Synthesis of indoles with a polyfluorinated benzene ring

Article abstract of DOI:10.1016/j.tet.2013.07.037

A two-step sequence consisting of a Sonogashira coupling of polyfluorinated 2-iodoanilines with terminal alkynes, followed by a KOH promoted cyclization of the 2-alkynylanilines thus formed, has been developed as a one-pot synthesis of 2-R-indoles (R=n-Bu

Full text of DOI:10.1016/j.tet.2013.07.037

Accepted Manuscript
Synthesis of indoles with a polyfluorinated benzene ring
Larisa V. Politanskaya, Igor P. Chuikov, Vitalij D. Shteingarts
PII:
S0040-4020(13)01130-7
10.1016/j.tet.2013.07.037
TET 24618
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 April 2013
Revised Date: 26 June 2013
Accepted Date: 9 July 2013
Please cite this article as: Politanskaya LV, Chuikov IP, Shteingarts VD, Synthesis of indoles with a
polyfluorinated benzene ring, Tetrahedron (2013), doi: 10.1016/j.tet.2013.07.037.
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ACCEPTED MANUSCRIPT
Synthesis of indoles with a polyfluorinated
Leave this area blank for abstract info.
benzene ring
Larisa V. Politanskaya, Igor P. Chuikov and Vitalij D. Shteingarts
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences,
Ac. Lavrentiev Avenue 9, 630090 Novosibirsk, Russian Federation

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of indoles with a polyfluorinated benzene ring
Larisa V. Politanskaya, Igor P. Chuikov and Vitalij D. Shteingarts
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Ac. Lavrentiev Avenue 9, 630090 Novosibirsk,
Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A two-step sequence consisting of a Sonogashira coupling of polyfluorinated 2-iodoanilines
with terminal alkynes, followed by a KOH promoted cyclization of the 2-alkynylanilines thus
formed, has been developed as a one–pot synthesis of 2-R-indoles (R = n-Bu, Ph, СН2OTHP →
СН2OH, C(CH3)2OH → H) containing a polyfluorinated benzene moiety.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
coupling reactions
cyclization of polyfluorinated ortho-alkynylanilines
polyfluorinated indoles
one-pot synthesis
1. Introduction
first of all because of difficulties in accessing
polyfluoroarylamines unsubstituted ortho to an amino group and
The indole nucleus is a structural component in a vast number
of biologically active natural and synthesized compounds and
pharmaceuticals, and so their efficient construction represents an
important challenge. Considerable attention is attracted by
fluorinated indoles because it is firmly established that fluorine
substitution can influence the biological activity of organic
secondly the difficulty of their transformation into the
corresponding polyfluoroarylhydrazines. The latter is implicitly
illustrated by the fact that 4,5,6,7-tetrafluoroindole has not been
prepared by the Fisher method to date. To synthesize this
compound and its substituted analogues, methods involving a
nucleophilic
heterocyclization
of
pentafluoroaniline14
and
molecules.1,2 There are
a number of biologically active
pentafluorophenylethylamine derivatives15,16 have been developed.
Recently the problem of the inaccessibility of 2-unsubstituted
polyfluorinated arylamines was solved by working out methods for
the selective ortho-hydrodefluorination of polyfluorinated N-
acetylarylamines17,18 and dechlorination of polyfluorochloroanilines.19
Thanks to this favorable prerequisite, modern methods of the indole
skeleton construction based on the 2-alkynylanilines
cyclizations20,21 seem more promising. Polyfluorinated 2-
alkynylanilines – the potentially universal building blocks to
assemble a diversity of polyfluorobenzo azaheterocycles – can be
easily prepared by the catalytic cross-condensation of
polyfluorinated 2-iodanilines with terminal alkynes.22
functionalized indoles with 1–4 fluorine atoms in the benzene
ring.3–5 In particular, the 4,5,6,7-tetrafluoroindole derivatives
exhibit cytotoxic activity,5 antiandrogenic, gene induction, gene
expression, antiproliferative, antibacterial activity,6 antiviral, anti
HIV effects7 and receptor binding properties.5,8 For molecular
design in this area, it is important to note that polyfluorination
affords increased fluorine nucleofugicity.9 This opens
opportunities for nucleophilic substitution in the benzene ring,10
with the possibility of traditional electrophilic modifications of the
pyrrole ring being retained.11,12 In view of the above reasons, the
development of a practical and efficient approach for the
construction of an indole skeleton with a polyfluorinated benzene
moiety is an important problem for organic synthesis.
In this paper, we describe the synthesis of indoles containing a
polyfluorinated benzene ring by a cyclization of respective 2-
alkynylanilines. In addition, we trialled the possibility of a one-
The classical Fisher indole synthesis was only sporadically
applied to obtain the indoles with a substituted pyrrole moiety,13
———
Corresponding author. Tel.: +7-383-330-9171; fax: +7-383-330-9752; e-mail: shtein@nioch.nsc.ru

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2
Tetrahedron
pot version of this reaction starting directly from
polyfluorinated 2-iodoanilines, without isolation of 2-
alkynylanilines thus formed.
Table 1. Cyclization of aniline 1aa
2. Results and discussion
2.1. Cyclization of polyfluorinated 2-alkynylanilines
The cyclization of 2-alkynylanilines is known to be promoted
by copper halides,23,24 NaAuCl4ꢀH2O,25 Pd(II) salts,26 Lewis acids.27
The suggested heterocyclization mechanism by transition metal
compounds proceeds via the π-coordination of a metal cation to
the triple bond, thus providing the electrophilic activation of its
terminal carbon atom.28 One can expect that the introduction of
fluorine atoms or a trifluoromethyl group, as electron-withdrawing
substituents, into the aniline benzene ring decreases a π-donating
function of the triple bond and makes problematic the efficiency
of this type of catalysis. Besides, the cyclization of 2-alkynyl-
NR-anilines was reported to be promoted by bases such as
EtONa (R = CO2Me),21 ButOK (R = CO2Pri),29 Bu4NF (R =
CO2Et, CO2But, CHO, Ac, SO2Me).30 Hydrogen bonding with a
base increases the nucleophilicity of the amino group and its
ability to attack the terminal carbon of the triple bond.31 Within
this mechanism, the indolization can be facilitated by electron
withdrawing substituents on the aromatic ring, enhancing the NH
acidity of the amino group and, facilitating its deprotonation.32–34
One can expect, therefore, that the fluorine atoms and CF3 group
on the benzene ring are favourable for the base catalysis in the
reaction under study.
Entry Catalyst
Solvent
Conditions
Yielda,
mol %
n. r.b
1
CuCl (0.5 equiv)
DMF
110 °C, 3 h
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
Reflux, 24 h
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
2
CuI (0.5 equiv)
DMF
n. r.
n. r.
n. r.
4
3
CuI (0.5 equiv)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
4
AgNO3 (0.5 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
KOH (5 equiv)
5
6
15
7
100
100
100
100
8
Et4NF·H2O (2 equiv)
PdCl2 (0.2 equiv)
9
10
PdCl2 (0.2 equiv)
FeCl3 (0.2 equiv)
ClCH2CH2Cl Reflux, 3 h
11
12
13
KOH (5 equiv)
MeCN
MeCN
MeCN
50 °C, 3 h
50 °C, 3 h
50 °C, 3 h
n. r.
100
n. r.
Et4NF·H2O (2 equiv)
PdCl2 (0.2 equiv)
aContent in the product mixture (NMR 19F).
b1aa was recovered.
2,3,5-Trifluoro-6-(hex-1-yn-1-yl)-4-(trifluoromethyl)aniline (1aa)
was used as the model substrate to select an appropriate catalyst
for the ring closure of the polyfluorinated 2-alkynylanilines 1
into indoles 2 (Table 1). The results of Table 1 show that Cu (I)
salts and AgNO3 (entries 1–4) had no catalytic activity and
K2CO3 (entries 5, 6) had low catalytic activity in the
heterocyclization of 2-alkynylaniline 1aa. When КОН or
Et4NF·H2O, stronger bases than K2CO3, (entries 7, 8) and PdCl2
(entries 9, 10), were used as the catalysts, the complete
transformation of the aniline into the respective indole 2aa was
observed under reflux conditions. Note also that Et4NF·H2O
showed good catalytic activity under lowered temperature (entry
12), in contrast to the absence of catalytic activity of KOH and
PdCl2 (entries 11, 13) at the same temperature.
Table 2. Cyclization of aniline1ab
Entry Catalyst
Solvent Condi-
tions
Content in the mixture, mol %
1ab 1ac 2ab 2ac
3
1
2
3
4
5
6
PdCl2
(0.2 equiv)
MeCN
MeCN
MeCN
Reflux
3 h
100
–
–
–
–
–
Et4NF·H2O
(2 equiv)
Reflux
3 h
–
100
69
–
–
–
KOH
(3 equiv)
Reflux
3 h
–
–
31
–
–
The last three catalysts, which promote the cyclization of
alkynylaniline 1aa, were used to test the possibility of the
cyclization of polyfluorinated 2-(3-hydroxyalkyne-1-yl)anilines
without protection of the hydroxy group. In this regard, the
transformations of 4-[2-amino-3,4,6-trifluoro-5-(trifluoromethyl)-
phenyl]-2-methylbut-3-yn-2-ol (1ab) in the presence of the catalysts
were studied (Table 2). PdCl2 was not effective for the aniline
1ab transformation (entry 1). Et4NF·H2O exhibited the high
catalytic activity in the transformation and allowed us to obtain
2-(2-hydroxy-2-propyl)-4,6,7-trifluoro-5-(trifluoromethyl)indole
(2ab) as the only product (entry 2). Aniline 1ab in the presence of
КОН in MeCN medium gave, besides indole 2ab, the 4,6,7-
trifluoro-5-(trifluoromethyl)indole (2ac) unsubstituted on the pyrrole
ring (entry 2 of Table 2). The precursor of 2ac is, most likely, 2-
ethynyl-4-(trifluoromethyl)-trifluoroaniline (1ac) derived from the
starting alkynylaniline 1ab via the retro-Favorsky reaction. The
formation of polyfluorinated 2-ethynylanilines was observed in
the reaction of the analogues of aniline 1ab in boiling benzene in
the presence of KOH.22 However, the transformation of 1ab into
1ac did not proceed under similar conditions (entry 4), and a higher
KOH
(5 equiv)
Benzene Reflux
3 h
100
–
–
–
KOH
(5 equiv)
Toluene Reflux
0.5 h
90
–
–
–
10
100
KOH
DMF
100 °C
–
–
–
(5 equiv)
3 h
temperature (boiling toluene) was needed to obtain the latter
(along with a small amount of the reported17 2,3,5-trifluoro-4-
(trifluoromethyl)aniline (3)) (entry 5). Apparently, aniline 3
formation is a consequence of 1ac deprotonation, followed by
fragmentation of the arising acetylenide (1ac)–H with the carbon
removal. The latter is believed to be facilitated by the relatively high
stability of 2-amino-3,5,6-trifluoro-4-trifluoromethylphenyl anion
((3)–H) thus formed (Scheme 1).35

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3
addition of 3 equivalents of КОН under reflux conditions for 3
h, resulted in a one–pot synthesis of indoles 2(a–c)(a–e) (Table 4).
Table 4. Оne–pot synthesis of indoles 2(а–c)(a–e)
Duration
Scheme 1
Support for this assumption comes from the following result
Entry Substrate
Alkyne
Product
Yield,
%
of the
second
step, h
on the solvent influence on the reaction. The use of a bipolar
aprotic solvent (DMF), which effectively solvates anions, instead
of toluene led to the predominant formation of aniline 3 (entry 6
of Table 2). It is noteworthy that indole 2аc (entry 3 of Table 2)
and 2-etynylaniline 1ac (entry 5) were formed in MeCN and
toluene solvents, correspondingly, in the presence of KOH as the
catalyst. This suggested that the synthesis of the indoles without
substituent on the pyrrole ring can be performed.
NH2
F
F
I
1
2
3
2
68
52
F
CF3
4a
4a
Based on the above data (entries 2 and 3 of Table 2),
Et4NF·H2O and KOH were found to be the most efficient
catalysts for the 1ab indolization in MeCN solvent.
2.2. Оne–pot synthesis of polyfluorinated indoles
45
73
The above results on the study of the indolization of anilines
1aa and 1ab prompted us to attempt the one–pot synthesis of
indoles via the sequence of catalytic cross-condensation of 2-
iodo-3,5,6-trifluoro-4-(trifluoromethyl)aniline (4а) with hex-1-
yne (5а) and cyclization of aniline 1аа thus formed without its
isolation. We found out that the replacement of NEt3, which was
previously22 used as the solvent, with MeCN significantly
decreases the duration and lowers the temperature of the
Sonogashira reaction of polyfluorinated 2-iodoanilines. Besides,
Et4NF·H2O or PdCl2 were not effective in the one–pot synthesis
of indole 2aa, while КОН gave fine result (Table 3). Therefore,
KOH was used as the heterocyclization catalyst at the second
stage of the synthesis of a series of polyfluorinated indoles.
F
F3C
F
3
3
3
4
4a
4a
N
H
F
2ad
76
Table 3. Оne–pot synthesis of indole 2аа
3
2
85
17
5
6
5a
5b
Entry
Catalyst
Conditions
Content in the
mixture, mol %
4b
1aa
100
100
–
2aa
–
1
2
3
4
5
PdCl2 (0.2 equiv)
Et4NF·H2O (2 equiv)
KOH (3 equiv)
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
50 °C, 3 h
Reflux, 1 h
–
74
90
100
–
KOH (3 equiv)
100
40
KOH (3 equiv)
60
3
7
4b
5d
The interaction of anilines 4(а–c) with alkynes 5a,b,d,e in the
presence of Pd(PPh3)2Cl2, CuI and NEt3 in MeCN medium at 50 ºC
for 1 h, followed by the cyclization of 2-alkynylanilines 1 upon

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4
Tetrahedron
Presuming the conventional mechanism of the retro-Favorsky
reaction (Scheme 2), one can expect that the stability of the
incipient acetylenide anions should decrease at the reduction of
total electronegativity of substituents in benzene ring in the order
1ab > 1bb > 1cb. Therefore, the retro-Favorsky reaction has to
slow down in the order 1ac > 1bc > 1cc. However, contrary to this
expectation, the yields of indoles 2(а–c)c increased in the series
2ac < 2bc < 2cc, and the yields of indoles 2(а–c)b decreased in the
3
87
8
4b
5e
3
4
72
9
5a
5b
8
10
4c
77
85
Scheme 2
series 2ab > 2bb > 2cb (entries 2, 6 and 10 of Table 4). This
suggests that, at the reduction of total electronegativity of
substituents in benzene ring in the above order, the cyclization of
the intermediate 2-alkynylanilines 1(a–c)b into indoles 2(a-c)b
slows down more progressively than the retro-Favorsky reaction
does. As a result, a longer time was necessary to complete the
transformation of 1cb into the respective indoles 2cb and 2cc
(entry 10 of Table 4). Based on the literary data,16 it can be
assumed that, in the course of the 2-alkynylaniline cyclization,
two intermediate complexes are formed (structures A and B),
depending on the catalyst used. In the complex A, the triple bond,
as an electrophilic function, is activated by its π-coordination
with a metal cation.28 In the complex B, the amino group, as a
nucleophilic function, is activated by hydrogen bonding with a
base.31 Within these notions, the retardation of cyclization at the
reduction of total electron withdrawing effect of substituents in
benzene ring is obviously caused by reducing both the triple bond
electrophilicity and the N–H acidity.
3
3
11
12
4c
4c
5e
5d
75
Attempts to increase the yields of indoles 2(b–c)b by using
Et4NF·H2O as the catalyst in order to cyclize alkynes 1(b–c)b in
MeCN medium, in analogy to the synthesis of 2аb (entry 2 of
Table 2), failed. In this case, as well as in the case of КОН,
indoles 2(b–c)c were the main products, indoles 2bb and 2cb
having been isolated in 30% and 16% yields based on iodanilines
4b and 4с, respectively. Besides, we attempted to selectively
prepare indole 2аc by cyclization of aniline 1аc, obtained in turn
from alkynylaniline 1аb via the retro-Favorsky reaction in the
KOH/toluene system (entry 2 of Table 5). However, probably
because of a volatility of aniline 1ac, causing its loss upon
evaporation of toluene, the yield of the target product was low
(14% based on aniline 4а), even compared with the nonselective
one–pot synthesis. Thus, it is more effective to obtain indole 2аc
as a side-product of the alkynylaniline 2аb cyclization in
comparison with the synthesis of indole 2аc via a sequence of
three separate reactions.
Figure
2.3. Hydrolysis of the СН2ОТНР group located in the 2-position
of indoles 2(а–с)e
For a molecular design of indoles containing a polyfluorinated
benzene moiety, it is interesting to introduce a substituent, which
easily undergoes further transformations, into pyrrole ring. In this
connection, the indoles 2(а–с)e containing the СН2ОТНР group in
the 2-position were hydrolyzed by HCl in MeOH (by analogy
with36) to give corresponding 2-hydroxymethylindoles 2(а–с)f
(Table 5).
Examining the above data, one can see that the ratio of the
formed alcohols 2(a–c)b and on-pyrrole-unsubstituted indoles 2(a–
c)c changes with the benzene moiety substitution. The question
arises, whether this change is associated with a degree of the putative
2(a–c)b transformation to 2(a–c)c. Testing the possibility of this
transformation to occur, no indole 2bc was observed to form by
heating alcohol 2bb in MeCN for 3 h under reflux conditions in
the presence of 3-fold amount of KOH. This suggests indoles
2(a–c)c to be derived through the partial retro-Favorsky cleavage
of the intermediate anilines 1(a–c)b, followed by cyclization of 2-
ethynylanilines 1(a–c)c thus formed (Scheme 2).
2.4. Spectral data
The structures of all herein prepared polyfluorinated indoles
were corroborated by their 19F, 1H and 13C NMR (Tables 6, 7), high
resolution mass spectrometry, and IR-spectroscopy data.

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5
Signals in the 19F NMR spectra of indoles 2(a–c)(a–f) were
assigned on the basis of spin coupling constants, which are
typical for polyfluorinated benzenes.37 The 1H and 19F NMR
spectra of indoles 2bc and 2bd correspond to those reported
previously.38,39 Besides, the 19F NMR characteristics of indoles
herein synthesized were in good compliance with those of
polyfluorinated on the benzene ring benzothiophens40 and
dibenzofurans.41 At that, the fluorine resonances showed a high-
field shift from benzothiophens through dibenzofurans to indoles,
as expected relying on the increase of the heteroatom π-donation
along this series.
pot version of this synthesis have been realized as a sequence of
cross-coupling of polyfluorinated 2-iodoanilines with terminal
alkynes followed by in situ cyclization of polyfluorinated 2-
alkynylanilines thus formed without their isolation. This allowed
us to obtain the target indoles in good yields. The possibility has
been shown to obtain the indoles of this type with a non-
substituted pyrrole moiety in reasonable yields as by-products of
the synthesis of their 2-(CMe2OH)-substituted derivatives.
4. Experimental section
4.1. General methods
Table 5. Synthesis of indoles 2(а–c)f
All the cross-coupling reactions were carried out in oven-dried
glassware under an argon atmosphere. All solvents were purified
using standard procedures and dried before use. Et3N, MeCN,
ClCH2CH2Cl and DMF were distilled and kept over CaH2 before
to use. Toluene was distilled and used without drying. 2-Iodo-
3,5,6-trifluoro-4-(trifluoromethyl)aniline (4a).22 2-Iodo-3,4,5,6-
tetrafluoroaniline (4b),22 2-iodo-3,4,6-trifluoroaniline (4c),22 2-(prop-2-
46
in-1-yloxy)oxane (5e),45 Pd(PPh3)2Cl2 were prepared accoding to
literature procedures. CuCl was washed with 0.1% aqueous
sulfuric acid, then Н2О, acetone, diethyl ether and air dried.
Entry
1
Substrate
Product
Yield, %
90
KOH (≥90 %, flakes) and Et4NF·H2O (97%) were kept over
P2O5. Other starting materials were obtained from commercial
supplies and used without purification.
2ae
The TLC product isolation was carried out on Sorbfil plates
(UV 254). Visualization of the developed chromatograms was
performed by UV light. Compounds 2(а–c)c were purified by
silica gel (100–300 mesh) column chromatography. To obtain
analytically pure samples, the synthesized indoles were sublimed
at 100–150 °C under vacuum (~15 Torr).
2
3
2be
2ce
96
96
NMR spectra were recorded on a Bruker Avance-300 (300.13
1
MHz for H and 282.37 MHz for 19F) and Avance-400 (400.13
MHz for 1H, 376.44 MHz for 19F and 100.62 MHz for 13C)
spectrometers. Deuterochloroform (CDCl3) was used as solvent,
with residual CHCl3 (δH = 7.26 ppm) or CDCl3 (δC = 77.0 ppm)
being employed as internal standards. 13C NMR spectra were
registered with C–H spin decoupling. Masses of molecular ions
were determined by HRMS on a DFS Thermo scientific
instrument (EI, 70 eV). Melting points were recorded on a
Melter-Toledo FP81 Thermosystem apparatus. The IR spectra
were recorded on a Bruker Vector 22 spectrometer (KBr or thin
layer). Elemental analyses were performed on а Euro EA-3000
CHNS analyzer, or on Carlo Erba 1106 CHN elemental analyzer.
The 13С NMR signals were assigned taking into account that
1
2
the absolute JC,F values change in a sequence JC,F >> JC,F
>
4
42
3JC,F > JC,F
.
The assignment of carbon resonances of the C–F
1
fragments was confirmed by comparing the respective JC,F
values with those observed in satellite signals of the
corresponding fluorine resonances in the 19F NMR spectra. The
С7a and С3a signals were distinguished by the consecutive C7a–F7
and C3a–F4 spin decoupling. Indicatively, the relative location of
the 13C resonances of indoles 2b(a–f) is analogous to that
reported for the parent indole: С7a > С3a, С4 > С7, С2 > С3.43 As
one can see from Table 7, the 2-substituent variation does not
appreciably influence carbon chemical shifts of the fluorinated
benzene ring.
4.2. General procedure for synthesis 2-alkynylanilines 1аa, 1аb,
1bb and 1cb
To a stirred solution of aniline 4а (341 mg, 1 mmol) [or 4b
(291 mg, 1 mmol), or 4c (273 mg, 1 mmol)], alkyne 5a (246 mg,
3 mmol) [or 5b (252 mg, 3 mmol)] in dry MeCN (7 mL) were
added Pd(PPh3)2Cl2 (28 mg, 0.04 mmol), CuI (17 mg, 0.09
mmol) and Et3N (1.5 mL) at room temperature under an argon
atmosphere. The mixture was heated at 50 °C for 1 h with stirring.
The reaction mixture was allowed to cool down to room
temperature, and CH2Cl2 (10 mL) was added. The mixture was
poured into H2O (20 mL) and extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were washed with H2O (10 mL)
and dried (MgSO4). After evaporation of the solvent in vacuo, the
crude product was obtained (the 1H and 19F NMR spectra closely
agree with the literature data22) and used further without
purification.
Comparing the 13С NMR spectra of 2bc and the parent indole
exhibits the introduction of four fluorine atoms into the benzene
moiety to cause about a 13–14 ppm high-field shift of the С3а and
С7а signals. The similar was reported earlier for 3-methyl-4,5,6,7-
tetrafluoro-1H-indazole.44
3. Conclusion
Thus, we have developed the synthesis of a wide range of the
indoles containing a polyfluorinated benzene ring. This makes
this class of previously reported (in a small part) but difficultly
attainable or unknown (mainly) compounds quite accessible for
regular study of their chemistry and molecular design of new
potentially biologically active compounds on this ground. A one–
4.3. 2-Еthynyl-3,5,6-trifluoro-4-(trifluoromethyl)aniline (1ac)

ACCEPTED MANUSCRIPT
6
Tetrahedron
A solution of crude 1ab in toluene (20 mL) was heated to 70
poured into H2O (20 mL), neutralized with 5% aqueous AcОН up
to рН = 7 and extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were washed with H2O (10 mL) and dried (MgSO4).
°C, KОН (168 mg, 3 mmol) was added, and the mixture was
heated under reflux with stirring for 45 min. The mixture was
cooled to room temperature, diluted with CH2Cl2 (10 mL),
Table 6. 1H and 19F NMR chemical shifts (ppm) and coupling constants (Hz) for indoles 2(а–c)(a–f) (CDCl3)
Compound NH
H3
F4
X
Y
F7
R
0.95 (3H, t, CH3)
2aa
8.34
6.36 (1H, ddt)
–126.2 (1F, qddd)
JF4,CF3 = 24.4
JF4,F7 = 17.9
JF4,F6 = 5.4
–56.0 (3F, dd)
JCF3, F4 = 24.4
JCF3,F6 = 20.7
–151.4 (1F, qdd) –164.7 (1F, ddd)
JH,H = 7.3; 1.41 (2H,
(1H, bs) JH3,F4 = 2.4
JH3,F7 = 3.2
JF7,CF3 = 20.7
JF6,F7 = 19.8
JF6,F4 = 5.4
JF7,F4 = 17.9
JF7,F6 = 19.8
JF7,H3 = 3.2
qt, CH2CH3), JCH2 CH3
7.3, JCH2 CH2 ≈ 7.5; 1.70
(2H, tt, CH2CH2CH3),
JCH2 CH2 ≈ 7.5;
,
=
,
JH3,CH2 ≈ 1
JF4,H3 = 2.4
,
2.75 (2H, t, CH2Car)
JH,H ≈ 7.5
2ab
2ac
2ad
2ae
8.97
6.42 (1H, dd)
–125.6 (1F, qddd)
JF4,CF3 = 24.5,
JF4,F7 = 18.1,
–56.0 (3F, dd)
JCF3,F4 = 24.5
JCF3,F6 = 20.6
–150.0 (1F, qdd) –164.1 (1F, ddd)
1.68 (s, 6H, CH3);
1.95 (1H, s, OH)
(1H, bs) JH3,F4 = 2.3,
JH3,F7 = 3.1
JF7,CF3 = 20.6
JF6,F7 = 19.8
JF6,F4 = 5.0
JF7,F4 = 18.1
JF7,F6 = 19.8
JF7,H3 = 3.1
JF4,F6 = 5.0,
JF4,H3 = 2.3
8.81
6.71 (1H, ddd)
–124.5 (1F, qddd)
JF4,CF3 = 24.7
JF4,F7 = 18.3
JF4,F6 = 4.8
–56.1 (3F, dd)
JCF3,F4 = 24.7
JCF3,F6 = 20.5
–149.8 (1F, qdd) –164.0 (1F, ddd)
7.27 (1H, dd, H2)
JH2,H3 = 3.3
(1H, bs) JH3,F4 = 2.3
JH3,F7 = 3.2
JF6,CF3 = 20.5
JF6,F7 = 19.5
JF6,F4 = 4.8
JF7,F4 = 18.3
JF7,F6 = 19.5
JF7,H3 = 3.2
JH2,H1 = 2.3
JH3,H2 = 3.3
JF4,H3 = 2.3
8.75
6.91 (1H, dd)
–124.9 (1F, qddd)
JF4,CF3 = 24.6
JF4,F7 = 18.3
JF4,F6 = 5.0
–56.1 (3F, dd)
JCF3, F4 = 24.6
JCF3,F6 = 20.6
–149.0 (1F, qdd) –163.8 (1F, ddd)
7.37–7.52 (3H, m, Ph);
7.62–7.67 (2H, m, Ph)
(1H, bs) JH3,F4 = 2.3
JH3,F7 = 3.0
JF6,CF3 = 20.6
JF6,F7 ≈ 20
JF6,F4 = 5.0
JF7,F4 = 18.3
JF7,F6 ≈ 20
JF7,H3 = 3.0
JF4,H3 = 2.3
9.30
6.53 (1H, ddm) –122.0 (1F, qddd)
–53.0 (3F, dd)
JCF3,F4 = 24.6
JCF3,F6 = 20.5
–146.8 (1F, qdd) –161.2 (1F, ddd)
1.50–1.90 (6Н, m,
СН2СН2СН2); 3.55–
3.63 (1H, m, ОСН2);
3.94–4.01 (1H, m,
ОСН2); 4.66 – 4.69
(1H, m, CH); 4.80 (2H,
s, CH2Car)
(1H, bs) JH3,F4, = 2.4
JH3,F7 = 3.2
JF4,CF3 = 24.6
JF4,F7 = 18.2
JF4,F6 = 5.0
JF4,H3 = 2.4
JF6,CF3 = 20.5
JF6,F7 = 19.5
JF6,F4 = 5.0
JF7,F4 = 18.2
JF7,F6 ≈ 19.5
JF7,H3 = 3.2
2af
9.30
6.51 (1H, ddm) –125.0 (1F, qddd)
–56.1 (3F, dd)
JCF3,F4 = 24.6
JCF3,F6 = 20.7
–149.4 (1F, qdd) –164.0 (1F, ddd)
2.44 (1H, bs, OH);
4.84 (2H, s, CH2Car)
(1H, bs) JH3,F4 = 2.4
JH3,F7 = 3.3
JF4,CF3 = 24.6
JF4,F7 = 18.2
JF4,F6 = 5.0
JF4,H3 = 2.4
JF6,CF3 = 20.7
JF6,F7 = 19.5
JF6,F4 = 5.0
JF7,F4 = 18.2
JF7,F6 = 19.5
JF7,H3 = 3.3
2ba
8.25
6.35 (1H, dd)
–152.4 (1F, ddd)
JF4,F5 = 20.4
JF4,F7 = 16.1
JF4,F6 = 2.2
–171.7 (1F, ddd)
JF5,F4 = 20.4
JF5,F6 = 19.6
JF5,F7 = 4.1
–169.3 (1F, ddd)
JF6,F5 = 19.6
JF6,F7 = 19.9
JF6,F4 = 2.2
–163.8 (1F, dddd) 0.99 (3H, t, CH3)
(1H, bs) JH3,F4 = 2.4
JH3,F7 = 3.3
JF7,F6 = 19.9
JF7,F4 = 16.1
JF7,F5 = 4.1
JF7,H3 = 3.3
JH,H = 7.3; 1.45 (2H, qt,
CH2CH3) JCH2 CH3 = 7.3,
JCH2 CH2 ≈ 7.5; 1.74
(2H, tt, CH2CH2CH3)
JCH2 CH2 ≈ 7.5; 2.77 (2H,
,
,
JF4,H3 = 2.4
,
t, CH2Car) JH,H ≈ 7.5
2bb
8.76
6.37 (1H, dd)
–151.9 (1F, ddd)
JF4,F5 = 20.3
JF4,F7 = 16.3
JF4,H3 = 2.3
JF4,F6 = 2.0
–170.9 (1F, ddd)
JF5,F4 = 20.3
JF5,F6 = 19.7
JF5,F7 = 4.0
–167.7 (1F, ddd)
JF6,F7, JF6,F5 =
19.7
–163.2 (1F, ddm)
JF7,F6 = 19.7
JF7,F4 = 16.3
JF7,F5 = 4.0
1.67 (6H, s, CH3);
1.96 (1H, s, OH)
(1H, bs) JH3,F4 = 2.3
JH3,F7 = 3.1
JF6,F4 = 2.0
JF7,H3 = 3.1

ACCEPTED MANUSCRIPT
7
2bc
2bd
2be
8.14
6.07 (1H,
–148.7 (1F, dddd)
JF4,F5 = 20.2
JF4,F7 = 16.1
JF4,F6 ≈ 2
–168.0 (1F, ddd)
JF5,F4 = 20.2
JF5,F6 = 19.7
JF5,F7 = 4.1
–164.4 (1F, ddd)
JF6,F7, JF6,F5 =
19.7
–160.7 (1F, dddd) 6.41 (1H, dd, H2)
(1H, bs) dddd), JH3,F4 =
2.2, JH3,F7 = 3.1
JH3,H2 = 3.0
JF7,F6 = 19.7
JF7,F4 = 16.1
JF7,F5 = 4.1
JF7,H3 = 3.1
JH2,H3 = 3.0
JH2,H1 = 2.5
JF6,F4 ≈ 2
JH3,H1 = 3.0
JF4,H3 = 2.2
8.51
6.87 (1H, dd)
–151.3 (1F, dddd)
JF4,F5 = 20.1
JF4,F7 = 16.4
JF4,F6 = 1.8
–170.1 (1F, ddd)
JF5,F4 = 20.1
JF5,F6 = 19.8
JF5,F7 = 3.7
–163.6 (1F, ddd)
JF6,F5 = 19.8
JF6,F7 = 19.6
JF6,F4 = 1.8
–162.9 (1F, dddd) 7.31–7.41 (1H, m, Ph);
(1H, bs) JH3,F4 = 2.3
JH3,F7 = 3.0
JF7,F6 = 19.6
JF7,F4 = 16.4
JF7,F5 = 3.7
JF7,H3 = 3.0
7.43–7.53 (2H, m, Ph);
7.61–7.66 (2H, m, Ph)
JF4,H3 = 2.3
8.96
6.49 (1H, dd)
–151.4 (1F, dddd)
JF4,F5 = 20.2
JF4,F7 = 16.3
JF4,F6 = 1.8
–171.0 (1F, ddd)
JF5,F4 = 20.2
JF5,F6 = 19.7
JF5,F7 = 4.0
–167.3 (1F, ddd)
JF6,F5 = 19.7
JF6,F7 = 19.7
JF6,F4 = 1.8
–163.2 (1F, dddd) 1.54–1.84 (6Н, m,
(1H, bs) JH3,F4 = 2.2
JH3,F7 = 3.4
JF7,F6 = 19.7
JF7,F4 = 16.3
JF7,F5 = 4.0
JF7,H3 = 3.4
СН2СН2СН2); 3.54–
3.62, (1H, m, ОСН2);
3.92–3.99 (1H, m,
ОСН2); 4.67–4.69 (1H,
m, CH); 4.76 and 4.80
(2H, AB-system,
JF4,H3 = 2.2
CH2Car) JAB = 13.3
2bf
2ca
8.66
6.47 (1H, ddm) –151.3 (1F, dddd)
–170.5 (1F, ddd)
JF5,F4 = 20.3
JF5,F6 = 19.8
JF5,F7 = 3.8
–167.0 (1F, ddd)
JF6,F5 = 19.8
JF6,F7 = 19.6
JF6,F4 = 1.8
–163.0 (1F, dddd) 2.26 (1H, bs, OH);
(1H, bs) JH3,F4 = 2.0
JH3,F7 = 3.3
JF4,F5 = 20.3
JF4,F7 = 16.4
JF4,F6 = 1.8
JF4,H3 = 2.0
JF7,F6 = 19.6
JF7,F4 = 16.4
JF7,F5 = 3.8
JF7,H3 = 3.3
4.82 (2H, s, CH2Car)
8.25
6.34 (1H, dd)
–155.5 (1F, dddd)
JF4,F5 = 20.6
JF4,F7 = 19.4
JF4,H6 = 5.6
–150.8 (1F, ddd)
JF5,F4 = 20.6
JF5,H6 = 10.8
JF5,F7 = 1.4
6.67 (1H, ddd)
JH6,F5 = 10.8
JH6,F7 = 10.1
JH6,F4 = 5.6
–139.2 (1F, dddd) 0.95 (3H, t, CH3)
(1H, bs) JH3,F4 = 2.2
JH3,F7 = 3.3
JF7,F4 = 19.4
JF7,H6 = 10.1
JF7,H3 = 3.3
JF7,F5 = 1.4
JH,H = 7.4; 1.40 (2H, qt,
CH2CH3) JCH2 CH3 = 7.4,
JCH2 CH2 ≈ 7.5; 1.69
(2H, tt, CH2CH2CH3)
JCH2 CH2 ≈ 7.5; 2.73
(2H, t, CH2Car)
JCH2 ≈ 7.5
,
,
JF4,H3 = 2.2
,
,
CH2
2cb
2сc
2cd
2ce
8.73
6.40 (1H, dd)
–152.2 (1F, dddd)
JF4,F5 = 20.4
JF4,F7 = 19.7
JF4,H6 = 5.7
–147.3 (1F, ddd) 6.73 (1H, ddd)
–135.8 (1F, dddd) 1.67 (6H, s, CH3);
(1H, bs) JH3,F4 = 2.3
JH3,F7 = 3.2
JF5,F4 = 20.4
JF5,H6 = 10.8
JF5,F7 = 1.3
JH6,F5 = 10.8
JH6,F7 = 10.0
JH6,F4 = 5.7
JF7,F4 = 19.7
JF7,H6 = 10.0
JF7,H3 = 3.2
JF7,F5 = 1.3
2.05 (1H, s, OH)
JF4,H3 = 2.3
8.37
6.67 (1H, ddd)
–154.0 (1F, dddd)
JF4,F5 = 20.3
JF4,F7 = 19.9
JF4,H6 = 5.7
–149.8 (1F, ddd)
JF5,F4 = 20.3
JF5,H6 = 10.7
JF5,F7 = 1.3
6.79 (1H, ddd)
JH6,F5 = 10.7
JH6,F7 = 10.0
JH6,F4 = 5.7
–138.1 (1F, dddd) 7.23 (1H, dd, H2)
(1H, bs) JH3,F4 = 2.2
JH3,F7 = 3.2
JF7,F4 = 19.9
JF7,H6 = 10.0
JF7,H3 = 3.2
JF7,F5 = 1.3
JH2,H3 = 3.2
JH2,H1 = 2.3
JH3,H2 = 3.2
JF4,H3 = 2.2
8.47
6.91 (1H, dd)
–154.5 (1F, dddd)
JF4,F5 = 20.3
JF4,F7 = 19.8
JF4,H6 = 5.7
–149.4 (1F, ddd)
JF5,F4 = 20.3
JF5,H6 = 10.7
JF5,F7 = 1.2
6.78 (1H, ddd)
JH6,F5 = 10.7
JH6,F7 = 10.0
JH6,F4 = 5.7
–138.5 (1F, dddd) 7.34–7.41 (1H, m, Ph);
(1H, bs) JH3,F4 = 2.2
JH3,F7 = 3.1
JF7,F4 = 19.8
JF7,H6 = 10.0
JF7,H3 = 3.1
JF7,F5 = 1.2
7.43–7.50 (2H, m, Ph);
7.63–7.68 (2H, m, Ph)
JF4,H3 = 2.2
8.86
6.51 (1H, dd)
–154.6 (1F, dddd)
JF4,F5 = 20.4
JF4,F7 = 19.7
JF4,H6 = 5.7
–150.3 (1F, ddd)
JF5,F4 = 20.4
JF5,H6 = 10.8
JF5,F7 = 1.5
6.75 (1H, ddd)
JH6,F5 = 10.8
JH6,F7 = 10.1
JH6,F4 = 5.7
–138.7 (1F, ddd)
JF7,F4 = 19.7
JF7,H6 = 10.1
JF7,H3 = 3.2
1.30–1.90 (6Н, m,
СН2СН2СН2); 3.51–
3.61, (1H, m, ОСН2);
3.91–4.02 (1H, m,
ОСН2); 4.67–4.70 (1H,
m, CH); 4.76 and 4.82
(2H, AB-system,
(1H, bs) JH3,F4 = 2.3
JH3,F7 = 3.2
JF4,H3 = 2.3
JF7,F5 = 1.5
CH2Car) JAB = 13.4
2сf
8.90
6.48 (1H, dd)
–154.2 (1F, dddd)
JF4,F5 = 20.4
JF4,F7 = 19.8
JF4,H6 = 5.7
–149.7 (1F, ddd)
JF5,F4 = 20.4
JF5,H6 = 10.7
JF5,F7 = 1.4
6.75 (1H, ddd)
JH6,F5 = 10.7
JH6,F7 = 10.0
JH6,F4 = 5.7
–138.7 (1F, dddd) 1.92 (1H, bs, OH);
(1H, bs) JH3,F4 = 2.1
JH3,F7 = 3.1
JF7,F4 = 19.8
JF7,H6 = 10.0
JF7,H3 = 3.1
JF7,F5 = 1.4
4.84 (2H, s, CH2Car)
JF4,H3 = 2.1

ACCEPTED MANUSCRIPT
8
Tetrahedron
Table 7. 13C NMR chemical shifts (ppm) and coupling constants (Hz) for indoles 2(а–c)(a–f) (CDCl3)
Compound
C2
C3
C4
C5
C6
C7
C3a
C7a
R, CF3
2aa
142.8 97.4
147.8
99.4
142.4
134.4
116.3
127.3
13.9 (CH3),
JC4,F4 = 257.0 JC5,CF3 = 33.3
JC6,F6 = 248.4 JC7,F7 = 242.7 JC3a,F4 = 24.1 JC7a,F7 = 14.6 22.5 (CH2),
JC4,F6 = 5.7
JC5,F4, JC5,F6
JC6,F7 = 13.3
JC6,F4 = 5.5
JC6,CF3 = 1.8
JC7,F6 = 16.4
JC7,F4 = 4.2
3JC9,F7 = 4.2
27.8 (CH2),
31.1 (CH2),
122.8 (CF3)
1JCF3,F = 272.9
= 13.9
2ab
148.4 95.0
148.6
99.5
142.7
134.7
116.1
127.0
31.1 (CH3),
JC4,F4 = 257.1 JC5,CF3 = 33.7
JC5,F4, JC5,F6
JC6,F6 = 249.0 JC7,F7 = 243.5 JC3a,F4 = 24.1 JC7a,F7 = 14.0 69.9
JC6,F7 = 13.0
JC7,F6 = 16.5
JC7,F4 = 4.5
(C(CH3)2OH),
122.7 (CF3)
= 14.3
1JCF3,F = 273.6
2ac
2ad
126.5 100.9
140.5 97.2
148.7
100.0
142.9
134.9
115.7
127.5
122.4 (CF3)
JC4,F4 = 258.9 JC5,CF3 = 33.2
JC6,F6 = 249.6 JC7,F7 = 243.8 JC3a,F4 = 24.3 JC7a,F7 = 13.8 1JCF3,F = 273.0
JC5,F4, JC5,F6
≈ 14
JC6,F7 = 13.2
JC6,F4 = 5.3
JC7,F6 = 16.5
JC7,F4 = 4.5
148.4
100.2
142.9
134.5
116.7
127.8
125.5 (Ph),
JC4,F4 = 258.5 JC5,CF3 = 33.4
JC6,F6 = 250.0 JC7,F7 = 243.6 JC3a,F4 = 24.1 JC7a,F7 = 13.9 129.2 (Ph),
JC5,F4, JC5,F6
≈ 14
JC6,F7 = 13.0
JC6,F4 ≈ 5
JC7,F6 = 16.5
JC7,F4 = 4.3
129.4 (Ph),
130.3 (Ph),
122.4 (CF3)
1JCF3,F = 273.0
2ae
138.5 99.0
148.4
99.8
142.8
134.7
115.8
127.9
30.8, 25.3,
JC4,F4 = 258.0 JC5,CF3 =33.5
JC6,F6 = 248.7 JC7,F7 = 243.7 JC3a,F4 = 23.8 JC7a,F7 = 14.2 20.2
JC6,F7 = 13.1
JC6,F4 = 5.2
JC7,F6 = 16.4
JC7,F4 = 4.3
(СН2СН2СН2)
64.0, 63.1
(ОСН2), 100.3
(ОСНO),
122.6 (CF3)
1JCF3,F = 272.7
2af
140.3 98.0
142.4 96.6
148.5
99.9
142.9
134.7
115.8
127.8
58.2 (CH2OH),
JC4,F4 = 258.8 JC5,CF3 = 33.5
JC5,F4, JC5,F6
JC6,F6 = 250.0 JC7,F7 = 243.7 JC3a,F4 = 23.9 JC7a,F7 = 14.3 122.6 (CF3)
JC6,F7 = 13.0
JC7,F6 = 16.5
JC7,F4 = 4.6
1JCF3,F = 273.0
= 14.5
2ba
139.1
135.1
136.2
134.1
114.9
120.4
13.9 (CH3),
JC4,F4 = 244.9 JC5,F5 = 240.0 JC6,F6 = 241.3 JC7,F7 = 243.0 JC3a,F4 = 20.2 JC7a,F7 = 11.5 22.5 (CH2),
JC4,F5 = 11.6
JC4,F6, JC4,F7
= 3.7, 3.1
JC5,F4, JC5,F6
= 15.6, 14.5
JC5,F7 = 2.1
JC6,F5, JC6,F7
= 15.1, 13.7
JC6,F4 = 3
JC7,F6 = 13.8
JC7,F5 = 4.4
JC7,F4 = 2.6
27.9 (CH2),
31.2 (CH2)
2bb
2bc
2bd
148.0 94.3
126.0 100.3
140.2 96.8
139.6
135.2
136.7
134.4
114.7
120.2
31.1 (CH3),
JC4,F4 = 245.7 JC5,F5 = 241.0 JC6,F6 ≈ 243
JC7,F7 = 244.0 JC3a,F4 = 20.2 JC7a,F7 = 11.8 69.9
JC4,F5 = 11.7
JC5,F4, JC5,F6
≈ 15
JC6,F5, JC6,F7
≈ 14.5
JC7,F6 ≈ 11.5
(C(CH3)2OH)
139.8
135.3
137.0
134.5
114.3
120.8
JC4,F4 = 246.5 JC5,F5 = 241.2 JC6,F6 = 243.2 JC7,F7 = 244.1 JC3a,F4 = 20.6 JC7a,F7 = 12.0
JC4,F5 = 11.5
JC5,F4, JC5,F6
JC6,F5, JC6,F7
JC7,F6 ≈ 14
= 14.8
= 14.3
139.8
135.6
137.1
134.4
115.5
121.4
125.6 (Ph),
129.0 (Ph),
129.5 (Ph),
JC4,F4 = 246.8 JC5,F5 = 242.0 JC6,F6 = 243.5 JC7,F7 = 244.0 JC3a,F4 = 20.4 JC7a,F7 ≈ 11
JC4,F5 = 11.6 JC5,F4, JC5,F6 JC6,F5, JC6,F7 JC7,F6 ≈ 14

ACCEPTED MANUSCRIPT
9
JC4,F6, JC4,F7
≈ 3
≈ 15
= 14.0, 15.0
JC7,F5 = 4.4
JC7,F4 = 2.4
130.9 (Ph)
20.2 (CH2),
JC6,F4 = 3
2be
2bf
137.9 98.3
139.6
135.1
136.8
134.3
114.4
121.1
JC4,F4 = 246.0 JC5,F5 = 240.7 JC6,F6 = 242.7 JC7,F7 = 244.5 JC3a,F4 = 20.2 JC7a,F7 = 11.3 25.4 (CH2),
JC4,F5 = 11.6
JC4,F6, JC4,F7
≈ 3.5
JC5,F4, JC5,F6
≈ 15
JC6,F5, JC6,F7
≈ 14.5
JC7,F6 = 13.7
30.8 (CH2),
63.1 (OCH2),
63.8 (OCH2),
100.0 (OCHO)
139.9 97.3
139.6
135.3
136.9
134.4
114.4
121.5
58.3 (CH2OH)
JC4,F4 = 246.2 JC5,F5 = 241.3 JC6,F6 = 242.7 JC7,F7 = 244.5 JC3a,F4 = 20.2 JC7a,F7 = 11.3
JC4,F5 = 11.6
JC4,F6, JC4,F7
≈ 3.5
JC5,F4, JC5,F6
≈ 15
JC6,F5, JC6,F7
≈ 14.5
JC7,F6 = 14.0
2ca
2cb
2cd
2ce
142.8 97.0
148.3 94.7
140.4 97.2
138.1 98.6
139.0
142.8
96.7
143.4
120.9
121.6
13.9 (CH3),
JC4,F4 = 242.0 JC5,F5 = 236.2 JC6,F5, JC6,F7
JC7,F7 = 241.4 JC3a,F4 = 20.3 JC7a,F7 = 14.9 22.5 (CH2),
JC4,F5 = 14.1
JC4,F7 = 4.1
JC5,F4 = 13.2
JC5,F7 = 10.7
= 25.2, 22.7
JC7,F5 = 11.6
JC7,F4 = 2.8
27.9 (CH2),
31.2 (CH2)
139.5
142.9
97.8
143.8
120.7
121.4
31.1 (CH3)
JC4,F4 = 243.1 JC5,F5 = 237.0 JC6,F5, JC6,F7
JC7,F7 = 242.3 JC3a,F4 = 20.0 JC7a,F7 = 15.2 69.9
JC4,F5 = 14.1
JC4,F7 = 4.2
JC5,F4 = 13.1
JC5,F7 = 10.5
= 25.2, 22.6
JC7,F5 = 11.5
JC7,F4 = 2.9
(C(CH3)2OH)
139.6
143.2
98.4
143.8
121.5
122.6
125.7 (Ph),
JC4,F4 = 243.7 JC5,F5 = 237.8 JC6,F5, JC6,F7
JC4,F5 = 14.1
JC4,F7 = 4.1
JC7,F7 = 242.4 JC3a,F4 = 20.2 JC7a,F7 = 15.0 129.0 (Ph),
JC7,F5 = 11.4
JC7,F4 = 3.0
JC5,F4 = 13.0
JC5,F7 = 10.7
= 25.3, 22.6
129.5 (Ph),
131.2 (Ph)
139.5
142.8
98.0
143.8
120.5
122.3
20.1 (CH2),
JC4,F4 = 243.3 JC5,F5 = 237.0 JC6,F5, JC6,F7
JC7,F7 = 242.4 JC3a,F4 = 20.3 JC7a,F7 = 15.1 25.4 (CH2),
JC4,F5 = 14.1
JC4,F7 = 4.2
JC5,F4 = 13.1
JC5,F7 = 10.5
= 25.2, 22.6
JC7,F5 = 11.3
JC7,F4 = 3.0
30.8 (CH2),
63.0 (OCH2),
63.7 (OCH2),
99.9 (OCHO)
2cf
140.2 97.6
139.5
142.9
98.1
143.8
120.4
122.2
58.4 (CH2OH)
JC4,F4 = 243.4 JC5,F5 = 237.2 JC6,F5, JC6,F7
JC7,F7 = 242.6 JC3a,F4 = 20.1 JC7a,F7 = 15.1
JC4,F5 = 14.1
JC4,F7 = 4.1
JC5,F4 = 13.2
JC5,F7 = 10.5
= 25.2, 22.5
JC7,F5 = 11.6
JC7,F4 = 3.0
The solvent was evaporated in vacuo to give the crude product,
which was purified by TLC (hexane/ethyl acetate, 5:1) to give the
title compound 1ac (84 mg, 35%) as a colourless oil; Rf
(hexane/ethyl acetate, 5:1, three times) 0.45; νmax (liquid film):
3514 (br) and 3410 (NН2), 3308 (C–H), 2116 (C(C), 1643, 1504,
1337, 1236, 1177, 1132, 922, 854, 706, 619 сm–1; dH (300.13
MHz, CDCl3) 4.88 (2Н, s, NН2), 3.64 (1Н, s, С(С)Н); dC (100.62
MHz, CDCl3) 157.0 (1JC3,F3 = 258.2, 3JC3,CF3 = 2.2 Hz, C3), 148.4
(1JC5,F5 = 259.7, 2JC5,F6 = 13.3, 3JC5,CF3 = 1.7 Hz, C5), 141.9
(2JC1,F6 = 11.7 Hz, C1), 135.4 (1JC6,F6 = 238.6, 2JC6,F5 = 15.2 Hz,
C6), 121.6 (1JCF3,F = 273.0 Hz, CF3), 96.9 (2JC4,CF3 = 34.5, 2JC4,F3 =
reflux, and KОН (168 mg, 3 mmol) was added. The reaction
mixture was maintained under reflux for 3 h with stirring. After
the mixture was cooled to room temperature, diluted with CH2Cl2
(10 mL), poured into H2O (20 mL), neutralized with 5% aqueous
AcОН up to рН = 7 and extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with H2O (10 mL) and
dried (MgSO4). After evaporation of solvent in vacuo, the residue
was purified by TLC (hexane/ethyl acetate) to give the title
product.
4.4.1. 2-Butyl-4,6,7-trifluoro-5-(trifluoromethyl)-indole (2aa)
2
15.8, JC4,F5 = 12.6 Hz, C4), 93.6 (2JC2,F3 = 21.6 Hz, C2), 89.2
The reaction of 4а (341 mg, 1 mmol) and 5a (246 mg, 3
mmol), conducted according to the above general procedure,
afforded the title compound (2aa) (201 mg, 68 %) as a yellow
liquid; [found: C, 52.71; H, 3.97; N, 4.76. C13H11F6N requires C,
52.89; H, 3.76; N 4.74 %]; Rf (hexane/ethyl acetate, 7:1, then
10:1) 0.55; νmax (liquid film): 3473 (NН), 2962, 2935, 2873,
1660, 1568, 1521, 1464, 1358, 1277, 1169, 1132, 999, 877, 793,
744, 702, 654, 511 sm-1; HRMS (EI): M+, found 295.0791.
C13H11F6N requires 295.0790.
(C8), 71.2 (C7); dF (282.37 MHz, CDCL3) –56.4 (3F, dd, JCF3,F3,
JCF3,F5 ≈ 21 Hz, СF3), –114.2 (1F, dq, JF3,CF3 = 21.7, JF3,F6 = 11.4
Hz, F3), –136.7 (1F, dq, JF5,CF3 , JF5,F6 ≈ 21 Hz, F5), –164.8 (1F,
dd, JF6,F5 = 20.1, JF6,F3 = 11.4 Hz, F6); HRMS (EI): М+, found
239.0162. C9H3F6N requires 239.0164.
4.4. General procedure for synthesis of indoles 2(a–c)a,d,e
To a stirred solution of aniline 4 (1 mmol) and alkyne 5 (3
mmol) in MeCN (9 mL) were added Pd(PPh3)2Cl2 (28 mg, 0.04
mmol), CuI (17 mg, 0.09 mmol) and Et3N (1.5 mL) at room
temperature under an argon atmosphere. The reaction mixture
was stirred at 50 °C for 1 h. Then the mixture was heated to
4.4.2. 4,6,7-Trifluoro-2-phenyl-5-(trifluoromethyl)-indole (2ad)
The reaction of 4а (341 mg, 1 mmol) and 5d (306 mg, 3
mmol), conducted according to the above general procedure,

ACCEPTED MANUSCRIPT
10
Tetrahedron
afforded the title compound (2ad) (230 mg, 73%) as a
680, 488 сm–1; HRMS (EI): М+, found 247.0604. C14H8F3N
colourless solid; m.p. 127–128 °C; [Found: C, 57.23; H, 2.22; N,
4.34. C15H7F6N requires C, 57.16; H, 2.24; N 4.44%]; Rf
(hexane/ethyl acetate, 7:1, three times) 0.72; νmax (KBr): 3470
(NН), 1660, 1520, 1452, 1354, 1295, 1180, 1144, 996, 870, 793,
765, 744, 525 сm–1; HRMS (EI): М+, found 315.0479. C15H7F6N
requires 315.0477.
requires 247.0603.
4.4.9. 4,5,7-Trifluoro-2-[(oxan-2-yloxy)methyl]-indole (2ce)
The reaction of 4c (273 mg, 1 mmol) and 5e (420 mg, 3
mmol), conducted according to the above general procedure,
afforded the title compound (2ce) (214 mg, 75%) as a colourless
solid; m.p. 119–120 °C; [Found: C, 59.12; H, 4.92; N, 5.31.
4.4.3. 4,6,7-Trifluoro-2-[(oxan-2-yloxy)methyl]-5-
(trifluoromethyl)indole (2ae)
C14H14F3NO2 requires C, 58.95; H, 4.95;
N 4.91%]; Rf
(hexane/ethyl acetate, 7:1, three times) 0.51; νmax (KBr): 3422
(br) and 3233 (br) (NН), 2947, 1726, 1666, 1535, 1441, 1340,
1265, 1202, 1113, 1022, 961, 901, 804, 714, 496 сm–1; HRMS
(EI): М+, found 285.0968. C14H14F3NO2 requires 285.0971.
The reaction of 4а (341 mg, 1 mmol) and 5e (420 mg, 3
mmol), conducted according to the above general procedure,
afforded the title compound (2ae) (268 mg, 76%) as a colourless
solid; m.p. 146–148 °C; [Found: C, 50.97; H, 3.76; N, 3.93.
4.5. General procedure for synthesis of indoles 2(a–c)b,c
C15H13F6NO2 requires C, 51.00; H, 3.71;
N 3.96%]; Rf
(hexane/ethyl acetate, 7:1, four times) 0.50; νmax (KBr): 3421 (br)
(NН), 3217, 2945, 1661, 1524, 1464, 1366, 1308, 1167, 1135,
1022, 1000, 880, 810, 793, 681, 507 сm–1; HRMS (EI): М+, found
353.0843. C15H13F6NO2 requires 353.0845.
To a stirred solution of aniline 4 (1 mmol), 2-methyl-3-butyn-2-ol
5b (252 mg, 3 mmol) in dry MeCN (9 mL) were added Pd(PPh3)2Cl2
(28 mg, 0.04 mmol), CuI (17 mg, 0.09 mmol) and Et3N (1.5 mL)
at room temperature under an argon atmosphere. The reaction
mixture was stirred at 50 °C for 1 h. Then the mixture was heated
up to boiling, and KОН (168 mg, 3 mmol) was added. The
mixture was maintained under reflux with stirring, cooled to
room temperature and diluted with CH2Cl2 (5 mL). The suspension
was placed into a chromatography column filled with silica gel
(to minimize volatilization of indoles 2(a–c)c). The column was
washed with hexane/ethyl acetate (15:1) and then with hexane/ethyl
acetate (5:1) under the TLC control to isolate indoles 2(a–c)c and
2(a–c)b, respectively, after evaporation of solvents in vacuo.
4.4.4. 2-Butyl-4,5,6,7-tetrafluoroindole (2ba)
The reaction of 4а (341 mg, 1 mmol) and 5e (420 mg, 3
mmol), conducted according to the above general procedure,
afforded the title compound (2ba) (208 mg, 85%) as a yellow
liquid; [Found: C, 58.73; H, 4.73; N, 5.68. C12H11F4N requires C,
58.78; H, 4.52; N 5.71%]; Rf (hexane/ethyl acetate, 7:1, then
10:1) 0.60; νmax (liquid film): 3474 (NН), 2961, 2872, 1661,
1539, 1491, 1338, 1199, 1117, 995, 794, 727, 657, 466 сm–1;
HRMS (EI): М+, found 245.0821. C12H11F4N requires 245.0822.
4.5.1. 2-[4,6,7-Trifluoro-5-(trifluoromethyl)indol-2-yl]propan-2-
ol (2ab); 4,6,7-trifluoro-5-(trifluoromethyl)indole (2ac)
4.4.5. 4,5,6,7-Tetrafluoro-2-phenylindole (2bd)
The reaction of 4b (291 mg, 1 mmol) and 5d (306 mg, 3
mmol), conducted according to the above general procedure,
afforded the title compound (2bd) (238 mg, 90%) as a colourless
solid; m.p. 126–129 °C (lit. data13); Rf (hexane/ethyl acetate,
10:1, two times) 0.40; νmax (KBr): 3482 (NН), 1724, 1539, 1481,
1334, 1268, 996, 796, 761, 726, 688, 560 сm–1.
The above general procedure was followed using 4а (341 mg,
1 mmol) and 5b (252 mg, 3 mmol), stirring the reaction mixture
after addition of KОН (168 mg, 3 mmol) under reflux condition
for 2 h, and separating the products by column chromatography
(hexane/ethyl acetate, 15:1) to afford 2ac (107 mg, 45%) as a
colourless solid; m.p. 73–75 °C; [Found: C, 45.32; H, 1.47; N, 5.64.
C9H3F6N requires C, 45.21; H, 1.26; N 5.86%]; Rf (hexane/ethyl
acetate, 10:1 → 10:1) 0.33; νmax (KBr): 3484 (NН), 3256 (br),
2962, 2934, 2876, 1660, 1529, 1462, 1363, 1304, 1215, 1175,
1130, 992, 852, 793, 732, 696 сm–1; HRMS (EI): М+, found
239.0165. C9H3F6N requires 239.0164. The further elution of the
chromatography column (hexane/ethyl acetate, 5:1) afforded 2ab
(154 mg, 52%) as a colourless solid; m.p. 149–151 °C; [Found:
C, 48.71; H, 3.18; N, 4.61. C12H9F6NO requires C, 48.50; H, 3.05;
N 4.71%]; Rf (hexane/ethyl acetate, 5:1, three times) 0.55; νmax (KBr):
3611 (NН), 3280 (br) (OH), 2988, 2939, 1660, 1523, 1467, 1392,
1355, 1279, 1146, 998, 952, 879, 791, 716, 649, 520 сm–1;
HRMS (EI): М+, found 297.0585. C12H9F6NO requires 297.0583.
4.4.6. 4,5,6,7-Tetrafluoro-2-[(oxan-2-yloxy)-methyl]indole (2be)
The reaction of 4b (291 mg, 1 mmol) and 5e (420 mg, 3
mmol), conducted according to the above general procedure,
afforded the title compound (2be) (263 mg, 87%) as a colourless
solid; m.p. 117–120 °C; [Found: C, 55.49; H, 4.33; N, 4.42.
C14H13F4NO2 requires C, 55.45; H, 4.32;
N 4.62%]; Rf
(hexane/ethyl acetate, 7:1, three times) 0.56; νmax (KBr): 3428
(br) (NН), 3226 (br), 2945, 1725, 1543, 1492, 1341, 1264, 1113,
999, 940, 900, 871, 807, 728, 689, 518 сm–1; HRMS (EI): М+,
found 303.0875. C14H13F4NO2 requires 303.0877.
4.4.7. 2-Butyl-4,5,7-trifluoroindole (2ca)
The reaction of 4c (273 mg, 1 mmol) and 5a (246 mg, 3
mmol), conducted according to the above general procedure,
afforded the title compound (2ca) (163 mg, 72%) as a yellow
liquid; [Found: C, 63.72; H, 5.53; N, 5.59. C12H12F3N requires C,
63.43; H, 5.32; N 6.16%]; Rf (hexane/ethyl acetate, 7:1, two
times) 0.60; νmax (liquid film): 3470 (NН), 3369 (br), 2961, 2934,
2872, 1715, 1666, 1531, 1436, 1333, 1269, 1200, 1113, 959, 812,
781, 731, 702 сm–1; HRMS (EI): М+, found 227.0917. C12H12F3N
requires 227.0916.
4.5.2. 2-(4,5,6,7-Tetrafluoroindol-2-yl)propan-2-ol (2bb);
4,5,6,7-tetrafluoro-1H-indole (2bc)
The above general procedure was followed using 4b (291 mg,
1 mmol) and 5b (252 mg, 3 mmol), stirring the reaction mixture
after addition of KОН (168 mg, 3 mmol) under reflux condition
for 2 h, and separating the products by column chromatography
(hexane/ethyl acetate, 15:1) to afford 2bc (140 mg, 74%) as a
colourless solid; m.p. 86–89 °C (lit. data10,15,16); Rf (hexane/ethyl
acetate, 7:1, three times) 0.56; νmax (KBr): 3434 (br) (NН), 2960,
2857, 1725, 1578, 1456, 1408, 1368, 1264, 1097, 1037, 898, 730,
505 сm–1. The further elution of chromatography column
(hexane/ethyl acetate, 5:1) afforded 2bb (42 mg, 17%) as a
colourless solid; m.p. 137–140 °C; [Found: C, 53.76; H, 3.71; N,
5.56. C11H9F4NO requires C, 53.45; H, 3.67; N 5.67%]; Rf
(hexane/ethyl acetate, 7:1 → 7:1 → 7:1) 0.21; nmax (KBr): 3603
(NН), 3245 (br) (OH), 2985, 2938, 1546, 1487, 1431, 1343,
4.4.8. 4,5,7-Trifluoro-2-phenylindole (2cd)
The reaction of (273 mg, 1 mmol) and 5d (306 mg, 3 mmol),
conducted according to the above general procedure, afforded the
title compound (2cd) (210 mg, 85%) as a colourless solid; m.p.
105–106 °C; [Found: C, 68.21; H, 3.17; N, 5.66. C14H8F3N
requires C, 68.02; H, 3.26; N 5.67%]; Rf (hexane/ethyl acetate,
15:1, three times) 0.42; νmax (KBr): 3481 (NН), 1662, 1535, 1487,
1454, 1406, 1325, 1265, 1178, 1119, 1076, 964, 814, 754, 721,

ACCEPTED MANUSCRIPT
11
1267, 1221, 1174, 1127, 997, 946, 844, 791, 726, 642, 535 сm–1;
HRMS (EI): М+, found 247.0613. C11H9F4NO requires 247.0615.
Conducting the reaction of 2аe (35 mg, 0.1 mmol)
according the above general procedure, the standard workup and
TLC separation (hexane/ethyl acetate, 5:1) afforded the title
compound (2af) (24 mg, 90%) as a colourless solid; m.p. 123–
125 °C; [Found: C, 44.90; H, 2.05; N, 5.19. C10H5F6NO requires
C, 44.63; H, 1.87; N 5.20%]; Rf (hexane/ethyl acetate, 5:1, three
times) 0.25; νmax (KBr): 3626 (NН), 3248 (br) (OH), 2922, 2851,
1718, 1660, 1523, 1467, 1365, 1288, 1132, 999, 878, 798, 743,
709, 511 сm–1; HRMS (EI): М+, found 269.0267. C10H5F6NO
requires 269.0270.
4.5.3. 2-(4,5,7-Trifluoroindol-2-yl)propan-2-ol (2cb); 4,5,7-
trifluoroindole (2cc)
The above general procedure was followed using 4c (273 mg,
1 mmol) and 5b (0.25 g, 3 mmol), stirring the reaction mixture
after addition of KОН (168 mg, 3 mmol) under reflux condition
for 4 h, and separating the products by column chromatography
(hexane/ethyl acetate, 15:1) to afford 2cc (132 mg, 77%) as a
colourless oil; [Found: C, 56.02; H, 2.56; N, 8.07. C8H4F3N
requires C, 56.15; H, 2.36; N 8.19%]; Rf (hexane/ethyl acetate,
5:1, three times) 0.81; νmax (liquid film): 3479 (NН), 3306 (br),
2924, 2853, 1713, 1537, 1503, 1346, 1132, 955, 716 cm–1;
HRMS (EI): М+, found 171.0288. C8H4F3N requires 171.0290.
The further elution of chromatography column (hexane/ethyl
acetate, 5:1) to afford 2cb (18 mg, 8%) as a colourless solid; m.p.
132–134 °C; [Found: C, 57.91; H, 4.49; N, 5.80. C11H10F3NO
requires C, 57.64; H, 4.40; N 6.11%]; Rf (hexane/ethyl acetate,
5:1 → 5:1 → 5:1) 0.25; nmax (KBr): 3595 (NН), 3398 (br), 3265
(br) (OH), 2976, 2928, 2855, 1661, 1533, 1439, 1371, 1340,
1254, 1177, 1130, 945, 785, 729, 694, 498 сm–1; HRMS (EI): М+,
found 229.0707. C11H10F3NO requires 229.0709.
4.7.2. (4,5,6,7-Tetrafluoroindol-2-yl)methanol (2bf)
Conducting the reaction of 2be (30 mg, 0.1 mmol) according
the above general procedure, the `standard workup and TLC
separation (hexane/ethyl acetate, 5:1) afforded the title compound
(2bf) (21 mg, 96%) as a colourless solid; m.p. 136–138 °C;
[Found: C, 49.54; H, 2.41; N, 6.39. C9H5F4NO requires C, 49.33;
H, 2.30; N 6.39%]; Rf (hexane/ethyl acetate, 5:1, three times)
0.23; νmax (KBr): 3607 (NН), 3420 (br), 3248 (br) (OH), 2924,
2853, 1724, 1610, 1543, 1490, 1435, 1383, 1342, 1267, 1202,
1123, 995, 797, 727, 523 сm–1; HRMS (EI): М+, found 219.0303.
C9H5F4NO requires 219.0302.
4.7.3. (4,5,7-Trifluoroindol-2-yl)methanol (2cf)
4.6. General procedure for synthesis of indoles 2(а–c)b from
alkynes 1(а–c)b
Conducting the reaction of 2ce (29 mg, 0.1 mmol) according
the above general procedure, the standard workup and TLC
separation (hexane/ethyl acetate) afforded the title compound
(2cf) (19 mg, 96%) as a colourless solid; m.p. 105–107 °C;
[Found: C, 53.88; H, 3.05; N, 6.88. C9H6F3NO requires C, 53.74;
H, 3.01; N 6.96%]; Rf (hexane/ethyl acetate, 5:2, two times, then
4:1, two times) 0.45; νmax (KBr): 3597 (NН), 3307 (br) (OH),
2926, 2855, 1713, 1666, 1537, 1441, 1337, 1252, 1203, 1163,
1115, 1015, 962, 806, 708, 498 сm–1; HRMS (EI): М+, found
201.0393. C9H6F3NO requires 201.0396.
The crude 1(а–c)b, obtained in the experiment 4.2, was
dissolved in MeCN (10 mL), Et4NF·H2O (370 mg, 3 mmol) was
added, and the mixture was refluxed for 3 h. The mixture was
cooled to room temperature, diluted with CH2Cl2 (10 mL), poured
into H2O (20 mL), neutralized with 5% aqueous AcОН up to рН =
7 and extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were washed with H2O (10 mL) and dried (MgSO4). After
evaporation of solvent in vacuo, the residue was purified by TLC
(hexane/ethyl acetate, 5:1, three times) to give the title product.
Acknowledgments
4.6.1. 2-[4,6,7-Trifluoro-5-(trifluoromethyl)indol-2-yl]propan-2-
ol (2ab)
Analytical and spectral researches were performed in the
Collective Service Center of the Siberian Branch of the Russian
Academy of Science. The authors thank Russian Foundation of
Basic Research for financial support (grant 09-03-00248).
Conducting the reaction of crude 1аb according the above
general procedure, the standard workup and TLC separation
(hexane/ethyl acetate, Rf = 0.55) gave the title compound 2ab
(220 mg, 74%) as a colourless solid.
References and notes
4.6.2. 2-(4,5,6,7-Tetrafluoroindol-2-yl)propan-2-ol (2bb)
Conducting the reaction of crude 1bb according the above
general procedure, the standard workup and TLC separation
(hexane/ethyl acetate, Rf = 0.35) gave the title compound 2bb (74
mg, 30%) as a colourless solid.
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4.6.3. 2-(4,5,7-Trifluoroindol-2-yl)propan-2-ol (2cb)
Conducting the reaction of crude 1cb according the above
general procedure, the standard workup and TLC separation
(hexane/ethyl acetate, Rf = 0.25) gave the title compound 2cb (37
mg, 16%) as a colourless solid.
4.7. General procedure for synthesis of indoles 2(а–c)f
To a stirred solution of indole 2(а–c)e (0.1 mmol) in МеОН (5
mL) was added 15% aqueous HCl (6 drops) at room temperature.
After stirring for 1 h the mixture was diluted with CH2Cl2 (5
mL), poured into H2O (5 mL), neutralized by addition of an
aqueous solution of NaHСO3 up to рН = 7 and extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed
with H2O (10 mL) and dried (MgSO4). After evaporation of
solvent in vacuo, the residue was purified by TLC (hexane/ethyl
acetate) to give the title product.
6. Bjeldanes, L. F.; Le, H. T.; Firestone, G. L. U.S. Patent
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Yang, Y.; Wang, J.; Freel, S.; Fisher, S.; Sullivan, A.; Zhou,J.;Stanfield-
Oakley, S.;Greenberg, M.; Bolognesi, D.; Bray, B.; Koszalka,B.;Jeffs, P.;
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4.7.1. [4,6,7-Trifluoro-5-(trifluoromethyl)indol-2-yl]methanol (2af)

ACCEPTED MANUSCRIPT
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