Noncatalytic destruction of 5-acylcomanic acid esters in the presence of 2-methylindoles as a new method for the synthesis of indolylchalcones

Article abstract of DOI:10.1007/s10593-017-2147-0

(Figure Presented.) Ethyl esters of 5-acylcomanic acids reacted with 2-methylindoles in 3:1 propanol–water mixture in the absence of catalyst, resulting in pyrone ring opening and destruction of the molecular framework and leading to trans-indolylchalcones in 52–70% yields.

Full text of DOI:10.1007/s10593-017-2147-0

DOI 10.1007/s10593-017-2147-0
Chemistry of Heterocyclic Compounds 2017, 53(8), 924–926
SHORT COMMUNICATIONS
Noncatalytic destruction of 5-acylcomanic acid esters
in the presence of 2-methylindoles as a new method
for the synthesis of indolylchalcones
1
1
1
Dmitrii L. Obydennov *, Ekaterina O. Pan’kina , Vyacheslav Ya. Sosnovskikh
1
Institute of Natural Sciences and Mathematics,
Ural Federal University named after the first President of Russia B. N. Yeltsin,
5
1 Lenina Ave., Yekaterinburg 620000, Russia; е-mail: dobydennov@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
017, 53(8), 924–926
Submitted May 29, 2017
Accepted after revision August 1, 2017
2
Ethyl esters of 5-acylcomanic acids reacted with 2-methylindoles in 3:1 propanol–water mixture in the absence of catalyst, resulting in
pyrone ring opening and destruction of the molecular framework and leading to trans-indolylchalcones in 52–70% yields.
Keywords: chalcones, indoles, 4-pyrones, alkenylation, ring destruction.
Indolylchalcones (1-aryl-3-indolylprop-2-en-1-ones) are an
important class of indole derivatives that attracts significant
should be noted that some 4-pyrone ring opening reactions
are accompanied by cleavage of С–С bonds, but such
processes usually occur in the presence of nucleophiles in
1
attention of researchers due to notable anticancer activity
2
8а
8b
and possibilities for use as synthetic intermediates. The
either acidic or basic medium. For this reason, we were
interested in a more detailed study of the conditions
facilitating the tandem transformation of pyrones 1 by a
reaction with 2-methylindole derivatives in the absence of
any catalysts. This approach allowed us to develop an alter-
native method for the preparation of indolylchalcones 4
that are valuable compounds for medicinal chemistry
efforts. Obviously, this reaction is not an example of atom-
economical transformations, but it demonstrates a new type
of reactivity for the highly active 5-acylcomanoates 1 and
clearly deserves attention.
main method used for the preparation of these compounds
is aldol condensation of indolecarbaldehydes with
1
acetophenones. New approaches have been actively
explored over recent years, based on acid-catalyzed
3
reactions of indoles with 1,3-diketones or with enones
containing a good leaving group at the β-position.4
However, in contrast to indole alkylation and arylation
5
reactions that have been relatively well developed, there is
very limited information available about direct alkenylation
6
of indoles.
We have recently demonstrated7 that ethyl 5-acyl-
We established that the optimal procedure for the
synthesis of chalcones 4a–g starts with maintaining the
appropriate 2-methylindoles 3a,b and pyrones 1a–f in a 3:1
comanoates 1 react with indole, as well as with 1- and
2
-methylindoles in ethanol in the presence of MeSO H,
3
forming Z-indolyldiketohexenoates 2 over the temperature
range from 0 to 60°С. During this study we found that
performing the reaction of pyrones 1a–f with 2-methyl-
indole (3а) by prolonged heating in ethanol or hexafluoro-
isopropanol produced not only diketohexenoates 2a–f, but
also a small amount of E-indolylchalcones 4a–f resulting
from partial destruction of the molecular framework and
isomerization relative to the С=С bond (Scheme 1). It
propanol–Н
O mixture at room temperature for 2 days
2
(pyrone ring opening occurs at this stage), followed by
refluxing of the reaction mixture for 10 h (control by TLC
method). The target indolylchalcones 4a–g, including
compounds 4e–g that were synthesized for the first time,
formed under these conditions in 52–70% yields without
impurities of the intermediate compounds 2a–g (Scheme 1,
Table 1). When the reaction was performed without the
0
009-3122/17/53(08)-0924©2017 Springer Science+Business Media New York
924

Chemistry of Heterocyclic Compounds 2017, 53(8), 924–926
Scheme 1
initial maintaining of the starting material mixture at room
temperature, the product yields were reduced by 5–20%.
The most suitable solvent for this transformation was
propanol, due to its relatively high boiling point,
miscibility with water, and the ability to dissolve the
starting materials. When propanol was replaced with
ethanol or hexafluoroisopropanol, incomplete conversion
of ester 2 to chalcone 4 was observed even after prolonged
refluxing. The use of anhydrous propanol led to longer
refluxing, apparently due to the fact that water is a
nucleophile that participates in the destruction of the
molecular framework. The aroyl substituent at the pyrone
ring practically did not affect the course of the
transformation, while the nature of substituent at position 2
of the indole ring was very important. Thus, the less
nucleophilic starting materials 2-phenylindole and
unsubstituted indole did not participate in this reaction, and
were either recovered in unchanged form, as in the case of
Table 1. Yields of chalcones 4а–g
Chalcone
Ar
Ph
6
R
H
Yield, %
59
4a
4b
4-MeC H4
H
64
4
c
4-ClC
6
H
4
H
65
4
d
4-MeOC
6
H
4
H
52
4
e
2-naphthyl
2-thienyl
Ph
H
70
4f
H
61
4g
MeO
68
field of medicinal chemistry, as well as in the role of
synthetic intermediates.
Experimental
IR spectra were recorded on a PerkinElmer Spectrum
1
13
2-phenylindole, or gave intractable products.
BX II instrument with an ATR accessory. Н and C NMR
The obtained compounds 4a–g had a trans-configuration
spectra were acquired on a Bruker Avance II spectrometer
of the double bond, as evidenced by the large value of their
vicinal spin-spin coupling constants (J = 15.1–15.5 Hz)
between the α-СН (δ 7.35–7.65 ppm) and β-СН (δ 7.99–
(400 and 100 MHz, respectively) in DMSO-d , with TMS
6
as internal standard. The indole ring protons are denoted as
H Ind, naphthalene ring protons – as H Nаphth, thiophene
ring protons – as Н Th. Elemental analysis was performed
on a PE 2400 automatic analyzer. Melting points were
determined on an SMP30 apparatus.
8
.10 ppm) protons, distinguishing these compounds from
the diketohexenoates 2, the molecules of which contained
aroyl and indole moieties in a cis orientation relative to
7
each other.
The starting pyrones 1a–f were obtained according to a
The possible mechanism of the described transformation
includes ketonic cleavage of the diketohexenoate ester 2 by
a molecule of water, resulting in the formation of 2-acyl-
published procedure.9
Preparation of compounds 4a–g (General method). A
mixture of the appropriate pyrone 1a–f (0.35 mmol) and
2-methylindole (3a) or 5-methoxy-2-methylindole (3b)
(0.42 mmol) was maintained in a 3:1 mixture of 1-PrOH–
3
-indolylacrylic acid A, which underwent decarboxylation
with the formation of trans-chalcone 4. The inversion of
double bond configuration when changing from esters 2 to
chalcones 4 can be explained by the isomerization of either
compound 2 or the intermediate А. The main factor
facilitating the destruction of molecular framework is
probably associated with the unfavorable interactions due
to the presence of methyl group at position 2 of indole.
Thus, we have developed a new method for the
preparation of trans-indolylchalcones on the basis of
catalyst-free reaction between ethyl 5-acylcomanoates and
H
2
O (1 ml) for 2 days at room temperature. An additional
amount (1 ml) of 3:1 mixture of 1-PrOH–H O was added to
2
the obtained precipitate of diketohexenoate 2a–g, and the
obtained mixture was heated for 10 h at 100°С, maintained
overnight at room temperature, the precipitate was then
filtered off and washed with cold EtOH.
(E)-3-(2-Methyl-1H-indol-3-yl)-1-phenylprop-2-en-
1-one (4а). Yield 54 mg (59%), yellow powder,
4a
1
mp 182–183°С (mp 183°С ). H NMR spectrum, δ, ppm
2
-methylindoles, which is accompanied by pyrone ring
(J, Hz): 2.59 (3H, s, CH ); 7.16–7.24 (2H, m, H-5,6 Ind);
3
opening and destruction of the molecular framework. The
obtained products are of interest for further studies in the
7.37–7.43 (1H, m, H-7 Ind); 7.54 (1H, d, J = 15.5, α-СН);
7.54–7.60 (2H, m, H-3,5 Ph); 7.60–7.66 (1H, m, H-4 Ph);
9
25

Chemistry of Heterocyclic Compounds 2017, 53(8), 924–926
7
.99–8.04 (1H, m, Н-4 Ind); 8.06 (1H, d, J = 15.5, β-СН);
.09–8.13 (2H, m, H-2,6 Ph); 11.86 (1H, s, NH).
E)-3-(2-Methyl-1H-indol-3-yl)-1-(p-tolyl)prop-2-en-
-one (4b). Yield 62 mg (64%), orange powder,
181.3. Found, %: С 71.64; Н 4.86; N 5.38. С16
H13NOS.
8
Calculated, %: С 71.88; Н 4.90; N 5.24.
(
(E)-3-(5-Methoxy-2-methyl-1H-indol-3-yl)-1-phenylprop-
2-en-1-one (4g). Yield 69 mg (68%), yellow powder,
1
4a
1
−1
mp 233–234°С (mp 210°С ). H NMR spectrum, δ, ppm
mp 190–191°С. IR spectrum, ν, cm : 3244, 2982, 2921,
1
(
J, Hz): 2.44 (3H, s, CH
3
C
6
H
4
); 2.60 (3H, s, CH
3
Ind);
1635, 1544, 1278, 695. H NMR spectrum, δ, ppm (J, Hz):
7
.08–7.18 (2H, m, H-5,6 Ind); 7.30 (2H, d, J = 8.1, H-3,5
2.60 (3Н, s, CH
3
); 3.87 (3H, s, CH O); 6.75 (1H, dd, J = 8.7,
3
Ar); 7.34 (1H, dd, J = 7.0, J = 1.6, Н-7 Ind); 7.44 (1H, d,
J = 15.3, α-СН); 7.89 (1Н, dd, J = 6.9, J = 1.2, Н-4 Ind);
H Ind); 7.24 (1H, d, J = 8.7, H Ind); 7.31 (1H, d, J = 2.2,
H-4 Ind); 7.35 (1H, d, J = 15.3, α-СH); 7.47–7.59 (3Н, m,
H Ph), 7.97–8.04 (3Н, m, H Ph); 11.53 (1Н, s, NH).
7
.93 (2H, d, J = 8.1, H-2,6 Ar); 8.00 (1H, d, J = 15.3,
1
3
β-СН); 11.61 (1H, s, NH).
E)-1-(4-Chlorophenyl)-3-(2-methyl-1H-indol-3-yl)-
prop-2-en-1-one (4c). Yield 67 mg (65%), yellow powder,
C NMR spectrum, δ, ppm: 12.0; 55.5; 103.2; 109.0; 110.6;
(
112.0; 113.8; 126.6; 127.8; 128.5; 130.9; 131.9; 137.8;
138.9; 144.2; 154.9; 188.7. Found, %: С 78.23; Н 5.86;
4a
1
mp 227–228°С (mp 215°С ). H NMR spectrum, δ, ppm
J, Hz): 2.64 (3Н, s, CH ); 7.11–7.20 (2H, m, Н-5,6 Ind);
N 5.05. С19
H
17NO . Calculated, %: С 78.33; Н 5.88; N 4.81.
2
(
3
7
.37 (1H, dd, J = 6.8, J = 1.5, Н-7 Ind); 7.44 (1H, d,
References
J = 15.3, α-CH); 7.52 (2H, d, J = 8.5, Н-3,5 Ar); 7.93 (1Н,
dd, J = 7.1, J = 1.3, Н-4 Ind); 8.06 (1H, d, J = 15.3, β-CH);
1. (a) Yan, J.; Chen, J.; Zhang, S.; Hu, J.; Huang, L.; Li, X.
J. Med. Chem. 2016, 59, 5264. (b) Robinson, M. W.;
Overmeyer, J. H.; Young, A. M.; Erhardt, P. W.; Maltese, W. A.
J. Med. Chem. 2012, 55, 1940. (c) Valdameri, G.; Gauthier, C.;
Terreux, R.; Kachadourian, R.; Day, B. J.; Winnischofer, S. M. B.;
Rocha, M. E. M.; Frachet, V.; Ronot, X.; Di Pietro, A.;
Boumendjel, A. J. Med. Chem. 2012, 55, 3193. (d) Kumar, D.;
Kumar, N. M.; Akamatsu, K.; Kusaka, E.; Harada, H.; Ito, T.
Bioorg. Med. Chem. Lett. 2010, 20, 3916. (e) Trabbic, C. J.;
George, S. M.; Alexander, E. M.; Du, S.; Offenbacher, J. M.;
Crissman, E. J.; Overmeyer, J. H.; Maltese, W. A.; Erhardt, P. W.
Eur. J. Med. Chem. 2016, 122, 79.
8
.07 (2H, d, J = 8.5, Н-2,6 Ar); 11.70 (1Н, s, NH).
(E)-1-(4-Methoxyphenyl)-3-(2-methyl-1H-indol-3-yl)-
prop-2-en-1-one (4d). Yield 53 mg (52%), orange powder,
4
a
1
mp 171–172°С (mp 170°С ). H NMR spectrum, δ, ppm
J, Hz): 2.58 (3H, s, CH ); 3.86 (3H, s, CH O); 7.08 (2H, d,
J = 8.8, H-3,5 Ar); 7.14–7.23 (2H, m, H-5,6 Ind); 7.36–
(
3
3
7
.42 (1H, m, Н-7 Ind); 7.54 (1H, d, J = 15.3, α-СН); 8.02
(
(
1H, d, J = 15.3, β-СН); 8.00–8.04 (1H, m, Н-4 Ind); 8.11
2H, d, J = 8.8, H-2,6 Ar); 11.81 (1H, s, NH).
2
. (a) Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem.
(
E)-3-(2-Methyl-1H-indol-3-yl)-1-(naphth-2-yl)prop-
1995, 60, 1939. (b) Rajeshwaran, G. G.; Mohanakrishnan, A. K.
2
-en-1-one (4e). Yield 80 mg (70%), yellow powder,
Org. Lett. 2011, 13, 1418.
−1
mp 238–239°С. IR spectrum, ν, cm : 3179, 1699, 1599,
3
. Sanap, A. K.; Shankarling, G. S. RSC Adv. 2014, 4, 34938.
. Devi, A. S.; Helissey, P.; Nongkhlaw, R. L.; Vishwakarma, J. N.
Synth. Commun. 2013, 43, 1653. (b) Sosnovskikh, V. Ya.;
Irgashev, R. A. Lett. Org. Chem. 2007, 4, 344.
1
1
564, 1456, 1434, 1284, 1260, 743. H NMR spectrum, δ,
4
ppm (J, Hz): 2.65 (3H, s, CH ); 7.08–7.24 (2H, m, Н-5,6
3
Ind); 7.37 (1H, d, J = 7.8, Н-7 Ind), 7.53–7.63 (2H, m,
H Naphth); 7.65 (1H, d, J = 15.1, α-CH); 7.93 (1H, d,
J = 7.5, H Ar); 7.97 (1H, d, J = 8.5, H Ar); 8.02 (1H, d,
J = 7.8, H Ar); 8.10 (1H, d, J = 15.1, β-СH); 8.10 (1Н, dd,
J = 8.7, J = 1.4, H Naphth); 8.15 (1H, d, J = 7.8,
H Naphth); 8.69 (1H, s, H-1 Naphth); 11.69 (1H, s, NH).
5. (a) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev.
2
010, 39, 4449. (b) Shiri, M. Chem. Rev. 2012, 112, 3508.
(
c) Broggini, G.; Beccalli, E. M.; Fasana, A.; Gazzola, S.
Beilstein J. Org. Chem. 2012, 8, 1730. (d) Indoles;
Sundberg, R. J., Ed.; Academic Press: London, 1996.
(
e) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009,
1
3
C NMR spectrum, δ, ppm: 11.9; 109.3; 111.5; 114.1; 120.3;
21.2; 122.1; 124.4; 125.9; 126.7; 127.6; 128.2 (2C); 129.1;
48, 9608.
1
6. (a) Xiang, S.-K.; Zhang, B.; Zhang, L.-H.; Cui, Y.; Jiao, N.
Chem. Commun. 2011, 47, 8097. (b) García-Rubia, A.;
Arrayás, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2009,
1
29.6; 132.4; 134.7; 136.0; 136.2; 137.9; 144.3; 188.5.
Found, %: С 81.08; Н 5.60; N 4.35. С22
Calculated, %: С 81.33; Н 5.74; N 4.31.
H
17NO·0.75H O.
2
4
8, 6511. (c) Su, Y.; Gao, S.; Huang, Y.; Lin, A.; Yao, H.
Chem.–Eur. J. 2015, 21, 15820. (d) Nakao, Y.; Kanyiva, K. S.;
Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2006, 128, 8146.
(E)-3-(2-Methyl-1H-indol-3-yl)-1-(thiophen-2-yl)prop-
2
-en-1-one (4f). Yield 57 mg (61%), orange powder,
(
e) Yu, H.; Yu, Z. Angew. Chem., Int. Ed. 2009, 48, 2929.
−1
mp 197–198°С. IR spectrum, ν, cm : 3222, 2919, 1619,
(f) Taheri, A.; Liu, C.; Lai, B.; Cheng, C.; Pan, X.; Gu, Y.
Green Chem. 2014, 16, 3715.
1
1
2
533, 1452, 1272, 710. H NMR spectrum, δ, ppm (J, Hz):
.62 (3Н, s, CH ); 7.09–7.18 (2H, m, Н-5,6 Ind); 7.21 (1H,
7
8
. Obydennov, D. L.; Pan'kina, E. O.; Sosnovskikh, V. Ya.
J. Org. Chem. 2016, 81, 12532.
3
t, J = 4.2, H Th); 7.36 (1H, d, J = 15.5, α-CH); 7.32–7.37
. (a) Obydennov, D. L.; Röschenthaler, G.-V.; Sosnovskikh, V. Ya.
Tetrahedron Lett. 2014, 55, 472. (b) Usachev, S. A.; Usachev, B. I.;
Eltsov, O. S.; Sosnovskikh, V. Ya. Tetrahedron 2014, 70, 8863.
. Obydennov, D. L.; Goncharov, A. O.; Sosnovskikh, V. Ya.
Russ. Chem. Bull., Int. Ed. 2016, 65, 2233. [Izv. Akad. Nauk,
Ser. Khim. 2016, 2233.]
(
1Н, m, Н-7 Ind); 7.79 (1H, d, J = 4.8, H Th); 7.92 (1H, d,
J = 7.3, Н-4 Ind); 7.99 (1H, d, J = 15.5, β-СH); 7.99–8.04
1
3
(
1Н, m, H Th); 11.66 (1Н, s, NH). C NMR spectrum,
δ, ppm: 11.9; 109.0; 111.5; 113.8; 120.2; 121.2; 122.1;
25.8; 128.7; 131.7; 133.8; 136.1; 137.0; 144.2; 146.4;
9
1
9
26