Green, Catalyst-Free Reaction of Indoles with β-Fluoro-β-nitrostyrenes in Water

Article abstract of DOI:10.1002/ejoc.201800385

The reaction of 2-fluoro-2-nitrostyrenes with various indoles was investigated. We found that the reaction proceeds as a Michael addition in a highly regioselective manner to form 3-(1-aryl-2-fluoro-2-nitroethyl)-1H-indoles. Thus, a green and catalyst-free synthesis of these compounds was developed using water as a reaction medium. The high effectiveness of this approach was demonstrated through the preparation of target products in up to 92 % isolated yield. Subsequent reduction of the nitro group was investigated. We found that due to the instability of the intermediate α-fluoro amines, the reduction led to non-fluorinated tryptamine derivatives.

Full text of DOI:10.1002/ejoc.201800385

A Journal of
Accepted Article
Title: Green, catalyst-free reaction of indoles with ꢀ-fluoro-ꢀ
-nitrostyrenes in water
Authors: Alexander Aldoshin, Andrey Tabolin, Sema Ioffe, and
Valentine G. Nenajdenko
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800385
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Grafical Abstract
Table of contents
The alkylation of various indoles with 2-fluoro-2-nitrostyrenes resulted in highly regioselectively 3-
(1-aryl-2-fluoro-2-nitroethyl)-1H-indoles in water in up to 92% isolated yield. As a result highly
efficient green and catalyst-free synthesis of these compounds was elaborated. Subsequent
reduction of nitro group with NaBH4-NiCl2 system leads to loss of fluorine to form non-fluorinated
tryptamine derivatives.
Green, catalyst-free reaction of indoles with β-fluoro-β-nitrostyrenes in water
Alexander S. Aldoshin,a Andrey A. Tabolin,b Sema L. Ioffeb
and Valentine G. Nenajdenko*,a
a Department of Chemistry, Lomonosov Moscow State University, Moscow, 11999, (Russian
Federation) Fax: (+)7-495-9328846, E-mail: nenajdenko@org.chem.msu.ru
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
Leninsky prosp. 47, Moscow 119991 (Russian Federation)
ABSTRACT: Reaction of 2-fluoro-2-nitrostyrenes with various indoles was investigated. It was
found that the reaction proceeds as Michael addition to form highly regioselectively 3-(1-aryl-2-
fluoro-2-nitroethyl)-1H-indoles. Green and catalyst-free synthesis of these compounds was
elaborated using water as a reaction media. The high effectiveness of this approach was
demonstrated to prepare target products in up to 92% isolated yield. Subsequent reduction of nitro
group was investigated. It was found that due to instability of intermediate α-fluoro amines the
reduction leads to non-fluorinated tryptamine derivatives.
KEYWORDS: Michael addition, fluorine, nitrostyrene, indole, regioselectivity.
INTRODUCTION
At the present time about 25% of drugs and more than 30% of agrochemicals includes at least
one fluorine atom. Noteworthy the incorporation of a fluorine atom changes some important
features of the target molecule - lipophilicity, solubility, binding to receptors, metabolism,
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
permeability of membranes, acid-base characteristics, and conformational properties of compounds.
All these unique features are used as a working tool in the design of new drugs and materials.[1]
Indole ring is one of the most important and widely distributed structural subunits in the
nature. Due to their biological and pharmacological activity the molecules containing indole
nucleus have found wide application as antiasthmatic, antiallergic, antiviral, antiarrhythmic, anti-
inflammatory, antidepressant, antipsychotic, anticancer, antihypertensive, antiemetic, analgesic, and
anti-HIV drugs. A number of indole derivatives display antiulcer, antimycotic, antimalarial,
antibacterial, antiplatelet, antileishmanial, antioxidant, antitubercular, and immunomodulator
activities.[2,3] Therefore, nowadays the development of new pathways to indole derivatives is still
actual and retains the high interest.[4]
One of the most important tools used for the synthesis of 3-substituted indole derivatives is a
nucleophilic addition of 3-unsubstituted derivatives to Michael acceptors.[5] In turn, we have
recently reported the effective and stereoselective method of preparation of β-fluoro-β-nitrostyrenes
based on radical nitration of 2-bromo-2-fluorostyrenes. This process occurs with the simultaneous
elimination of bromine giving the target structures solely as the Z-isomers in high yields (up to
92%).[6] Similarly to their nonfluorinated analogues, β-fluoro- β-nitrostyrenes have highly polar
double C-C bond owing to the presence of a strong electron-withdrawing nitro group. These
molecules are very attractive Michael acceptors to construct molecules having one fluorine atom in
the structure.[7] This study is devoted to reaction of β-fluoro- β-nitrostyrenes with various indoles.
Such approach opens straightforward way to valuable mono-fluorinated Michael adducts. In turn
the latter can be employed as precursors to the further synthesis of diverse fluorine substituted
indole derivatives. Herein we report for the first time a catalyst-free synthesis of novel 3-(1-aryl-2-
fluoro-2-nitroethyl)-1H-indoles in water media.
RESULTS AND DISCUSSION
Starting 2-fluoro-2-nitrostyrenes can be easily prepared using procedure elaborated by us
recently (Scheme 1).[6] 2-Bromo-2-fluorostyrenes are available from the corresponding
commercially available aldehydes and CFBr3 using either catalytic olefination reaction or the
Corey-Fuchs reaction.[8] Subsequent radical nitrative debromination of prepared 2-bromo-2-
fluorostyrenes 1 with ferric nitrate nonahydrate opens straightforward route to the corresponding
nitroalkenes 2.[6]
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
Scheme 1. Preparation of 2-fluoro-2-nitrostyrenes
In order to find an optimal reaction conditions, parent indole 3a was reacted with styrene 2a
as a model substrate. Different solvents in the absence of any additives or catalysts were studied.
The reaction was performed at 100 °C (Scheme 2, Table 1). The reaction outcome (conversion and
yield) was monitored by 19F NMR using α,α,α-trifluorotoluene as an internal standard. When
reaction was carried out in toluene and 1,4-dioxane, no conversion of styrene 2a into the desired
adduct 4a was observed (Entries 1-2). Use of DMF and acetic acid as solvents showed the
negligible conversion and products yield (Entries 3-4). Whereas the reactions in DMSO and 1-
butanol resulted in the higher yields, 21 and 40 % respectively (Entries 5-6), the reaction rate was
still low. To our delight, when the reaction was heated in water media, the full styrene conversion
and high product yield 4a (87 %) were achieved in 7 hours (Entry 7). The structure of compound 4a
was elucidated using combination of NMR spectra and confirmed by HRMS. It should be noted that
the reaction is highly regioselective and styrene 2a attacked indole 3a in the position 3 only.
Scheme 2. Reaction of 1H-indole 3a with styrene 2a
Table 1. Reactions between indole and 2-fluoro-2-nitrostyrene 2a in various solventsa
Conversion
Entry
Solvent
Yieldb, %
of 2a,b %
1
Toluene
0
0
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
2
3
4
1,4-Dioxane
DMF
0
9
0
7
7
CH3COOH
14
5
6
7
DMSO
1-BuOH
H2O
26
41
21
40
100
87с
a –Reaction conditions: Styrene : Indole 1.0 : 1.2, 0.25 mmol of 2 in 1 ml of solvent, 7 h at 100 °C
b – calculated via 19F NMR analysis using α,α,α-trifluorotoluene as an internal standard
c – isolated yield obtained by column chromatography.
Over the last few decades academia as well as industry urged by stringent environmental
regulations has been giving more and more consideration to the development of cleaner, safer, and
environmentally benign chemical processes. In this connection the use of water as a green media in
organic synthesis has attracted the great interest and become an important research area. Many
examples of synthesis of indole and its derivatives in water or water-containing media have been
demonstrated.[2a, 5b]
Further, the additional reactions in neat were conducted to assess the role of water in this type
of indole alkylation. Thus, mixture of indole and model styrene 2a was heated at 100 °C in absence
of water varying the molar ratio of the reagents (Scheme 3, Table 2). The data obtained demonstrate
that water serves only as a reaction media and does not play any catalytic role. The reaction
proceeds in neat also in high yield, but a larger excess of indole to achieve the full conversion of the
reagents in comparison with the reaction in water was needed (Table 1, Entry 7; Table 2, Entry 2).
Scheme 3. Reaction of 1H-indole 3a with styrene 2a in neat
Table 2. Reactions between indole 3a and 1-fluoro-1-nitrostyrene 2a in neata
Conversion
Entry
Mol. ratio 2a:3a
Yield, %
of 2a,b %
1
2
1.0 : 1.0
1.0 : 1.2
87
93
67c
80b (78)c
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
3
1.0 : 1.5
100
87b (84)c
a – Reaction conditions: reaction time – 7 h, at 100 °C
b – calculated via 19F NMR analysis using α,α,α-trifluorotoluene as an internal standard
c – isolated yield obtained by column chromatography
Noteworthy the use of water improve the technological effectiveness of the process probably
due to the better reactants diffusion in a water emulsion compared to a viscous reaction mixture
melt. Nevertheless, despite the more consumption of expensive indoles, neat conditions are also
interesting in viewpoint of green chemistry, since enable to avoid some additional stages of
purification (extraction or filtration and drying).
Having in hand these water-mediated conditions for alkylation of indole, the reaction of
indole 3a with various 2-fluoro-2-nitrostyrenes 2a-2h was investigated (Scheme 4). Gratifyingly,
the reaction has broad scope and led to the formation of desired adducts 4a-4h in high yields.
Various substituted nitrostyrenes 2a-2g reacted smoothly as well. Somehow lower yield was
observed in case of adduct 4h deriving from styrene 2h containing a strong electron-withdrawing
nitro-group. In all cases regioselective reaction at the position 3 of indoles was observed.
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
R
F
NO2
F
H2O
+
NO2
N
H
100 °C, 7 h
N
H
R
3a
2
4
Br
Cl
F
F
F
F
NO2
NO2
NO2
NO2
N
H
N
N
H
N
H
H
4a (87 %)
4b (92 %)
4c (88 %)
4d (78 %)
(74 %)a
H3COOC
F3C
H3CO
O2N
F
F
F
F
NO2
NO2
NO2
NO2
N
H
N
H
N
H
N
H
4h (69 %)
4e (86 %)
4f (84 %)
4g (81 %)
(83 %)b
Scheme 4. Reaction of indole 3a with styrenes 2 (0.5 mmol), a – 2 (2.5 mmol), b – 2 (5 mmol)
Next the scope of indoles was studied in the reaction with model styrene 2a. It was found
that the water-mediated conditions are applicable for a broad variety of substituted indoles. For this
aim indole derivatives having substituents either in pyrrole ring (at the nitrogen or at the C-2
carbon) or in benzene ring of indole system were studied as substrates for the reaction (Scheme 5).
Moreover, due to the considerable importance of 2-aryl-indole derivatives in pharmaceutical
research,[9] the reaction of several 2-aryl-substituted indoles with 2a was investigated under the
above conditions. In all cases studied reasonably high isolated yields were observed. As a result a
family of mono-fluorinated molecules having indole ring in the structure was prepared. We believe
that these small molecules can be attractive for subsequent biological studies. In almost all cases
examined NMR analysis showed the formation of a diastereoisomeric mixture of alkylated products
4 in ratio ca 1:1. Probably the formation of two diastereomers can be explained by high acidity of
CH proton having fluorine and nitro group attached (estimated pKa of CH2FNO2 is around 9.5).[10]
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
Cl
F
R1
F
NO2
R1
R2
H2O
NO2
R2
+
N
R3
100 °C, 7 h
N
R3
Cl
3b-3t
2a
4
Cl
Cl
Cl
Cl
F
F
F
F
NO2
NO2
NO2
NO2
Br
I
Br
N
H
N
N
Cl
N
H
H
4l
(74 %)
4i
(43 %)
4
4k
(67 %)
j (74 %)
Cl
Cl
Cl
Cl
F
F
F
F
F
NO2
Ph
NO2
NO2
Ph
NO2
N
H
N
N
H
N
H
H
4m (89 %)
4n
(71 %)
4o
(82 %)
4p
(84 %)
Cl
Cl
Cl
Cl
F
F
F
F
NO2
NO2
NO2
NO2
F
Br
Cl
F
Cl
Cl
N
N
N
H
N
H
H
H
4q (82 %)
4r
(80 %)
4s
(73 %)
4t
(51 %)
Cl
Cl
Cl
F
F
F
OCH3
NO2
NO2
NO2
Cl
OCH3
OCH3
F
N
N
N
H
H
H3CO
H
4v (
4w
83 %)
(77 %)
4u
(81 %)
Cl
Cl
Cl
Cl
O
F
F
F
F
NO2
NO2
NO2
NO2
NO2
COOH
N
N
H
N
Ts
N
H
Ts
4aa
(0%)
4z
(0%)
4y
(0 %)
4x
(0 %)
Scheme 5. Reaction of differently substituted indoles with styrene 2a
Gratifyingly, the reaction has only small restrictions in terms of indole structure. For
example, we failed to involve into the reaction indoles having strong electron withdrawing groups
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
such as COOH, NO2, CHO, Ts (Scheme 5) – either no reaction (4x-z) or decomposition (4aa) was
observed. However, all other indoles were converted into target 3-substituted derivatives. The
experimental data obtained for the product 4i indicate appreciably lower reactivity of N-methylated
indole compared to N-unsubstituted ones. Thus after conducting the reaction for 19 hours, 77% of
styrene 2a conversion was attained and adduct 4i was isolated in moderate yield (43%). It should be
noted that all other substituted 1H-indoles tested (Scheme 5, products 4j-s,4u-w) exhibited a good
reactivity resulting in high yields of the target adducts (67-89 %) except for 5-bromo-2-(4-
chlorophenyl)-1H-indole 3m giving moderate yield of adduct 4t.
Finally in order to estimate an applicability of the developed method in larger scale, several
scaled-up reactions were carried out. Thus the preparation of adducts 4a expanded fivefold (2.5
mmol) and 4f expanded tenfold (5 mmol) gave respectively 74% and 83% yields of isolated
products (Scheme 2).
Tryptamines are of great interest compounds due to their pharmacological activity and their
application in synthesis of carbolines and other biologically active molecules.11 Many research
works have been devoted to their preparation12. In this connection the possibility of reduction of the
adducts 4 into the corresponding monofluorinated tryptamine derivatives was investigated. A lot of
systems for reduction of nitro group in compounds 4 was investigated. The reduction of adducts 4
by NaBH4 - NiCl2∙system resulted in formation of non-fluorinated tryptamines 5 in moderate yields
(40-55%). This result can be explained by instability of intermideate α-fluorotryptamines, which
are transfrormed into imines after HF elimination. Finally the formation of tryptamines 5 takes
place (Scheme 5) yielding. Products 5 are the only identified products, however the reaction is
complex and also a mixture of unidentified by-products was observed by NMR. Other reductive
systems also resulted in formation of non-fluorinated tryptamines 5, but with the appreciably lower
selectivity (hydrogen or HCOONH4 (Pd/C), NH2NH2∙H2O – Ra-Ni, Zn in acetic acid). Thus
searching of the suitable reaction conditions for reducing of 3-(2-fluoro-2-nitro-1-aryl)-1H-indoles
into primary amines with preservation of a fluorine atom still remains important goal and in a case
of success will be reported in our following works.
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
Scheme 5. Reduction of adducts 4 into tryptamines 5.
CONCLUSIONS
In summary, a new synthetic route to 3-(1-aryl-2-fluoro-2-nitroethyl)-1H-indoles was
elaborated. It was demonstrated that structurally diverse indoles and 1-fluoro-1-nitrostyrenes
participated efficiently in this transformation. The Michael addition efficiently proceeds in catalyst-
free and water-mediated conditions. Besides, a possibility of performing such processes in neat was
also shown. According to the developed method a family of novel adducts of indoles was
synthesized. The above synthetic approach represents a remarkable example of green, safe,
environmentally benign chemical processes and opens the way to monofluorinated indole
derivatives. An attempt to prepare fluorinated tryptamines by reduction of prepared adducts resulted
in formation of the corresponding tryptamines with loss of fluorine atom.
EXPERIMENTAL SECTION
All reagents were purchased from commercial sources and used without any further purification.
1D NMR (1H, 19F, and 13C) spectra were obtained with Bruker AV-400 and Agilent 400-MR
spectrometers. Chemical shifts for 1H NMR spectroscopic data were referenced to internal
tetramethylsilane (δ = 0.0 ppm) and the solvent resonance (7.26 ppm for CDCl3 and 1.94 ppm for
13
CD3CN); chemical shifts for C NMR spectroscopic data were referenced to CDCl3 (δ = 77.16
19
ppm) or CD3CN (δ = 1.32, 118.30 ppm); chemical shifts for F NMR spectroscopic data were
referenced to PhCF3 (δ = –63.90 ppm). Data are reported as follows: chemical shift, integration
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, qui = quintet, sext = sextet, sept =
septet, br = board, m = multiplet, dd = doublet of doublets, ddd = doublet of doublet of doublets)
and coupling constants (Hz).
Starting 2-fluoro-2-nitrostyrenes were prepared according to the described procedures.[6, 8f] 1a[13],
1b[11], 1e[11], 1f[11], 1g[7], 1h [11]are known compounds.
(Z)-1-Bromo-4-(2-fluoro-2-nitrovinyl)benzene (2c). The product was synthesized from 1-bromo-
4-(2-bromo-2-fluorovinyl)benzene (1с) (3.634 g) according to method B[6]. The pure compound
was obtained in 95% yield (3.044 g) as a pale yellow solid using hexane/dichloromethane (3:1) as
79
elution mixture. M.p. = 123-126 °C. HRMS (ESI) m/z [M+Na]+: Calcd for C8H6 BrFNO2Na
245.9566; found 245.9560. 1H NMR (400 MHz, CDCl3): δ = 7.37 (d, 3JCF = 26.0 Hz, 1H), 7.52 (d, J
= 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ = 108.93 (d, 2JCF = 6.3
Hz), 126.35 (d, JCF = 3.8 Hz), 126.89 (d, JCF = 6.3 Hz), 132.15 (d, JCF = 7.8 Hz), 132.81. 19F NMR
(376 MHz, CDCl3): δ -110.43 (d, J = 26.0 Hz, 1F).
(Z)-1-(Tert-butyl)-4-(2-fluoro-2-nitrovinyl)benzene (2d). The product was prepared from 4-(tert-
butyl)benzaldehyde (3.250 g) via corresponding intermediate 1-(2-bromo-2-fluorovinyl)-4-(tert-
butyl)benzene (1d) [8f]. Crude 1d obtained was immediately subjected to radical nitrative
debromination without isolation according to method B [6]. The pure 2d was obtained in 50% yield
(2.240 g) as a pale yellow solid using hexane/dichloromethane (6:1) as elution mixture. M.p. = 33-
35 °C. HRMS (ESI) m/z [M+H]+: Calcd for C12H15FNO2 224.1087; found 224.1081.1H NMR (400
3
1.36 (s, 9H), 7.41 (d, JHF = 26.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.61 (d, J =
MHz, CDCl3) δ
=
13
2
8.4 Hz, 2H). C NMR (100 MHz, CDCl3) δ = 31.12, 35.12, 110.16 (d, JCF = 6.4 Hz), 125.20 (d,
4JCF = 6.3 Hz), 126.52, 130.94 (d, 3JCF = 7.6 Hz), 152.69 (d, 1JCF = 292.6 Hz), 155.55 (d, 6JCF = 2.0
Hz). 19F NMR (376 MHz, CDCl3) δ -112.39 (d, J = 26.8 Hz, 1F).
Alkylation of indoles with α-fluoronitrostyrene. In a typical experiment, a mixture of indole 3
(0.6 mmol) and β-fluoro-β-nitrostyrene 2 (0.5 mmol) in water (2 mL) was heated at 100 °C while
being stirred. The progress of the reaction was monitored by TLC. After completion of the reaction,
the reaction mixture was extracted with ethyl acetate. The organic layer was separated, dried over
anhydrous sodium sulfate and concentrated under vacuum. The desired adduct was isolated as a
mixture of diasteroisomers by column chromatography. The relative configuration of the
stereocenters was not determined.
3-(1-(4-Chlorophenyl)-2-fluoro-2-nitroethyl)-1H-indole (4a). The mixture of diastereoisomers
(d.r. = 1:1) was obtained in 87% yield (0.127 g) as a viscous pale brown oil by column
chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture. HRMS (ESI)
1
m/z [M+H]+: Calcd for C16H1335ClFN2O2 319.0650; found 319.0644. H NMR (400 MHz, CDCl3):
δ = 5.22 (dd, J = 30.6 Hz, 2.9 Hz, 1H), 5.30 (dd, J = 31.3 Hz, 2.9 Hz, 1H), 6.25 (dd, J = 49.7 Hz,
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
3.1 Hz, 1H), 6.37 (dd, J = 49.9 Hz, 3.0 Hz, 1H), 7.05-7.46 (m, 18H), 8.60 (br s, 1H), 8.66 (br s,
1H). 13C NMR (100 MHz, CDCl3): δ = 45.54 (d, 2JCF = 18.4 Hz), 45.58 (d, 2JCF = 18.8 Hz), 108.29,
1
110.93, 111.49, 111.64, 111.73 (d, JCF = 245.0 Hz), 112.56 (d, JCF = 246.1 Hz), 118.44, 118.62,
1
120.23, 120.34, 122.53 (d, 4JCF = 2.3 Hz), 122.81, 123.05, 123.35 (d, 4JCF = 3.1 Hz), 125.93, 126.53,
19
129.01, 129.22, 129.84, 130.54, 132.86, 134.06, 134.33, 135.10, 135.85, 136.06. F NMR (376
MHz, CDCl3): δ = -152.27 (dd, J = 49.8 Hz, 31.4 Hz, 1F), -152.16 (dd, J = 49.9 Hz, 30.6 Hz, 1F).
3-(2-Fluoro-2-nitro-1-phenylethyl)-1H-indole (4b). The mixture of diastereoisomers (d.r. = 1:1)
was obtained in 92% yield (0.145 g) as a viscous redish oil by column chromatography on silica gel
using hexane/dichloromethane (1:1) as elution mixture. HRMS (ESI) m/z [M−H+]−: Calcd for
C16H12FN2O2 283.0888; found 283.0886.1H NMR (400 MHz, CDCl3): δ = 5.27 (dd, J = 30.4 Hz,
3.3 Hz, 1H), 5.38 (dd, J = 31.4 Hz, 3.2 Hz, 1H), 6.31 (dd, J = 50.1 Hz, 3.2 Hz, 1H), 6.40 (dd, J
13
=50.2 Hz, 3.4 Hz, 1H), 7.07-7.54 (m, 20H), 8.11 (br s, 1H), 8.14 (br s, 1H). C NMR (100 MHz,
CDCl3): δ = 46.21 (d, 2JCF = 18.5 Hz), 46.19 (d, 2JCF = 18.6 Hz), 108.72, 112.2 (d, 1JCF = 244.7 Hz),
111.28, 111.42, 111.58, 112.98 (d, 1JCF = 245.4 Hz), 118.54, 118.74, 120.09, 120.21, 122.63, 122.67
4
4
(d, JCF = 2.9 Hz), 122.87, 123.42 (d, JCF = 3.2 Hz), 126.13, 126.76, 128.13, 128.36, 128.48,
128.82, 129.07, 129.19, 134.44, 135.86, 136.06, 136.66. 19F NMR (376 MHz, CDCl3): δ = -151.94
(dd, J = 50.0 Hz, 31.5 Hz, 1F), -151.56 (dd, J = 50.2 Hz, 30.5 Hz, 1F).
3-(1-(4-Bromophenyl)-2-fluoro-2-nitroethyl)-1H-indole (4c). The mixture of diastereoisomers
(d.r. = 1:1) was obtained in 88% yield (0.157 g) as a red-orange solid by column chromatography
on silica gel using hexane/dichloromethane (1:1) as elution mixture. M.p. = 94 – 97 °C. HRMS
1
(ESI) m/z [M+H]+: Calcd for C16H1379BrFN2O2 363.0144; found 363.0139. H NMR (400 MHz,
CDCl3): δ = 5.21 (dd, J = 30.6 Hz, 3.1 Hz, 1H), 5.30 (dd, J = 31.3 Hz, 3.1 Hz, 1H), 6.24 (dd, J =
50.0 Hz, 3.1 Hz, 1H), 6.37 (dd, J =50.1 Hz, 3.1 Hz, 1H), 7.07-7.52 (m, 18H), 8.18 (br s, 1H), 8.21
13
2
2
(br s, 1H). C NMR (100 MHz, CDCl3): δ = 45.64 (d, JCF = 18.5 Hz), 45.70 (d, JCF= 18.7 Hz),
1
1
108.30, 110.98, 111.48, 111.64, 111.67 (d, JCF = 245.1 Hz), 112.49 (d, JCF = 245.7 Hz), 118.47,
118.65, 120.29, 120.42, 122.29, 122.54 (d, 4JCF = 2.8 Hz), 122.62, 122.87, 123.13, 123.34 (d, 4JCF =
3.5 Hz), 125.96, 126.57, 130.21, 130.90, 132.02, 132.23, 133.40, 135.69, 135.89, 136.10. 19F NMR
(376 MHz, CDCl3): δ = -152.20 (dd, J = 49.9 Hz, 31.4 Hz, 1F), -152.05 (dd, J = 50.1 Hz, 30.5 Hz,
1F).
3-(1-(4-(Tert-butyl)phenyl)-2-fluoro-2-nitroethyl)-1H-indole
(4d).
The
mixture
of
diastereoisomers (d.r. = 1:1) was obtained in 78% yield (0.130 g) as a pale yellow solid by column
chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture.
M.p. = 103-108 °C. HRMS (ESI) m/z [M+H]+: Calcd for C20H22FN2O2 341.1665; found 341.1660.
1H NMR (400 MHz, CDCl3): δ = 1.31 (s, 9H), 1.33 (s, 9H), 5.23 (dd, J = 30.4, 3.2 Hz, 1H), 5.35
(dd, J = 32.2, 2.6 Hz, 1H), 6.29 (dd, J = 50.1 Hz, 2.9 Hz, 1H), 6.38 (dd, J = 50.3, 3.4 Hz, 1H), 7.05
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
13
– 7.58 (m, 18H), 8.19 (br s, 1H), 8.22 (br s, 1H). C NMR (100 MHz, CDCl3): δ = 31.33, 34.56,
2
34.60, 45.74 (d, JCF = 18.5 Hz), 45.77 (d, JCF = 18.3 Hz), 109.00, 111.37, 111.55, 111.63, 112.3
2
(d, 1JCF = 244.4 Hz), 113.04 (d, 1JCF = 245.8 Hz), 118.62, 118.82, 120.07, 120.21, 122.63, 122.72 (d,
4
4JCF = 2.4 Hz), 122.89, 123.37 (d, JCF = 3.6 Hz), 125.78, 126.02, 126.22, 126.87, 128.82, 131.34,
131.34, 133.66, 135.87, 136.08, 151.08, 151.15. 19F NMR (376 MHz, CDCl3): δ = -152.19 (dd, J =
50.1 Hz, 32.2 Hz, 1F), -151.31 (dd, J = 50.2 Hz, 30.4 Hz, 1F).
3-(2-Fluoro-1-(4-methoxyphenyl)-2-nitroethyl)-1H-indole (4e). The mixture of diastereoisomers
(d.r. = 1:1) was obtained in 86 % yield (0.137 g) as a viscous yellowish oil by column
chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture. HRMS (ESI)
m/z [M−H+]−: Calcd for C17H14FN2O3 313.0994; found 313.0991. 1H NMR (400 MHz, CDCl3): δ =
3.76 (s, 3H), 3.80 (s, 3H), 5.22 (dd, J = 31.2, 3.4 Hz, 1H), 5.30 (dd, J = 31.0, 3.8 Hz, 1H), 6.27 (dd,
J = 50.0, 3.5 Hz, 1H), 6.37 (dd, J = 50.4, 3.2 Hz, 1H), 6.84-6.93 (m, 4H), 7.02-7.58 (m, 14H), 8.19
13
2
(br s, 1H), 8.22 (br s, 1H). C NMR (100 MHz, CDCl3): δ = 45.51 (d, JCF = 18.6 Hz), 45.54 (d,
2JCF = 18.7 Hz), 55.20, 55.30, 110.43 (d, 1JCF = 249.1 Hz), 111.39, 111.55, 111.99, 112.15 (d, 1JCF =
4
244.2 Hz), 114.18, 114.41, 118.59, 118.80, 120.03, 120.15, 122.49 (d, JCF = 2.6 Hz), 122.60,
4
122.83, 123.15 (d, JCF = 3.3 Hz), 126.13, 126.32, 126.74, 128.57, 129.63, 130.33, 135.91, 136.11,
19
159.32, 159.48. F NMR (376 MHz, CDCl3): δ = -152.24 (dd, J = 50.4 Hz, 31.0 Hz, 1F), -151.86
(dd, J = 50.0 Hz, 30.8 Hz, 1H).
Methyl 4-(2-fluoro-1-(1H-indol-3-yl)-2-nitroethyl)benzoate (4f). The mixture of diastereoisomers
(d.r. = 1:1) was obtained in 84% yield (0.143 g) as a yellowish solid by column chromatography on
silica gel using hexane/dichloromethane (1:1) as elution mixture. M.p. = 68-72 °C. HRMS (ESI)
1
m/z [M+H]+: Calcd for C18H16FN2O4 343.1094; found 343.1089. H NMR (400 MHz, CDCl3): δ =
3.91 (s, 3H), 3.94 (s, 3H), 5.30 (dd, J = 30.0, 3.2 Hz, 1H), 5.40 (dd, J = 31.3, 3.0 Hz, 1H), 6.31 (dd,
J = 49.9, 3.1 Hz, 1H), 6.41 (dd, J = 49.9, 3.4 Hz, 1H), 7.05 - 7.53 (m, 14H), 7.98 - 8.06 (m, 4H),
2
8.55 (br s, 1H), 8.60 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ = 46.00 (d, JCF = 18.3 Hz), 46.05
2
1
(d, JCF = 18.8 Hz), 52.27, 52.31, 107.88, 110.49, 111.53, 111.68, 111.69 (d, JCF = 249.1 Hz),
1
112.34 (d, JCF = 245.7 Hz), 118.29, 118.52, 120.13, 120.23, 122.69, 122.77 (d, JCF = 2.5 Hz),
4
4
122.92, 123.63 (d, JCF = 3.0 Hz), 125.94, 126.56, 128.57, 129.31, 129.83, 129.99, 130.24, 135.91,
136.10, 139.69, 141.83, 166.81, 166.86. 19F NMR (376 MHz, CDCl3): δ = -152.00 (dd, J = 49.9 Hz,
31.3 Hz, 1F), -151.62 (dd, J = 49.9 Hz, 30.1 Hz, 1F).
3-(2-Fluoro-2-nitro-1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indole (4g). The mixture of
diastereoisomers (d.r. = 1:1) was obtained in 81% yield (0.148 g) as a red solid by column
chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture.
M.p. = 92-96 °C. HRMS (ESI) m/z [M+H]+: Calcd for C17H13F4N2O2 353.0913; found 353.0908. 1H
NMR (400 MHz, CDCl3): δ = 5.33 (dd, J = 30.1, 2.8 Hz, 1H), 5.44 (dd, J = 31.7, 1.8 Hz, 1H), 6.30
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
(dd, J = 49.8, 3.5 Hz, 1H), 6.41 (dd, J = 49.8, 3.5 Hz, 1H), 7.02-7.75 (m, 18H), 8.27 (br s, 1H),
13
2
2
8.32 (br s, 1H). C NMR (100 MHz, CDCl3): δ = 45.95 (d, JCF = 19.0 Hz), 45.89 (d, JCF = 18.4
1
1
Hz), 107.88, 110.58, 111.58, 111.69 (d, JCF = 245.2 Hz), 111.72, 112.30 (d, JCF = 246.0 Hz),
118.35, 118.54, 120.35, 120.47, 122.73 (d, 4JCF = 2.5 Hz), 122.92, 123.16, 123.61 (d, 4JCF = 3.3 Hz),
125.38, 126.04 (d, 3JCF = 3.5 Hz), 125.93, 126.04 (d, 3JCF = 3.5 Hz), 126.54, 128.94, 129.65, 130.34
(q, 2JCF = 16.0 Hz), 135.92, 136.13, 138.53, 140.70. 19F NMR (376 MHz, CDCl3): δ = -152.42 (dd,
J = 49.9 Hz, 31.8 Hz, 1F), -151.85 (dd, J = 49.9 Hz, 30.2 Hz, 1F), -62.52 (s, 3F), -62.49 (s, 3F).
3-(2-Fluoro-2-nitro-1-(4-nitrophenyl)ethyl)-1H-indole (4h). The mixture of diastereoisomers
(d.r. = 1:1) was obtained in 69% yield (0.109 g) as a pale brown solid by column chromatography
on silica gel using hexane/dichloromethane (1:1) as elution mixture. M.p. = 72-76 °C. HRMS (ESI)
m/z [M−H+]− Calcd for C16H11FN3O4 328.0739, found 328.0737. 1H NMR (400 MHz, CD3CN): δ =
:
5.42 (dd, J = 28.6, 3.9 Hz, 1H), 5.54 (dd, J = 31.9, 3.2 Hz, 1H), 6.66 (dd, J = 49.4, 3.4 Hz, 1H),
6.76 (dd, J = 49.2, 4.0 Hz, 1H), 7.00-7.06 (m, 2H), 7.13-7.20 (m, 2H), 7.36-7.49 (m, 6H), 7.56 –
7.70 (m, 4H), 8.09-8.19 (m, 4H), 9.52 (br s, 2H). 13C NMR (100 MHz, CD3CN): δ = 46.18 (d, 2JCF
2
= 18.3 Hz), 46.37 (d, JCF = 18.3 Hz), 112.51, 112.72, 112.78, 112.99 (d, JCF = 242.9 Hz), 113.17
1
1
(d, JCF = 242.8 Hz), 119.24, 119.95, 120.06, 120.75, 120.77, 122.72, 123.32, 123.43, 124.36,
124.54 (d, 4JCF = 2.7 Hz), 124.62, 124.72, 124.81, 125.42 (d, 4JCF = 2.2 Hz), 130.34, 130.62, 131.19,
19
137.05, 137.21, 144.00, 145.54. F NMR (376 MHz, CD3CN): δ = -153.31 (dd, J = 49.3 Hz, 31.8
Hz, 1F), -152.01 (dd, J = 49.1 Hz, 28.5 Hz, 1F).
5-Bromo-3-(1-(4-chlorophenyl)-2-fluoro-2-nitroethyl)-1-methyl-1H-indole (4i). The mixture of
diastereoisomers (d.r. = 1:1) was obtained in 43% yield (0.089 g) as a viscous pale yellow oil by
column chromatography on silica gel using hexane/dichloromethane (2:1) as elution mixture.
HRMS (ESI) m/z [M−H+]−: Calcd for C17H1279Br35ClFN2O2 408.9760, found 408.9757; m/z
[M+H]+: Calcd for C17H1479Br35ClFN2O2 410.9911, found 410.9910. 1H NMR (400 MHz, CDCl3):
δ = 3.76 (s, 1H), 3.78 (s, 1H), 5.12 (dd, J = 30.5, 3.1 Hz, 1H), 5.22 (dd, J = 31.7, 3.0 Hz, 1H), 6.20
(dd, J = 50.0, 3.0 Hz, 1H), 6.30 (dd, J = 50.1, 3.2 Hz, 1H), 7.11–7.37 (m, 14H), 7.47 (d, J = 1.4 Hz,
13
2
1H), 7.54 (d, J = 1.5 Hz, 1H). C NMR (100 MHz, CDCl3): δ =32.25, 33.24 45.34 (d, JCF = 18.6
Hz), 45.42 (d, 2JCF = 18.8 Hz), 106.41, 109.10, 111.16, 111.34, 111.57 (d, 1JCF = 244.9 Hz), 112.34
4
(d, 1JCF = 245.4 Hz), 113.35, 113.42, 121.07, 121.24, 125.35, 125.61, 128.14, 128.38 (d, JCF = 2.8
4
Hz), 128.81, 129.05 (d, JCF = 3.7 Hz), 129.17, 129.39, 129.79, 130.47, 132.71, 134.31, 134.56,
19
135.01, 135.5, 135.70. F NMR (376 MHz, CDCl3): δ = -152.81 (dd, J = 49.9 Hz, 31.8 Hz, 1F), -
152.29 (dd, J = 50.1 Hz, 30.5 Hz, 1F).
5-Bromo-3-(1-(4-chlorophenyl)-2-fluoro-2-nitroethyl)-1H-indole (4j). The mixture of
diastereoisomers (d.r. = 1.0:1.2) was obtained in 74 % yield (0.146 g) as a red-orange solid by
column chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture. M.p.
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
= 115-121 °C. HRMS (ESI) m/z [M−H+]−: Calcd for C16H1079Br35ClFN2O2 394.9604; found
394.9603. 1H NMR (400 MHz, CDCl3) : δ = 5.13 (dd, J = 30.5, 2.7 Hz, 1H), 5.24 (dd, J = 31.8, 2.5
Hz, 1H), 6.23 (dd, J = 49.9, 2.8 Hz, 1H), 6.33 (dd, J = 50.0, 2.9 Hz, 1H), 7.14–7.40 (m, 14H), 7.48
13
(s, 1H), 7.53 (s, 1H), 8.29 (br s, 1H), 8.33 (br s, 1H). C NMR (100 MHz, CDCl3): δ = 45.34 (d,
2
1
2JCF = 18.5 Hz), 45.44 (d, JCF = 18.7 Hz), 108.05, 110.07, 110.76, 111.55 (d, JCF = 245.2 Hz),
112.4 (d, 1JCF = 247.6 Hz), 113.0, 113.15, 113.71, 121.04, 121.19, 123.75 (d, 4JCF = 3.0 Hz), 124.58
(d, 4JCF = 3.7 Hz), 125.86, 126.10, 127.75, 128.34, 129.20, 129.43, 129.80, 130.49, 132.42, 134.38,
19
134.56, 134.64, 134.67, 134.77. F NMR (376 MHz, CDCl3): δ = -152.81 (dd, J = 49.9 Hz, 31.8
Hz, 1F), -152.29 (dd, J = 50.1 Hz, 30.5 Hz, 1F).
3-(1-(4-Chlorophenyl)-2-fluoro-2-nitroethyl)-5-iodo-1H-indole
(4k).
The
mixture
of
diastereoisomers (d.r. = 1.3:1.0) was obtained in 67 % yield (0.126 g) as a red solid by column
chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture. M.p. = 59-62
1
°C. HRMS (ESI) m/z [M−H+]−: Calcd for C16H1035ClFIN2O2 442.9465; found 442.9460. H NMR
(400 MHz, CDCl3): δ = 5.13 (dd, J = 30.5, 3.0 Hz, 1H), 5.23 (dd, J = 31.7, 2.9 Hz, 1H), 6.22 (dd, J
= 49.9, 3.0 Hz, 1H), 6.32 (dd, J =50.1, 3.2 Hz, 1H), 7.08 –7.17 (m, 2H)
.
, 7.19–7.36 (m, 14H), 7.40–
13
7.50 (m, 2H), 7.68 (s, 1H), 7.74 (s, 1H), 8.33 (br s, 1H), 8.38 (br s, 1H). C NMR (100 MHz,
2
2
CDCl3): δ = 45.27 (d, JCF = 18.6 Hz), 45.36 (d, JCF = 18.8 Hz), 83.88, 83.91, 107.70, 110.39,
1
111.55 (d, JCF = 244.9 Hz), 112.38 (d, JCF = 246.8 Hz), 112.76, 113.46, 113.61, 123.4 (d, JCF =
1
4
3.0 Hz), 124.17 (d, 4JCF = 3.8 Hz), 127.23, 127.37, 128.52, 129.16, 129.39, 129.79, 130.47, 131.28,
19
131.52, 132.42, 134.35, 134.59, 134.65, 134.97, 135.19. F NMR (376 MHz, CDCl3): δ = -152.77
(dd, J = 49.8 Hz, 31.8 Hz, 1F), -152.3 (dd, J = 50.1 Hz, 30.6 Hz, 1F).
6-Chloro-3-(1-(4-chlorophenyl)-2-fluoro-2-nitroethyl)-1H-indole (4l). The mixture of
diastereoisomers (d.r. = 1:1) was obtained in 74 % yield (0.131 g) as a viscous pale brown oil by
column chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture.
1
HRMS (ESI) m/z [M−H+]−: Calcd for C16H1035Cl2FN2O2 351.0109; found 351.0109. H NMR (400
MHz, CDCl3) δ = 5.16 (dd, J = 30.2, 3.0 Hz, 1H), 5.26 (dd, J = 31.3, 2.8 Hz, 1H), 6.26 (dd, J =
49.9, 3.1 Hz, 1H), 6.36 (dd, J = 50.1, 3.2 Hz, 1H), 7.00–7.10 (m, 2H), 7.21–7.37 (m, 14H), 8.25 (br
13
2
s, 1H), 8.28 (br s, 1H). C NMR (100 MHz, CDCl3): δ = 45.46 (d, JCF = 18.7 Hz), 45.52 (d,
1
2JCF = 18.7 Hz), 108.58, 111.24, 111.42, 111.56, 111.61 (d, JCF = 245.1 Hz), 112.41 (d,
4
4
1JCF = 246.0 Hz), 119.43, 119.61, 121.03, 121.12, 123.14 (d, JCF = 3.0 Hz), 124.10 (d, JCF = 3.3
Hz), 124.61, 125.15, 128.75, 129.00, 129.12, 129.34, 129.76, 130.48, 132.58, 134.27, 134.55,
134.81, 136.28, 136.49. 19F NMR (376 MHz, CDCl3): δ = -152.51 (dd, J = 49.9 Hz, 31.3 Hz, 1F), -
152.21 (dd, J = 50.0 Hz, 30.2 Hz, 1F).
3-(1-(4-Chlorophenyl)-2-fluoro-2-nitroethyl)-5-phenyl-1H-indole (4m). The mixture of
diastereoisomers (d.r. = 1: 1) was obtained in 89 % yield (0.177 g) as a viscous pale brown oil by
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
column chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture.
1
HRMS (ESI) m/z [M−H+]−: Calcd for C22H1535ClFN2O2 393.0812; found 393.0809. H NMR (400
MHz, CDCl3) δ = 5.30 (dd, J = 30.5, 3.1 Hz, 1H), 5.40 (dd, J = 31.5, 3.0 Hz, 1H), 6.25 (dd, J =
49.8, 3.1 Hz, 1H), 6.37 (dd, J = 49.9, 3.2 Hz, 1H), 7.20 – 7.73 (m, 26H), 8.22 (br s, 2H). 13C NMR
2
2
(100 MHz, CDCl3): δ = 45.47 (d, JCF = 18.5 Hz), 45.52 (d, JCF = 18.7 Hz), 108.66, 111.75 (d,
1
1JCF = 245.0 Hz), 111.76, 111.91, 112.52 (d, JCF = 246.4 Hz), 116.78, 116.98, 122.74, 122.97,
123.29 (d, 4JCF = 2.6 Hz), 124.09 (d, 4JCF = 3.3 Hz), 126.50, 126.69, 126.81, 127.11, 127.47, 128.81,
128.88, 129.08, 129.28, 129.85, 130.54, 132.81, 133.87, 134.02, 134.14, 134.41, 135.04, 135.38,
135.56, 142.04, 142.16. 19F NMR (376 MHz, CDCl3): δ = -152.29 (dd, J = 49.8 Hz, 31.5 Hz, 1F), -
152.01 (dd, J = 49.9 Hz, 30.5 Hz, 1F).
3-(1-(4-Chlorophenyl)-2-fluoro-2-nitroethyl)-5-(4-fluorophenyl)-1H-indole (4n). The mixture of
diasteroisomers (d.r. = 1.3:1.0) was obtained in 71 % yield (0.147 g) as a pale brown solid by
column chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture. Mp =
1
77-80 °C. HRMS (ESI) m/z [M−H+]−: Calcd for C22H1435ClF2N2O2 411.0717; found 411.0713. H
NMR (400 MHz, CDCl3) δ = 5.28 (dd, J = 30.4, 2.8 Hz, 1H), 5.38 (dd, J = 31.5, 2.2 Hz, 1H), 6.26
(dd, J = 49.8 Hz, 2.4 Hz, 1H), 6.39 (dd, J = 49.9 Hz, 2.5 Hz, 1H), 7.00–7.08 (m, 2H), 7.20–7.66 (m,
24H), 8.29 (br s, 1H), 8.32 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ = 45.47 (d, 2JCF = 18.6 Hz),
2
45.53 (d, JCF = 18.8 Hz), 108.84, 111.52, 111.75 (d, JCF = 245.1 Hz), 111.88, 112.05, 112.50 (d,
1
2
2
1JCF = 245.9 Hz), 113.39 (d, JCF = 21.0 Hz), 113.52 (d, JCF = 21.1 Hz), 114.12 (d, JCF = 1.8Hz),
114.34 (d, JCF = 1.5 Hz), 116.89, 117.09, 122.61, 122.86, 123.07 (d, JCF = 2.2 Hz), 123.46 (d, JCF =
2.7 Hz), 124.30 (d, JCF = 3.6 Hz), 126.54, 127.15, 129.15, 129.37, 129.87, 130.22 (d, JCF = 8.1 Hz),
130.30 (d, JCF = 8.1 Hz), 130.55, 132.66 (d, JCF = 1.7 Hz), 132.76, 132.82 (d, JCF = 1.7 Hz), 134.27,
134.53, 135.00, 135.66, 135.86, 144.37 (d, JCF = 7.9 Hz), 144.49 (d, JCF = 7.5 Hz), 163.26 (d,
1JCF = 245.1 Hz). 19F NMR (376 MHz, CDCl3): δ = -152.52 (dd, J = 49.8 Hz, 31.6 Hz), -152.05 (dd,
J = 50.0 Hz, 30.6 Hz), -113.25 (td, J = 9.3 Hz, 6.2 Hz,1F), -113.12 (td, J = 9.3, 6.1 Hz).
3-(1-(4-Chlorophenyl)-2-fluoro-2-nitroethyl)-2-methyl-1H-indole (4o). The mixture of
diasteroisomers (d.r. = 1:1) was obtained in 82% yield (0.136 g) as a redish solid by column
chromatography on silica gel using hexane/dichloromethane (1:1) as elution mixture.
M.p. = 134-138 °C. HRMS (ESI) m/z [M+H]+: Calcd for C17H1535ClFN2O2 333.0806; found
1
333.0806. H NMR (400 MHz, CDCl3) δ = 2.27 (s, 3H), 2.31 (s, 3H), 5.11 (dd, J = 22.2, 4.6 Hz,
1H), 5.26 (d, J = 32.6 Hz, 1H), 6.50 (dd, 50.5 Hz, 5.1 Hz, 1H), 6.60 (d, 50.0 Hz, 1H), 6.99–7.56 (m,
13
2
16H), 7.95 (br s, 2H). C NMR (100 MHz, CDCl3): δ = 12.03, 12.06, 44.65 (d, JCF = 20.0 Hz),
2
45.07 (d, JCF = 19.9 Hz), 104.20, 105.72, 110.64, 110.97, 112.10 (d, JCF = 245.8 Hz), 112.94 (d,
1
4
4
1JCF = 244.4 Hz), 118.57 (d, JCF = 2.2 Hz), 119.49 (d, JCF = 5.3 Hz), 120.17, 120.36, 121.72,
121.89, 126.81, 127.53, 128.96, 129.07, 129.17, 129.98, 133.51, 133.71, 133.86, 134.47, 134.56,
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
19
135.33, 135.38. F NMR (376 MHz, CDCl3): δ = -149.07 (dd, J = 50.5 Hz, 32.6 Hz, 1F), -143.56
(dd, J = 50.1 Hz, 22.3 Hz, 1F).
3-(1-(4-Chlorophenyl)-2-fluoro-2-nitroethyl)-2-phenyl-1H-indole (4p). The mixture of
diastereoisomers (d.r. = 1.9 : 1.0) was obtained in 84% yield (0.168 g) as a pale yellow solid by
column chromatography on silica gel using hexane/dichloromethane (2:1) as elution mixture. M.p.
= 158-161 °C. HRMS (ESI) m/z [M+H]+: Calcd for C22H1735ClFN2O2 395.0963; found 395.0957.1H
NMR (400 MHz, CD3CN): δ = 5.20 (dd, J = 21.4, 6.9 Hz, 1H), 5.41 (dd, J = 33.0, 3.6 Hz, 1H), 6.79
(dd, J = 49.9, 3.7 Hz, 1H), 6.85 (dd, J = 49.3, 6.9 Hz, 1H), 7.04 –7.27 (m, 4H), 7.29-7.61 (m, 20H),
7.70 (d, J = 8.1 Hz, 2H), 9.69 (br s, 1H), 9.72 (br s, 1H). 13C NMR (100 MHz, CD3CN): δ = 45.56
2
(d, JCF = 19.8 Hz), 46.50 (d, JCF = 20.4 Hz), 105.38, 106.88, 106.94, 112.43, 112.7, 113.51 (d,
2
1
4
1JCF = 244.6 Hz), 113.86 (d, JCF = 241.9 Hz), 120.92 (d, JCF = 3.3 Hz), 120.99, 121.22, 121.97,
122.06, 123.30, 123.45, 127.39, 127.87, 129.70, 129.78, 129.87, 129.91, 129.98, 130.68, 131.19,
19
132.58, 132.73, 133.93, 134.09, 136.60, 137.09, 137.31, 137.37, 139.03, 139.94. F NMR (376
MHz, CD3CN): δ = -149.47 (ddd, J = 49.9 Hz, 33.1 Hz, 3.2 Hz, 1F), -144.24 (dd, J = 49.3 Hz,
21.4 Hz, 1F).
2-(4-Chlorophenyl)-3-(1-(4-chlorophenyl)-2-fluoro-2-nitroethyl)-1H-indole (4q). The mixture of
diasteroisomers (d.r. = 1.6:1.0) was obtained in 82% yield (0.177 g) as a pale yellow solid by
column chromatography on silica gel using hexane/dichloromethane (2:1) as elution mixture. Mp =
191-194 °C. HRMS (ESI) m/z [M+H]+: Calcd for C22H1535Cl2FN2O2 429.0573; found 429.0567.1H
NMR (400 MHz, CD3CN): δ = 5.13 (dd, J = 21.1, 6.9 Hz, 1H), 5.36 (dd, J = 33.0, 3.6 Hz, 1H),
6.79 (dd, J = 49.8, 3.7 Hz, 1H), 6.83 (dd, J = 49.3, 6.9 Hz, 1H), 7.01–7.59 (m, 22H), 7.64–7.70 (m,
2
2H), 9.71 (br s, 1H), 9.72 (br s, 1H). 13C NMR (100 MHz, CD3CN): δ = 45.42 (d, JCF = 19.8 Hz),
46.39 (d, 2JCF = 20.5 Hz), 112.48, 112.75, 113.39 (d, 1JCF = 245.1 Hz), 113.75 (d, 1JCF = 241.9 Hz),
4
120.94 (d, JCF = 3.2 Hz), 121.08, 121.31, 122.00, 122.08, 123.52, 123.67, 127.30, 129.70, 129.77,
129.91, 130.03, 130.68, 131.19, 131.34, 131.53, 131.56, 133.96, 134.13, 135.16, 135.28, 136.45,
136.94, 137.36, 137.43, 137.70. 19F NMR (376 MHz, CD3CN): δ = -149.98 -149.61 (m, 1F), -144.3
(ddd, J = 49.1, 21.0, 6.3 Hz, 1F).
3-(1-(4-Chlorophenyl)-2-fluoro-2-nitroethyl)-2-(4-fluorophenyl)-1H-indole (4r). The mixture of
diastereoisomers (d.r. = 1.8:1.0) was obtained in 80% yield (0.164 g) as a colorless solid by column
chromatography on silica gel using hexane/dichloromethane (2:1) as elution mixture. Mp = 172–
175 °C. HRMS (ESI) m/z [M−H+]−: Calcd for C22H1435ClF2N2O2 411.0717; found 411.0713.1H
NMR (400 MHz, CD3CN) δ = 5.15 (dd, J = 21.2, 6.9 Hz, 1H), 5.36 (dd, J = 33.0, 3.6 Hz, 1H), 6.79
(dd, J = 49.8, 3.7 Hz, 1H), 6.85 (dd, J = 49.3, 6.9 Hz, 1H), 7.02 – 7.57 (m, 22H), 7.67 – 7.73 (m,
2H), 9.69 (br s, 1H), 9.67 (br s, 1H). 13C NMR (100 MHz, CD3CN): δ = 45.49 (d, 2JCF = 20.5 Hz),
46.44 (d, 2JCF = 19.8 Hz), 105.65, 107.17 (d, JCF = 6.3 Hz), 112.44, 112.71, 113.43 (d, 1JCF = 244.9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800385
European Journal of Organic Chemistry
1
2
2
Hz), 113.8 (d, JCF = 241.9 Hz), 116.69 (d, JCF = 21.8 Hz), 116.82 (d, JCF = 21.9 Hz), 120.87 (d,
JCF = 3.0 Hz), 121.05, 121.28, 121.97 (d, JCF = 8.7 Hz), 123.39, 123.53, 127.30, 127.80, 128.93 (d,
JCF = 2.9 Hz), 129.05 (d, JCF = 3.2 Hz), 129.69, 129.76, 130.65, 131.17, 132.06 (d, JCF = 8.0 Hz),
132.16 (d, JCF = 8.3 Hz), 133.95, 134.11, 136.49, 136.98, 137.25, 137.31, 138.02, 138.90, 163.83
(d, 1JCF= 246.6 Hz), 163.87 (d, 1JCF = 246.7 Hz). 19F NMR (376MHz, CD3CN): δ = -149.60 (dd, J =
49.8, 33.0 Hz, 1F), -144.22 (dd, J = 49.3 Hz, 21.2 Hz, 1F), -114.12 (tt, J = 8.9 Hz, 5.4 Hz, 1F), -
113.91 (tt, J = 8.9 Hz, 5.3 Hz 1F).
2-(4-Chlorophenyl)-3-(1-(4-chlorophenyl)-2-fluoro-2-nitroethyl)-5-fluoro-1H-indole (4s). The
mixture of diastereoisomers (d.r. = 2:1) was obtained in 73 % yield (0.166 g) as a yellowish solid by
column chromatography on silica gel using hexane/dichloromethane (2:1) as elution mixture. M.p.
= 198-204 °C. HRMS (ESI) m/z [M−H+]−: Calcd for C22H1335Cl2F2N2O2 445.0328; found
445.0325.1H NMR (400 MHz, CD3CN): δ = 5.11 (dd, J = 21.8, 6.7 Hz, 1H), 5.35 (dd, J = 33.6, 3.4
Hz, 1H), 6.78 (dd, J = 49.7, 3.5 Hz, 1H), ), 6.79 (dd, J = 49.2, 6.8 Hz, 1H), 6.96-7.06 (m, 2H), 7.12-
7.18 (m, 1H), 7.29–7.61 (m, 19H), 9.77 (br s, 1H), 9.79 (br s, 1H). 13C NMR (100 MHz, CD3CN):
δ = 45.20 (d, 2JCF = 19.6 Hz), 46.20 (d, 2JCF = 20.6 Hz), 105.55 (d, 3JCF = 3.7 Hz), 105.80 (d, 3JCF =
3.6 Hz), 106.52 (d, JCF = 10.1 Hz), 106.76 (d, JCF = 9.4 Hz), 111.74 (d, 2JCF = 26.5 Hz), 111.85 (d,
1
1
2JCF = 26.4 Hz)
, 111.98, 113.35 (d, JCF= 244.2 Hz), 113.56 (d, JCF = 9.8 Hz), 113.56 (d, JCF =
242.2 Hz), 113.84 (d, JCF = 9.9 Hz), 127.56, 127.65, 129.79, 129.87, 128.6, 129.96, 130.08, 130.66,
131.01, 131.16, 131.51, 131.57, 133.94, 134.02, 134.08, 134.25, 135.42, 135.55, 136.11, 136.59,
1
1
19
139.65, 158.75 (d, JCF = 233.0 Hz), 158.88 (d, JCF = 233.3 Hz). F NMR (376 MHz, CD3CN):
δ = -150.1 (ddd, J = 49.7 Hz, 33.7 Hz, 2.6 Hz, 1F), -144.90 (dd, J = 49.1, 21.8 Hz), -124.75 (ddd, J
= 10.4 Hz, 9.5 Hz, 4.7 Hz, 1F), -124.31 (ddd, J = 10.2 Hz, 9.6 Hz, 4.7 Hz, 1F).
5-Bromo-2-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-2-fluoro-2-nitroethyl)-1H-indole (4t). The
mixture of diastereoisomers (d.r. = 1.3:1.0) was obtained in 51 % yield (0.133 g) as a colorless solid
by column chromatography on silica gel using hexane/dichloromethane (2:1) as elution mixture.
Mp = 228 - 232 °C. HRMS (ESI) m/z [M−H+]−: Calcd for C22H1379Br35Cl2FN2O2 504.9527; found
1
504.9528. H NMR (400 MHz, CD3CN): δ = 5.10 (dd, J = 21.4, 6.9 Hz, 1H), 5.35 (dd, J = 33.7,
3.4 Hz, 1H), 6.79 (dd, J = 49.8, 3.4 Hz, 1H), 6.82 (dd, J = 49.0, 6.9 Hz, 1H), 7.26–7.61 (m, 21H),
7.80 (br s, 1H), 9.87 (br s, 2H). 13C NMR (100 MHz, CD3CN) δ = 45.07 (d, 2JCF = 19.4 Hz), 46.10
2
(d, JCF = 20.6 Hz), 113.19 (d, JCF = 244.2 Hz), 113.49 (d, JCF = 242.0 Hz), 113.85, 114.08,
1
1
4
114.34, 114.54, 123.05 (d, J = 3.2 Hz), 124.05, 124.15, 126.19, 126.36, 129.06, 129.57, 129.70,
129.78, 129.88, 130.09, 130.58, 130.68, 130.77, 130.87, 131.11, 131.52, 131.59, 131.91, 132.23,
134.11, 134.26, 135.51, 135.63, 136.0, 136.04, 136.09, 136.46. 19F NMR (376 MHz, CD3CN): δ = -
150.18 (dd, J = 49.8, 33.8 Hz, 1F), -144.61 (dd, J = 49.0, 21.4 Hz, 1F).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800385
European Journal of Organic Chemistry
5-Chloro-3-(1-(4-chlorophenyl)-2-fluoro-2-nitroethyl)-2-(4-fluorophenyl)-1H-indole (4u). The
mixture of diasteroisomers (d.r. = 1.2:1.0) was obtained in 81 % yield (0.186 g) as a colorless solid
by column chromatography on silica gel using hexane/dichloromethane (2:1) as elution mixture.
M.p. = 197-202 °C, HRMS (ESI) m/z [M−H+]−: Calcd for C22H1335Cl2F2N2O2 445.0328; found
445.0330. 1H NMR (400 MHz, CD3CN): δ = 5.09 (dd, J = 21.5, 6.9 Hz, 1H), 5.33 (dd, J = 33.7, 3.3
Hz, 1H), 6.79 (dd, J = 49.8, 3.4 Hz, 2H), 6.81 (dd, J = 49.1, 6.9 Hz, 2H), 7.10 –7.50 (m, 21H), 7.57
– 7.67 (m, 1H), 9.84 (br s, 2H). 13C NMR (100 MHz, CD3CN): δ = 45.13 (d, 2JCF = 19.7 Hz), 46.14
(d, 2JCF = 20.7 Hz), 105.43, 107.05 (d, JCF = 8.0 Hz), 113.25 (d, 1JCF = 244.4 Hz), 113.54 (d, 1JCF =
241.8 Hz), 113.87, 114.09, 116.77 (d, 2JCF = 21.9 Hz), 116.89 (d, 2JCF = 22.0 Hz), 119.94 (d, 4JCF =
3.4 Hz), 120.92, 121.01, 123.44, 123.59, 126.20, 126.45, 128.39, 128.5 (d, JCF = 3.0 Hz), 128.91,
4
129.77, 129.87, 130.59, 131.10, 132.09 (d, JCF = 8.9 Hz), 132.18 (d, JCF = 8.8 Hz), 134.08,
4
1
134.23, 135.64, 135.73, 136.13, 136.57, 139.70, 140.06, 163.65 (d, JCF = 245.1 Hz), 164.04 (d,
1JCF = 247.4 Hz). F NMR (376 MHz, CD3CN): δ = -150.10 (ddd, J = 49.8 Hz, 33.8 Hz, 2.7 Hz,
19
1F), -144.7 (dd, J = 49.1 Hz, 21.5 Hz), -113.80 (tt, J = 8.8 Hz, 5.4 Hz, 1F), -113.61 (tt, J = 8.9 Hz,
5.4 Hz, 1F)
3-(1-(4-Chlorophenyl)-2-fluoro-2-nitroethyl)-2-(3,4-dimethoxyphenyl)-1H-indole (4v). The
mixture of diasteroisomers (d.r. = 2.2:1.0) was obtained in 83 % yield (0.196 g) as a pale yellow
solid by column chromatography on silica gel using hexane/dichloromethane (2:1) as elution
mixture. M.p. = 86-89 °C. HRMS (ESI) m/z [M−H+]−: Calcd for C24H1935ClFN2O4 453.1023; found
1
453.1019. H NMR (400 MHz, CDCl3) δ = 3.77 (s, 6H), 3.90 (s, 6H), 5.22 (dd, J = 21.2, 6.3 Hz,
1H), 5.24 (dd, J = 29.8, 5.4 Hz, 1H), 6.52 (dd, J = 50.6, 6.5 Hz, 1H), 6.53 (dd, J = 49.5, 4.8 Hz,
1H), 6.78-6.95 (m, 6H), 7.09–7.45 (m, 14H), 7.64-7.74 (m, 2H), 8.51 (br s, 1H), 8.55 (br s, 1H). 13C
2
2
NMR (100 MHz, CD3Cl): δ = 45.50 (d, JCF = 17.4 Hz), 45.69 (d, JCF = 20.0 Hz), 55.74, 55.86,
104.70, 105.98 (d, 3JCF = 5.5 Hz), 111.32 (d, 3JCF = 4.1 Hz), 111.46, 111.54, 111.85, 112.06, 112.57
(d, 1JCF = 249.0 Hz), 112.84 (d, 1JCF = 244.5 Hz), 119.84 (d, 4JCF = 4.0 Hz), 120.53, 120.67, 120.79,
121.50, 121.63, 122.46, 122.56, 124.08, 124.22, 126.68, 126.83, 128.86, 129.07, 129.39, 130.13,
19
133.64, 133.74, 134.79, 135.36, 135.85, 137.95, 138.76, 148.96, 149.05, 149.44, 149.48. F NMR
(376 MHz, CDCl3): δ = -145.95 (dd, J = 50.7 Hz, 29.7 Hz, 1F), -142.84 (dd, J = 49.4 Hz, 21.1 Hz,
1F).
3-(1-(4-Chlorophenyl)-2-fluoro-2-nitroethyl)-2-(2,5-dimethoxyphenyl)-1H-indole (4w). The
mixture of diasteroisomers (d.r. = 2.1:1.0) was obtained in 77 % yield (0.179 g) as a pale yellow
solid by column chromatography on silica gel using hexane/dichloromethane (2:1) as elution
mixture. M.p. = 68-72 °C. HRMS (ESI) m/z [M]–: Calcd for C24H1935ClFN2O4 453.1023; found
1
453.1020. H NMR (400 MHz, CDCl3): δ = 3.61 (br s, 2H), 3.67 (br s, 4H), 3.77 (br s, 6H), 5.16
(dd, J = 25.8, 5.2 Hz, 1H), 5.19 (dd, J = 30.0, 4.0 Hz, 1H), 6.49 (dd, J = 50.2, 5.3 Hz, 1H), 6.52 (dd,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800385
European Journal of Organic Chemistry
J = 50.5, 4.3 Hz, 1H), 6.80-6.84 (m, 2H), 6.91–7.04 (m, 4H), 7.10–7.41 (m, 14H), 7.56-7.70 (m,
13
2
2H), 8.52 (br s, 1H), 8.54 (br s, 1H). C NMR (100 MHz, CDCl3): δ = 45.53 (d, JCF = 23.2 Hz),
2
45.76 (d, JCF = 19.4 Hz), 55.76, 56.05, 106.23, 108.10 (d, JCF = 3.9 Hz), 111.28, 111.47, 112.42
3
1
(d, JCF = 245.4 Hz), 112.79, 112.85, 112.91 (d, JCF = 245.4 Hz), 115.61, 115.67, 116.88, 120.07
1
4
4
(d, JCF= 5.0 Hz), 120.27, 120.44, 120.77, 120.86 (d, JCF = 7.3 Hz), 122.43, 122.56, 126.39,
126.72, 128.71, 128.92, 129.41, 130.2, 133.41, 133.49, 134.06, 134.59, 134.98, 135.45, 136.06,
19
151.37, 151.57, 153.52, 153.60. F NMR (376 MHz, CDCl3): δ = -146.84 (dd, J = 50.5 Hz, 30.1
Hz, 1F),-144.95 (dd, J = 50.2 Hz, 25.8 Hz, 1F).
Reduction of adducts of indole. To a solution of selected 3-(2-fluoro-2-nitro-1-aryl)-1H-indole 4
(100-150 mg, 1 mol. equiv.) and NiCl2∙6H2O (1 mol. equiv.) in methanol (2-3 mL) was added
NaBH4 (5 mol. equiv.) at 0 °C and the reaction mixture was stirred until completion of the reaction.
The progress of reaction was monitored by TLC. After completion the reaction mixture was poured
into water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous
sodium sulfate and concentrated under vacuum. The product was isolated by column
chromatography on silica using DCM/CH3OH (20:1-10:1-5:1) as elution mixture.
2-(1H-indol-3-yl)-2-phenylethanamine (5b). The product was obtained in 38% yield (42.04 mg) as a
1
viscous pale yellow oil. H NMR (400MHz, CDCl3): 3.00 (br s, 2H), 3.14 – 3.27 (m, 1H), 3.28 –
3.42 (m, 1H), 4.26 (t, J = 7.1 Hz, 1H), 6.94 – 7.05 (m, 2H), 7.10 – 7.28 (m, 6H), 7.33 (d, J = 8.1 Hz,
1H), 7.41 (d, J = 8.0 Hz, 1H), 8.74 (br s, 1H). Analysis of the sample was consistent with the data
reported in the literature.14
2-(1H-Indol-3-yl)-2-(4-methoxyphenyl)ethanamine (5e). The product was obtained in 42% yield
(45.52 mg) as a viscous pale yellow oil. 1H NMR (400 MHz, CDCl3) δ = 2.78 (br s, 2H), 3.32 –
3.45 (m, 1H), 3.12 – 3.27 (m, 1H), 3.75 (s, 3H), 4.22 (t, J = 8.0 Hz, 1H), 6.75 – 6.85 (m, 2H), 6.95 –
7.08 (m, 2H), 7.09 – 7.23 (m, 3H), 7.32 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 8.61 (br s, H).
Analysis of the sample was consistent with the data reported in the literature.15
Methyl 4-(2-amino-1-(1H-indol-3-yl)ethyl)benzoate (5f). The product was obtained in 55% yield
(36.48 mg) as a viscous pale yellow oil. HRMS (ESI) m/z [M+H]+: Calcd for
C18H19N2O2 295.1441; found 295.1441. 1H NMR (400 MHz, CDCl3) δ = 2.03 (br s, 2H), 3.28 (dd, J
= 12.7, 7.5 Hz, 1H), 3.42 (dd, J = 12.6, 7.4 Hz, 2H), 4.32 (t, J = 7.3 Hz, 1H), 6.94 – 7.10 (m, 2H),
7.13 – 7.19 (m, 1H), 7.28 – 7.46 (m, 4H), 7.95 (d, J = 8.3 Hz, 2H), 8.71 (br s, 1H). 13C NMR (100
MHz, CDCl3) δ = 46.52, 46.73, 52.15, 111.42, 116.28, 119.23, 119.56, 121.67, 122.33, 126.86,
128.24, 128.47, 129.95, 136.62, 148.52, 167.17.
Acknowledgements
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10.1002/ejoc.201800385
European Journal of Organic Chemistry
This work was supported by the Russian Science Foundation (RSF), grant number 17-73-10358.
The authors acknowledge partial support in measuring of NMR from M.V. Lomonosov Moscow
State University Program of Development. The authors acknowledge Thermo Fisher Scientific Inc.,
MS Analytica (Moscow, Russia), and personally Prof. A. Makarov for providing mass spectrometry
equipment for this work.
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