereomer of 13 is not in accordance with results obtained for
the -aldol addition of 3 to non-heterocyclic aromatic aldehydes
in presence of NEt3. In these cases, a preference (2:1) for the anti
diastereomer is reported.34

4-Pyridinecarboxaldehyde (4) as highly reactive N-
heterocyclic aromatic aldehyde leads to subsequent aldol
addition alternately in - and -position of 2 and 3 until all
acidic protons are replaced.

N-Methylpyrazole-4-carboxaldehyde
(5)
and
N-
methylimidazole-5-carboxaldehyde (6) as barely reactive N-
heterocyclic aromatic aldehydes lead to a single aldol
reaction in - or -position, respectively. This is explained
by the significantly reduced nucleophilicity of the anion of
the first aldol addition product.
The hydrogenation of arylidenedihydrofuranones is
a
convenient method to achieve functionalized butyrolactones or
subsequently tetrahydrofurans from the corresponding
furanones.14 The exocyclic double bond of (E)-3-
benzylidendihydrofuran-2-one (8) is readily reduced with Pd/C at
ambient temperature and atmospheric pressure to -benzyl--
butyrolactone.14 The hydrogenation of -angelica lactone to -
valerolactone proceeds at mild conditions as well.69
Consequently, we investigated the hydrogenation of (E)-5-
methyl-3-((N-methylpyrazol-4-yl)methylene)furan-2(3H)-one
(11). The highly delocalized system unsurprisingly did not show
any indication for hydrogenation at moderate conditions. At
elevated temperatures, and with alcohols as typical solvent for
the Pd-catalyzed hydrogenation, side reactions such as ring-
opening were notified. Consequently, dry THF was applied as
solvent although a lowering of the catalyst activity must be
assumed. Finally, a hydrogen pressure of 40 bar at 50 °C led to
complete hydrogenation of 11. 5-Methyl-3-((N-methylpyrazol-4-
yl)methyl)dihydrofuran-2-one (14) was isolated as racemic
mixture within 24 h without the formation of byproducts
(Scheme 5).

After aldol addition of N-methylpyrazole-4-carboxaldehyde
(5) in -position of -angelica lactone (2), subsequently
immediate condensation to the highly conjugated arylidene
takes place.
Overall, the reaction of furan-2-ones with N-heterocyclic
carbaldehydes offers a convenient way to N-donor functionalized
lactones. Current work focuses on attempts to exploit the large
difference in the reactivity of the carbaldehydes to obtain
multiply and differently substituted lactones.
4. Experimental section
If not noted differently, all chemicals were bought from
Sigma–Aldrich and used as received. Diethyl ether and toluene
were passed through a PS-MD-4 solvent purification system
(inert technology) for drying
(<10 ppm H2O). 4-
Pyridinecarboxaldehyde and benzaldehyde were distilled before
use. -Butyrolactone (VWR International GmbH) was dried over
molecular sieve (4 Å) and distilled before use. Furan-2(5H)-one
and -angelica lactone (TCI Europe GmbH) were distilled before
use. Sodium methoxide was freshly prepared from methanol and
sodium and dried in vacuo before use. Silica gel 60 was used for
column chromatography. IR spectra: Bruker Alpha-T FT-IR
spectrometer (Bruker Coporation). For ATR measurements, a
Platinum diamond-ATR unit was used. NMR spectra: Bruker
Avance 400 (Bruker Corporation) (400 MHz (1H), 100 MHz
(13C)) and Avance III 600 (600 MHz (1H), 150 MHz (13C)) FT-
NMR spectrometer. Chemical shifts are given in ppm relative to
tetramethylsilane (δ = 0.0) or the residual solvent signal of the
deuterated solvent. 2JH,C coupling constants have been determined
with a pure in phase HSQMBC (pipshsqmbc).70 Mass spectra:
Varian 320 MS TQ (Agilent Technologies) mass spectrometer at
30 eV and 70 eV for EI mass spectra and for CI mass spectra. HP
1100 Series (Hewlett-Packard) LC/MS mass spectrometer for
ESI mass spectra. For CI, methane was used as ion source gas.
Scheme 5. Hydrogenation of 11 to 5-methyl-3-((N-
methylpyrazol-4-yl)methyl)dihydrofuran-2-one (14).
The progress of the reaction is indicated by the vanishing of
the yellow colour of the solution. The IR spectra of 14 clearly
indicate the loss of delocalization by a shift of the carbonyl
1
vibration from 1748 cm-1 (11) to 1761 cm-1 (14). The H-NMR
spectra of 14 show a rather complicate set of signals which is
owed to the two sets of diastereotopic protons of HH and

7
4.2. General procedure for the reaction of furan-2-ones with N-
heterocyclic carbaldehydes
Melting points are uncorrected and were determined with a Stuart
SMP3 apparatus (Barloworld Scientific Ltd.).
ACCEPTED MANUSCRIPT
X-Ray structure analysis for 11 (C10H10N2O2, M = 190.20
g mol–1): A suitable single crystal of 11 was selected under a
polarization microscope and mounted in a glass capillary (d = 0.3
mm). The crystal structure was determined by X-ray diffraction
analysis using graphite monochromated Mo-K radiation
(0.71073 Å) [T = 223(2) K], whereas the scattering intensities
were collected with a single crystal diffractometer (STOE IPDS
II). The crystal structure was solved by Direct Methods using
SHELXS-97 and refined using alternating cycles of least squares
refinements against F2 (SHELXL-97).71 All non-H atoms were
located in Difference Fourier maps and were refined with
anisotropic displacement parameters. The H positions were
determined by a final Difference Fourier Synthesis.
A solution (0.05 mol-%) of the appropriate furan-2-one (1 eq.)
in dry diethyl ether (DEE) was mixed with the N-heterocyclic
carbaldehyde (1, 2 or 3 eq.) under a nitrogen atmosphere at 0 °C.
After stirring for 30 min, excess dry diethylamine (4 eq.) was
added dropwise. Stirring was continued for 30 min. The solution
was allowed to warm up over night and the product usually
precipitated as fluffy powder. The precipitate was washed with
cold DEE and dried in vacuo.
4.3. 3,5-Bis(hydroxy(pyridin-4-yl)methyl)-5-methylfuran-2(5H)-
one (9)
Following the general procedure, -angelica lactone (0.92
mL, 1.00 g, 10.19 mmol) and 4-pyridinecarboxaldehyde (1.92
mL, 2.182 g, 20.38 mmol) were used. 9 was obtained as white
powder as a mixture of two stereoisomers. Yield: 1.664 g (52 %).
Recrystallization from acetone or reversed phase column
chromatography (RP-18, MeOH : CHCl3 1 : 1 v/v, Rf = 0.50) led
to one pure isomer. Yield: 0.648 g (20 %). M.p. 178 – 180 °C
11 crystallized in the monoclinic space group P2/c (no. 14),
lattice parameters a = 3.921(1) Å, b = 24.441(6) Å, c = 9.642(3)
Å,  = 97.10(2)°, V = 916.9(4) Å3, Z = 4, dcalc. = 1.378 g cm–3,
F(000) = 400 using 1575 independent reflections and 168
parameters. R1 = 0.0672, wR2 = 0.1729 [I > 2(I)], goodness of
fit on F2 = 1.111, residual electron density = 0.221 and –0.243 e
Å–3. Further details of the crystal structure investigations have
been deposited with the Cambridge Crystallographic Data
Center, CCDC 1542094. Copies of this information may be
obtained free of charge from The Director, CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK (Fax: +44(1223)-336 033; e-
mail: fileserv@ccdc.ac.uk or http://www.ccdc.cam.ac.uk).
1
(decomp.). H-NMR (600 MHz, DMSO-d6):  = 1.46 (s, 3H,
Me), 4.78 (d, J = 5.6 Hz, 1H, 7-H), 5.16 (dd, J = 4.6, 1.4 Hz, 1H,
11-H), 6.11 (d, J = 4.6 Hz, 1H, HO-C11), 6.20 (d, J = 5.6 Hz,
1H, HO-C7), 6.93 (m, 2H, 13/13'-H), 7.22 (m, 2H, 9/9'-H), 7.53
(d, J = 1.4 Hz, 1H, H), 8.41-8.42 (m, 4H, 10/10'-H + 14/14'-H)
ppm; 13C-NMR (150 MHz, CDCl3):  = 20.5 (1C, Me), 66.3 (1C,
11-C), 74.2 (1C, 7-C), 88.3 (1C, C), 121.4 (2C, 13/13'-C), 122.5
(2C, 9/9'-C), 135.7 (1C, C), 148.7 (1C, 8-C), 149.0 (2C,
10/10'-C), 149.4 (2C, 14/14'-C), 150.7 (1C, 12-C), 153.0 (1C,
C), 170.5 (1C, CO) ppm; IR (ATR): 3096, 2866, 1743 (CO),
1604, 1462, 1449, 1115, 1004, 804 cm−1; ESI-MS: m/z = 647.2
[2M + Na]+ (100), 335.0 [M + Na]+ (56), 313.0 [M + H]+ (46);
HRMS (ESI): MH+, found 313.1188. C17H17N2O4 requires
313.1188.
All density-functional theory (DFT) calculations were carried
out by using the Jaguar 9.1.01372 software running on Linux
2.6.18-238.el5 SMP (x86_64) on five AMD Phenom II X6
1090T processor workstations (Beowulf-cluster) parallelized
with OpenMPI. MM2 optimized structures were used as starting
geometries. Complete geometry optimizations were carried out
on the LACVP** (Hay-Wadt effective core potential (ECP) basis
on heavy atoms, 6-31G** for all other atoms) basis set and with
the PBE0 hybrid density functional. All calculated structures
were proven to be true minima by the absence of imaginary
frequencies. Relative deprotonation energies refer to the
deprotonation of -butyrolactone in -position and if appropriate
to the (R/R)-configuration of the protonated species in all cases.
Fukui functions f− were calculated by removal of the fraction of
0.01 electron from the corresponding anion.58 Plots were obtained
using Maestro 10.5.013, the graphical interface of Jaguar. Atomic
Fukui indices fk were calculated from the Mulliken population
analysis.57 Partial charges were obtained with NBO 6.073 from the
results of the DFT calculations. The global electrophilicity index
was calculated55 by ° = µ²/2with the electronic chemical
potential µ = (EHOMO+ELUMO)/2 and the chemical hardness 
ELUMO−EHOMO roughly estimated for a comparable series of
substances on the same level of theory by Koopmans’
theorem.74,75
4.4. 3,5,5-Tris(hydroxy(pyridin-4-yl)methyl)furan-2(5H)-one (10)
Following the general procedure, furan-2(5H)-one (0.13 mL,
0.160 g, 1.90 mmol) and 4-pyridinecarboxaldehyde (0.54 mL,
0.612 g, 5.71 mmol) were used. 10 was obtained as white powder
and recrystallized from acetone. Yield: 0.668 g (87 %). M.p. 163
1
– 167 °C (decomp.). H-NMR (600 MHz, DMSO-d6):  = 4.86
(d, J = 5.1 Hz, 1H, 6A-H), 5.11 (dd, J = 5.1, 1.4 Hz, 1H, 10-H),
5.19 (d, J = 5.3 Hz, 1H, 6B-H), 6.09 (d, 5.1 Hz, 1H, HO-C10),
6.28 (d, J = 5.3 Hz, 1H, HO-C6B), 6.34 (d, J = 5.1 Hz, 1H, HO-
C6A), 6.80 (dd, J = 4.4, 1.7 Hz, 2H, 12/12'-H), 7.23 (d, J = 1.4
Hz, 1H, H), 7.26 (dd, J = 4.4, 1.7 Hz, 2H, 8A/8A'-H), 7.43 (dd, J
= 4.4, 1.7 Hz, 2H, 8B/8B'-H), 8.34 (dd, J = 4.4, 1.7 Hz, 2H,
13/13'-H), 8.39 (dd, J = 4.4, 1.7 Hz, 2H, 9A/9A'-H), 8.57 (dd, J =
4.4, 1.7 Hz, 2H, 9B/9B'-H) ppm; 13C-NMR (150 MHz, DMSO-
d6):  = 66.6 (1C, 10-C), 71.2 (1C, 6B-C), 71.3 (1C, 6A-C), 92.4
(1C, C), 121.4 (2C, 12/12'-C), 122.8 (2C, 8B/8B'-C), 122.8 (2C,
8A/8A'-C), 138.9 (1C, C), 146.3 (1C, C), 148.3 (1C, 7A-C),
148.6 (1C, 7B-C), 149.0 (2C, 9A/9A'-C), 149.2 (2C, 9B/9B'-C),
149.3 (2C, 13/13'-C), 149.9 (1C, 11-C), 170.3 (1C, CO) ppm; IR
(ATR): 3035, 2840, 2708, 1752 (CO), 1604, 1417, 1020, 1006
cm−1; ESI-MS: m/z = 406.2 [M + H]+ (100), 299.1 [M –HO-CH-
py + 2H]+ (15), 281.1 [M –OH –HO-CH-py +H]+ (40); HRMS
(ESI): MH+, found 406.1403. C22H20N3O5 requires 406.1403.
4.1. (E)-3-Benzylidendihydrofuran-2-one (8)
8 was synthesized according to literature, but at 0 °C.14
1H-NMR (400 MHz, CDCl3):  = 3.26 (dt, J = 7.3, 2.8 Hz, 2H,
H), 4.47 (t, J=7.3 Hz, 2H, H), 7.39-7.42 (m, 1 H, 10-H), 7.43-
7.46 (m, 2H, 9/9'-H), 7.49-7.51 (m, 2H, 8/8'-H), 7.58 (t, J = 2.8
Hz, 1H, 6-H) ppm; (E)-configuration has been confirmed by a
strong NOE between 8/8'-H and H; 13C-NMR (100 MHz,
CDCl3):  = 27.5 (1C, C), 65.4 (1C, C), 123.5 (1C, C), 129.0
(2C, 9/9'-C), 129.9 (1C, 10-C), 130.0 (1C, 8/8'-C), 134.7 (1C,
7-C), 136.7 (1C, 6-C), 172.5 (1 C, CO) ppm; EI-MS: m/z = 174.1
[M]+ (50), 115.1 [M -C2H2O2 -H]+ (100).
4.5. (E)-5-Methyl-3-((N-methylpyrazol-4-yl)methylene)furan-
2(3H)-one (11)
Following the general procedure, -angelica lactone (1.85
mL, 2.016 g, 20.55 mmol) and N-methylpyrazole-4-
carboxaldehyde (2.264 g, 20.55 mmol) were used. 11 was
obtained as yellow powder and recrystallized from acetone.

8
Tetrahedron
1
Crystals suitable for X-ray structure determination were
received as colourless oil. Yield: 0.509 g (83 %). H NMR (600
MHz, CDCl3):  = 1.33 (d, J = 6.1 Hz, 3H, Me), 1.55 (ddd, J =
12.7, 12.2, 9.4 Hz, 1H, HA), 2.38 (ddd, J = 12.7, 8.4, 5.4 Hz,
1H, H), 2.76 (dd, J = 14.2, 7.2 Hz, 1H, 7A-H), 2.80-2.88 (m,
1H, H), 2.92 (dd, J = 14.2, 4.3 Hz, 1H, 7B-H), 3.85 (s, 3H,
Mepyr), 4.46 (ddq, J = 9.4, 8.4, 6.1 Hz, 1H, H), 7.22 (s, 1H, Hpyr),
7.30 (s, 1H, Hpyr) ppm; 13C NMR (150 MHz, CDCl3):  = 21.0 (1
C, Me), 24.4 (1C, 7-C), 35.9 (1C, C), 39.0 (1C, Mepyr), 43.0 (1C,
C), 75.3 (1C, C), 117.4 (1C, 8-C) 129.5 (1C, Cpyr), 139.4 (1C,
Cpyr), 178.4 (1C, CO); IR (ATR): 2977, 2933, 2890, 1761 (CO),
1387, 1177, 1121, 1018, 986, 955 cm−1; ESI-MS: m/z = 217.1 [M
+ Na]+ (100), 195.1 [M + H]+ (10); HRMS (ESI): MNa+, found
217.0962. C10H14N2O2Na requires 217.0953.
ACCEPTED MANUSCRIPT
obtained from dioxane. Yield: 2.644 g (68 %). M.p. 136 – 138
°C. H NMR (600 MHz, CDCl3):  = 2.16 (s, 3H, Me), 3.93 (s,
1
3H, Mepyr), 6.04 (s, 1H, H), 7.12 (s, 1H, 7-H), 7.61 (s, 1H, Hpyr),
7.71 (s, 1H, Hpyr) ppm; (E)-configuration has been confirmed by
a strong NOE between both Hpyr and H; 13C NMR (150 MHz,
CDCl3):  = 14.8 (1C, Me), 39.4 (1C, Mepyr), 102.2 (1C, C),
118.5 (1C, 8-C), 122.5 (1C, C), 124.4 (1C, 7-C), 131.7 (1C,
Cpyr), 140.2 (1C, Cpyr), 156.0 (1C, C), 170.1 (1C, CO) ppm; IR
(ATR): 3120, 3105, 2920, 1748 (CO), 1634, 1622, 1548, 1440,
1013 cm−1; ESI-MS: m/z = 403.1 [2M + Na]+ (100), 213.0 [M +
Na]+ (98). HRMS (ESI): MH+, found 191.0821. C10H11N2O2
requires 191.0821.
4.6. 5-(Hydroxy(N-methylimidazol-5-yl)methyl)-5-methylfuran-
2(5H)-one (12)
Acknowledgments
We sincerely thank Dr. G. Dräger of the Institute of Organic
Chemistry of the Leibniz University Hannover for the
measurement of the high-resolution mass spectra.
Following the general procedure, -angelica lactone (0.61
mL, 0.668 g, 6.81 mmol) and N-methylimidazole-5-
carboxaldehyde (0.750 g, 6.81 mmol) were used and the mixture
was stirred for several days. 12 was obtained as yellow solid and
purified by column chromatography (MeCN : MeOH 2 : 1 v/v,
Supplementary Material
1
Rf = 0.70). Yield: 0.156 g (11 %). M.p. 137 – 139 °C. H-NMR
(600 MHz, MeOD-d4):  = 1.51 (s, 3H, Me), 3.71 (s, 3H, Meimi),
4.89 (s, 1H, 7-H), 6.08 (d, J = 5.7 Hz, 1H, H), 6.97 (s, 1H, Himi),
7.57 (s, 1H, Himi), 7.80 (d, J = 5.7 Hz, 1H, H) ppm; 13C-NMR
(150 MHz, MeOD-d4):  = 19.8 (1C, Me), 32.9 (1C, Meimi), 69.9
(1C, 7-C), 92.4 (1C, C), 122.3 (1C, C), 128.5 (1C, Cimi), 131.9
(1C, 8-C), 140.1 (1C, Cimi,), 161.4 (1C, C), 174.5 (1C, CO) ppm;
IR (ATR): 3100, 2988, 2824, 2720, 1730 (CO), 1631, 1513,
1376, 1251, 1108, 1043, 817 cm−1; ESI-MS: m/z = 209.1 [M +
H]+ (100); HRMS (ESI): MH+, found 209.0926. C10H13N2O3
requires 209.0926.
Supplementary data containing spectra and details of the DFT
calculations can be found at http://dx.doi.org/10.1016/j.tet.2017.
References
1. Jones, F. A.; Davies, J. A. Brit. J. Pharmacol. 1999, 128, 1223–
1228.
2. Chang, X.; Peng, W.; Yao, Y.-F.; Koek, J. Synth. Commun. 2010,
40, 3346–3352.
3. Wang, C. H.; Alluri, S.; Nikogosyan, G.; DeCarlo, C.; Monteiro,
C.; Mabagos, G.; Feng, H. H.; White, A. R.; Bartolini, M.;
Andrisano, M.; Zhang, L. K.; Ganguly, A. K. Tetrahedron Lett.
2016, 57, 3046–3049.
4. Mahalingam, A. K.; Axelsson, L.; Ekegren, J. K.; Wannberg, J.;
Kihlström, J.; Unge, T.; Wallberg, H.; Samuelsson, B.; Larhed,
M.; Hallberg, A. J. Med. Chem. 2010, 53, 607–615.
5. Wang, L.; Zhu, W. Terahedron Lett. 2013, 54, 6729–6731.
6. Boukouvalas, J.; Wang, J.-X.; Marion, O. Tetrahedron Lett. 2007,
48, 7747–7750.
4.7. 5-(Hydroxy(N-methylimidazol-5-yl)methyl)furan-2(5H)-one
(13)
Following the general procedure, furan-2(5H)-one (0.09 mL,
0.104 g, 1.24 mmol) and N-methylimidazole-5-carboxaldehyde
(0.137 g, 1.24 mmol) were used and the mixture was stirred for
several days. 13 was obtained as brown solid and washed several
times with chloroform to yield a light brown powder. Yield:
7. Machauer, R.; Veenstra, S.; Rondeau, J.-M.; Tintelnot-Blomley,
M.; Betschart, C.; Neumann, U.; Paganetti, P. Bioorg. Med. Chem.
Lett. 2009, 19, 1361–1365.
1
0.118 g (49 %). M.p. 141 – 145 °C (decomp.). H NMR (600
MHz, MeCN-d3):  = 3.65 (s, 3H, Meimi), 4.88 (d, J = 5.7 Hz, 1H,
6-H), 5.34 (ddd, J = 5.7, 2.0, 1.7 Hz, 1H, H), 6.19 (dd, J = 5.9,
2.0 Hz, 1H, H), 6.95 (s, 1H, Himi), 7.42 (s, 1H, Himi), 7.74 (dd, J
= 5.9, 1.7 Hz, 1 H, H) ppm; 13C NMR (150 MHz, MeCN-d3): 
= 32.5 (1C, Meimi), 66.2 (1C, 6-C), 85.5 (1C, C), 123.2 (1C, C),
128.2 (1C, Cimi), 131.2 (1C, 7-C), 140.1 (1C, Cimi), 155.8 (1C,
C), 173.7 (1C, CO) ppm; IR (ATR): 3090, 2709, 1753 (CO),
1514, 1170, 1102, 1078, 1035, 830 cm−1; ESI-MS: m/z = 217.1
[M + Na]+ (100), 195.1 [M + H]+ (85); HRMS (ESI): MH+, found
195.0770. C9H11N2O3 requires 195.0770.
8. Zimmer, H.; Rothe, J. Org. Chem. 1959, 24, 28–32.
9. Widdowson, D. A.; Wiebecke, G. H.; Williams, D. J. Tetrahedron
Lett. 1982, 23, 4285–4288.
10. Murray, A. W.; Reid, R. G. Synthesis 1985, 35–38.
11. Tanaka, K.; Tamura, N.; Kaji, A.; Chem. Lett. 1980, 595–598.
12. Lewis, F. D.; Oxman, J. D.; Gibson, L. L.; Hampsch, H. L.;
Quillen, S. L. J. Am. Chem. Soc. 1986, 108, 3005–3015.
13. Tian, F.; Dongmei, Y.; Liu, Y.; Xie, F.; Zhang, W. Adv. Synth.
Catal. 2010, 352, 1841–1845.
14. Yato, M.; Homma, K.; Ishida, A. Tetrahedron, 2001, 57, 5353–
5359.
15. Egorova, A. Y.; Reshetov, P. V.; Morozova, N. A.; Sedavkina, V.
A. Chem. Heterocycl. Compd. 1997, 33, 910-913.
16. v. Oettingen, W. F. J. Am. Chem. Soc. 1930, 52, 2024–2025.
17. Thiele, J.; Tischbein, R.; Lossow, E. Justus Liebigs Ann. Chem.
1901, 319, 180–195.
4.8. 5-Methyl-3-((N-methylpyrazol-4-yl)methyl)dihydrofuran-2-
one (14)
A 500 mL lab autoclave (ROTH Model IV) was equipped with
18. Russell, P. B.; Todd, A. R.; Waring, S. W. Biochem. J. 1949, 45,
530–532.
a
solution
of
(E)-5-methyl-3-((N-methylpyrazol-4-
19. Marrian, D. H.; Russell, P. B.; Todd, A. R. Biochem. J. 1949, 45,
533–537.
20. Koch, R.; Berstermann, H. M.; Wentrup, C. J. Org. Chem. 2014,
79, 65–71.
21. Boukouvalas, J.; Jean, M.-A. Tetrahedron Lett. 2014, 55, 4248–
4250.
22. Quintard, A.; Lefranc, A.; Alexakis, A. Org. Lett. 2011, 13, 1540–
1543.
yl)methylene)furan-2-one (11) (0.600 g, 3.16 mmol) in 200 mL
dry THF and Pd/C (10% Pd, 0.060 g) was added subsequently.
The autoclave was flooded five times with H2 up to a pressure of
5/10/15/20/40 bar. Finally, the autoclave was flooded with H2 at
a pressure of 40 bar. The reaction mixture was stirred for 24 h at
50 °C. After completion of the reaction, the suspension was
filtered through silica. The solvent was reduced in vacuo and the
slightly yellow oil purified by column chromatography (EE : PE
9 : 1 v/v, Rf = 0.60). After removal of the solvent, 14 was
23. Brown, D. W.; Campbell, M. M.; Taylor, A. P.; Zhang, X.
Tetrahedron Lett. 1987, 28, 985–988.

9
24. Pohmakotr, M.; Tuchinda, P.; Premkaisorn, P.; Reutrakul, V.
50. Moore, T.; Adhikari, R.; Gunatillake, P. Biomaterials 2005, 26,
3771–3782.
ACCEPTED MANUSCRIPT
Tetrahedron 1998, 54, 11297–11304.
25. Sundar, N.; Kundu, M. K.; Reddy, P. V.; Mahendra, G.; Bhat, S.
V. Synth. Commun. 2002, 32, 1881–1886.
51. Hong, M.; Chen, E. Y.-X. Nat. Chem. 2016, 8, 42–49.
52. Mitomo, H.; Kaneda, A.; Quynh, T. M.; Nagasawa, N.; Yoshii, F.
Polymer 2005, 46, 4695–4703.
53. Tymrak, B. M.; Kreiger, M.; Pearce, J. M. Mater. Des. 2014, 58,
242–246.
54. Lederle, F.; Meyer, F.; Brunotte, G.-P.; Kaldun, C.; Huebner, E.
G. Prog. Addit. Manuf. 2016, 1, 3–7.
55. Parr, R. G.; Szentpály , L. v.; Liu, S. J. Am. Chem. Soc. 1999, 121,
1922–1924.
56. Domingo, L. R.; Pérez, P. Org. Biomol. Chem. 2011, 9, 7168–
7175.
57. Contreras, R. R.; Fuentealba, P.; Galván, M.; Pérez, P. Chem.
Phys. Lett. 1999, 304, 405–413.
58. Michalak, A.; de Proft, F.; Geerlings, P.; Nalewajski, R. F. J.
Phys. Chem. A 1999, 103, 762–771.
26. Kaklyugina, T. Y.; Badovskaya, L. A.; Sorotskaya, L. N.;
Kozhina, N. D.; Jurášek, A.; Kada, R.; Kováč, J.; Kulnevich, V.
G. Collect. Czech. Chem. Commun. 1986, 51, 2181–2185.
27. Sorotskaya, L.N.; Badovskaya, L.A.; Kaklyugina, T.Y.; Belen'kij,
L.I.; Ignatenko, A.V.; Krutoshikova, A.; Panieva, L.A. J. Org.
Chem. USSR. (Engl. Transl.) 1989, 25, 159–165.
28. Sorotskaya, L. N.; Kaklyugina, T. Y.; Badovskaya, L. A.
Molecules 1999, 4, M108.
29. Luo, X.; Zhou, Z.; Yu, F.; Li, X.; Liang, X.; Ye, J.; Chem. Lett.
2011, 40, 518–520.
30. Jefford, C. W.; Jaggi, D.; Boukouvalas, J. J. Chem. Soc., Chem.
Commun. 1988, 1595–1596.
31. Yang, Y.; Zheng, K.; Zhao, J.; Shi, J.; Lin, L.; Liu, X.; Feng, X. J.
Org. Chem. 2010, 75, 5382–5384.
32. Claraz, A.; Oudeyer, S.; Levacher, V.; Adv. Synth. Catal. 2013,
355, 841–846.
33. Pansare, S. V.; Paul, E. K. Org. Biomol. Chem. 2012, 10, 2119–
2125.
59. Bugarin, A.; Connell, B. T. J. Org. Chem. 2009, 74, 4638–4641.
60. Sohtome, Y.; Takemura, N.; Takagi, R.; Hashimoto, Y.;
Nagasawa, K. Tetrahedron 2008, 64, 9423–9429.
61. Evans, D. A.; Coleman, P. J.; Côté, B. J. Org. Chem. 1997, 62,
788–789.
34. Pansare, S. V.; Paul, E. K. Chem. Commun. 2011, 47, 1027–1029.
35. Saito, S.; Shiozawa, M.; Yamamoto, H. Angew. Chem. Int. Ed.
1999, 38, 1769–1771.
36. Itoh, A.; Ozawa, S. Oshima, K.; Nozaki, H. Tetrahedron Lett.
1980, 21, 361–364.
37. Itoh, A.; Ozawa, S.; Oshima, K. Nozaki, H. Bull. Chem. Soc. Jpn.
1981, 54, 274–278.
38. Szlosek, M.; Figadère, B. Angew. Chem. Int. Ed. 2000, 39, 1799–
1801.
39. Ollevier, T.; Bouchard, J.-E.; Desyroy, V. J. Org. Chem. 2008, 73,
331–334.
40. Acosta, J. A. M.; Muddala, R.; Barbosa, L. C. A.; Boukouvalas, J.
J. Org. Chem. 2016, 81, 6883–6886.
41. Sato, K.; Isoda, M.; Tokura, Y.; Omura, K.; Tarui, A.; Omote, M.;
Kumadaki, I.; Ando, A. Tetrahedron Lett. 2013, 54, 5913–5915.
42. Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem. Int.
Ed. 2005, 44, 5306–5310.
62. Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996,
37, 8585–8588.
63. Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783–2792.
64. Williamson, R. T.; Marquez, B. L.; Sosa, A. C. B.; Koehn, F. E.
Magn. Res. Chem. 2003, 41, 379–385.
65. Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
Tachibana, K. J. Org. Chem. 1999, 64, 866–876.
66. Santos, C. M. M.; Silva, A. M. S. In Analysis of Marine Samples
in Search of Bioactive Compounds; Rocha-Santos, T.; Duarte, A.,
Eds.; Elsevier: Amsterdam, 2014; Vol. 65, pp 149–191.
67. Gustafson, K. R.; Chan, S. T. S.; Liu, Y. In Modern NMR
Approaches to the Structure Elucidation of Natural Products;
Williams, A.; Martin, G.; Rovnyak, D., Eds.; The Royal Society
of Chemistry: Cambridge, 2016; Vol 2, pp 39–70.
68. Contreras, R. H.; Peralta, J. E. Prog. Nucl. Magn. Reson.
Spectrosc. 2000, 37, 321–425.
43. McCombie, S. W.; Tagat, J. R.; Metz, W. A.; Nazareno, D.; Puar,
M. S. Tetrahedron 1993, 49, 8073–8086.
69. Al-Shaal, M. G.; Hausoul, P. J. C.; Palkovits, R. Chem. Commun.
2014, 50, 10206–10209.
44. Schueler, F. W.; Hanna, C. J. Am Chem. Soc. 1951, 73, 3528–
3530.
70. Castañar, L.; Saurí, J.; Williamson, R. T.; Virgili, A.; Parella, T.
Angew. Chem. Int. Ed. 2014, 53, 8379–8382.
45. Dornow, A.; Wedekind, G. Arch. Pharm. Pharm. Med. Chem.
1953, 286, 338–344.
71. Sheldrick, G. M.; Acta Crystallogr. 2008, A64, 112–122.
72. Jaguar, version 9.1, Schrodinger, Inc., New York, NY, 2016.
73. NBO 6.0. Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.;
Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Landis, C. R.;
Weinhold, F. Theoretical Chemistry Institute, University of
Wisconsin, Madison, WI, 2013.
74. Perdew, J. P.; Levy, M. Phys. Rev. B 1997, 56, 16021–16028.
75. Aboelnaga, A.; Hagar, M.; Soliman, S. M. Molecules 2016, 21,
848–861.
46. Barbier, M. Synth. Commun. 1991, 21, 2317–2327.
47. Barbier, M. Liebigs Ann. Chem. 1987, 545–546.
48. Medarde, M.; de Clairac, R. P.-L.; Tomé, F.; López, J. L.;
Feliciano, A. S.; Grávalos, D. G. Arch. Pharm. Pharm. Med.
Chem. 1995, 328, 403–407.
49. Madrigal, B.; Puebla, P.; Ramos, A.; Peláez, R.; Grávalos, D.;
Caballero, E.; Medarde, M. Bioorg. Med. Chem. 2002, 10, 303–
312.