Tetramic acids and indole derivatives from amino acid β-keto esters. Fine-tuning the conditions of the key Cu-catalyzed reaction

Article abstract of DOI:10.1016/j.tetlet.2014.02.059

1,3,5-Trisubstituted tetramic acids and 2,3-disubstituted indole derivatives were prepared from β-keto esters derived from amino acids by their reaction with iodophenyl-2-trifluoroacetylamine under Cu-catalysis. Both heterocyclic systems were generated fr

Full text of DOI:10.1016/j.tetlet.2014.02.059

Tetrahedron Letters 55 (2014) 2142–2145
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tetramic acids and indole derivatives from amino acid b-keto esters.
Fine-tuning the conditions of the key Cu-catalyzed reaction
⇑
M. Isabel García-Aranda, M. Teresa García-López, M. Jesús Pérez de Vega, Rosario González-Muñiz
Instituto de Química Médica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
1,3,5-Trisubstituted tetramic acids and 2,3-disubstituted indole derivatives were prepared from b-keto
esters derived from amino acids by their reaction with iodophenyl-2-trifluoroacetylamine under
Cu-catalysis. Both heterocyclic systems were generated from the same starting materials by choice of
the appropriate reaction conditions.
Received 20 January 2014
Revised 10 February 2014
Accepted 17 February 2014
Available online 24 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
2,3-Disubstituted indoles
Tetramic acids
b-Keto esters
Amino acids
Diversity oriented synthesis
Diversity-Oriented Synthesis (DOS) strategies have successfully
been used to identify new ligands for a variety of targets, including
protein–protein interactions.1 These strategies provide skeletal,
appendage and stereochemical diversity to give access to collec-
tions of complex and diverse small molecules. In the search for
bioactive compounds, special efforts have also been directed to
develop libraries based on privileged scaffolds, structural motifs
common to bioactive molecules, such as indole, quinolone,
benzimidazole, dihydropyridine, dihydropyrimidine, benzodiaze-
pine, and others.2 Although DOS usually explores the chemical
space not occupied by synthetic drugs and natural products, some
DOS-based strategies around privileged scaffolds have been descri-
bed.1a,3 These strategies populate the chemical space through the
creation of new core skeletons that have embedded privileged mo-
tifs, or by generating innovative substitution patterns on privileged
structures.
of the tetramic acid derivatives hitherto described are 1-unsubsti-
tuted or 1-alkyl/benzyl derivatives, but very few 1-benzyloxycar-
bonyl analogs have been reported until now.7
It is known that b-keto esters are versatile synthetic intermedi-
ates that have been widely used for the preparation of different
heterocyclic systems, like dihydropyrimidinones, indoles, penta-
substituted pyrrole rings, and pyrazolones.8 In particular, we have
worked on the transformation of b-keto esters derived from amino
acids and dipeptides in different chiral heterocyclic systems,
namely 1,3-dioxoperhydropyrido[1,2-c]pyrimidines, and 2-oxopip-
erazine derivatives.9 More recently, we have initiated a program di-
rected to study the use of these b-keto esters as valuable starting
materials for DOS approaches, allowing the appendage of the amino
acid side-chain in the heterocyclic system, which, in turn, can pro-
vide a source of diversification. In this sense, the preparation of
highly functionalized b,c-diamino esters has already been de-
Within privileged scaffolds, the indole ring is probably one of
the most important structures in drug discovery,4 as well as one
of the heterocyclic systems more commonly found in natural prod-
ucts.5 Therefore, any method aimed at the preparation of innova-
tive indole derivatives is of invaluable interest in medicinal
chemistry. In a similar manner, the tetramic acid is a challenging
structure that is present in a high variety of natural products
displaying a wide range of biological activities, ranging from
antibiotic and antivirals to antineoplastic and fungicides.6 Most
scribed, along with their conversion into pyrrolidinone deriva-
tives.10 Now, we illustrate the application of amino-acid-derived
b-keto esters to the synthesis of non-conventional 2,3-disubstituted
indoles and 1-benzyloxycarbonyl tetramic acid derivatives.
Inspired by the indole synthesis described by Tanimori from
2-iodoaniline and alkyl or aryl b-keto esters,8e we decided to ex-
plore the preparation of indole derivatives of general formula C,
with an unusual
a-amino substituent at position 2, using amino
acid-derived b-keto esters 1 as key starting materials (Scheme 1).
In this copper catalyzed reaction, two intermediates can be envis-
aged for the generation of the indole ring. These are, the previously
proposed condensation to conjugated enamines A,11 followed by a
⇑
Corresponding author. Tel.: +34 915680063; fax: +34 915644853.
E-mail address: rosario.gonzalezmuniz@iqm.csic.es (R. González-Muñiz).
http://dx.doi.org/10.1016/j.tetlet.2014.02.059
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M. I. García-Aranda et al. / Tetrahedron Letters 55 (2014) 2142–2145
R1
2143
i
iii
CO2Me
RHN
CO2Me
R1
I
CO2Me
R1
I
O
1
or
N
H
O
NHR
Cu catalyst
B:
NH2
NH2
NHR
ii
A
B
iii
i
ii
or
R
N
R
N
O
O
CO2Me
R1
R1
R1
N
H
NHR
O
OH
NH2
NH2
C
D
Scheme 1. Initial proposed route to 2,3-disubstituted indoles and tetramic acid derivatives.
O
OMe
R1
O
I
O
O
H
N
(1 equiv)
NHCOCF3
N
H
O
*
O
*
OMe
OH
CuI, (0.2 equiv)
L-Pro (0.4 equiv)
Cs2CO3 (1 equiv)
DMSO, rt
NH
O
R1
F3C
O
1a: R1 = CH3; * S
1b: R1 = CH3; * R
32-60%
2a, b, c
1
1c
: R = CH2Ph; * S
CuI, (0.2 equiv)
L-Pro (0.4 equiv)
Cs2CO3 (4 equiv)
DMSO, 50 ºC
60-72%
I
HCl/MeOH
80 ºC, 2h
63-67%
Cs2CO3 (2 equiv)
NHCOCF3
MeOH/H2O
80 ºC, 2h
(1 equiv)
2a
from
47%
O
OMe
R1
O
O
O
N
*
*
HCl/MeOH
80 ºC, 2h
N
NH
H
R1
O
O
3b
from
57%
OH
NH
COCF3
3a, b, c
4a, b, c
H2, 15 psi
Pd(C), MeOH
80-99%
H2, 15 psi
Pd(C), MeOH
72%
O
NH
O
OMe
R1
*
OH
NH
*
N
NH2
H
5a, b, c
6a
COCF3
Scheme 2. Synthesis of 2,3-disubstituted indoles and tetramic acids from amino acid-derived b-keto esters.
Heck-type coupling (i), but also the arylation of the 1,3-dicarbonyl
compound to intermediates B and subsequent condensation (ii). In
procedure previously described by Chen et al.14 This modification
would diminish the risk of side reactions and, at the same time,
it would permit to take profit of the accelerating effect described
for an ortho-amide group in Ullman-type reactions.15
As depicted in Scheme 2, treatment of a mixture of the corre-
sponding b-keto ester, 1a–c, and iodophenyl-2-trifluoroacetyl-
amine with copper iodide, in the presence of an excess of cesium
fact, the CuI/L-proline catalytic system was previously described as
a useful procedure to diverse 2-aryl-1,3-dicarbonyl compounds.12
If intermediates B were formed, under the basic conditions of the
reaction, they could also lead to tetramic acid derivatives D
through lactamization (route iii).
To explore the possibilities of this synthetic scheme, we pre-
pared the corresponding b-keto esters derived from Z-Ala-OH, both
L and D, and Z-Phe-OH, using described strategies.9c,13 In our
hands, following the Tanimori conditions,8e the reaction of b-keto
esters 1 with 2-iodoaniline led to complex mixtures, both using
carbonate (4 equiv) as base and L-Pro (0.4 equiv) as additive in
DMSO,14 did not lead to the expected open 2-aryl-1,3-dicarbonyl
derivatives 2. Instead, under these conditions, the tetramic acid
derivatives 3a–c were isolated in good yield. The structure of
compounds 3, which should come from the nucleophilic addition
of the carbamate NH to the methyl ester group of compounds 2,
through type-B intermediates, was confirmed by mass spectrome-
try that showed the loss of 31 mass units, which corresponds to the
loss of a MeO-group, as well as the absence of the corresponding
signal in the 1H NMR spectra. On the contrary, when we tried
BINOL and L-Pro as additives. Similar disappointing results were
obtained when the reaction was carried out by conventional heat-
ing and under MW irradiation. Considering that the primary amine
group could be the responsible for the undesired side reactions, we
decided to protect it with a trifluoroacetyl group, following a

2144
M. I. García-Aranda et al. / Tetrahedron Letters 55 (2014) 2142–2145
O
O
upon acid hydrolysis. The obtained indole systems are substituted
in position 2 by an amino methyl group, also supporting an amino
acid side-chain (R1) at the methylene group. Therefore, different
R1 substituents could be introduced by using different amino acids
as starting materials. Additionally, the primary amino group on the
substituent in position 2, as well as the carboxylate group in
position 3 of the indole ring are both susceptible of further modifi-
cation, providing new opportunities for diversification. The
synthetic approach described here could have application in the
generation of libraries based on two biologically relevant heterocy-
clic systems, indole and tetramic acids, with new substitution
patterns.
OMe
OMe
t-BuC6H4NCO
TEA/DCM
rt, 16h
76%
N
N
NH2
NH
NH
H
H
O
6a
7a
C6H5SO2Cl
C6H5CH2COCl
Propylene oxide
rt, 4h
Propylene oxide
rt, 16 h
31%
52%
O
OMe
O
OMe
N
NH
H
Acknowledgments
N
H
NH
O
S O
O
8a
9a
This work was supported by (SAF 2009-09323), Consolider-
Ingenio 2010 (Project CSD2008_00005) and BFU2012-39092-
C02-02. M.I.G.-A. thanks the CSIC for a predoctoral fellowship
(JAE-Predoc, from ‘Junta para la Ampliación de Estudios’,
co-financed by FSE).
Scheme 3. Incorporation of diversity at the free amino group.
milder conditions for the coupling reaction, using room tempera-
ture and only 1 equiv of cesium carbonate as the base, the expected
coupling products 2a–c were isolated as the main reaction prod-
ucts.16 Heating compounds 2a–c with 2 equiv of cesium carbonate
in methanol led, again, to the tetramic acid derivatives 3a–c.17 This
is in agreement with the direct formation of these compounds
from 1a–c when the first reaction was performed under excess of
base (Scheme 2).
Supplementary data
Supplementary data (1H NMR and 13C NMR spectra for all new
compounds 2a–9a) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.059.
References and notes
Deprotection of the o-amino group of compounds 2 either under
basic or acidic conditions would permit the cyclization to the de-
sired indole derivative.9b Thus, removal of the trifluoroacetyl group
of compounds 2a–c by treatment with hydrochloric acid finally led
to the expected indole derivatives 4a–c in good yield.18 In addition,
these compounds were also obtained by a similar acidic treatment
of the tetramic acid analogs 3a–c. In general terms, for the prepara-
tion of indole derivatives 4 the route 1 ? 3 ? 4 led to better yields
than the alternative 1 ? 2 ? 4 pathway.
Chiral HPLC experiments on these indole derivatives indicated
an almost total loss of optical purity (40–46% racemization), prob-
ably due to the instability of the intermediate compounds 2 or 3
under acidic reaction conditions. A similar stereochemical integrity
loss was described in the reductive amination reaction of these
b-keto esters.10
The carbamate group (Z) in compounds 3 and 4 can be easily re-
moved by hydrogenation, as illustrated by the preparation of tetra-
mic acids 5a–c, and indole 6a, respectively, having appropriate
functional groups for further transformations. Thus, the primary
amino group in compounds 6a is susceptible of new reactions,
offering the possibility of increasing the molecular diversity by
introducing different substituents and functionalities to that posi-
tion. To exemplify this, and to explore the reactivity of the amino
group at this position, compound 6a was reacted with an isocya-
nate, an acyl chloride, and a sulfonyl chloride to lead to urea 7a,
amide 8a, and sulfonamide 9a, in good/acceptable yields
(Scheme 3). Reactions with the acyl and sulfonyl chlorides were
performed in the presence of excess of propylene oxide as the acid
scavenger, leading to cleaner crude products and higher yield than
with TEA.
In summary, starting from b-keto esters derived from
amino acids we have developed a simple and practical method
that permits the preparation of either 1-benzyloxycarbonyl-3,5-
disubstituted tetramic acid derivatives or 2,3-disubstituted indole
systems. The thorough control of the reaction conditions, by means
of the amount of base and the temperature, allowed us to stop the
reaction in the linear 2-aryl-1,3-dicarbonyl derivatives or progress
it to the tetramic acids, both precursors of the indole derivatives
1. (a) Spandl, R. J.; Bender, A.; Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149–1158;
(b) Dandapani, S.; Marcaurelle, L. A. Curr. Opin. Chem. Biol. 2010, 14, 362–370;
(c) Tzakos, A. G.; Fokas, D.; Johannes, C.; Moussis, V.; Hatzimichael, E.;
Briasoulis, E. Molecules 2011, 16, 4408–4427; (d) Ng, P. Y.; Tang, Y.; Knosp, W.
M.; Stadler, H. S.; Shaw, J. T. Angew. Chem., Int. Ed. 2007, 46, 5352–5355.
2. (a) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14,
347–361; (b) Duarte, C. D.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med. Chem.
2007, 7, 1108–1119; (c) Costantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13,
65–85.
3. Tan, D. S. Nat. Chem. Biol. 2005, 1, 74–84.
4. Rodrigues de Sa Alves, F.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med. Chem.
2009, 9, 782–793.
5. (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911; (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
6. (a) Royles, B. J. L. Chem. Rev. 1995, 95, 1981–2001; (b) Schobert, R.; Schlenk, A.
Bioorg. Med. Chem. 2008, 16, 4203–4221; (c) Spatz, J. H.; Welscha, S. J.; Duhaut,
D.-E.; Jäger, N.; Boursier, T.; Fredrich, M.; Allmendinger, L.; Ross, G.; Kolb, J.;
Burdack, C.; Umkehrer, M. Tetrahedron Lett. 2009, 50, 1705–1707; (d) De
Vicente, J.; Hendricks, R. T.; Smith, D. B.; Fell, J. B.; Fischer, J.; Spencer, S. R.;
Stengel, P. J.; Mohr, P.; Robinson, J. E.; Blake, J. F.; Hilgenkamp, R. K.; Yee, C.;
Adjabeng, G.; Elworthy, T. R.; Li, J.; Wang, B.; Bamberg, J. T.; Harris, S. F.; Wong,
A.; Leveque, V. J. P.; Najera, I.; Le Pogam, S.; Rajyaguru, S.; Ao-Ieong, G.;
Alexandrova, L.; Larrabee, S.; Brandl, M.; Briggs, A.; Sukhtankar, S.; Farrell, R.
Bioorg. Med. Chem. Lett. 2009, 19, 5652–5656; (e) Mallinger, A.; Nadal, B.;
Chopin, N.; Le Gall, T. Eur. J. Org. Chem. 2010, 1142–1148.
7. (a) Storgaard, M.; Dorwald, F. Z.; Peschke, B.; Tanner, D. J. Org. Chem. 2009, 74,
5032–5040; (b) Yoon-Miller, S. J. P.; Dorward, K. M.; White, K. P.; Pelkey, E. T. J.
Heterocycl. Chem. 2009, 46, 447–454.
8. (a) Liu, X. T.; Huang, L.; Zheng, F. J.; Zhan, Z. P. Adv. Synth. Catal. 2008, 350,
2778–2788; (b) Tietze, L. F.; Evers, H.; Hippe, T.; Steinmetz, A.; Topken, E. Eur. J.
Org. Chem. 2001, 1631–1634; (c) Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc.
2005, 127, 16386–16387; (d) Goss, J. M.; Schaus, S. E. J. Org. Chem. 2008, 73,
7651–7656; (e) Tanimori, S.; Ura, H.; Kirihatali, M. Eur. J. Org. Chem. 2007,
3977–3980.
9. (a) Martín-Martínez, M.; Bartolomé-Nebreda, J. M.; Gómez-Monterrey, I.;
González-Muñiz, R.; García-López, M. T.; Ballaz, S.; Barber, A.; Fortuño, A.; Del
Río, J.; Herranz, R. J. Med. Chem. 1997, 40, 3402–3407; (b) Patiño-Molina, R.;
Herranz, R.; García-López, M. T.; González-Muñiz, R. Tetrahedron 1999, 55,
15001–15010; (c) Patiño-Molina, R.; Martín-Martínez, M.; Herranz, R.; García-
López, M. T.; González-Muñiz, R. Lett. Pept. Sci. 2000, 7, 143–149.
10. Pérez-Faginas, P.; Aranda, M. T.; García-López, M. T.; Infantes, L.; Fernández-
Carvajal, A.; González-Ros, J. M.; Ferrer-Montiel, A.; González-Muñiz, R. PLoS
ONE 2013, 8, e53231.
11. Barluenga, J.; Rodríguez, F.; Fañanás, F. J. Chem.-Asian J. 2009, 4, 1036–1048.
12. Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693–4695.
13. (a) Theberge, C. R.; Zercher, C. K. Tetrahedron 2003, 59, 1521–1527; (b) Wirtz,
L.; Kazmaier, U. Eur. J. Org. Chem. 2011, 7062–7065.
14. Chen, Y.; Xie, X.; Ma, D. J. Org. Chem. 2007, 72, 9329–9334.

M. I. García-Aranda et al. / Tetrahedron Letters 55 (2014) 2142–2145
2145
15. Ma, D.; Qian, C. Acc. Chem. Res. 2008, 41, 1450–1460.
16. Representative procedure for the preparation of (2-trifluoroacetamido)phenyl-
HCl, and extracted with EtOAc. The workup was continued as described in
method A. As an example: (5S)-1-Benzyloxycarbonyl-4-hydroxy-5-methyl-3-
(2-trifluoroacetamido)phenyl-3-pyrrolin-2-one (3a): from 1a (0.4 mmol) by
Method A or 2a (0.017 mmol) by Method B. (100 mg, 60% and 3.5 mg, 47%
2-pentenoate derivatives 2.
(0.3 mmol) in dry
iodotrifluoroacetamidobenzene (0.33 mmol), CuI (0.066 mmol),
A solution of the corresponding b-keto ester
1
DMSO
(3 ml)
was
treated
with
2-
-Pro
L
respectively). Brownish solid, HPLC: tR = 9.57 min, mp 168–171 °C, ½a D25
ꢀ
= +36.7
(0.13 mmol), and Cs2CO3 (0.33 mmol), and stirred at room temperature for 3
days. Then the reaction mixture was neutralized with 1 M HCl and extracted
with EtOAc. The organic phase was washed with brine and dried over Na2SO4.
The solvent was evaporated and the raw material was purified by
chromatography (20% EtOAc/Hexane). As an example: (4S)-methyl 4-
(benzyloxycarbonyl)amino-3-hydroxy-2-(2-trifluoroacetamido)phenyl-2-
pentenoate (2a): from 1a (0.3 mmol). Brownish solid (84 mg, 60%). HPLC:
(c 1.0, MeOH). 1H NMR (DMSO-d6, 300 MHz): d = 13.27 (s, 1H, 4-OH), 7.81 (dd,
1H, J = 6.2, 3.3 Hz, Ar), 7.57 (m, 1H, Ar), 7.49–7.26 (m, 7H, 5H Ar-Z, 1H Ar, and
1H NHCOCF3); 7.11 (dd, 1H, J = 5.7, 3.5 Hz, 3-H Ar), 5.24 (d, 1H, J = 12.9 Hz,
CH2), 5.17 (d, 1H, J = 12.9 Hz, CH2), 3.94 (q, 1H, 5-H, J = 6.3 Hz), 1.33 (d, 3H,
J = 6.5 Hz, 5-CH3) ppm. 13C NMR (DMSO-d6, 75 MHz): d = 187.6 (4-C-OH), 169.7
(CO), 154.2 (q, J = 36 Hz, COCF3), 151.2 (COO), 136.5 (C Ar), 132.4 (C Ar), 129.17
(CH Ar), 128.8 (2C, CH Ar), 127.8 (CH Ar), 127.5 (2C, CH Ar), 124.7 (C Ar), 124.41
(CH Ar), 124.0 (CH Ar), 123.6 (CH Ar), 116.4 (q, J = 286 Hz, COCF3), 94.4 (3-C),
66.0 (Z-CH2), 56.1 (5-C), 17.7 (5-CH3) ppm. C21H17F3N2O5 (434.37): calcd C,
58.07; H, 3.94; N, 6.45; found C, 57.98; H, 3.88; N, 6.32. ESI-MS: m/z = 435.2
[M+H]+.
tR = 11.55 min, mp 130–132 °C, ½a D25
ꢀ
= ꢁ13.5 (c 1.0, MeOH). 1H NMR (CDCl3,
300 MHz): d = 13.0 (d, 1H, J = 1.6 Hz, 3-OH), 9.66 (s, 1H, NH–COCF3), 7.77 (d,
1H, J = 7.8 Hz, Ar), 7.48 (td, 1H, J = 7.8, 1.3 Hz, Ar), 7.44–7.30 (m, 6H, Ar); 7.17
(dd, 1H, J = 7.8, 1.3 Hz, Ar), 5.16–5.04 (m, 3H, 2H CH2, 1H 4-NH), 3.99 (m, 1H,
J = 6.8, 1.5 Hz, 4-H), 3.67 (s, 3H, OCH3), 1.37 (d, 3H, J = 6.8 Hz, 5-CH3) ppm. 13
C
18. General procedure for the synthesis of 2,3-disubstituted indole derivatives 4. A
solution of the corresponding compounds 2 or 3 (0.17 mmol) in MeOH (5 ml)
was treated with concentrated HCl (1 ml) and heated at 80 °C for 2 h. After
recovering room temperature, the reaction mixture was neutralized with 10%
NaHCO3 and EtOAc was added. The organic phase was separated, washed with
brine, dried with Na2SO4. After removing the solvent, the residue was purified
by column chromatography (20% EtOAc/Hexane). As an example: (10S)-2-[10-
(Benzyloxycarbonyl) amino]ethyl-3-methoxycarbonylindole (4a): from 2a
(0.17 mmol). White solid (38 mg, 63%), HPLC: tR = 9.95 min, mp 143–146 °C,
NMR (CDCl3, 75 MHz): d = 173.7 (3-C), 172.0 (CO), 156.0 (CO), 155.57 (q,
J = 32 Hz, COCF3), 135.7 (C Ar), 134.6 (C Ar), 131.9 (CH Ar), 129.2 (CH Ar), 128.5
(2C, CH Ar), 128.4 (2C, CH Ar), 128.3 (CH Ar), 128.1 (CH Ar), 127.0 (CH Ar),
126.2 (C Ar), 116.1 (q, J = 288 Hz, COCF3), 99.9 (2-C), 67.2 (Z-CH2), 52.1 (OCH3),
47.6 (4-C), 17.5 (5-C) ppm. C22H21F3N2O6 (466.41): calcd C, 56.65; H, 4.54; N,
6.01; found C, 56.55; H, 4.41; N, 5.92. ESI-MS: m/z = 489.0 [M+Na]+, 467.0
[M+H]+.
17. General procedure for the synthesis of 3-(2-trifluoroacetamido)phenyl-3-
pyrrolin-2-one derivatives 3.
½
a 2D5
ꢀ
=
ꢁ8.7 (c 1.0, MeOH) (S:R = 54:46). 1H NMR (DMSO-d6, 300 MHz):
Method A: A solution of the corresponding b-keto ester 1 (0.4 mmol), in dry
DMSO (2 ml) was treated with 2-trifluoroacetamidobenzene (0.44 mmol), CuI
d = 11.69 (s, 1H, NH), 7.93 (dd, 1H, J = 5.2, 3.8 Hz, 4-HIndol), 7.64 (d, 1H,
J = 4.5 Hz, NHCO), 7.46 (m, 1H, 7HIndol), 7.34 (m, 5H, H Ar), 7.15 (m, 2H, 5-HIndol
,
(0.088 mmol),
L
-Pro (0.17 mmol), and Cs2CO3 (1.76 mmol), and heated at 50 °C
6-HIndol), 5.58 (m, 1H, CHCH3), 5.00 (m, 2H, CH2), 3.82 (s, 3H, OCH3), 1.44 (d, 3H,
J = 7.0 Hz, CHCH3) ppm. 13C NMR (DMSO-d6, 75MHz): d = 165.6 (3-CO), 155.7
(NHCO), 150.6 (2-CIndol), 137.2 (C Ar), 135.0 (70-CIndol), 128.7 (2C, CH Ar), 128.2
(2C, CH Ar), 128.0 (CH Ar), 126.8 (30-CIndol),122.4 (6-CIndol), 121.6 (4-CIndol),
121.0 (5-CIndol), 112.4 (7-CIndol), 101.5 (3-CIndol), 65.9 (Z-CH2), 51.0 (OCH3), 45.0
(CHCH3), 21.4 (CHCH3) ppm. C20H20N2O4 (352.38): calcd C, 68.17; H, 5.72; N,
7.95; found C, 68.02; H, 5.68; N, 7.84. ESI-MS: m/z = 375.3 [M+Na]+, 353.3
[M+H]+.
for 24 h. Then the reaction mixture was neutralized with 1 M HCl and
extracted with EtOAc. The organic phase was washed with brine and dried over
Na2SO4. The solvent was evaporated and the raw material was purified by
chromatography (5% MeOH/DCM).
Method B: A solution of compound 2a (80 mg, 0.017 mmol) in MeOH (5 ml) and
H2O (2.5 ml) was treated with Cs2CO3 (0.034 mmol) and heated at 80 °C for 2 h.
The reaction was allowed to recover room temperature, neutralized with 1 M