A versatile domino process for the synthesis of substituted 3-aminomethylene-chromanones and 2-pyridones catalyzed by CsF

Article abstract of DOI:10.1016/j.tetlet.2013.03.096

The addition of various primary amines onto 3-α,β-unsaturated diester chromone derivative was studied under mild conditions. Basically, this reaction provided 2-pyridone-based compounds through an interesting domino 'Addition/Ring Opening/Ring Closure' process (ARORC). In this study, aniline and tryptamine series exhibited different reactivity profiles leading unexpectedly to 3-aminomethylene chromanones with or without the 2-pyridone derivatives. This constitutes the first description and study of 3-aminomethylene chromanone formation that is supposed to follow a domino process combining 'Addition/Ring Opening/Ring Closure by Oxa-Michael addition' (ARORCOM).

Full text of DOI:10.1016/j.tetlet.2013.03.096

Tetrahedron Letters 54 (2013) 2853–2857
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A versatile domino process for the synthesis of substituted
3-aminomethylene-chromanones and 2-pyridones catalyzed by CsF
⇑
⇑
Catalin Pintiala, Ata Martin Lawson , Sébastien Comesse, Adam Daïch
URCOM, EA 3221, INC3M CNRS FR-3038, UFR des Sciences et Techniques de l’Université du Havre, 25 Rue Philippe Lebon, B.P. 540, F-76058 Le Havre Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The addition of various primary amines onto 3-a,b-unsaturated diester chromone derivative was studied
Received 9 January 2013
Revised 17 March 2013
Accepted 22 March 2013
Available online 2 April 2013
under mild conditions. Basically, this reaction provided 2-pyridone-based compounds through an inter-
esting domino ‘Addition/Ring Opening/Ring Closure’ process (ARORC). In this study, aniline and trypt-
amine series exhibited different reactivity profiles leading unexpectedly to 3-aminomethylene
chromanones with or without the 2-pyridone derivatives. This constitutes the first description and study
of 3-aminomethylene chromanone formation that is supposed to follow a domino process combining
‘Addition/Ring Opening/Ring Closure by Oxa-Michael addition’ (ARORCOM).
Keywords:
2-Pyridone
Domino process
Catalytic process
3-Aminomethylene-chromanone
Ó 2013 Elsevier Ltd. All rights reserved.
a,b-Unsaturated chromone
A high number of biologically active compounds bear the 2-
To reach the targeted 3-ethoxycarbonyl-2-pyridone derivatives
pyridone ring system.1 This scaffold is an interesting key interme-
diate which can easily provide complex heterocyclic compounds
that exhibit important biological properties. For example, these
compounds turn out to be potent anti-hepatitis B,2 MEK-1 inhibi-
tors,3 Receptor Tyrosine Kinase c-Kit inhibitors,4 Anaplastic Lym-
phoma Kinase inhibitors,5 and they also show marked anti Pim-1
kinase activities.6 For many years our research group has been
interested in pyridone-based compounds such as the natural topo-
isomerase-I poison rosettacin and its derivatives.7 One of our ongo-
ing research activities is focused on the synthesis of simple
heterocyclic compounds bearing a pyridone skeleton starting from
cheap chromone derivatives (Fig. 1).
Moreover, the presence of a chromone ring in many biologically
active compounds8 and various natural flavonoids9,10 represents an
interest for their use as new synthetic scaffolds. Especially, the 3-
vinylchromone derivative and the more explored 3-formyl-chro-
mone are now proven to be useful building blocks in organic and
medicinal chemistry.11–15 The chemical importance of these elec-
tron-deficient-fused dienes is due to their reactivity through four
potential electrophilic sites: C-2, C-4, C-10 and the carbonyl moie-
of type 2 (Fig. 1), the simple and efficient route that gives priority
to aza-Michael addition on
starting material17–19 has held our attention. Surprisingly, the use
of ,b-unsaturated chromone to provide compounds bearing a
a,b-unsaturated chromone as the main
a
pyridone core is not widely described in the literature as shown
by the fact that there are very few studies related to this reac-
tion.2,11,12,19 Most of these publications reported on the different
sites of reactivity of this substrate in relation to the nucleophilicity
of the nitrogen atom of amines, hydrazines, hydroxylamines, and
para-toluidine. Recently, different alkylamines and substituted ani-
lines were used on a monoester derivative of a,b-unsaturated chro-
mone in the presence of Et3N in refluxing MeOH. This reaction led
to pyridone compounds only and no other compounds are men-
tioned in this Letter.2
We report herein a simple, fast and broadly tolerable protocol
for the synthesis of benzoyl-substituted 2-pyridone derivatives 2
(Scheme 1). Compared to the existing methods, which are limited
in terms of amines diversity,2,11,12,18,19 our approach has proven to
be efficient with a wide range of either sterically hindered or
poorly nucleophilic amines. Another significant aspect of our
methodology is the access, in some cases, to 3-aminomethylene-
chromanone compounds 3 never described before. In fact, our
methodology allowed the formation of 2 or 3 independently or to-
gether. It also gave the possibility to modulate in some cases the
formation of both products according to reaction conditions. In
addition, the possible synthetic usefulness of 3-aminomethylene-
chromanones 3 and their formation provide some insights into
the plausible mechanism of the domino reaction.
ties from ester groups (Fig. 1, substrate 1). The
a,b-unsaturated
chromone can also be involved in Diels–Alder reactions as de-
scribed recently by Bodwell group.16
⇑
Corresponding authors. Tel.: +33 02 32 74 44 00; fax: +33 02 32 74 43 91
(A.M.L.); tel.: +33 02 32 74 44 03; fax: +33 02 32 74 43 91 (A.D.).
E-mail addresses: lawsona@univ-lehavre.fr (A.M. Lawson), adam.daich@univ-
lehavre.fr (A. Daïch).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.096

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C. Pintiala et al. / Tetrahedron Letters 54 (2013) 2853–2857
Table 1
R
Benzoyl-substituted pyridones 2a–1 synthesis accompanied by the unexpected
enaminochromanone 3a–1
N
O
O
1
1
CO2Et
2
3
6
2
3
4
4
'
2
CO2Et
CO2Et
1'
'
3
OH
O
O
CO2Et
CO2Et
R
N
RNH2
1.1 equiv.
DCM, rt
3-Ethoxycarbonyl-2-pyridone
α,β-Unsaturated chromone
O
O
O
O
O
2
CO2Et
derivatives ( )
1
derivative ( )
and/or
CO2Et
CO2Et
Figure 1. Unsaturated chromone and 2-pyridones structures.
OH
O
N
R
H
1
2a-l
3a-l
known
R2
N
R1=H
Refs: 2 (
)
)
O
O
O
CO2Et
R1
R1=CO Et
19 (
2
R2NH2
R1
Entry/
Product
RNH2
Time
(h)
Yielda
Ratiob Products
2:3
OH
O
(%)
95
92
95
1
2: Thermodynamic product
NH2
R2NH2
this work
this work
1/a
3
3
3
1:0
1:0
1:0
CO2Et
R1
R1=CO2Et
R1=CO2Et
O
2/b
NH2
NH2
N
O
N
R2
=
H
3/c
R2
O
H
3
: Kinetic product (isolated)
NH2
4/d
5/e
1
3
88
76
1:1
3:5
Scheme 1. Synthesis of pyridones 2 and/or 3-aminomethylene-chromanones 3
under mild conditions via a domino process.
N
H
NH2
NH2
N
Me
Besides the originality of the kinetic intermediate 3, it is very
important to underline the attractiveness of the system regarding
its versatility. Indeed, it is possible to stop the process in some
cases at the isolable enaminochromanones 3 stage or let it evolve
in order to ultimately provide 2-pyridone compounds 2.
6/f
6
85
3:7
N
Treatment of substrate 1 with different primary amines affor-
ded the corresponding pyridone 2 in good yields through a domino
process including three reactions: aza-Michael addition, then chro-
mone ring opening followed by ring closure. As shown in Table 1,
the expected pyridones 2 were obtained through this approach in
excellent yields (92–95%) when benzylamine (entry 1), phenethyl-
amine (entry 2), and furfurylamine (entry 3) were used. Surpris-
ingly, different results were observed when starting from other
amines (Table 1, entries 4–10).
7/g
8/h
24
16
30
64
0:1
1:5
NH2
MeO
NH2
NH2
MeO
MeO
9/i
16
84
0:1
1:2
OMe
NH2
In tryptamine series (entries 4–6) both products 2 and 3 were
obtained at room temperature in DCM. When tryptamine was
used, 2d20 and 3d20 were formed in the same proportion and in a
good yield (88%). Moreover, substitution of the indolic nitrogen
atom with a methyl (entry 5) or benzyl (entry 6) group promoted
the formation of compounds 3e and 3f, since the ratio increased
from 1:1 up to 3:5 and 3:7, respectively, in favor of compound 3.
In aniline series, the course of the reaction was different according
to the nucleophilicity of amine function. In fact, only 30% of iso-
lated compound 3g (entry 7) was obtained after 24 h of reaction
with aniline. Conducted with an aniline bearing electron donating
group such as p-methoxyaniline (entry 8), the reaction provided
the desired pyridone 2h accompanied by bicyclic enaminone 3h
(Table 1) in 64% isolated yield and 1:5 ratio. Additional methoxy
groups on aromatic ring (entry 9) enhanced the nucleophilicity
and 3i was exclusively obtained in 84% yield. Contrary to aniline,
the presence of another NH2 group in ortho-position of aniline (en-
try 10) favored the formation of both compounds 2j and 3j in 54%
yield and 1:2 ratio to the detriment of pyridone 2. Nevertheless, in
the case of the sterically hindered aniline and aniline bearing elec-
tron withdrawing group, limitations of the reaction appeared. In-
deed, the use of 2-(sec-butyl)aniline (entry 11) and para-
nitroaniline (entry 12) resulted in total inhibition of the reaction.
From these results, it seemed that the reaction was very sensi-
tive to the electronic and steric effects of amine derivatives. In this
context we decided to extend the experimental conditions by test-
10/j
11/k
12/l
48
24
24
54
0
NH2
NH2
c
_
NH2
c
0
_
O2N
a
The yields were reported for the isolated products after separation by silica gel
column chromatography.
b
The ratios were calculated for the pure isolated products.
Recovery of starting materials.
c
CO2Et
CO2Et
NH
Tryptamine
DCM
N
O
O
O
+
1
CO2Et
Conditions
O
OH
N
H
3d
2d
N
H
Scheme 2. Synthesis of pyridone derivative 2d and corresponding enaminochro-
manone product 3d.

C. Pintiala et al. / Tetrahedron Letters 54 (2013) 2853–2857
2855
Table 3
ing the influence of other parameters such as catalysts and solvents
Solvent and temperature effects on the reaction
to overcome the limitations of the process. Depending on the con-
ditions used, we were hoping to tune the reactivity in order to form
pyridone product 2d or 3-aminomethylene-chromanone com-
pounds 3 exclusively. As a 1:1 ratio of 2d and 3d was observed
in the tryptamine case, the impact of these parameters was inves-
tigated by using this amine as model substrate (Scheme 2).
Different catalysts were then tested for the reaction between
Entry
Solvent
Temperature (°C)
Yielda (%)
Ratiob(2d:3d)
1
2
3
4
5
6
7
DCM
DCM
DCM
DCM
Toluene
EtOH
THF
ꢀ78
0
rt
40
115c
rt
88
75
88
98
99
88
80
1:1
1:1
1:1
4:3
1:0
1:0
1:0
tryptamine and a,b-unsaturated chromone diester 1 at room tem-
rt
perature or heating at 40 °C. The results are highlighted in Table 2.
This study showed in all cases a slight or significant enhance-
ment of 2-pyridone compound ratio in the mixture.21 At room tem-
perature, by using ZnCl2 or CuI as the catalyst, the amount of 2d
was improved from 1:1 ratio (entry 1), to respectively 5:4 and
4:3 ratios with an overall yield of 80%. A 2:1 ratio (2d:3d) was ob-
tained in the case of LiClO4. Better results were achieved with
Bi(OTf)3 and Ti(OiPr)4 where more than 80% yield for both products
was obtained in a 4:1 ratio.
After reaction screening (Table 2), the best catalysts to promote
the formation of pyridone 2d (ratio 1:0) remarkably at ambient
temperature were CsF (entry 4) and TFA (entry 8). Carrying out
the reactions at 40 °C in DCM in the presence of the mentioned cat-
alysts clearly showed that the conversion of the starting substrate
1 into pyridone 2d was significantly improved compared to the
non-catalyzed domino reaction (entry 1). Comparable or slightly
improved results were observed in the case of LiClO4 and Bi(OTf)3
(entries 5 and 6). These results proved that catalysts and tempera-
ture influenced considerably the formation of the expected pyri-
done 2d.
To improve the yield of pyridone 2d and understand the forma-
tion of enaminone 3d, we then studied the potential effects of sol-
vent and temperature (Table 3). As previously mentioned, using
DCM as solvent and carrying out the reactions at ambient temper-
ature or at 40 °C without catalyst, both products (2d and 3d) were
obtained in 1:1 and 4:3 ratios, respectively. Additionally, we as-
sumed that increasing the reaction temperature could be a strate-
gic parameter in order to form the pyridone product 2d selectively
or more challengingly to reverse the proportion of 2d versus 3d.
The reactions were then conducted at low temperature and as
described in Table 3 at 0 °C (entry 2), the usual 1:1 ratio obtained
at room temperature did not really change in favor of 3d. Surpris-
ingly, at ꢀ78 °C (entry 1) the same result was obtained. At 40 °C
(entry 4), formation of pyridone 2d was slightly favored (ratio
2d:3d = 4:3). These results evidenced the existence of a possible
equilibrium between two intermediate compounds governed by
the reaction temperature (Scheme 3). To ascertain this hypothesis,
a
The yields of isolated products were reported after separation by silica gel
column chromatography or filtration.
b
The ratios were calculated from 1H NMR spectra of crude mixture. (integration
of H-2 proton for enaminochromanone derivative and H-4 proton for 2-pyridone
compound)
c
Reaction time = 1 h.
R
O
NH2R
Ring opening
NH
O
OH
b
RNH2
a
1,6-Aza-Michael
Addition
O
O
O
OEt
OEt
EtO
EtO
EtO2C
CO2Et
O
O
O
O
Cs
1
I
Cs
a, b
a
F
F
CO2Et
R
H
O
CO2Et
H
NH
O
OH
O
CO2Et
CO Et Δ
2
CO2Et
CO2Et
CsF
Oxa-Michael
O
N
R
O
N
R
H
H
III:
IIa: Z-form
E-form
IIb
Ring closure
- EtOH
CO2Et
H
R
N
O
O
O
CO2Et
CO2Et
N
OH
O
R
H
3
2 Thermodynamic
Kinetic
Scheme 3. Mechanistic proposal.
we then decided to perform the reaction under high boiling point
solvents such as toluene. As expected, only pyridone derivative
2d (entry 5) was obtained as a thermodynamic compound. Fur-
thermore, we noticed that the nature of the solvent also influenced
the domino reaction ratio. Indeed, pyridone 2d could be exclu-
sively obtained when the reaction was conducted at room temper-
ature in protic solvents such as EtOH. Based on these studies, the
most successful conditions to reach the 2-pyridone compound
exclusively starting from tryptamine were: 5 mol % of CsF in
DCM at room temperature, 10 mol % of Ti(OiPr)4 at reflux in DCM
and refluxing reaction in toluene.
The selected three conditions providing the best results with
tryptamine were then tested with aniline as a starting amine.
Among them, only CsF at room temperature in DCM appeared to
be very efficient and was applied to aniline derivatives that did
not previously react as outlined in Table 1. As shown in Table 4,
application of these previously well-established conditions pro-
vided interesting and promising results. In this case, it was possible
to reach kinetic compound 3 selectively in the first step. The latter
was then converted into thermodynamic compound 2 by refluxing
the reaction mixture in the second step. In fact, aniline and 2-(sec-
butyl)aniline22 led to a total conversion of the substrate 1 into cor-
responding 3-aminomethylene-chromanone 3 after 8 or 24 h of
reaction, respectively. Moreover, refluxing the reaction mixture
Table 2
Impact of the temperature and/or catalyst on the domino course
Entry
Catalyst (mol %)
Yielda (%)
rt
Ratiob (2d:3d)
40 °C
rt
40 °C
1
2
3
4
5
6
7
8
No catalyst
ZnCl2 (10)
CuI (10)
88
80
78
93
82
88
85
70
98
89
82
nrc
93
90
96
nrc
1:1
5:4
4:3
1:0
2:1
4:1
4:1
1:0
4:3
2:1
2:1
nrc
7:3
4:1
1:0
nrc
CsF (5)
LiClO4 (10)
Bi(OTf)3 (5)
Ti(OiPr)4 (10)
TFA (10)
a
The yields were reported for the isolated products after separation by silica gel
column chromatography or filtration. In all cases full conversion of starting mate-
rials was observed after 30 min of the reaction.
b
The ratios were calculated from 1H NMR spectra of crude mixture. (integration
of H-2 proton for enaminochromanone derivative and H-4 proton for 2-pyridone
compound).
c
Not realized.

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C. Pintiala et al. / Tetrahedron Letters 54 (2013) 2853–2857
ably acted as a base.23 In this way it promoted an intramolecular
1,4-oxa-Michael addition leading to enamino-chromanone 3 ring
closure. Under heating, CsF catalyzed the aminomethylene-chro-
manone ring opening leading to pyridone ring closure via a second
nucleophilic attack between the secondary amine group and one of
the carboxyl moieties. In tryptamine series where the nitrogen
atom is more nucleophile, one possible explanation could be that
the equilibrium between Z and E-forms was very rapid even at
low temperature providing a mixture of kinetic and thermody-
namic products. Activation of 4-carbonyl group from chromone
moiety by Lewis acids, metallic ions, Brønsted acids, or hydrogen
bonds24,25 (EtOH) reversed the equilibrium in favor of E-isomer
giving access to pyridone derivatives 2 exclusively.26
Table 4
Kinetic and thermodynamic products after treatment of diester
1
with aniline
derivatives
CO2Et
O
Ar
N
O
CO2Et
ArNH2
1
Δ
40°C
CO2Et
CsF, DCM, rt
1st step
2nd step
OH
O
O
N
Ar
2
3
H
Entry/product
ArNH2
% of conversiona (Time in hours)
Enaminochromanone 3
Pyridone 2
NH2
NH2
1/g
2/k
100 (8 h)
100 (3 h)
100 (3 h)
In summary, in this study, we report a convenient and versatile
domino process leading to a wide variety of 2-pyridone com-
pounds or 3-aminomethylene-chromanones. These compounds
can be obtained together or independently according to reaction
conditions. Their syntheses were based on a domino process
100 (24 h)
33b (24 h)
H
N
3/m
100 (3 h)
NH2
NH2
involving the 1,6-aza-Michael addition on
a,b-unsaturated chro-
mone derivative/pyran ring opening followed by pyridone or chro-
manone ring closure. During these investigations, we checked
different parameters to yield exclusively the desired 2-pyridones
as thermodynamic products or the kinetic ones; aminomethyl-
ene-chromanones. According to reaction conditions, a plausible
mechanism providing both compounds was proposed.
Finally, the domino reaction studied in this Letter constitutes a
versatile route to provide new synthetic intermediates to reach
polysubstituted pyridones. A large library of polyheterocyclic com-
pounds with promising biological properties based on 2-pyridone
scaffold is now under construction. The biological results and
chemical synthesis applications will be published in due course.
4/n
5/l
33 (24 h)
45 (30 h)
15c (3 h)
nod (3 h)
NH2
O2N
a
The reaction conversions were based on the consumption of 1 and were cal-
culated from 1H NMR spectra of crude mixture.
b
Mixture of 3m and 2m (ratio 1:1) was observed in 66% conversion.
Mixture of 3n and 2n (ratio 5:2) was observed in 52% conversion.
No = not observed.
c
d
containing exclusively the formed 3-amino-methylene-chroma-
none, provided the corresponding pyridone compounds 2 in nearly
quantitative yield after 3 h.
Acknowledgments
According to the results summarized in Table 4, when ortho-N-
phenylaminoaniline (entry 3) was used only 67% conversion into
aminomethylene-chromanone 3m and pyridone 2m was obtained
in a 1:1 ratio. Even in the case of sterically hindered amine such as
2-(tert-butyl)aniline (entry 4) or very weak nucleophile amine such
as para-nitro-aniline (entry 5), 3-amino-methylene-chromanone 3
was obtained in 33% and 45% conversion, respectively. Satisfacto-
rily, 2-(tert-butyl)aniline and para-nitro-aniline provided 2 and 3
in 100% conversion in 1:0 ratio and 1:3 ratio, respectively, by
refluxing (56 h) the reaction in DCM in the presence of 1 and
10 mol % of CsF. The purification by column chromatography using
silica gel led to the isolation of 2n (46% yield) and 2l (15% yield).
Interestingly, pyridone 2 or enamino-chromanone 3 could be
obtained conveniently according to the reaction conditions and
nucleophilicity of the employed amines. Positively, the use of CsF
as catalyst has helped to enlarge the application area of this dom-
ino process even on hindered or weak nucleophilic anilines which
did not react under classical conditions. Based on all these observa-
tions, the mechanism presented in Scheme 3 was proposed.
The addition of primary amines onto diester 1 occurred in the
first step at position 2 followed by chromone ring opening to gen-
erate a non-isolated intermediate I. After possible internal rota-
tions, Z-form II and E-form III were envisioned. According to the
reaction conditions these isomers could be in equilibrium or in fa-
vor of the intermediate E to the detriment of Z and vice versa. At
this stage, two possible routes can be considered: (1) Z-isomer
could lead directly to the kinetic product 3 while (2) E-isomer
could afford pyridone 2 as the thermodynamic product via an
intramolecular peptidic coupling. In aniline series, when the reac-
tion proceeded at room temperature in the presence of CsF, the
1,6-aza-Michael addition was promoted by the Cs coordination
with diester groups. After the ring-opening step, fluoride ion prob-
Authors are grateful to the ‘Ministère de l’Enseignement Supé-
rieur et de la Recherche’ and ‘Région Haute Normandie’ for the
Graduate Fellowship awarded to one of them, C.P. The authors
are grateful to CS of the University of Le Havre for research facili-
ties. We would like to thank Magdalena Livadaris for HRMS exper-
iments and Dawn Hallidy for her help.
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11. Gašparová, R.; Lácová, M. Molecules 2005, 10, 937–960.
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(d, J = 7.5 Hz, 1H), 8.52 (br s, 1H, –NH), 10.20 (m, 1H, –NH); 13C NMR (75 MHz,
CDCl3) d (ppm) 14.0, 14.1, 27.2, 49.8, 57.2, 61.6, 61.7, 77.6, 97.2, 111.4, 111.5,
117.9, 118.3, 119.4, 121.9, 122.1, 122.6, 123.2, 126.2, 126.9, 133.9, 136.4, 153.3,
156.4, 166.6, 166.7, 180.1; HRMS of [C27H28N2O6+H+]: calcd: 477.2025; found:
477.2027.
21. The ratios were calculated from 1H NMR spectra of crude product obtained
after full conversion (integration of H-2 proton for enaminochromanone
derivative and H-4 proton for 2-pyridone compound). The reaction yields in
Table 2 were calculated by referring to the isolated quantity of each compound.
22. Typical procedure for the synthesis of products 2k and 3k. These compounds
were prepared by treating 3-a,b-unsaturated chromone (1 equiv) with the
15. (a) Dückert, H.; Pries, V.; Khedkar, V.; Menninger, S.; Bruss, H.; Bird, A. W.;
Maliga, Z.; Brockmeyer, A.; Janning, P.; Hyman, A.; Grimme, S.; Schürmann, M.;
Preut, H.; Hübel, K.; Ziegler, S.; Kumar, K.; Waldmann, H. Nat. Chem. Biol. 2012,
8, 179–184; (b) Figueiredo, A. G. P. R.; Tomé, A. C.; Silva, A. M. S.; Cavaleiro, J. A.
S. Tetrahedron 2007, 63, 910–917; (c) Waldmann, H.; Kühn, M.; Liu, W.; Kumar,
K. Chem. Commun. 2008, 1211–1213; (d) Liu, W.; Khedkar, V.; Baskar, B.;
Schürmann, M.; Kumar, K. Angew. Chem., Int. Ed. 2011, 50, 6900–6905; (e)
Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Tolmachev, A. A. Synthesis
2007, 1861–1871; (f) Plaskon, A. S.; Ryabukhin, S. V.; Volochnyuk, D. M.;
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6010–6013.
corresponding amine (1.1 equiv) and 10 mol % of CsF in DCM (Scheme 2). The
reaction was stirred at room temperature for the required time (monitored by
TLC). At the end of the reaction the mixture was evaporated under vacuum and
purified by column chromatography (gradient of hexane and ethyl acetate) to
afford the desired products. Ethyl 5-(o-hydroxybenzoyl)-1-(20-sec-
butylphenyl)pyridin-2(1H)-one-3-carboxylate (2k). Yellow oil; 1H NMR
(300 MHz, CDCl3) d (ppm) 0.75–0.84 (m, 3H), 1.19–1.27 (m, 3H), 1.37 (t,
J = 7.2 Hz, 3H), 1.54–1.64 (m, 2H), 2.43–2.50 (m, 1H), 4.38 (q, J = 6.7 Hz, 2H),
6.88–6.94 (dd, J = 7.0, 7.3 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H),
7.31 (t, J = 7.2 Hz, 1H), 7.41–7.54 (m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 8.03 (d,
J = 1.8 Hz, 1H), 8.63 (d, J = 1.8 Hz, 1H), 11.35 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3) d (ppm) 12.5, 14.2, 21.6, 31.0, 35.8, 61.7, 115.5, 118.6, 118.9, 119.1,
121.3, 127.0, 127.2, 127.3, 130.4, 131.3, 136.6, 138.4, 144.1, 144.2, 147.4, 158.5,
162.6, 164.2, 194.4; HRMS of [C25H25NO5+H+]: calcd: 420.1811; found:
16. (a) Dang, A.-T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org. Lett. 2008, 10, 233–
236; (b) Bodwell, G. J.; Hawco, K. M.; da Silva, R. P. Synlett 2003, 179–182.
17. Haas, G.; Stanton, J. L.; von Sprecher, A.; Wenk, P. J. Heterocycl. Chem. 1981, 18,
607–612.
420.1802
(Z)-2-Diethoxycarbonyl-3-(20-sec-butylphenyl)aminomethylene-
18. Nohara, A.; Ishiguro, T.; Sanno, Y. Tetrahedron Lett. 1974, 15, 1183–1186.
19. (a) Ghosh, C. K.; Sahana, S.; Bandyopadhyay, C. Indian J. Chem., Sect. B 1993, 32B,
624–629; (b) Ghosh, C. K.; Bandyopadhyay, C.; Biswas, S. Indian J. Chem., Sect. B
1990, 29B, 814–818.
benzochroman-4-one (3k). Orange oil; 1H NMR (300 MHz, CDCl3) d (ppm)
0.80 (m, 3H), 1.07 (d, J = 7.1 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz,
3H), 1.60 (m, 2H), 2.93 (m, 1H), 3.91 (d, J = 10.4 Hz, 1H), 4.01 (q, J = 7.0 Hz, 2H),
4.19 (q, J = 7.0 Hz, 2H), 5.58 (d, J = 10.4 Hz, 1H), 6.80(d, J = 8.2 Hz, 1H.), 7.00 (d,
J = 7.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 7.8 Hz,
1H), 7.18 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.52 (d, J = 12.2 Hz, 1H), 7.90
(d, J = 7.7 Hz, 1H), 12.13 (d, J = 12 Hz, 1H, NH); 13C NMR (75 MHz, CDCl3) d
(ppm) 12.0, 14.0, 14.1, 20.8, 30.3, 34.7, 57.1, 61.7, 61.8, 77.6, 100.8, 116.3,
118.2, 122.1, 122.9, 124.9, 126.5, 126.9, 127.1, 134.6, 136.5, 137.8, 145.7, 156.7,
166.4, 166.5, 181.2; HRMS of [C27H31NO6+H+]: calcd: 466.2230; found:
466.2230.
20. Typical procedure for the synthesis of 2d and 3d These compounds were
prepared by treating 3-a,b-unsaturated chromone (1 equiv) with the
corresponding amine (1.1 equiv) in DCM (Scheme 2.). The reaction was
stirred at room temperature for the required time (monitored by TLC). At the
end of the reaction the mixture was evaporated under vacuum and purified by
column chromatography (gradient of hexane and ethyl acetate) to afford the
desired products 2d and 3d in 88% and 1:1 ratio. Ethyl 5-(o-hydroxybenzoyl)-
1-(indol-30-yl-ethyl)pyridin-2(1H)-one-3-carboxylate (2d). Yellow solid mp:
237–239 °C; 1H NMR (300 MHz, CDCl3) d (ppm) 1.41 (t, J = 7.1 Hz, 3H), 3.34 (t,
J = 6.3 Hz, 2H), 4.31 (t, J = 6.3 Hz, 2H), 4.42 (q, J = 7.1 Hz), 6.52–6.53 (m, 2H),
6.96–6.98 (m, 2H), 7.10 (t, J = 7.4 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.37–7.43 (m,
2H), 7.49–7.52 (m, 2H), 8.30 (s, 1H, NH), 8.52 (d, J = 2.4 Hz, 1H), 11.22 (s, 1H,
OH); 1H NMR (75 MHz, CDCl3) d (ppm) 14.3, 24.1, 53.1, 61.6, 111.2, 111.6,
114.9, 118.2, 118.3, 118.6, 119.0, 120.1, 120.2, 122.7, 123.0, 127.0, 130.9, 136.1,
136.4, 143.9, 147.2, 158.8, 162.2, 164.2, 193.9; HRMS of [C25H22N2O5+H+]:
calcd: 431.1618; found: 431.1607 (Z)-2-Diethoxycarbonyl-3-(indol-30-yl-
ethyl)aminomethylene-benzochroman-4-one (3d). Orange amorphous oil; 1H
NMR (300 MHz, CDCl3) d (ppm) 1.13 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H),
3.01 (t, J = 6.6 Hz, 2H), 3.53 (m, 2H), 3.91 (d, J = 10.3 Hz, 1H), 4.03 (q, J = 7.1 Hz,
2H), 4.24 (m, 2H), 5.45 (d, J = 10.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.94 (d,
J = 13.2 Hz, 1H), 6.96–7.06 (m, 2H), 7.11 (d, J = 7.5 Hz, 1H), 7.17 (t, J = 7.3 Hz,
1H), 7.32 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.89
23. Labade, V. B.; Pawar, S. S.; Shingare, M. S. Monatsh. Chem. 2011, 142, 1055–
1059.
24. (a) Dziewulska-Kulaczkowska, A.; Mazur, L. J. Mol. Struct. 2011, 985, 233–242;
(b) Siddiqui, Z. N.; Farooq, F. J. Chem. Sci. 2012, 124, 1097–1105.
25. Maiti, S.; Panja, S. K.; Bandyopadhyay, C. Indian J. Chem. 2009, 48B, 1447–1452.
26. We supposed that the hydrogen bonds between the amino group and 4-
carbonyl moiety of Z-intermediate (II) were cleaved under these conditions
promoting the E-isomer (III) quite exclusively. These suppositions were
confirmed by carrying out two complementary reactions: (1) the pure
isolated product 3l was refluxed in DCM for 2 h; and (2) 5 mol % of CsF were
added at room temperature to the reaction mixture. As expected, total
conversions into pyridone 2l were achieved. In agreement with our hypothesis,
we proved in this series also that the isolable 3-aminomethylene-chromanone
3l as the kinetic product can be easily transformed into pyridone 2l as the
thermodynamic derivative.