Oxydehydrogenative aromatization of fused 3-aminopyran-2-ones on carbon surfaces: A simple approach towards 3-amino-5-hydroxycoumarin derivatives

Article abstract of DOI:10.1007/s00706-014-1227-4

Aromatization of selected 3-acylamino-5,6,7,8-tetrahydro-2H-1-benzopyran-2, 5-diones, yielding the corresponding 3-acylamino-5-hydroxycoumarins, was achieved by dehydrogenation with molecular oxygen in the presence of activated carbon. The use of nonpolar solvents and high temperatures was crucial for attaining satisfactory conversions. The 3-benzoylamino-5,6,7,8- tetrahydrocoumarin without a 5-keto group and the 8-oxo analogue as well as the 5-oxo-5,6,7,8-tetrahydrocoumarins containing a free 3-amino group were less efficiently aromatized.

Full text of DOI:10.1007/s00706-014-1227-4

Monatsh Chem
DOI 10.1007/s00706-014-1227-4
ORIGINAL PAPER
Oxydehydrogenative aromatization of fused 3-aminopyran-2-ones
on carbon surfaces: a simple approach towards 3-amino-5-
hydroxycoumarin derivatives
ˇ
Bogdan Stefane Franc Pozgan
•
ˇ
Received: 21 February 2014 / Accepted: 6 April 2014
Ó Springer-Verlag Wien 2014
Abstract Aromatization of selected 3-acylamino-5,6,7,8-
tetrahydro-2H-1-benzopyran-2,5-diones, yielding the cor-
responding 3-acylamino-5-hydroxycoumarins, was achieved
by dehydrogenation with molecular oxygen in the presence
of activated carbon. The use of nonpolar solvents and high
temperatures was crucial for attaining satisfactory conver-
sions. The 3-benzoylamino-5,6,7,8-tetrahydrocoumarin
without a 5-keto group and the 8-oxo analogue as well as
the 5-oxo-5,6,7,8-tetrahydrocoumarins containing a free
3-amino group were less efficiently aromatized.
combretastatin A-4 [7], which is an important antitubulin
agent. For this reason, several methods, especially cata-
lytic-based methods, have been developed for synthesis of
4-arylcoumarins, and their biological activity evaluated [8–
11]. In addition, coumarin derivatives are also important
fluorophores used in fluorescent chemosensors, being
chemoselective for Cu2? ions, for example [12], as well as
receiving a lot of interest as laser dyes [13] and triplet
sensitizers [14].
ˇ
Kocevar and coworkers developed efficient methods (for
the most part one-pot reactions) for preparation of 3-acyla-
mino-5,6,7,8-tetrahydro-2H-1-benzopyran-2-ones [15–17],
which have already been shown to be valuable synthons for a
variety of heterocyclic systems [18–24]. However, despite
the prominence of coumarins as biologically interesting
compounds, they have never been transformed to the cor-
responding 3-aminocoumarin derivatives by means of
oxidative aromatization. Moreover, 3-aminocoumarins are a
particularly interesting group of coumarins, showing dif-
ferent therapeutic effects [25–28]. A 3-acylamino-4-
hydroxycoumarin nucleus, for instance, constitutes the
central scaffold of the antibiotic novobiocin [29]. 3-Ami-
nocoumarins are generally prepared by utilizing the
corresponding salicylaldehydes and N-acetylglycines [30].
On the other hand, 5-hydroxycoumarins appeared as
intermediates in the synthesis of lymphocyte potassium
channel Kv1.3 inhibitors [31], and can be prepared in a
one-pot reaction from dialkyl acetylenedicarboxylates with
2,4-dihydroxybenzophenones or -acetophenones [32].
Furthermore, 3-piperazinyl-5,7-dihydroxycoumarins were
shown to be antagonists of chemokine-like factor 1, and
thus have potential for treatment of asthma [33].
Keywords Activated carbon ꢀ Coumarins ꢀ
Dehydrogenation ꢀ Heterogeneous catalysis ꢀ Pyran-2-ones
Introduction
The importance of 2H-pyran-2-ones and their annulated
analogues has been recognized, being not only useful
building blocks in organic synthesis but also widespread in
plant and animal systems [1–4]. Thus, the pyran-2-one ring
can be found in coumarins as a major class of benzopy-
rones that show antifungal, anticoagulant, antitumor,
antibacterial, anti-human immunodeficiency virus (HIV),
and other pharmacological activities [5]. Furthermore,
polyoxygenated 4-arylcoumarins (neoflavones) [6] are
structurally similar, but the nonisomerizable analogues of
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-014-1227-4) contains supplementary
material, which is available to authorized users.
ˇ
ˇ
B. Stefane ꢀ F. Pozgan (&)
In this paper we report on an environmentally friendly
method for aromatization of selected 3-(acyl)amino-
5,6,7,8-tetrahydro-2H-1-benzopyran-2-ones, yielding the
Faculty of Chemistry and Chemical Technology, University of
ˇ
Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia
e-mail: franc.pozgan@fkkt.uni-lj.si
ˇ
123

ˇ
B. Stefane, F. Pozgan
ˇ
corresponding 3-(acyl)aminocoumarins, using molecular
oxygen promoted by activated carbon as a heteroge-
neous catalyst system. To the best of our knowledge,
there are no reports on catalytic aromatization of
3-aminotetrahydrocoumarins.
We assumed that the dehydrogenative aromatization of
tetrahydro-2H-1-benzopyran-2,5-dione 1a was promoted
by palladium acetate. Indeed, various cyclohexanones and
a,b-unsaturated cyclohexenones have been successfully
dehydrogenated in the presence of a palladium catalyst
under aerobic conditions, yielding the corresponding phe-
nols [39, 40].
Results and discussion
At the outset of our experiments, we chose fused pyran-
2-one 1a as a model substrate to optimize the aromatization
reaction under catalytic conditions. The results are pre-
sented in Table 1. To be able to compare the results, the
reactions were systematically run for 24 h.
As part of our continuing interest in catalytic functionali-
zation of small organic molecules [34–37], we envisioned
that readily accessible 3-benzoylamino-5-oxo-5,6,7,8-tet-
rahydrocoumarin (1a) [15] could be a potential substrate
for transition-metal-catalyzed arylation to afford the 4-aryl
substituted product 2 (tetrahydro analogue of neoflavones)
because of the proximity of the 3-carboxamide (or 5-keto)
coordinating group to the 4-C–H bond. Recently, oxidative
cross-coupling of coumarins through the carbon atom 4-C
with unactivated arenes was achieved via palladium-cata-
lyzed, twofold C–H functionalization [38]. To evaluate the
above-mentioned hypothesis, tetrahydrocoumarin 1a was
reacted with 4-bromoacetophenone in the presence of cat-
alytic amounts of Pd(OAc)2 and phenanthroline ligand,
KOAc base in glacial acetic acid at 150 °C in argon
atmosphere. Although the conversion of 1a after 24 h was
only around 15 %, we were able to isolate a sufficient
amount of the product, and nuclear magnetic resonance
(NMR) and high-resolution mass spectrometry (HRMS)
analyses revealed that 3-benzoylamino-5-hydroxycoumarin
(3a) was formed instead of the proposed 4-arylated tetra-
hydrocoumarin 2.
In our case, aromatization of 1a was performed in the
presence of catalytic amounts of Pd(OAc)2 and phenan-
throline, as a ligand not susceptible to oxygen, under oxygen
atmosphere (O2 balloon) in acetic acid at 110 °C (Table 1,
run 1). Unfortunately, after 24 h, only traces of aromatized
1
product 3a were detected based on H NMR of the crude
reaction mixture, and the starting compound 1a was almost
quantitatively recovered. On the other hand, when the reac-
tion mixture was saturated with oxygen and then heated at
150 °C in a closed vessel, the conversion of 1a into 3a
reached 70 % (Table 1, run 2). Interestingly, the reaction
performed in the presence of 10 mol% Pd on carbon (5 wt%)
in acetic acid at 150 °C was very clean and gave a slightly
higher conversion of 1a into 3a than in the presence of the
Pd(OAc)2/phenanthroline/O2 system (75 versus 70 %;
Table 1, runs 3 and 2). Next, we turned our attention to
dehydrogenation on carbon surfaces as a simple, inexpen-
sive, and environmentally benign, yet heterogeneous,
catalyst system, to avoid use of precious metals.
It is clear that the applied reaction conditions force the
aromatization of the fused cyclohexenone ring and not the
direct 4-C-arylation of the tetrahydrocoumarin 1a. The
formation of 3a turned out to be interesting, since aroma-
tization of 1a represents a simple access to a coumarin
scaffold that comprises both already established substitu-
tion motifs, 3-amino and 5-hydroxy (Scheme 1).
Use of carbon as an active catalytic phase has been
extensively documented in production of styrene from
ethylbenzene, for example [41–45]. Hayashi et al. dis-
closed oxidative aromatization of indolines [46],
imidazolines [47], and dihydropyrimidines [48] to the
corresponding heteroaromatic compounds and conversion
of 9,10-dihydroanthracenes to the anthracenes [49] using
Scheme 1
O
O
NHCOPh
COMe
O
Pd(OAc)2 (10 mol%)
phenanthroline (20 mol%)
O
O
+
KOAc (3 equiv.), AcOH
argon, 150 °C, 24 h
NHCOPh
2 COMe
1a
O
Br
O
O
(1.05 equiv.)
NHCOPh
3a
OH
123

Oxydehydrogenative aromatization of fused 3-aminopyran-2-ones on carbon surfaces
overoxidation or hydrolysis of 1a, for example. Next, dif-
Table 1 Catalytic aromatization of 1a
ferent solvents and temperatures were tested to suppress
the formation of side products, and the reactions were
performed in the presence of DarcoÒ in previously oxy-
genated mixtures. Ethanol was found to be a less suitable
solvent than acetic acid, while 100 % conversion of 1a into
3a was achieved in butanol. However, in both cases, a
significant amount of side product was formed (Table 1,
runs 5 and 6). When argon was bubbled through the
reaction mixture in butanol, the conversion reached a
degree of only 10 %, which proves that oxygen actively
participates in the aromatization process on the carbon
surfaces. When using acetonitrile as a solvent, the con-
version of 1a into 3a was satisfactory, but again the
formation of a large amount of side products was observed
(Table 1, run 8). It is clear that polar solvents are not
suitable media for aromatization of 1a with the DarcoÒ/O2
system, and for this reason we switched to nonpolar sol-
vents. To our delight, toluene was found to be a solvent of
choice in which the reaction afforded the coumarin product
3a with quantitative conversion and only traces of side
Run Catalyst /mol%
Solvent React.
cond.
Conv./
a
%
b
1
2
Pd(OAc)2 (5)/phenanthroline AcOH
(10)
110 °C, O2 Traces
150 °C, O2 70
Pd(OAc)2 (10)/
phenanthroline (20)
AcOH
3
4
5
6
7
Pd/C (10)
DarcoÒ
DarcoÒ
DarcoÒ
DarcoÒ
AcOH
AcOH
EtOH
BuOH
BuOH
150 °C, air 75
150 °C, O2 60c
150 °C, O2 40c
150 °C, O2 100c
150 °C,
argon
10
8
DarcoÒ
MeCN 150 °C, O2 65c
Toluene 150 °C, O2 100d
Toluene 150 °C, air 85
Toluene 150 °C,
argon
9
DarcoÒ
10 DarcoÒ
11 DarcoÒ
1
products, as detected by H NMR (Table 1, run 9). The
10
reaction performed in the presence of air in a closed vessel,
however, gave a lower conversion (85 %) of 1a into 3a,
while it dramatically reduced in argon atmosphere
(Table 1, runs 10 and 11). Lowering the quantity of
DarcoÒ to 100 or 50 mg/(0.25 mmol 1a) resulted in lower
conversions of 1a into 3a (80 and 45 %) after 24 h at
150 °C. Heating the mixture of 1a and toluene without
DarcoÒ, though previously bubbled through with oxygen,
at 150 °C for 24 h did not result in any transformation,
proving that there is no thermal dehydrogenation. For
comparison, ordinary active carbon exhibited lower activ-
ity than DarcoÒ, with the conversion reaching nearly 50 %
at 150 °C (Table 1, run 12), which can be ascribed to its
lower specific area in comparison with DarcoÒ, as also
noted by others [52].
12 Active carbon
13 DarcoÒ
14 DarcoÒ
Toluene 150 °C, O2 45
Toluene 110 °C, O2 Traces
Toluene 120 °C, O2 15
c
Bold indicates the best reaction conditions
Reaction conditions: 1a (0.25 mmol), catalyst [Pd(OAc)2 (0.0125 or
0.025 mmol)/phenanthroline
(0.025
or
0.05 mmol);
Pd/C
(0.025 mmol, 5 wt% Pd on carbon); DarcoÒ (200 mg)], solvent
(3 cm3), 3 min bubbling of O2 or argon through the reaction mixture
prior to heating
a
Conversion of 1a into 3a determined on the basis of 1H NMR
analysis of the crude reaction mixture
b
Balloon with O2 was used
c
Significant amount of side products observed
d
Small amount of side products detected
It was also observed that reaction temperatures lower
than 150 °C are not sufficient for the aromatization to
proceed in our particular system. Namely, when the reac-
tion was performed at 110 °C under oxygen atmosphere
(O2 balloon) in toluene for 24 h, only traces of the desired
product 3a were detected, while increasing the temperature
to 120 °C and running the reaction in a closed vessel gave
15 % conversion of 1a into 3a (Table 1, runs 13 and 14).
Encouraged by these results, we next explored the scope
and limitations of the dehydrogenation method with dif-
ferent fused-six-membered-ring 3-(acyl)aminopyran-2-
ones using optimized reaction conditions [200 mg DarcoÒ/
(0.25 mmol pyran-2-one 1), toluene as solvent, 150 °C;
oxygen bubbled through the reaction mixture prior to
heating]; the results are presented in Table 2. As we also
wanted to compare the reactivity of different fused pyran-
molecular oxygen and activated carbon as a promoter.
Carabineiro et al. used activated carbon for aromatization
ˇ
of 2-phenyl-1-pyrroline [50], while Pozgan et al. observed
a positive effect of activated carbon DarcoÒ KB (in com-
bination with molecular oxygen) in dehydrogenation of
1,4-dihydropyridazines [51].
First, a mixture of 1a, activated carbon DarcoÒ, and
glacial acetic acid was bubbled through with oxygen for
approximately 3 min and then vigorously stirred at 150 °C
in a closed, high-pressure tube. Although the conversion of
1a into 3a reached a promising 60 % after 24 h, a signif-
icant amount of side product was formed, as established by
1H NMR analysis of the crude reaction mixture (Table 1,
run 4). We were not, however, interested in isolation of this
side product, which might be formed by either
123

ˇ
B. Stefane, F. Pozgan
ˇ
Table 2 Aromatization of
fused pyran-2-ones 1
Pyran-2-one 1
Coumarin 3
Conv. /%a;
[Yield /%]b
O
O
O
O
100 [53]
1a
3a
NH Ph
CO
NH Ph
CO
H
H
O
O
O
O
O
O
O
O
O
O
23
1b
1c
1d
3b
3c
3d
25c [7]
NH Ph
CO
NH Ph
CO
O
O
28
35c [12]
NH Ph
CO
NHCOPh
O O
O
O
80 [46]
NH Ph
CO
NH Ph
CO
H
O
O
O
O
O
O
50
1e
1f
3e
3f
82c [35]
e
e
NH
M
NHCOM
O
CO
H
O
O
O
O
O
30
53c [20]
NH2
NH2
H
O
O
Reaction conditions: 1
(0.25 mmol), 200 mg DarcoÒ,
3 cm3 toluene, 150 °C, O2, 24 h
O
O
O
O
O
a
42 [18]
1g
1h
3g
3h
Conversion of 1 into 3
determined on the basis of H
NH2
O
NH2
1
H
O
O
NMR analysis of the crude
reaction mixture
O
O
b
100 [38]
Yield of product 3 isolated by
radial chromatography
NH2
NH2
c
48 h
2-ones 1 in dehydrogenation with the DarcoÒ/O2 system,
we stopped the reactions after 24 h. For maximum con-
versions, however, the reaction time was prolonged in
some cases. To determine the conversions, the crude
reaction mixtures obtained after several-hour continuous
2-one 1d was still satisfactory, but less efficient (80 %
conversion) than in the case of 1a, probably due to the
steric hindrance of the 7-methyl group. When the pyran-2-
one 1e bearing an N-acetyl instead of benzoyl group was
employed, about half of the starting material was consumed
in 24 h to give the product 3e, and after 2 days the con-
version of 1e into 3e reached 82 %.
1
extractions were analyzed using H NMR spectroscopy.
Surprisingly, an isomeric tetrahydro-2H-1-benzopyran-
2,8-dione 1b was aromatized in a very low, 23 % con-
version in 24 h, which might imply that a 5-keto group,
when using 1a, plays a certain role in the dehydrogenation
process. The importance of the 5-keto group was further
demonstrated by employing tetrahydro-2H-1-benzopyran-
2-one 1c, which was also converted into the product 3c to a
small extent of 28 %. Even prolongation of the reaction
time to 48 h did not significantly improve the conversion,
in the case of either 1b or 1c. The aromatization of pyran-
Finally, we wanted to check the reactivity of tetrahydro-
2H-1-benzopyran-2-one derivatives bearing a free 3-amino
group towards the DarcoÒ/O2 dehydrogenation system.
The conversions of 1f and 1g were much lower in com-
parison with their N-benzoylated analogues 1d and 1a after
24 h. Interestingly, the 5-deoxo analogue 1h was easily
aromatized into 3h within 24 h of heating in the presence
of DarcoÒ/O2, despite the requirement to remove four
hydrogens.
123

Oxydehydrogenative aromatization of fused 3-aminopyran-2-ones on carbon surfaces
It is worth mentioning that a major problem when iso-
lating coumarin products was their desorption from the
carbon surfaces, which consequently lowered the yields.
The most efficient method seemed to be several-hour
extraction of reaction mixtures with a Soxhlet apparatus,
and among the different solvents tested (acetone, acetoni-
trile, toluene, xylene, ethanol, and chloroform), acetone
was proven to be the best. The 3-amino-5-hydroxycoum-
arin products are rather insoluble in most common organic
solvents. They are, however, completely soluble in dime-
thyl sulfoxide (DMSO) or dimethylformamide (DMF), but
due to their high boiling points we did not apply them for
continuous extraction.
chromatography (TLC) was carried out on Fluka silica gel
TLC cards. Merck silica gel 60 PF254 containing gypsum
was used to prepare 1-mm Chromatotron plates. Radial
chromatography was performed with a Harrison Research
model 7924T Chromatotron. The catalytic reactions were
run in ACE pressure tubes (*21 cm3). Starting compounds
1a [15], 1b [16], 1c [17], 1d [15], 1f [53], 1g [53], and 1h
[17] were prepared according to published procedures. All
other reagents and solvents were used as received from
commercial suppliers.
N-(2,5-Dioxo-5,6,7,8-tetrahydro-2H-chromen-3-yl)
acetamide (1e, C11H11NO4)
To 0.896 g 1f (5.00 mmol) and 0.5 cm3 pyridine
(6.21 mmol) dissolved in 20 cm3 CH2Cl2, 0.4 cm3 acetyl
chloride (5.63 mmol) was added. After stirring at room
temperature for 4 h, 20 cm3 H2O was added. Layers were
separated, and the aqueous layer was extracted with CH2Cl2
(2 9 15 cm3). Combined organic layers were dried over
anhydrous Na2SO4 and evaporated under reduced pressure.
Recrystallization of the solid residue from ethanol afforded
0.74 g (77 %) 1e (CH2Cl2:MeOH = 20:1, Rf = 0.40). M.p.:
194–196 °C; 1H NMR (300 MHz, DMSO-d6): d = 2.05 (tt,
J1 = J2 = 6.5 Hz, 2H, CH2), 2.11 (s, 3H, Me), 2.48 (t,
J = 6.5 Hz, 2H, CH2), 2.82 (t, J = 6.5 Hz, 2H, CH2), 8.38
(s, 1H, 40-H), 9.66 (broad s, 1H, NH) ppm; 13C NMR
(75.5 MHz, DMSO-d6): d = 19.9, 23.8, 26.8, 36.1, 113.9,
119.8, 123.4, 157.4, 167.9, 170.1, 194.3 ppm; IR (neat):
vꢀ = 3,332, 1,718, 1,681, 1,517, 1,393, 1,364, 1,242, 1,161,
1,106, 1,005, 770, 684 cm-1; HRMS (ESI?) calcd. for
C11H12NO4 (MH?) 222.0766, found 222.0765.
In conclusion, we demonstrated that 3-(acyl)amino-5-
oxo-5,6,7,8-tetrahydrocoumarins can be aromatized with
molecular oxygen in the presence of activated carbon
DarcoÒ to selectively afford the corresponding 3-(acyl)a-
mino-5-hydroxycoumarins. A 5-keto group plays an
important role in the dehydrogenation process for N-acylated
5-oxotetrahydrocoumarins since the 8-oxo analogue or tet-
rahydrocoumarin without 5-keto group was less efficiently
aromatized. On the other hand, 5-oxotetrahydrocoumarins
bearing a free 3-amino group exhibited lower reactivity,
while it increased in the case of the 5-deoxo analogue.
Although the yields of isolated coumarins were low, the
method has potential due to its simplicity and the use of an
inexpensive, green catalyst system. Investigations directed
towards more detailed understanding of the oxydehydroge-
native process for 5,6,7,8-tetrahydrocoumarins on carbon
surfaces to enhance the aromatization yield under milder
conditions are in progress. Since the synthesized coumarin
products have a unique substitution motif (combined
3-amino and 5-hydroxy), their biological activity will be
examined in due course.
General procedure for dehydrogenation on carbon
surfaces
Oxygen was bubbled through a mixture of 5,6,7,8-tetra-
hydrocoumarin 1 (0.25 mmol), 200 mg DarcoÒ, and 3 cm3
toluene for approximately 3 min. The mixture was heated
in a closed vessel at 150 °C, and then it was extracted by a
Soxhlet apparatus using acetone as solvent for 5–6 h. After
evaporation of volatiles, the residue was subjected to radial
chromatography.
Experimental
Melting points were determined on a Kofler micro hot
stage. NMR spectra were recorded at 302 K on either a
Bruker Avance DPX 300 or Avance III 500-MHz spec-
trometer. 1H NMR spectra were recorded at 300 or
500 MHz and are referenced against the central line of
DMSO-d6 pentet (d = 2.50 ppm). 13C NMR spectra were
recorded at 75.5 MHz and are referenced against the cen-
tral line of the solvent signal (DMSO-d6 septet at
d = 39.5 ppm). The coupling constants (J) are given in Hz.
Infrared (IR) spectra were obtained with a Bruker ALPHA
FT-IR spectrophotometer. Mass spectroscopy (MS) spectra
were recorded with an Agilent 6224 Accurate Mass TOF
LC/MS instrument or VG-Analytical AutoSpec Q instru-
ment. Elemental analyses (C, H, N) were performed using a
PerkinElmer 2400 series II CHNS/O analyzer. Thin-layer
N-(5-Hydroxy-2-oxo-2H-chromen-3-yl)benzamide
(3a, C16H11NO4)
Radial chromatography (petroleum ether:EtOAc = 3:1,
Rf = 0.16); yield 53 %; m.p.: 288–290 °C; 1H NMR
(500 MHz, DMSO-d6): d = 6.82 (dd, J1 = 0.8 Hz,
J2 = 8.2 Hz, 1H, Ar), 6.87 (m, 1H, Ar), 7.35 (dd,
J1 = J2 = 8.2 Hz, 1H, Ar), 7.55 (m, 2H, Ph), 7.63 (m,
1H, Ph), 7.96 (m, 2H, Ph), 8.74 (s, 1H, 40-H), 9.61 (broad s,
1H, NH), 10.77 (broad s, 1H, OH) ppm (long-range
coupling constants were observed but not studied in detail);
123

ˇ
B. Stefane, F. Pozgan
ˇ
13C NMR (75.5 MHz, DMSO-d6): d = 106.5, 108.5,
110.3, 122.1, 127.5, 128.6, 130.8, 132.1, 133.6, 151.4,
154.3, 157.9, 165.7 ppm; IR (neat): vꢀ = 3,364, 3,284,
1,709, 1,651, 1,540, 1,490, 1,466, 1,347, 1,284, 1,260,
(neat): vꢀ = 3,311, 3,111, 1,704, 1,650, 1,613, 1,542, 1,466,
1,352, 1,139, 1,044, 779, 729 cm-1; HRMS (ESI?) calcd. for
C11H10NO4 (MH?) 220.0604, found 220.0606.
3-Amino-5-hydroxy-7-methyl-2H-chromen-2-one
(3f, C10H9NO3)
Radial chromatography (petroleum ether:EtOAc = 1:1,
1,042, 777, 698 cm-1
;
HRMS (ESI?) calcd. for
C16H12NO4 (MH?) 282.0761, found 282.0761.
Rf = 0.09 then petroleum ether:EtOAc = 1:2, Rf = 0.19);
1
yield 20 % (48 h of heating); m.p.: 153–156 °C; H NMR
N-(8-Hydroxy-2-oxo-2H-chromen-3-yl)benzamide
(3b, C16H11NO4)
(300 MHz, DMSO-d6): d = 2.24 (s, 3H, Me), 5.35 (broad s,
2H, NH2), 6.50 (m, 1H, Ar), 6.56 (m, 1H, Ar), 6.88 (s, 1H, 4-
H), 9.98 (broad s, 1H, OH) ppm (long-range coupling
constants were observed but not studied in detail); 13C NMR
(75.5 MHz, DMSO-d6): d = 21.1, 104.3, 106.8, 108.3,
110.5, 130.8, 135.7, 149.2, 151.6, 158.9 ppm [50]; IR (neat):
vꢀ = 3,413, 3,318, 2,926, 1,685, 1,601, 1,426, 1,349, 1,299,
1,257, 1,174, 1,066, 866, 819 cm-1; HRMS (ESI ?) calcd.
for C10H10NO3 (MH?) 192.655, found 192.0655.
Radial chromatography (petroleum ether:EtOAc = 4:1,
Rf = 0.11); yield 7 % (48 h of heating). This compound
was previously reported [54], but insufficient analytical
1
data were given. M.p.: 220–222 °C (Ref. [54] 224 °C); H
NMR (500 MHz, DMSO-d6): d = 7.05 (m, 1H, Ar), 7.18
(m, 2H, Ar), 7.56 (m, 2H, Ph), 7.64 (m, 1H, Ph), 7.96 (m,
2H, Ph), 8.57 (s, 1H, 40-H), 9.66 (broad s, 1H, NH), 10.27
(broad s, 1H, OH) ppm; 13C NMR (75.5 MHz, DMSO-d6):
d = 117.0, 118.3, 120.4, 124.2, 125.3, 127.7, 128.9, 132.5,
133.6, 139.1, 144.6, 158.0, 162.7, 166.1 ppm; HRMS
(ESI?) calcd. for C16H12NO4 (MH?) 282.0761, found
282.0762.
3-Amino-5-hydroxy-2H-chromen-2-one (3g, C9H7NO3)
Radial chromatography (CH2Cl2:MeOH = 50:1, Rf = 0.20
then CH2Cl2:MeOH = 20:1, Rf = 0.30); yield 18 %; m.p.:
129–131 °C; 1H NMR (300 MHz, DMSO-d6): d = 5.49
(broad s, 2H, NH2), 6.66 (dd, J1 = 1 Hz, J2 = 8 Hz, 1H,
Ar), 6.72 (m, 1H, Ar), 6.90 (s, 1H, 4-H), 7.03 (dd,
J1 = J2 = 8.1 Hz, 1H, Ar), 10.07 (broad s, 1H, OH) ppm
(long-range coupling constants were observed but not
studied in detail); 13C NMR (75.5 MHz, DMSO-d6):
103.7, 106.3, 109.4, 110.8, 125.5, 131.6, 149.1, 151.9,
158.7 ppm; IR (neat): vꢀ = 3,459, 3354, 2,919, 2,849, 1,687,
1,633, 1,594, 1,464, 1,269, 1,170, 1,078, 774 cm-1; HRMS
(ESI?) calcd. for C9H8NO3 (MH?) 178.0499, found
178.0497.
N-(2-Oxo-2H-chromen-3-yl)benzamide (3c)
Radial chromatography (petroleum ether:EtOAc = 10:1,
Rf = 0.15 then petroleum ether:EtOAc = 5:1, Rf = 0.30);
yield 12 % (48 h of heating). M.p.: 174–176 °C (Ref. [55]
175–176 °C).
N-(5-Hydroxy-7-methyl-2-oxo-2H-chromen-3-yl)-
benzamide (3d, C17H13NO4)
Radial chromatography (petroleum ether:EtOAc = 3:1,
Rf = 0.16); yield 46 %; m.p.: 274–276 °C; 1H NMR
(300 MHz, DMSO-d6): d = 2.32 (s, 3H, Me), 6.63 (m,
1H, Ar), 6.70 (m, 1H, Ar), 7.51–7.65 (m, 3H, Ph), 7.95 (m,
2H, Ph), 8.68 (s, 1H, 40-H), 9.51 (broad s, 1H, NH), 10.63
(broad s, 1H, OH) ppm (long-range coupling constants
were observed but not studied in detail); 13C NMR
(75.5 MHz, DMSO-d6): d = 21.4, 106.1, 106.9, 111.1,
121.2, 122.8, 127.5, 128.6, 132.1, 133.6, 141.6, 151.4,
154.1, 158.0, 165.6 ppm; IR (neat): vꢀ = 3,378, 3,335,
1,705, 1,652, 1,621, 1,536, 1,510, 1,488, 1,371, 1,349,
1,275, 1,251, 1,183, 1,085, 1,070, 828, 698 cm-1; HRMS
(ESI?) calcd. for C17H14NO4 (MH?) 296.0917, found
296.0917.
3-Amino-2H-chromen-2-one (3h)
Radial chromatography (petroleum ether:EtOAc = 5:1,
Rf = 0.13); yield 38 %; m.p.: 135–137 °C (Ref. [30]
135–136 °C).
Acknowledgments We thank the Ministry of Higher Education,
Science, and Technology of the Republic of Slovenia and the Slo-
venian Research Agency for financial support (P1-0230-0103). Dr. D.
ˇ
ˇ
Zigon (Center for Mass Spectroscopy, ‘‘Jozef Stefan’’ Institute,
Ljubljana, Slovenia) is gratefully acknowledged for the mass mea-
surements. This work was partly supported with the infrastructure of
the EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, SI-
ˇ
1000 Ljubljana, Slovenia. We also thank L. Znidersic for laboratory
assistance.
ˇ ˇ
N-(5-Hydroxy-2-oxo-2H-chromen-3-yl)acetamide
(3e, C11H10NO4)
Radialchromatography(CH2Cl2:MeOH = 20:1, Rf = 0.25);
1
yield 35 % (48 h of heating); m.p.: 330–332 °C; H NMR
References
(300 MHz, DMSO-d6): d = 2.15 (s, 3H, Me), 6.79 (m, 2H,
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NMR (75.5 MHz, DMSO-d6): d = 23.9, 106.3, 108.7, 110.1,
119.2, 122.5, 130.0, 150.8, 154.1, 157.5, 169.9 ppm; IR
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