Cu-catalyzed carbenoid functionalization of indoles by methyl 3,3,3-trifluoro-2-diazopropionate

Article abstract of DOI:10.1002/ejoc.201301734

An efficient protocol for the direct CH-functionalization of indole and its derivatives has been developed by using Cu(F₃-acac) ₂-catalyzed insertion of CF₃-carbene derived from methyl 3,3,3-trifluoro-2-diazopropionate. The reaction proceeds with high regioselectivity within a few minutes under low catalyst loading and allows the introduction of CF₃ and carboxylate functions simultaneously into the 3- or 2-position of the indole core. This method can be successfully applied for the synthesis of trifluoromethyl-containing paullones, which are new members of the known family of potent inhibitors of cyclin-dependent kinases. An efficient Cu-catalyzed direct CH-functionalization of indoles with methyl 3,3,3-trifluoro-2-diazopropionate has been developed. The reactions proceed within a few minutes under low catalyst loading to give the corresponding C3 or C2 substitution products with high regioselectivity. This method has been successfully applied for the synthesis of trifluoromethyl-containing paullone. Copyright

Full text of DOI:10.1002/ejoc.201301734

FULL PAPER
DOI: 10.1002/ejoc.201301734
Cu-Catalyzed Carbenoid Functionalization of Indoles by
Methyl 3,3,3-Trifluoro-2-diazopropionate
Irina E. Tsyshchuk,[a] Daria V. Vorobyeva,[a] Alexander S. Peregudov,[a] and
Sergey N. Osipov*[a]
Keywords: Nitrogen heterocycles / Diazo compounds / Carbenoids / C–H activation / Fluorine / Copper
An efficient protocol for the direct CH-functionalization of
indole and its derivatives has been developed by using
Cu(F3-acac)2-catalyzed insertion of CF3-carbene derived
from methyl 3,3,3-trifluoro-2-diazopropionate. The reaction
proceeds with high regioselectivity within a few minutes un-
der low catalyst loading and allows the introduction of CF3
and carboxylate functions simultaneously into the 3- or 2-
position of the indole core. This method can be successfully
applied for the synthesis of trifluoromethyl-containing
paullones, which are new members of the known family of
potent inhibitors of cyclin-dependent kinases.
ciated with donor–acceptor carbenoids. To the best of our
knowledge, only two more reactive acceptor–acceptor carb-
enoids derived from methyl diazomalonate under Rh-[8b]
and Cu-[9b] catalysis, respectively, have been utilized for di-
rect CH-functionalization of the indole core.
Introduction
The incorporation of fluorine functionalities into bioac-
tive compounds has become an important tool in the drug
discovery process.[1] Particular attention is focused on tri-
fluoromethyl-containing compounds due to the unique
properties of the CF3 group, such as high electronegativity,
relatively low steric bulk, and hydrophobic character, which
can profoundly improve the efficacy of the therapeutic
agent.[2] Consequently, there is considerable interest in de-
veloping new methods for the selective introduction of the
CF3 group into organic molecules.
On the other hand, indoles and their derivatives are
found in many bioactive substances, originating from both
natural and synthetic sources.[3] Among synthetic strategies
for the construction of substituted indoles, the direct func-
tionalization of a preformed indole core seems to be a re-
markably efficient approach to structurally diverse indoles[4]
including their fluorinated derivatives.[5] In this context, in-
sertion of carbenoids generated from the metal-catalyzed
decomposition of diazo compounds[6] represents one of the
most attractive and straightforward tools for easy access to
a variety of functionalized indoles. The result of such trans-
formation strictly depends on the original substrate substi-
tution patterns.[7] Rhodium carboxylates,[8] copper salts,[9]
indium bromide,[10] iron complexes,[11] and, more recently,
ruthenium complexes[12] have all been found to be efficient
catalysts for the process. Despite a number of reports on
metal-carbenoid functionalization of indoles, most are asso-
Alkyl 3,3,3-trifluorodiazopropionates have recently been
recognized as attractive reagents for simultaneous introduc-
tion of trifluoromethyl and carboxylic functionalities into a
diverse range of organic molecules. On copper- or rhodium-
catalyzed extrusion of nitrogen, the resulting highly electro-
philic acceptor–acceptor carbenoid has been shown to be
effective at cycloaddition,[13] ylide generation,[14] ring ex-
pansion[15] as well as X–H[16] insertion. In the course of our
ongoing studies on the development of new methods for
selective introduction of CF3 groups into bioactive com-
pounds by means of appropriate building blocks[17] includ-
ing α-CF3-diazo compounds,[18] herein, we report our find-
ings on the direct carbenoid CH-functionalization of ind-
oles by using methyl trifluorodiazopropionate (1).
Results and Discussion
The investigation of CF3-carbenoid functionalization of
indoles commenced with a study on the reactions of unsub-
stituted indole with diazopropionate 1.[13a] In our initial
attempts, we examined rhodium(II) acetate as one of the
most active catalysts commonly used for the mild diazo de-
composition. As a result, we found that the reaction of
equimolar amounts of the reagents took place only under
heating in toluene at 90 °C in the presence of 5 mol-%
Rh2(OAc)4 and proceeded to completion within 30 min,
giving a mixture of N1, C2 and C3 insertion products in
comparable ratio (Scheme 1). These products were sepa-
rated by using column chromatography on silica gel and
[a] A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences,
Vavilov str. 28, Moscow, Russia
E-mail: osipov@ineos.ac.ru
www.ineos.ac.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301734.
2480
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2480–2486

Carbenoid Functionalization of Indoles
Scheme 1. Rh-catalyzed functionalization of indole by 1.
fully characterized by NMR spectroscopic and elemental that the substitution of Cu(acac)2 for Cu(F3-acac)2 led to
analyses. It should be noted that a similar regioselectivity notably better yields (entries 8 and 9) in reduced reaction
was previously observed in the reaction of NH-indoles acti- times, even with the lowest catalyst loading (entry 10). The
vated by alkyl groups in the 3- or 2-positions with methyl content of byproduct 3 in the reaction mixtures was found
diazomalonate under Rh-catalysis.[8b]
to be less than 5% in all these cases. Carbene insertion into
Encouraged by a more recent report by Johansen and the NH-bond was not observed under any of these condi-
Kerr,[9b] wherein better selectivity was found in the same tions.
reaction under Cu catalysis, we tested the activity of Cu-
With optimal conditions in hand, we performed CF3-
(acac)2 along with (commercially available) copper tri- carbene functionalization of commercially available indoles
fluoroacetylacetonate [Cu(F3-acac)2] in the reaction of bearing different substituents at the 1-, 2- and 5-positions
indole with CF3-substituted diazopropionate 1. The reac- to afford the corresponding C3 insertion products 5 in good
tions were performed in either dichloromethane or toluene to excellent yields (Table 2). The nature of the substituents
with the catalyst loading in a range of 0.2–5 mol-% and their position in the indole core did not significantly
(Table 1). Heating of the reagents in CH2Cl2 in the presence affect the outcome of the reaction. The only exception was
of 5 mol-% Cu(acac)2 gave none of the desired product even
after extended reaction time (entry 3), as was established for
Table 2. Cu-catalyzed selective C(3)H functionalization of indoles.
the Rh-catalyzed reaction (entry 1). However, the applica-
tion of more drastic conditions led to the formation C3 in-
sertion product 2 in appreciable yield (entry 4). In this case,
approximately 9% of the C2 insertion byproduct 3 was de-
tected in the reaction mixture (based on 19F NMR spectro-
scopic analysis before isolation).
Table 1. Optimization of reaction conditions.
Entry R1
R2
R3
Product Yield [%][a]
1
2
3
4
5
6
7
8
9
10
Me
H
H
Me
Me
Me
H
H
H
Boc
H
H
H
H
H
H
Br
NO2
OMe
CO2Me
H
5a
5b
5c
5d
5e
5f
98
93
85
88
97
91
72
80
79
n.r.
Ph
Me
Ph
Me
H
H
Me
H
5g
5h
5i
Entry Solvent Temp.
[°C]
Time
[min]
Catalyst (mol-%)
2
[%][a]
H
5j
1
2
CH2Cl2
toluene
CH2Cl2
toluene
toluene
toluene
CH2Cl2
toluene
toluene
toluene
40
90
40
95
95
95
40
95
95
95
24 h
30
24 h
30
35
40
24 h
15
20
Rh2(OAc)4 (5)
Rh2(OAc)4 (5)
Cu(acac)2 (5)
Cu(acac)2 (5)
Cu(acac)2 (1)
Cu(acac)2 (0.2)
Cu(F3-acac)2 (5)
Cu(F3-acac)2 (5)
Cu(F3-acac)2 (1)
Cu(F3-acac)2 (0.2)
n.r.
21
n.r.
68
65
60
n.r.
77
75
[a] Isolated yield after column chromatography on silica gel.
3
4
5
6
7
8
9
10
20
75
[a] Isolated yield after column chromatography on silica gel; n.r.:
no reaction.
Similar results were obtained with decreased catalyst
loading (Table 1, entries 5 and 6). We were pleased to find Scheme 2. Cu-catalyzed C(2)H functionalization of indoles.
Eur. J. Org. Chem. 2014, 2480–2486
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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I. E. Tsyshchuk, D. V. Vorobyeva, A. S. Peregudov, S. N. Osipov
FULL PAPER
Scheme 3. Synthesis of CF3-paullone.
found for N-Boc derivative (entry 10); in this case, a com- position of the indole core. This method can be successfully
plex mixture of products was formed, which can be ration- applied for the synthesis of trifluoromethyl-containing
alized by a decreased reactivity of the indole due to the paullones, which are new representatives of a known family
electron-withdrawing influence of the Boc group.
of potent inhibitors of cyclin-dependent kinases.
These conditions could also be applied for the function-
alization of skatole and N-methylskatole to give good yields
of C2-substitution products 6a and 6b (Scheme 2). How-
ever, a N-methylindole derivative deactivated by an elec-
tron–acceptor methoxycarbonyl group at the 3-position ap-
peared to be completely inactive towards carbene insertion
even with increased catalyst loading.
Having established an efficient CF3-carbenoid C3 func-
tionalization of indoles, we investigated the feasibility of ap-
plying this method for the construction of CF3-containing
paullones. The paullones are known inhibitors of cyclin-
dependent kinases (CDKs).[19] Over the past decade, nu-
merous derivatives of paullone have been found to possess
antitumor,[20] antiproliferative,[21] and antileishmanial[22] ac-
tivities, and to inhibit glycogen synthase kinase-3 (GSK-3),
which may be important for the treatment of diabetes.[23] As
such, significant effort has been directed towards efficient
syntheses of new representatives of this class of com-
pounds.[24]
For this purpose, we accomplished the synthesis of indole
7 from available 2-(ortho-nitrophenyl)indole[25] and diazo
compound 1 by applying the same protocol for selective
CF3-carbene insertion (Scheme 3). Subsequent Pd-cata-
lyzed hydrogenation of the NO2 group of 7 was performed
in methanol at room temperature for 24 h, furnishing
amino-derivative 8. Finally, the intramolecular cyclization
of 8 was achieved by acidolysis in dioxane at 40 °C for
30 min to afford the desired CF3-paullone 9 in high yield.
Experimental Section
General Remarks: All solvents used in reactions were freshly dis-
tilled from appropriate drying agents before use. All other reagents
were recrystallized or distilled as necessary. Analytical TLC was
performed with Merck silica gel 60 F254 plates; visualization was
accomplished with UV light or spraying with Ce(SO4)2 solution in
5% H2SO4. Chromatography was carried out by using Merck silica
gel (Kieselgel 60, 0.063–0.200 mm) and petroleum ether/ethyl acet-
ate as eluent. IR spectra were measured with a Fourier spectrome-
ter Nicolet 6700. NMR spectra were obtained with Bruker AV-300
and AV-600 spectrometers operating at 300 and 600 MHz, respec-
tively, for 1H (TMS reference), at 150 MHz for 13C, and at
282 MHz for 19F (CF3COOH reference).
General Procedure for Cu-Catalyzed CH-Functionalization of Ind-
oles: To a solution of the corresponding indole (2.56 mmol,
1 equiv.) in anhydrous toluene (10 mL), diazo compound
(2.82 mmol, 1.1 equiv.) and copper trifluoroacetylacetonate
(0.5 mmol, 0.2 mol-%) were added sequentially. The reaction mix-
ture was stirred under heating (90–95 °C) for 15–30 min. Upon
completion of the reaction (monitored by TLC) the solvent was
removed under reduced pressure and the crude product was puri-
fied by column chromatography on silica gel (petroleum ether/ethyl
acetate).
1
Methyl 3,3,3-Trifluoro-2-(1H-indol-3-yl)propanoate (2): Eluent pe-
troleum ether/ethyl acetate, 3:1, yield 75%; pink solid; m.p. 92–
94 °C. 1H NMR (300 MHz, CDCl3): δ = 3.84 (s, 3 H, OCH3), 4.75
3
(q, JH,F = 8.5 Hz, 1 H, CH), 7.24–7.34 (m, 2 H, Ar), 7.46–7.48
3
(m, 2 H, Ar), 7.73 (d, JH,H = 7.7 Hz, 1 H, Ar), 8.39 (br. s, 1 H,
NH) ppm. 19F NMR (282 MHz, CDCl3): δ = 9.61 (s, 3 F,
CF3) ppm. 13C NMR (150 MHz, CDCl3): δ = 47.4 (q, JC,F
=
2
Conclusions
1
30 Hz, CH), 52.9, 103.9, 111.6, 118.6, 120.6, 122.8, 124.3 (q, JC,F
= 280 Hz, CF3), 124.9, 126.4, 135.9, 167.6 ppm. C12H10F3NO2
(257.21): calcd. C 56.04, H 3.92, N 5.45; found C 55.97, H 3.72, N
5.25.
We have developed an efficient protocol for the direct
CH-functionalization of indole and its derivatives through
Cu(F3-acac)2-catalyzed insertion of CF3-carbene derived
from methyl 3,3,3-trifluoro-2-diazopropionate. The reaction
proceeds with high regioselectivity within a few minutes un-
der low catalyst loading and allows CF3 and carboxylate
Methyl 3,3,3-Trifluoro-2-(1H-indol-2-yl)propanoate (3): Eluent pe-
troleum ether/ethyl acetate, 10:1 then 5:1, yield 32%; orange solid;
m.p. 75–76 °C. 1H NMR (300 MHz, CDCl3): δ = 3.91 (s, 3 H,
3
functions to be introduced simultaneously into the 3- or 2- OCH3), 4.71 (q, JH,F = 8.3 Hz, 1 H, CH), 6.67 (s, 1 H, C(3)-H),
2482
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Eur. J. Org. Chem. 2014, 2480–2486

Carbenoid Functionalization of Indoles
3
7.21 (t, JH,H = 9 Hz, 1 H, Ar), 7.29–7.34 (m, 1 H, Ar), 7.47 (d, 3JH,H = 8.1 Hz, 1 H, Ar) ppm. 19F NMR (282 MHz, CDCl3): δ =
3JH,H = 6 Hz, 1 H, Ar), 7.69 (d, 3JH,H = 9 Hz, 1 H, Ar), 8.82 (br. s, 9.87 (s, 3 F, CF3) ppm. 13C NMR (150 MHz, CDCl3): δ = 31.0,
1 H, NH) ppm. 19F NMR (282 MHz, CDCl3): δ = 10.09 (s, 3 F,
47.8 (q, 2JC,F = 30 Hz, CH), 52.6, 101.3, 109.6, 120.5, 120.7, 122.4,
124.7 (q, JC,F = 280 Hz, CF3), 125.8, 128.6, 128.9, 129.3, 130.1,
2
1
CF3) ppm. 13C NMR (150 MHz, CDCl3): δ = 49.8 (q, JC,F
=
30 Hz, CH), 53.5, 102.6, 105.4, 111.4, 120.3, 120.4, 120.8, 123.8 130.3, 130.9, 137.1, 142.0, 167.3 ppm. C19H16F3NO2 (347.33):
1
(q, JC,F = 279 Hz, CF3), 127.5, 136.7, 166.2 ppm. C12H10F3NO2
(257.21): calcd. C 56.04, H 3.92, N 5.45; found C 56.02, H 3.99, N
5.70.
calcd. C 65.70, H 4.64, N 4.03; found C 65.66, H 4.58, N 4.04.
Methyl 2-(1,2-Dimethyl-1H-indol-3-yl)-3,3,3-trifluoropropanoate
(5e): Eluent petroleum ether/ethyl acetate, 15:1, yield 97%; orange
1
Methyl 3,3,3-Trifluoro-2-(1H-indol-1-yl)propanoate (4): Eluent pe-
troleum ether/ethyl acetate, 20:1, yield 10%; pink oil. IR (Nujol):
solid; m.p. 113–115 °C. H NMR (300 MHz, CDCl3): δ = 2.5 (s, 3
3
H, CH3), 3.76 (s, 3 H, N-CH3), 3.80 (s, 3 H, OCH3), 4.65 (q, JH,F
3
3
ν
˜
= 3418, 1755, 1612, 1522, 1118, 1001, 741 cm–1. 1H NMR
= 9 Hz, 1 H, CH), 7.19 (t, JH,H = 6 Hz, 1 H, Ar), 7.27 (t, JH,H
=
=
max
(300 MHz, CDCl3): δ = 3.92 (s, 3 H, OCH3), 5.65 (q, 3JH,F = 9 Hz,
6 Hz, 1 H, Ar), 7.35 (d, JH,H = 8.1 Hz, 1 H, Ar), 7.69 (d, JH,H
3
3
3
3
1 H, CH), 6.73 (d, JH,H = 3 Hz, 1 H, C(3)-H), 7.26 (t, JH,H
=
7.8 Hz, 1 H, Ar) ppm. 19F NMR (282 MHz, CDCl3): δ = 10.02 (s,
9 Hz, 1 H, Ar),7.33–7.35 (m, 1 H, Ar), 7.38 (s, 1 H, C(2)-H), 7.41– 3 F, CF3) ppm. 13C NMR (150 MHz, CDCl3): δ = 10.4, 29.8, 47.2
7.44 (m, 1 H, Ar), 7.73 (d, JH,H = 9 Hz, 1 H, Ar) ppm. 19F NMR (q, 2JC,F = 30 Hz, CH), 52.6, 99.5, 109.0, 118.8, 120.1, 121.4, 124.7
3
(282 MHz, CDCl3): δ = 6.83 (s, 3 F, CF3) ppm. 13C NMR
(q, JC,F
=
280 Hz, CF3), 126.4, 136.6, 136.7, 167.4 ppm.
1
2
(150 MHz, CDCl3): δ = 53.7, 58.4 (q, JC,F = 33 Hz, CH), 104.8,
108.5, 120.9, 121.5, 122.4 (q, JC,F = 281 Hz, CF3), 122.9, 126.5,
C14H14F3NO2 (285.26): calcd. C 58.95, H 4.95, N 4.91; found C
58.78, H 4.81, N 4.93.
1
128.6, 136.7, 163.9 ppm. C12H10F3NO2 (257.21): calcd. C 56.04, H
3.92, N 5.45; found C 56.21, H 3.84, N 5.38.
Methyl 2-(5-Bromo-1-methyl-1H-indol-3-yl)-3,3,3-trifluoropropano-
ate (5f): Eluent petroleum ether/ethyl acetate, 20:1, yield 91%; pink
1
Methyl 3,3,3-Trifluoro-2-(1-methyl-1H-indol-3-yl)propanoate (5a):
Eluent petroleum ether/ethyl acetate, 20:1, yield 98%; white solid;
m.p. 69–70 °C. 1H NMR (600 MHz, [D6]acetone): δ = 3.76 (s, 3 H,
solid; m.p. 103–104 °C. H NMR (600 MHz, CDCl3): δ = 3.78 (s,
3 H, CH3), 3.81 (s, 3 H, OCH3), 4.63 (q, 3JH,F = 8.5 Hz, 1 H, CH),
3
7.20 (d, JH,H = 8.7 Hz, 1 H, Ar), 7.30 (s, 1 H, C(2)-H), 7.36 (d,
CH3), 3.83 (s, 3 H, OCH3), 5.04 (q, 3JH,F = 8.9 Hz, 1 H, CH), 7.19 3JH,H = 8.7 Hz, 1 H, Ar), 7.81 (s, 1 H, Ar) ppm. 19F NMR
(t, 3JH,H = 7.5 Hz, 1 H, Ar), 7.27 (t, 3JH,H = 7.6 Hz, 1 H, Ar), 7.43 (282 MHz, CDCl3): δ = 9.46 (s, 3 F, CF3) ppm. 13C NMR
3
3
2
(d, JH,H = 8.3 Hz, 1 H, Ar), 7.46 (s, 1 H, C(2)-H), 7.80 (d, JH,H
= 8.1 Hz, 1 H, Ar) ppm. 19F NMR (282 MHz, CDCl3): δ = 9.45
(s, 3 F, CF3) ppm. 13C NMR (150 MHz, [D6]acetone): δ = 32.1,
46.8 (q, 2JC,F = 30 Hz, CH), 52.1, 102.2, 109.9, 118.8, 119.9, 122.1,
(150 MHz, CDCl3): δ = 33.2, 47.1 (q, JC,F = 30 Hz, CH), 53.0,
1
101.9, 111.2, 113.7, 121.3, 124.9 (q, JC,F = 278 Hz, CF3), 125.3,
128.6, 130.4, 135.4, 167.1 ppm. C13H11BrF3NO2 (350.13): calcd. C
44.59, H 3.17, N 4.00; found C 44.39, H 3.07, N 4.10.
1
125.7 (q, JC,F = 278 Hz, CF3), 127.1, 129.8, 139.9, 167.1 ppm.
Methyl 3,3,3-Trifluoro-2-(5-nitro-1H-indol-3-yl)propanoate (5g):
Eluent petroleum ether/ethyl acetate, 6:1 then 3:1, yield 72%; yel-
C13H12F3NO2 (271.24): calcd. C 57.57, H 4.46, N 5.16; found C
57.81, H 4.41, N 5.29.
Methyl 3,3,3-Trifluoro-2-(2-phenyl-1H-indol-3-yl)propanoate (5b): 1521, 1332, 1240, 1112, 1038, 1008, 818 cm–1. 1H NMR (300 MHz,
low solid; m.p. 130–131 °C. IR (Nujol): ν
= 3367, 1753, 1623,
˜
max
3
Eluent petroleum ether/ethyl acetate, 20:1, yield 93%; white solid;
CDCl3): δ = 3.88 (s, 3 H, OCH3), 4.78 (q, JH,F = 8.3 Hz, 1 H,
m.p. 136–137 °C. 1H NMR (600 MHz, CDCl3): δ = 3.72 (s, 3 H,
CH), 7.54 (d, JH,H = 9 Hz, 1 H, Ar), 7.68 (s, 1 H, C(2)-H), 8.23
3
3
3
3
OCH3), 4.79 (q, JH,F = 9 Hz, 1 H, CH), 7.24 (t, JH,H = 6.0 Hz, (d, JH,H = 8.9 Hz, 1 H, Ar), 8.72 (s, 1 H, Ar), 8.88 (br. s, 1 H,
1 H, Ar), 7.29 (t, 3JH,H = 6.0 Hz, 1 H, Ar), 7.39 (d, 3JH,H = 6.0 Hz,
1 H, Ar), 7.57–7.45 (m, 1 H, Ar), 7.60 (d, JH,H = 6.0 Hz, 1 H,
NH) ppm. 19F NMR (282 MHz, CDCl3): δ = 9.73 (s, 3 F,
3
2
CF3) ppm. 13C NMR (150 MHz, CDCl3): δ = 46.6 (q, JC,F
=
=
3
1
Ar), 7.92 (d, JH,H = 6.0 Hz, 1 H, Ar), 8.44 (br. s, 1 H, NH) ppm.
30 Hz, CH), 53.2, 106.4, 111.9, 116.1, 118.3, 124.6 (q, JC,F
19F NMR (282 MHz, CDCl3): δ = 11.46 (s, 3 F, CF3) ppm. 13C 278 Hz, CF3), 126.1, 128.3, 139.0, 142.4, 166.8 ppm. C12H9F3N2O4
2
NMR (150 MHz, CDCl3): δ = 47.49 (q, JC,F = 30 Hz, CH), 52.7, (302.21): calcd. C 47.69, H 3.00, N 9.27; found C 47.46, H 3.34, N
1
101.1, 111.1, 120.9, 122.9, 124.7 (q, JC,F = 279 Hz, CF3), 126.8,
127.2, 128.4, 129.1, 129.2, 131.4, 135.7, 139.4, 167.2 ppm.
C18H14F3NO2 (333.30): calcd. C 64.86, H 4.23, N 4.20; found C
64.67, H 4.09, N 4.11.
8.99.
Methyl 3,3,3-Trifluoro-2-(5-methoxy-2-methyl-1H-indol-3-yl)prop-
anoate (5h): Eluent petroleum ether/ethyl acetate, 5:1, yield 80%;
white solid; m.p. 119–120 °C. 1H NMR (300 MHz, CDCl3): δ =
2.47 (s, 3 H, CH3), 3.81 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 4.59
Methyl 3,3,3-Trifluoro-2-(2-methyl-1H-indol-3-yl)propanoate (5c):
Eluent petroleum ether/ethyl acetate, 5:1, yield 85%; gray solid;
m.p. 116–117 °C. 1H NMR (300 MHz, CDCl3): δ = 2.51 (s, 3 H,
3
3
3
(q, JH,F = 9 Hz, 1 H, CH), 6.88 (dd, JH,H = 9, JH,H = 3 Hz, 1
3
H, Ar), 7.17 (s, 1 H, Ar), 7.23 (d, JH,H = 9 Hz, 1 H, Ar), 8.07
CH3), 3.81 (s, 3 H, OCH3), 4.62 (q, 3JH,F = 8.9 Hz, 1 H, CH), 7.17– (br. s, 1 H, NH) ppm. 19F NMR (282 MHz, CDCl3): δ = 10.27 (s,
7.25 (m, 2 H, Ar), 7.32–7.38 (m, 1 H, Ar), 7.69 (d, 3JH,H = 7.2 Hz, 3 F, CF3) ppm. 13C NMR (150 MHz, CDCl3): δ = 11.7, 47.0 (q,
1 H, Ar), 8.12 (br. s, 1 H, NH) ppm. 19F NMR (282 MHz, CDCl3): 2JC,F = 30 Hz, CH), 52.6, 55.8, 99.9, 101.1, 111.3, 111.6, 124.8 (q,
δ = 10.13 (s, 3 F, CF3) ppm. 13C NMR (150 MHz, CDCl3): δ =
1JC,F = 280 Hz, CF3), 127.7, 130.1, 135.9, 154.5, 167.4 ppm.
C14H14F3NO3 (301.26): calcd. C 55.81, H 4.65, N 4.65; found C
55.97, H 4.69, N 4.57.
2
11.7, 47.0 (q, JC,F = 30 Hz, CH), 52.6, 100.3, 110.6, 118.8, 120.4,
1
121.8, 124.7 (q, JC,F = 280 Hz, CF3), 127.2, 135.0, 135.2,
167.4 ppm. C13H12F3NO2 (271.24): calcd. C 57.57, H 4.46, N 5.16;
found C 57.47, H 4.27, N 4.87.
Methyl 3-(1,1,1-Trifluoro-3-methoxy-3-oxopropan-2-yl)-1H-indole-
5-carboxylate (5i): Eluent petroleum ether/ethyl acetate, 8:1, yield
Methyl 3,3,3-Trifluoro-2-(1-methyl-2-phenyl-1H-indol-3-yl)propano-
ate (5d): Eluent petroleum ether/ethyl acetate, 15:1, yield 88%;
white solid; m.p. 106–107 °C. 1H NMR (300 MHz, CDCl3): δ =
79%; white solid; m.p. 149–150 °C. IR (Nujol): ν
= 3292, 1755,
˜
max
1739, 1694, 1616, 1293, 1253, 1153, 1100, 745 cm–1. 1H NMR
(600 MHz, [D6]acetone ): δ = 3.78 (s, 3 H, OCH3), 3.91 (s, 3 H,
3
3.65 (s, 3 H, N-CH3), 3.76 (s, 3 H, OCH3), 4.49 (q, JH,F = 9 Hz,
OCH3), 5.22 (q, 3JH,F = 8.9 Hz, 1 H, CH), 7.59 (d, 3JH,H = 8.6 Hz,
3
1 H, CH), 7.28 (t, 3JH,H = 6.9 Hz, 1 H, Ar), 7.37 (t, 3JH,H = 6.9 Hz, 1 H, Ar), 7.72 (s, 1 H, C(2)-H), 7.91 (d, JH,H = 8.6 Hz, 1 H, Ar),
1 H, Ar), 7.43–7.51 (m, 3 H, Ar), 7.60 (br. s, 3 H, Ar), 7.91 (d, 8.57 (s, 1 H, Ar), 10.93 (br. s, 1 H, NH) ppm. 19F NMR (282 MHz,
Eur. J. Org. Chem. 2014, 2480–2486
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2483

I. E. Tsyshchuk, D. V. Vorobyeva, A. S. Peregudov, S. N. Osipov
FULL PAPER
CDCl3): δ = 9.58 (s, 3 F, CF3) ppm. 13C NMR (150 MHz, [D6]- C18H15F3N2O2 (348.32): calcd. C 62.07, H 4.34, N 8.04; found C
acetone ): δ = 46.7 (q, 2JC,F = 30 Hz, CH), 51.2, 52.3, 104.9, 111.7, 62.19, H 4.47, N 8.25.
1
121.7, 122.2, 123.2, 124.7 (q, JC,F = 279 Hz, CF3), 126.3, 127.7,
139.0, 166.9, 167.2 ppm. C14H12F3NO4 (315.24): calcd. C 53.33, H
3.81, N 4.44; found C 53.14, H 3.68, N 4.47.
7-(Trifluoromethyl)-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-
6(5H)-one (9): Indole 8 (0.077 g, 0.48 mmol) was dissolved in anhy-
drous dioxane (2 mL) under an argon atmosphere, then AcOH
(300 μL) was added and the resulting mixture was stirred at 40 °C
for 30 min. After cooling, saturated aqueous NaHCO3 (10 mL) was
added, the aqueous phase was extracted with EtOAc, and the or-
ganic phase was dried with MgSO4. The solvent was evaporated
under reduced pressure and the crude product was purified by
recrystallization (hexane) to give the final product (60 mg, 89%) as
Methyl 3,3,3-Trifluoro-2-(3-methyl-1H-indol-2-yl)propanoate (6a):
Eluent petroleum ether/ethyl acetate, 20:1, yield 78%; white solid;
m.p. 90–91 °C. 1H NMR (300 MHz, CDCl3): δ = 2.41 (s, 3 H,
3
CH3), 3.91 (s, 3 H, OCH3), 4.81 (q, JH,F = 9 Hz, 1 H, CH), 7.24
(d, 3JH,H = 6 Hz, 1 H, Ar), 7.33 (s, 1 H, Ar), 7.45 (d, 3JH,H = 6 Hz,
3
1 H, Ar), 7.66 (d, JH,H = 6 Hz, 1 H, Ar), 8.72 (br. s, 1 H,
1
NH) ppm. 19F NMR (282 MHz, CDCl3): δ = 10.27 (s, 3 F,
a white solid; m.p. 285–286 °C. H NMR (300 MHz, [D6]acetone):
3
3
2
CF3) ppm. 13C NMR (150 MHz, CDCl3): δ = 8.4, 47.4 (q, JC,F
=
δ = 5.25 (q, JH,F = 6 Hz, 1 H, CH), 7.21 (t, JH,H = 6 Hz, 1 H,
3
31.5 Hz, CH), 53.4, 111.2, 112.9, 119.2, 119.7, 120.7, 122.5 (q, 1JC,F
= 279 Hz, CF3), 123.3, 128.0, 135.9, 166.5 ppm. C13H12F3NO2
(271.24): calcd. C 57.57, H 4.46, N 5.16; found C 57.41, H 4.45, N
5.48.
Ar), 7.27–7.32 (m, 2 H, Ar), 7.43 (d, JH,H = 6 Hz, 2 H, Ar), 7.55
(d, JH,H = 6 Hz, 1 H, Ar), 7.88 (d, JH,H = 6 Hz, 1 H, Ar), 7.93
3
3
3
(d, JH,H = 6 Hz, 1 H, Ar), 9.88 (s, 1 H, NH), 11.06 (s, 1 H,
NH) ppm. 19F NMR (282 MHz, CDCl3): δ = 9.46 (s, 3 F,
CF3) ppm. 13C NMR (150 MHz, [D6]acetone): δ = 49.9 (q, JC,F
=
2
Methyl
2-(1,3-Dimethyl-1H-indol-2-yl)-3,3,3-trifluoropropanoate
30 Hz, CH), 101.9, 111. 6, 117.7, 120.3, 121.5, 121.8, 123.3, 124.2,
(6b): Eluent petroleum ether/ethyl acetate, 20:1, yield 69%; white
1
125.5 (q, JC,F = 282 Hz, CF3), 126.6, 128.0, 128.8, 133.9, 134.8,
solid; m.p. 96–97 °C. IR (Nujol): ν
= 2857, 1750, 1469, 1269,
˜
max
137.7, 164.5 ppm. IR (Nujol): νmax = 3329, 3188, 2357, 1647, 1575,
˜
1244, 1149, 1117, 1109, 1022, 895, 810 cm–1. H NMR (300 MHz,
1
1368, 1254, 1165, 1117, 738 cm–1. C17H11F3N2O (316.28): calcd. C
64.56, H 3.51, N 8.86; found C 64.45, H 3.69, N 8.60.
CDCl3): δ = 2.38 (s, 3 H, CH3), 3.79 (s, 3 H, CH3), 3.86 (s, 3 H,
3
OCH3), 4.81 (q, JH,F = 9 Hz, 1 H, CH), 7.19–7.24 (m, 1 H, Ar),
3
7.32–7.40 (m, 2 H, Ar), 7.66 (d, JH,H = 9 Hz, 1 H, Ar) ppm. 19F
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all new compounds
NMR (282 MHz, CDCl3): δ = 11.83 (s, 3 F, CF3) ppm. 13C NMR
(150 MHz, CDCl3): δ = 8.8, 30.2, 46.7 (q, 2JC,F = 30 Hz, CH), 53.0,
109.5, 112.8, 119.5, 119.9, 122.9, 123.5, 123.7 (q, 1JC,F = 277.5 Hz,
CF3), 127.7, 137.3, 165.9 ppm. C14H14F3NO2 (285.26): calcd. C
58.95, H 4.95, N 4.91; found C 59.04, H 4.97, N 4.71.
Acknowledgments
Methyl 3,3,3-Trifluoro-2-[2-(2-nitrophenyl)-1H-indol-3-yl]propano-
ate (7): Eluent petroleum ether/ethyl acetate, 20:1, yield 67%;
This work was financially supported by the Russian Foundation of
Basic Research (RFBR) (grant numbers 12-03-00557) and Groupe
de Recherche International (GDRI) (grant number 12-03-93111) in
the frame of a bilateral collaboration between the Centre National
de la Recherche Scientifique (CNRS), France and the Russian
Academy of Sciences.
orange solid; m.p. 171–172 °C. IR (Nujol): νmax = 3368, 1731, 1525,
˜
1261, 1111, 1002, 869, 787 cm–1. 1H NMR (600 MHz, [D6]acetone):
3
δ = 3.68 (s, 3 H, OCH3), 4.58 (br. s, 1 H, CH), 7.16 (t, JH,H
=
=
=
=
3
3
6 Hz, 1 H, Ar), 7.24 (t, JH,H = 6 Hz, 1 H, Ar), 7.49 (d, JH,H
3
3
6 Hz, 1 H, Ar), 7.74 (d, JH,H = 6 Hz, 1 H, Ar), 7.79 (d, JH,H
3
3
6 Hz, 1 H, Ar), 7.85 (t, JH,H = 6 Hz, 1 H, Ar), 7.93 (t, JH,H
6 Hz, 1 H, Ar), 8.25 (d, JH,H = 6 Hz, 1 H, NH) ppm. 19F NMR
3
(282 MHz, CDCl3): δ = 10.98 (s, 3 F, CF3) ppm. 13C NMR
2
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Methyl 2-[2-(2-Aminophenyl)-1H-indol-3-yl]-3,3,3-trifluoropropano-
ate (8): To a solution of indole 7 (0.35 g, 0.93 mmol) in methanol
(20 mL), 10% Pd/C (0.038 g, 0.36 mmol) was added and the re-
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yield 85%; white solid; m.p. 126–127 °C. IR (Nujol): ν
= 3376,
˜
max
3367, 1731, 1616, 1260, 1156, 1008, 748 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 3.79 (s, 3 H, OCH3), 3.89 (br. s, 2 H, NH2), 4.62 (q,
3
3JH,F = 9 Hz, 1 H, CH), 6.86 (d, JH,H = 9 Hz, 1 H, Ar), 6.93 (t,
3
3JH,H = 6 Hz, 1 H, Ar), 7.26–7.39 (m, 5 H, Ar), 7.86 (d, JH,H
=
6 Hz, 1 H, Ar), 8.52 (br. s, 1 H, NH) ppm. 19F NMR (282 MHz,
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(150 MHz, CDCl3): δ = 47.5 (q, JC,F = 30 Hz, CH), 52.8, 102.9,
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111.2, 115.8, 115.9, 118.6, 120.4, 120.8, 122.8, 124.5 (q, JC,F
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2484
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2480–2486

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Received: November 19, 2013
Published Online: February 3, 2014
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