Sequential substitution/ring cleavage/addition reaction of 1-(cyclohex-1-enyl)-piperidine and -pyrrolidine with chloropyruvates for the efficient synthesis of substituted 4,5,6,7-tetrahydro-1H-indole derivatives

Article abstract of DOI:10.1016/j.tet.2015.10.004

Sequential substitution/ring cleavage/addition reaction of 1-(cyclohex-1-enyl)-piperidine and -pyrrolidine with chloropyruvates has been accomplished for the synthesis of various polysubstituted 4,5,6,7-tetrahydroindoles. This one-pot, general and highly regioselective method avoids harsh conditions and expensive catalysts. It proceeds with high atom-efficiency and shows a broad substrate scope and functional group tolerance, making it a highly practical approach for the preparation of various tetrahydroindole derivatives. A family of 17 tetrahydroindoles was synthesized in good yields, which is indicative of the general character of this reaction. 10 of the tetrahydroindole derivatives with various substituents were successfully transformed into the corresponding indoles. This methodology allows access to indoles bearing ω-halo- (mostly chloro-)butyl and pentyl substituents at the nitrogen atom (by variation of enamines) and at the C2, C3 positions (by variation of pyruvates, including bromoaryl and chloroalkyl derivatives). The reaction can be used in conjunction with enamine synthesis offering a practical three-component heteroannulation methodology to produce 4,5,6,7-tetrahydroindoles from cyclohexanone, pyrrolidine and arylchloropyruvates.

Full text of DOI:10.1016/j.tet.2015.10.004

Accepted Manuscript
Sequential substitution/ring cleavage/addition reaction of 1-(cyclohex-1-enyl)-
piperidine and -pyrrolidine with chloropyruvates for the efficient synthesis of
substituted 4,5,6,7-tetrahydro-1H-indole derivatives
Vakhid A. Mamedov, Elena A. Hafizova, Anastasiya I. Zamaletdinova, Il’dar Kh.
Rizvanov, Alla B. Mirgorodskaya, Lucia Ya. Zakharova, Shamil K. Latypov, Oleg G.
Sinyashin
PII:
S0040-4020(15)30105-8
10.1016/j.tet.2015.10.004
TET 27176
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 July 2015
Revised Date: 18 September 2015
Accepted Date: 1 October 2015
Please cite this article as: Mamedov VA, Hafizova EA, Zamaletdinova AI, Rizvanov I’dK, Mirgorodskaya
AB, Zakharova LY, Latypov SK, Sinyashin OG, Sequential substitution/ring cleavage/addition reaction
of 1-(cyclohex-1-enyl)-piperidine and -pyrrolidine with chloropyruvates for the efficient synthesis of
substituted 4,5,6,7-tetrahydro-1H-indole derivatives, Tetrahedron (2015), doi: 10.1016/j.tet.2015.10.004.
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ACCEPTED MANUSCRIPT
Sequential substitution/ring cleavage/addition reaction of 1-(cyclohex-1-
enyl)-piperidine and -pyrrolidine with chloropyruvates for the efficient
synthesis of substituted 4,5,6,7-tetrahydro-1H-indole derivatives
a,b,
a,b
a,b
Vakhid A. Mamedov, * Elena A.Hafizova, Anastasiya I. Zamaletdinova,
a
a,b
a,b
Il’dar Kh. Rizvanov, Alla B. Mirgorodskaya, Lucia Ya. Zakharova,
a
a,b
Shamil K. Latypov, Oleg G. Sinyashin
a
A. E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Research Center of the Russian Academy of Sciences,
Arbuzov str. 8, 420088 Kazan, Russian Federation
b
Kazan National Research Technological University,
Karl Marx str. 68, 420015 Kazan, Russian Federation
mamedov@iopc.ru
ABSTRACT: Sequential substitution/ring cleavage/addition reaction of 1-(cyclohex-1-enyl)-
piperidine and -pyrrolidine with chloropyruvates has been accomplished for the synthesis of various
polysubstituted 4,5,6,7-tetrahydroindoles. This one-pot, general and highly regioselective method
avoids harsh conditions and expensive catalysts. It proceeds with high atom-efficiency and shows a
broad substrate scope and functional group tolerance, making it a highly practical approach for the
preparation of various tetrahydroindole derivatives. A family of 17 tetrahydroindoles was synthesized
in good yields, which is indicative of the general character of this reaction. Ten of the tetrahydroindole
derivatives with various substituents were successfully transformed into the corresponding indoles.
This methodology allows access to indoles bearing ω-halo- (mostly chloro-)butyl and pentyl
substituents at the nitrogen atom (by variation of enamines) and at the C2, C3 positions (by variation
of pyruvates, including bromoaryl and chloroalkyl derivatives). The reaction can be used in
conjunction with enamine synthesis offering a practical three-component heteroannulation
methodology to produce 4,5,6,7-tetrahydroindoles from cyclohexanone, pyrrolidine and
arylchloropyruvates.

2
ACCEPTED MANUSCRIPT
KEYWORDS: Synthetic methods; Enamines; Chloropyruvates; Ring cleavage; 4,5,6,7-
Tetrahydro-1H-indoles
INTRODUCTION
Recent studies on the chemistry of indole derivatives have focused on the development of efficient and
convenient methods for the synthesis of natural products and their analogues possessing potent
1
biological and physiological activities. One of the urgent directions in this field is the creation of new
pathways leading to substances possessing the 4,5,6,7-tetrahydro-1H-indole scaffold. This structural
2
motif is present in two members (Tuberostemonine, Stenine) of the Stemona alkaloid family and in
3
two members (Lysergic acid, Isolysergic acid) of the ergot alkaloid family. Besides, tetrahydroindole
derivatives display a wide spectrum of biological activities: anti-implantation, hypoglycemic, anti-
4
5
6
inflammatory, and analgesic; potent neuroleptic (e.g., molindone); and antitumor. Tetrahydroindoles
7
are also valuable intermediates in the synthesis of natural alkaloids such as goniomitine, arcyriacyanin
8
A, 6,7-secoagroclavine, and chuangxinmycin, as well as synthetic drugs (pindolol) and highly
9
functionalized indoles. The great majority of procedures employed in construction of both N-
substituted and N-unnsubstituted tetrahydroindoles are based on metal-catalyzed cyclization
1
0
strategies. However, the synthesis of highly functionalized pyrroles remains challenging and often
requires multiple steps or harsh reaction conditions. Here the course of our ongoing research toward
1
1
the synthesis of heterocycles via Darzens condensation products, we describe a novel approach to the
synthesis of 2,3-fused pyrroles, mainly 1,2,3-substituted 4,5,6,7-tetrahydro-1H-indole derivatives, via
the sequential substitution/ring cleavage/addition reaction of commercially available 1-(cyclohex-1-
enyl)-piperidines and 1-(cyclohex-1-enyl)-pyrrolidine with arylchloropyruvates, which are readily
derived from methyl dichloroacetate and corresponding aldehydes under Darzens condensation (eq 1).
We further extend this methodology to the formation of substituted indoles from 4,5,6,7-tetrahydro-
1
H-indoles.
On the basis of the new ring formation in the reactions of 1-cyclohexenylpyrrolidine 1 with
arylchloropyruvates 2 we have recently developed a highly efficient and one-step versatile method for
the synthesis of 4,5,6,7-tetrahydro-2-phenyl-1H-indole derivatives 3 bearing a 1-chlorobutyl
12
substituent at the nitrogen atom. It is based on cascade conversions involving: (a) an intramolecular
־
nucleophilic substitution of the S 2 type with the formation of an epoxide ring and elimination of Cl ,
N
־
(
b) the opening of the pyrrolidine ring in A on exposure to Cl , (c) imino-enamine tautomerism
B
C, (d) the opening of the epoxide ring with a concomitant formation of the new pyrrole ring, D,
and (e) the elimination of water leading to the formation of tetrahydroindole derivatives 3 (Scheme 1),
1
2
previously reported by us. According to this procedure, we obtained 1-(4-chlorobutyl)-2-(4-aryl)-3-
methoxycarbonyl-4,5,6,7-tetrahydroindoles (3, 8 examples) in 72-90% yields (Scheme 1).

3
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Scheme 1. Our previous work.
RESULTS AND DISCUSSION
We have suggested that this procedure could be applied to the synthesis of N-alkyltetrahydroindoles 5
Table 1) and functionalized indoles 10 (Table 2). With this idea in mind, in order to identify the
(
optimal reaction conditions 1-cyclohexenylpiperidine 4a and methyl phenylchloropyruvate 2a were
chosen as the test substrates and parameters including the solvent, temperature, and molar ratio of the
reagent and substrate were examined in detail. Among the solvents investigated which included
ethanol, acetonitrile, dichloromethane, and dioxane, the best result in terms of yield was obtained with
dioxane. The reaction was also tried at different temperatures. At room temperature, the reaction of 1-
cyclohexenylpiperidine 4a and methyl phenylchloropyruvate 2a, depending on the reaction time gave
a corresponding 4,5,6,7-tetrahydroindole derivative 5a, piperidinium chloride 6a and unchanged
starting substrates as a mixture. When the ratio of substrates differs than 1:1, the yield of piperidinium
chloride 6a as a by product increased. Surprisingly, raising the temperature led to the formation of the
4
,5,6,7-tetrahydroindole derivative 5a, almost as a sole product in a 64% yield. However, a trace
amount of piperidinium chloride 6a was also obtained. The formation of 6a, might occur through a
piperidinium intermediate type of A, as a result of hydrolysis with the formation of piperidine and its
hydro chlorination. The highest yield (98%) of product 5a was obtained at reflux temperature with the
ratio of substrates 1:1 for 2 h.

4
ACCEPTED MANUSCRIPT
The scope of this protocol was then investigated under optimized reaction conditions. Substituted
3
-arylhalogenopyruvates 2a-j were subjected to the reaction with 1-(cyclohex-1-enyl)-piperidine 4a
under metal-free conditions in dioxane under reflux conditions (Table 1). In the cases of substrates
with halogen atoms in the aryl group of 2 the yields of the desired products depend on the positions of
atoms in the Periodic Table. The higher the position of the atom in the group, the higher the yields of
4
,5,6,7-tetrahydroindole derivatives 5 and vice-versa, the lower the position of the atom in the group,
the lower the yields of compounds 5. The substrate with an electron-donating group led to decreased
reaction rates (entry 11). This can be rationalized by considering the fact that these groups decrease the
positive charge at the C-3 carbon atom bearing a chlorine atom. The presence of stronger electron-
donating groups led to even longer reaction times. In contrast, an electron-withdrawing group (entries
7
,8,9,10) accelerated the reaction. The reactions proceed successfully wiht both 1-(4-tert-
butylcyclohex-1-enyl)-piperidine (entry 9) as an enamine component and methyl 3-bromo-2-oxo-3-
phenylpropanoate as a ketone component (entry 10). This affords the corresponding products in good
yields (Table 1). On the whole, substrates with an electron-withdrawing functional group formed
better yields (Table 1, entries 7,8,9,10) than the electron-donating ones (Table 2, entries 5,11).
Table 1
Synthesis of methyl 1-(5-halopentyl)-2-aryl-4,5,6,7-tetrahydroindole-3-carboxylates 5
Products
5:6,
2
3
1
a
Entry
2
R
R
Hal
4
R
Rf
yields, %
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
C H
CH3
CH3
CH3
CH3
CH3
CH3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
4a
4a
4a
4a
4a
4a
4a
4a
H
H
H
H
H
H
H
H
0.53
0.51
0.73
0.59
0.59
0.53
0.46
0.48
5a:6а 95:1
5b:6а 75:12
5c:6а 71:20
5d:6а 68:12
5e:6а 63:22
5f:6а 76:18
5g:6а 76:14
5h:6а 80:15
6
5
C H Cl-4
6
4
C H Br-4
6
4
C H F-4
6
4
C H I-4
6
4
C H Br-3
6
4
2g
2h
C H NO -4 CH3
6 4 2
C H NO -3 CH3
6
4
2

5
ACCEPTED MANUSCRIPT
9
1
1
1
1
2d
2j
C H F-4
CH3
Cl
Br
Cl
Cl
Br
4b
4a
4a
4b
4a
t-Bu
H
0.53
0.61
0.60
0.60
0.50
5i:6а 82:11
5j:6b 78:12
5k:6а 68:14
5l:6а 79:15
5m:6b 66:22
6
4
0
1
2
3
C H F-4
C H
2
6
4
5
2k
2a
2m
C H
6
13
CH3
CH3
H
C H
t-Bu
H
6
5
C H
C H
2
6
5
5
a
eluent 1:2=EtOAc:hexane
The mechanism of the formation of tetrhydroindole derivatives 5 in these reactions is clearly,
similar to the mechanism of the formation of 4,5,6,7-tetrahydroindoles 3 in the reactions of 1-(1-
pyrrolidino)cyclohexane 1 with arylchloropyruvates 2.
As can be seen from the data shown in the table, the yield of the desired products for the most
cases do not exceed 80% regardless of the nature of the substituent in the phenyl ring of the pyruvate
derivative. To clear up the reasons above, in four cases, namely in the cases of the reactions of
pyruvates 2a,g and enamine 4a, we have carefully analyzed the reaction mixture and found that in
addition to the main products 5a,g and the hydrochloride of piperidine 6a, 2-aryl-1-(piperidin-1-
yl)ethanones 7a,b were formed as by-products.
Although the mechanism of the formation of the products 7a,b is but not as yet fully clear, we
assume that under the reaction conditions there can occur side reactions involving single-electron
transfer, and the formation of the products 7 can be presented as follows.
.
+
Cl
O
Cl
O
N
N
+
+
Ar
O
Ar
O
O
2
O
1a
Cl-
N
O
O
H
7
Ar C C O
+
Ar
O
H
O
O
CO + OMe

6
ACCEPTED MANUSCRIPT
Scheme 2. Plausible mechanism of the formation of 2-aryl-1-(piperidin-1-yl)ethanones 7.
The analysis of reaction mixtures shows that the expected products of the Stork reaction, i.e.
methyl 3-aryl-2-oxo-3-(2-oxocyclohexyl)propanoates 8 or possible products of their further
transformation – methyl 3-aryl-4,5,6,7-tetrahydrobenzofuran-2-carboxylates 9 – are not formed.
The structures of all compounds were established unambiguously by various 1D/2D NMR
1
3
correlation methods. For example, for 5k first the proton spin systems of indole (Ind), substituents at
N and C fragments were revealed from 1D TOCSY experiments (SI). Then, a whole structure of
1
2
1
13
these moieties were established by combination of H- C HSQC/HMBC correlations. Finally these
1
13
1
15
structural fragments were “bonded” in a single whole according to H- C/ H- N HMBC
connectivities (Figure 1). In addition, a number of NOEs strongly supports these structural hypotheses.
1
1
13
1
15
Figure 1. H NMR spectra, structure of 5k with principal NMR correlations ( H- C and H- N
HMBC - black arrow, NOEs - blue arrow).
Assuming that enamines 4a,b can be generated from the corresponding cyclohexanone derivative
and piperidine, we tried to synthesize 4,5,6,7-tetrahydroindoles 5 in a three-component system
“piperidine – cyclohexanone – arylchloropyruvate” in boiling dioxane. Regardless of the order of
mixing the reagents and temperature conditions of the reaction, the desired products have not been

7
ACCEPTED MANUSCRIPT
obtained, apparently due to a set of competing processes. However, the replacement of piperidine on
pyrrolidine in the three-component system dramatically affects the result. The 4,5,6,7-tetrahydroindole
derivatives 3 with chlorobutyl substituents in position 1 are formed with almost quantitative yields.
Indeed, a test reaction between pyrrolidine and cyclohexanone in benzene, rapidly produced enamine
4
a, which underwent a sequential substitution/ring cleavage/addition reaction with arylchloropyruvate
a to give 4,5,6,7-tetrahydroindole 3a with high yield (Table 2). Several arylchloropyruvates with
2
phenyl and para-substituted phenyl groups 2a-d tested reacted with similar facility, affording the
corresponding products 3a-d with high isolated yields. Further studies of the scope of this novel three-
component heteroannulation reaction are underway in our laboratory.
Table 2
Synthesis of methyl 1-(5-halopentyl)-2-aryl-4,5,6,7-tetrahydroindole-3-carboxylates 3 under the three-
component “pyrrolidine – cyclohexanone – arylchloropyruvate” system
O
OCH3
O
Cl
O
dioxane
+
+
R
OCH3
R
N
reflux, 2 h
N
H
O
Cl
4
2a-d
3a-d
a
№
2
R
Rf
Yield 3, %
3a, 98
1
2
3
4
2a
2b
2c
2d
C H
0.53
0.51
0.73
0.59
6
5
C H Cl-4
3b, 82
6
4
C H Br-4
3c, 88
6
4
C H F-4
3d, 92
6
4
a
eluent 1:2=EtOAc:hexane
Having obtained 4,5,6,7-tetrahydroindole derivatives 3 and 5 the next stage was the synthesis of
the indole derivatives 10. Dehydrogenation of 3,5 with the use of chloranil (in boiling p-xylene, 17 h)
resulted in compounds 10 in good to high yields (Table 2).
Table 2
Synthesis of functionalized indole derivatives 10 from methyl 1-[5-halobutyl(and halopentyl)]-2-aryl-
4
,5,6,7-tetrahydroindole-3-carboxylates 3 and 5

8
ACCEPTED MANUSCRIPT
1
2
a
№
1
2
3
4
5
6
7
8
9
3 or 5
3a
R
R
R
n
4
4
4
4
5
5
5
5
5
5
Rf
10, %
H
H
H
H
H
H
H
H
Br
H
H
H
0.40
0.63
0.51
0.50
0.56
0.58
0.56
0.51
0.48
0.58
10a (85)
10c (82)
10d (86)
10g (92)
11b (71)
11c (69)
11d (75)
11f (66)
11g (90)
11i (78)
3c
Br
F
H
3d
3g
H
NO2
Cl
Br
F
H
5b
5c
H
H
5d
5f
H
H
H
5g
NO2
F
H
1
0
5i
t-Bu
a
eluent 1:2=EtOAc:hexane
CONCLUSIONS
We have developed a convenient and general approach to polysubstituted 4,5,6,7-tetrahydroindoles
via the sequential substitution/ring cleavage/addition reaction between 1-cyclohexenylpiperidines and
1
-cyclohexenylpyrrolidine and pyruvates. This reaction was successfully combined with the enamine
synthesis, which led to the development of an efficient sequential three-component heteroannulation
methodology for the construction of the methyl 1-(4-chlorobutyl)-2-aryl-4,5,6,7-tetrahydro-1H-indole-
3
-carboxylates. Dehydrogenation of 4,5,6,7-tetrahydroindole derivatives with chloranil provides an
easy access to the poly-functionalized indole scaffold. Studies aimed at the extensionof this reaction to
other heterocycles are presently underway in our laboratory.
EXPERIMENTAL SECTION
4
4
. Experimental
.1. General
1
All NMR experiments were performed with 600, 500 and 400 MHz (600, 500 and 400 MHz for H
19
13
NMR; 470 and 376 MHz for F NMR; 150, 125 and 100 MHz for C NMR; 60 and 50.7 MHz for

9
ACCEPTED MANUSCRIPT
1
5
N NMR, respectively) spectrometers equipped with a 5 mm diameter gradient inverse broad band
probehead and a pulsed gradient unit capable of producing magnetic field pulse gradients in the z-
-1
14
direction of 53.5 G·cm . NMR experiments were carried out at 303 K. DPFGROE and TOCSY
spectra were obtained using a Hermite-shaped pulse for selective excitation. Chemical shifts (δ in
1
13
ppm) are referenced to the solvents (CDCl (δ = 7.27 ppm for H and 77.0 ppm for C NMR) or
3
1
13
15
DMSO-d (δ = 2.49 ppm for H and 39.5 ppm for C NMR), to external CD NO (380.2 ppm) for N
6
3
2
19
NMR spectra (conversion factor to NH : -380.2 ppm) and to external C F (-164.9 ppm) for F NMR
3
6 6
spectra. The melting points were determined on a Boetius hot-stage apparatus and are uncorrected.
Infrared (IR) spectra were recorded on a Bruker Vector-22 spectrometer. Mass spectra of MALDI
were measured on a Bruker mass spectrometer UltraFlex III TOF/TOF. As the matrices 2,5-
dihydroxybenzoic acid and para-nitroaniline were used. For the accurate mass measuring PEG-400
was used. The insertion of the sample was performed with direct injection combined with a water
cooling system. The elemental analyses were carried out at the microanalysis laboratory of the
Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences. All solvents
were of regent grade and were dried and distilled before use.
4
.2. Preparation of 3-chloro(or bromo)-2-oxo-3-arylpropanoates 2
1
1a
11b
11c
11d
11e
11b
11f
11g
11a
The starting compounds 2a, 2b, 2c, 2d, 2f, 2g, 2h, 2k, and 2m, were prepared
according to the published procedures.
Methyl 3-chloro-3-(4-iodophenyl)-2-oxopropanoate (2e) was prepared from methyl 2,2-
dichloroacetate and p-iodobenzaldehyde in toluene using the method described for the synthesis of
1
1b
-1
2
m. Yellow oil; yield (72%) 2e; νmax(thin film) 1738, 1590, 1489, 1440, 1245, 1165, 856, 750 cm .
δ (400 MHz, CDCl ) 3.84 (3 H, s, OCH ), 6.08 (1 H, s, CH), 7.15 (2 Н, d, J 8.4 Hz, H3,5-Ar), 7.73 (2
H
3
3
Н, d, J 8.4 Hz, H2,6-Ar).
Ethyl 3-bromo-3-(4-fluorophenyl)-2-oxopropanoate (2j) was prepared from ethyl 2,2-
dibromoacetate and p-fluorobenzaldehyde in toluene using the method described for the synthesis of
1
1b
2
m. Yellow oil; yield 2.17 g (85%) 2j; νmax(thin film) 1736, 1605, 1510, 1300, 1231, 1160, 1055,
-1
8
56, 839 cm . δ (500 MHz, CDCl ) 1.33 (3 Н, t, J 7.1 Hz, ОСН СН ), 4.33 (2 Н, q, J 7.1 Hz,
H 3 2 3
ОСН СН ), 6.19 (1 H, s, CH), 7.06 (2Н, dd, J 8.6 Hz, JHF 8.6 Hz, H2,6-Ar), 7.45 (2 Н, dd, JHH 8.6
2
3
HH
Hz, JHF 3.3 Hz, H3,5-Ar).

1
0
ACCEPTED MANUSCRIPT
4
.3. General procedure for the synthesis of 5.
A
mixture of alkyl 3-chloro(or bromo)-2-oxo-3-arylpropanoate
1
(3.0 mmol), 1-
cyclohexenylpiperidine (or 4-tert-butyl-1-cyclohexenylpiperidine) 4a(b) (5.2 mmol) and dioxane (30
mL) was heated at reflux for 2 h. After cooling down to room temperature, the precipitate was filtered
and recrystallized in toluene (or washed with i-PrOH) to give piperidinium chloride (or bromide) 6.
The solvent was removed to give a slightly brown crude product 5, which was purified on column
chromatography with silica gel (eluent – hexane/EtOAc).
Methyl 1-(5-chloropentyl)-2-phenyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5а.
O
OCH
2
3
4
3
5
3
a
3
5
2
1
Ind
Ar
4
6
a N1
7
6
7
2
1
4
5
3
Alk
Cl
Colorless oil; yield 1.03 g, 95% (5а); 3.7 mg, 1% (6a); R (hexane/EtOAc 2:1) 0.53; [Found: C, 69.9;
f
H, 7.3; N, 3.8. C H ClNO requires C, 70.08; H, 7.28; Cl, 9.85; N, 3.89]. νmax(thin film) 3061, 3026,
2
1
26
2
2
1
937, 2853, 1697, 1606, 1580, 1525, 1481, 1443, 1407, 1373, 1331, 1270, 1238, 1204, 1154, 1121,
-1 1
091, 1053, 1025, 963, 919, 845, 825, 786, 763, 733, 703, 648, 612, 516 cm . H NMR (500 MHz,
CDCl ): δ 1.21-1.27 (2 H, m, СH -Alk3), 1.46-1.52 (2 H, m, СH -Alk2), 1.54-1.60 (2 H, m, СH -
3
H
2
2
2
Alk4), 1.80-1.81 (2 H, m, СH -Ind5), 1.87-1.88 (2 H, m, СH -Ind6), 2.56-2.59 (2 H, m, СH -Ind7),
2
2
2
2
.79-2.82 (2 H, m, СH -Ind4), 3.38 (2 H, t, J 6.6 Hz, СH -Alk5), 3.57 (3 H, s, OCH ), 3.64 (2 H, t, J
2 2 3
1
3
1
7
.6 Hz, СH -Alk1), 7.31-7.33 (2 H, m, H2,H6-Ar), 7.38-7.46 (3 H, m, H3,H4,H5-Ar). C{ H} NMR
2
(
100 MHz, CDCl ): δ 165.6 (C=O), 137.2 (C2-Ind), 132.7 (C1-Ar), 130.4 (C2-Ar), 128.0 (C7a-Ind),
3
1
27.7 (C4-Ar), 127.6 (C3-Ar), 118.8 (C3a-Ind), 110.3 (C3-Ind), 49.9 (OCH ), 44.2 (C5-Alk), 43.1
3
(C1-Alk), 31.4 (C4-Alk), 29.7 (C2-Alk), 23.5 (C3-Alk), 23.2 (C5-Ind), 23.2 (C4-Ind), 22.8 (C6-Ind),
1
5
2
2.0 (C7-Ind). N NMR (50.6 MHz, CDCl ): δ 164.9 (N1). HRMS (MALDI) calcd. for C H ClNO
3 21 26 2
+
[
M+Cs] 492,0701, found 492,0718.
1
1
Tetrahydroindoles 5b-k were obtained in a similar way from appropriate chloropyruvates.
Methyl 1-(5-chloropentyl)-2-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5b.

1
1
ACCEPTED MANUSCRIPT
O
OCH
2
3
4
Ind
7
3
5
3
a
3
5
6
2
1
4
Ar
Cl
a N1
1
7
6
2
4
5
3
Alk
Cl
Pale yellow oil; yield 0.89 g, 75% (5b); 43 mg, 12% (6a); R (hexane/EtOAc 2:1) 0.51; [Found: C,
f
6
2
1
3.9; H, 6.5; N, 3.4. C H Cl NO requires C, 63.96; H, 6.39; Cl, 17.98; N, 3.55]. νmax(thin film)
21 25 2 2
928, 2853, 1702, 1601, 1523, 1480, 1442, 1410, 1374, 1331, 1269, 1237, 1204, 1154, 1122, 1091,
-1 1
015, 965, 824, 785, 755, 734, 650, 612, 507 cm . H NMR (500 MHz, CDCl ): δ 1.24-1.30 (2 H, m,
3
H
СH -Alk3), 1.44-1.50 (2 H, m, СH -Alk2), 1.58-1.64 (2 H, m, СH -Alk4), 1.76-1.81 (2 H, m, СH -
2
2
2
2
Ind5), 1.84-1.89 (2 H, m, СH -Ind6), 2.55 (2 H, br t, J 6.0 Hz, СH -Ind7), 2.77 (2 H, br t, J 6.1 Hz,
2
2
СH -Ind4), 3.42 (2 H, t, J 6.6 Hz, СH -Alk5), 3.59 (3 H, s, OCH ), 3.61 (2 H, t, J 7.8 Hz, СH -Alk1),
2
2
3
2
1
3
1
7
.25 (2H, d, J 8.5 Hz, H3,H5-Ar), 7.39 (2H, d, J 8.5 Hz, H2,H6-Ar). C{ H} NMR (125.7 MHz,
CDCl ): δ 165.8 (C=O), 136.0 (C2-Ind), 134.1 (C4-Ar), 132.1 (C2-Ar), 131.4 (C1-Ar), 128.7 (C7a-
3
Ind), 128.2 (C3-Ar), 119.3 (C3a-Ind), 111.0 (C3-Ind), 50.3 (OCH ), 44.4 (C5-Alk), 43.5 (C1-Alk),
3
3
1.8 (C4-Alk), 30.1 (C2-Alk), 23.9 (C3-Alk), 23.4 (C5-Ind +C4-Ind), 23.0 (C6-Ind), 22.3 (C7-Ind).
1
5
N NMR (50.6 MHz, CDCl ): δ 164.6 (N1).
3
Methyl 2-(4-bromophenyl)-1-(5-chloropentyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5c.
Yellow oil; yield 0.93 g, 71% (5c); 72 mg, 20% (6a); R (hexane/EtOAc 2:1) 0.73; [Found: C, 57.4; H,
f
5
2
5
.9; N, 3.0. C H BrClNO requires C, 57.48; H, 5.74; Br, 18.21; Cl, 8.08; N, 3.19]. νmax(thin film)
21 25 2
938, 2853, 1697, 1521, 1479, 1442, 1410, 1270, 1204, 1122, 1073, 1011, 822, 785, 755, 735, 650,
-1 1
02 cm . H NMR (500 MHz, CDCl ): δ 1.22-1.28 (2H, m, СH -Alk3), 1.44-1.50 (2H, m, СH -
3
H
2
2
Alk2), 1.58-1.64 (2H, m, СH -Alk4), 1.76-1.81 (2H, m, СH -Ind5), 1.84-1.89 (2H, m, СH -Ind6), 2.55
2
2
2
(
2H, br t, J 6.0 Hz, СH -Ind7), 2.76 (2H, br t, J 6.1 Hz, СH -Ind4), 3.42 (2H, t, J 6.6 Hz, СH -Alk5),
2 2 2
3
.59 (3H, s, OCH ), 3.61 (2H, t, J 7.7 Hz, СH -Alk1), 7.18 (2H, d, J 8.4 Hz, H3,H5-Ar), 7.54 (2H, d, J
3 2
1
3
1
8
.4 Hz, H2,H6-Ar). C{ H} NMR (125.7 MHz, CDCl ): δ 165.8 (C=O), 136.0 (C2-Ind), 132.4 (C2-
3

1
2
ACCEPTED MANUSCRIPT
Ar), 131.9 (C1-Ar), 131.1 (C3-Ar), 128.7 (C7a-Ind), 122.4 (C4-Ar), 119.3 (C3a-Ind), 111.0 (C3-Ind),
5
0.3 (COCH ), 44.4 (C5-Alk), 43.5 (C1-Alk), 31.8 (C4-Alk), 30.1 (C2-Alk), 23.8 (C3-Alk), 23.4 (C4-
3
Ind+C5-Ind), 23.0 (C6-Ind), 22.2 (C7-Ind).
Methyl 1-(5-chloropentyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5d.
O
OCH
2
3
4
3
5
3
a
3
5
6
2 1
4
Ind
Ar
F
a N1
7
6
7
2
1
4
5
3
Alk
Cl
Maize yellow oil; yield 0.77 g, 68% (5d); 43 mg, 12% (6a); R (hexane/EtOAc 2:1) 0.59; [Found: C,
f
6
6.5; H, 6.4; N, 3.7. C H ClFNO requires C, 66.75; H, 6.67; Cl, 9.38; F, 5.03; N, 3.71]. νmax(thin
21 25 2
film) 2929, 2854, 1702, 1606, 1535, 1489, 1460, 1442, 1412, 1374, 1331, 1269, 1223, 1204, 1156,
-
1 1
1
1
121, 1092, 1016, 965, 833, 821, 787, 735, 651, 591, 523 cm . H NMR (500 MHz, CDCl ): δ 1.23-
3 H
.29 (2H, m, СH -Alk3), 1.44-1.50 (2H, m, СH -Alk2), 1.57-1.63 (2H, m, СH -Alk4), 1.77-1.81 (2H,
2
2
2
m, СH -Ind5), 1.85-1.89 (2H, m, СH -Ind6), 2.55 (2H, br t, J 6.2 Hz, СH -Ind7), 2.77 (2H, br t, J 6.1
2
2
2
Hz, СH -Ind4), 3.41 (2H, t, J 6.6 Hz, СH -Alk5), 3.59 (3H, s, OCH ), 3.61 (2H, br t, J 7.8 Hz, СH -
2
2
3
2
Alk1), 7.11 (2H, dd, JHH 8.7 Hz, JHF 8.7 Hz, H2,H6-Ar), 7.28 (2H, dd, JHH 8.7 Hz, JHF 3.0 Hz, H3,H5-
1
3
1
1
Ar). C{ H} NMR (125.7 MHz, CDCl ): δ 165.8 (C=O), 162.5 (d, J = 247.5 Hz, C4-Ar), 136.3
3
CF
3
4
(
C2-Ind), 132.5 (d, J = 8.2 Hz, C2-Ar), 128.9 (d, J = 3.6 Hz, C1-Ar), 128.4 (C7a-Ind), 119.2
CF CF
2
(
C3a-Ind), 115.0 (d, J = 21.5 Hz, C3-Ar), 110.9 (C3-Ind), 50.3 (OCH ), 44.4 (C5-Alk), 43.4 (C1-
CF
3
Alk), 31.8 (C4-Alk), 30.1 (C2-Alk), 23.9 (C3-Alk), 23.4 (C4-Ind+C5-Ind), 23.1 (C6-Ind), 22.2 (C7-
1
9
1
Ind). F{ H} NMR (470.5 MHz, CDCl ): δ 113.7 (F).
3
Methyl 1-(5-chloropentyl)-2-(4-iodophenyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5e.
Yellow oil; yield 0.92 g, 63% (5e); 79 mg, 22% (6a); R (hexane/EtOAc 2:1) 0.59; [Found: C, 52.3; H,
f
5
.3; N, 2.7. C H ClINO requires C, 51.92; H, 5.19; Cl, 7.30; I, 26.12; N, 2.88]. ν
(thin film)
max
2
1
25
2

1
3
ACCEPTED MANUSCRIPT
2
1
924, 2853, 1702, 1582, 1519, 1475, 1461, 1409, 1376, 1317, 1261, 1238, 1204, 1184, 1154, 1121,
-1 1
092, 1023, 1007, 966, 817, 799, 752, 734, 648, 613 cm . H NMR (500 MHz, CDCl ): δ 1.25-1.31
3
H
(
2H, m, СH -Alk3), 1.46-1.52 (2H, m, СH -Alk2), 1.60-1.66 (2H, m, СH -Alk4), 1.79-1.82 (2H, m,
2 2 2
СH -Ind5), 1.86-1.90 (2H, m, СH -Ind6), 2.57 (2H, br t, J 5.7 Hz, СH -Ind7), 2.78 (2H, br t, J 6.1 Hz,
2
2
2
СH -Ind4), 3.44 (2H, t, J 6.6 Hz, СH -Alk5), 3.62 (3H, s, OCH ), 3.63 (2H, t, J 7.7 Hz, СH -Alk1),
2
2
3
2
1
3
1
7
.07 (2H, d, J 8.3 Hz, H3,H5-Ar), 7.77 (2H, d, J 8.3 Hz, H2,H6-Ar). C{ H} NMR (125.7 MHz,
CDCl ): δ 165.8 (C=O), 137.1 (C3-Ar), 136.1 (C2-Ind), 132.6 (C2-Ar), 132.5 (C1-Ar), 128.7 (C7a-
3
Ind), 119.4 (C3a-Ind), 111.0 (C3-Ind), 94.2 (C 4-Ar), 50.4 (OCH ), 44.5 (C5-Alk), 43.5 (C1-Alk), 31.8
3
(C4-Alk), 30.1 (C2-Alk), 23.9 (C3-Alk), 23.4 (C5-Ind+C4-Ind), 23.0 (C6-Ind), 22.3 (C-Ind).
Methyl 2-(3-bromophenyl)-1-(5-chloropentyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5f.
Pale yellow oil; yield 1.00 g, 76% (5f); 65 mg, 18% (6a); R (hexane/EtOAc 2:1) 0.53; [Found: C,
f
5
7.2; H, 5.8; N, 3.1. C H BrClNO requires C, 57.48; H, 5.74; Br, 18.21; Cl, 8.08; N, 3.19]. ν
21 25 2 max
(thin film) 2927, 2854, 1703, 1600, 1579, 1561, 1520, 1471, 1441, 1409, 1374, 1330, 1320, 1269,
-1 1
1
238, 1204, 1154, 1122, 1092, 1051, 1030, 997, 964, 890, 784, 755, 714, 700, 652, 535, 437 cm . H
NMR (500 MHz, CDCl ): δ 1.24-1.30 (2H, m, СH -Alk3), 1.45-1.51 (2H, m, СH -Alk2), 1.58-1.64
3
H
2
2
(
2H, m, СH -Alk4), 1.76-1.80 (2H, m, СH -Ind5), 1.85-1.89 (2H, m, СH -Ind6), 2.55 (2H, br t, J 6.1
2 2 2
Hz, СH -Ind7), 2.77 (2H, br t, J 6.1 Hz, СH -Ind4), 3.42 (2H, t, J 6.6 Hz, СH -Alk5), 3.59 (3H, s,
2
2
2
OCH ), 3.62 (2H, t, J 7.7 Hz, СH -Alk1), 7.26 (1H, ddd, J 7.6 Hz, 1.6, 1.6 Hz, H6-Ar), 7.29 (1H, dd, J
3
2
7
.6, 7.6 Hz, H5-Ar), 7.47 (1H, dd, J 1.6, 1.6 Hz, H2-Ar), 7.52 (1H, ddd, J 7.6, 1.6, 1.6 Hz, H4-Ar).
1
3
1
C{ H} NMR (125.7 MHz, CDCl ): δ 165.7 (C=O), 135.5 (C2-Ind), 135.0 (C1-Ar), 133.6 (C2-Ar),
3
1
31.0 (C4-Ar), 129.6 (C5-Ar), 129.3 (C6-Ar), 128.8 (C7a-Ind), 121.7 (C3-Ar), 119.4 (C3a-Ind), 111.1
(
C3-Ind), 50.3 (OCH ), 44.4 (C5-Alk), 43.5 (C1-Alk), 31.7 (C4-Alk), 30.1 (C2-Alk), 23.8 (C3-Alk),
3
2
3.4 (C5-Ind), 23.3 (C4-Ind), 23.0 (C6-Ind), 22.2 (C7-Ind).
Methyl 1-(5-chloropentyl)-2-(4-nitrophenyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5g.

1
4
ACCEPTED MANUSCRIPT
O
OCH
2
3
4
3
5
3
a
3
5
6
2
1
4
Ind
Ar
NO2
a N1
1
7
6
7
2
4
5
3
Alk
Cl
Yellow oil; yield 0.92 g, 76% (5g); 50 mg, 14% (6a); R (hexane/EtOAc 2:1) 0.46; [Found: C, 62.0; H,
f
6
2
1
.4; N, 6.7. C H ClN O requires C, 62.30; H, 6.22; Cl, 8.76; N, 6.92]. ν
(thin film) 2954, 2925,
max
21
25
2
4
854, 1702, 1601, 1579, 1521, 1462, 1414, 1377, 1345, 1261, 1205, 1155, 1122, 1107, 1092, 1047,
-1 1
016, 967, 863, 853, 803, 755, 721, 708, 648 cm . H NMR (500 MHz, CDCl ): δ 1.23-1.29 (2H, m,
3
H
СH -Alk3), 1.43-1.49 (2H, m, СH -Alk2), 1.57-1.63 (2H, m, СH -Alk4), 1.77-1.82 (2H, m, СH -
2
2
2
2
Ind5), 1.86-1.90 (2H, m, СH -Ind6), 2.57 (2H, br t, J 6.1 Hz, СH -Ind7), 2.77 (2H, br t, J 6.1 Hz, СH -
2
2
2
Ind4), 3.41 (2H, t, J 6.5 Hz, СH -Alk5), 3.60 (3H, s, OCH ), 3.65 (2H, t, J 7.8 Hz, СH -Alk1), 7.50
2
3
2
1
3
1
(
2H, d, J 8.8 Hz, H3,H5-Ar), 8.28 (2H, d, J 8.8 Hz, H2,H6-Ar). C{ H} NMR (125.7 MHz, CDCl ): δ
3
1
65.5 (C=O), 147.4 (C4-Ar), 139.9 (C1-Ar), 134.5 (C2-Ind), 131.8 (C2-Ar), 129.8 (C7a-Ind), 123.1
(
C3-Ar), 119.9 (C3a-Ind), 111.8 (C3-Ind), 50.5 (OCH ), 44.4 (C5-Alk), 43.7 (C1-Alk), 31.7 (C4-Alk),
3
3
0.1 (C2-Alk), 23.8 (C3-Alk), 23.3 (C4-Ind), 23.3 (C5-Ind), 23.0 (C6-Ind), 22.3 (C7-Ind).
Methyl 1-(5-chloropentyl)-2-(3-nitrophenyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5h.
Yellow oil; yield 0.97 g, 80% (5h); 54 mg, 15% (6a); R (hexane/EtOAc 2:1) 0.48; [Found: C, 62.0; H,
f
6
1
1
.4; N, 6.8. C H ClN O requires C, 62.30; H, 6.22; Cl, 8.76; N, 6.92]. ν
(thin film) 2926, 2854,
max
21
25
2
4
702, 1619, 1579, 1536, 1519, 1474, 1442, 1407, 1349, 1265, 1238, 1206, 1155, 1126, 1098, 1054,
-1 1
025, 965, 908, 858, 807, 787, 739, 711, 697, 651 cm . H NMR (500 MHz, CDCl ): δ 1.22-1.28
3
H
(
2H, m, СH -Alk3), 1.46-1.52 (2H, m, СH -Alk2), 1.57-1.63 (2H, m, СH -Alk4), 1.76-1.82 (2H, m,
2 2 2
СH -Ind5), 1.86-1.90 (2H, m, СH -Ind6), 2.57 (2H, br t, J 6.0 Hz, СH -Ind7), 2.77 (2H, br t, J 6.0 Hz,
2
2
2
СH -Ind4), 3.41 (2H, t, J 6.5 Hz, СH -Alk5), 3.59 (3H, s, OCH ), 3.64 (2H, t, J 7.7 Hz, СH -Alk1),
2
2
3
2
7
.60 (1H, br dd, J 7.6, 7.6 Hz, H5-Ar), 7.68 (1H, br d, J 7.6 Hz, H6-Ar), 8.20 (1H, d, J 1.3 Hz, H2-Ar),
1
3
1
8
.26 (1H, dd, J 7.6, 1.3 Hz, H4-Ar). C{ H} NMR (125.7 MHz, CDCl ): δ 165.5 (C=O), 147.9 (C3-
3
Ar), 137.2 (C6-Ar), 134.6 (C1-Ar), 134.3 (C2-Ind), 129.4 (C7a-Ind), 128.8 (C5-Ar), 125.6 (C2-Ar),

1
5
ACCEPTED MANUSCRIPT
1
22.9 (C4-Ar), 119.7 (C3a-Ind), 111.7 (C3-Ind), 50.5 (OCH ), 44.4 (C5-Alk), 43.6 (C1-Alk), 31.9
3
(C4-Alk), 30.2 (C2-Alk), 23.9 (C3-Alk), 23.3 (C4-Ind), 23.3 (C5-Ind), 23.0 (C6-Ind), 22.2 (C7-Ind).
+
HRMS (MALDI) calcd. for C H ClN O [M + Cs] 537.0552, found 537.0528.
2
1
25
2
4
Methyl
5-tert-butyl-1-(5-chloropentyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-indole-3-
carboxylate 5i.
Maize yellow oil; yield 1.07 g, 82% (5i); 40 mg, 11% (6a); R (hexane/EtOAc 2:1) 0.65; [Found: C,
f
6
2
1
1.9; H, 6.3; N, 6.6. C H ClFNO requires C, 62.30; H, 6.22; Cl, 8.76; N, 6.92]. ν
(thin film)
max
2
5
33
2
953, 2868, 1702, 1658, 1604, 1536, 1508, 1488, 1468, 1413, 1396, 1366, 1310, 1224, 1158, 1125,
-1
1
095, 1073, 1058, 1015, 918, 838, 788, 753, 733, 651, 620, 591, 524 cm . H NMR (500 MHz,
CDCl ): δ 1.00 (9H, s, (CH ) ), 1.22-1.28 (2H, m, СH -Alk3), 1.39-1.50 (4H, m, СH -Alk2, CH -
3
H
3 3
2
2
X
Ind5, СH -Ind6), 1.56-1.62 (2H, m, СH -Alk4), 2.06-2.11 (1H, m, СH -Ind6), 2.37-2.41 (1H, m,
A
2
B
СH -Ind4), 2.49-2.55 (1H, m, СH -Ind7), 2.64-2.68 (1H, m, СH -Ind7), 2.96-3.01 (1H, m, СH -
A
A
B
B
Ind4), 3.40 (2H, t, J 6.5 Hz, СH -Alk5), 3.57 (3H, s, OCH ), 3.60 (2H, t, J 7.7 Hz, СH -Alk1), 7.09
2
3
2
(2H, dd, JHH 8.8 Hz, JHF 8.8 Hz, H2,H6-Ar), 7.27 (2H, dd, JHH 8.8 Hz, JHF 3.4 Hz, H3,H5-Ar).
1
3
1
1
C{ H} NMR (100.6 MHz, CDCl ): δ 165.8 (C=O), 162.5 (d, J = 247.6 Hz, C4-Ar), 136.4 (C2-
3
CF
3
4
Ind), 132.4 (d, J = 8.2 Hz, C2-Ar), 128.9 (d, J = 3.3 Hz, C1-Ar), 128.6 (C7a-Ind), 119.6 (C3a-
CF
CF
2
Ind), 114.9 (d, J = 21.6 Hz, C3-Ar), 110.9 (C3-Ind), 50.2 (OCH ), 45.3 (C5-Ind), 44.4 (C5-Alk),
CF
3
4
3.5 (C1-Alk), 32.5 (C-(CH ) ), 31.7 (C4-Alk), 30.0 (C2-Alk), 27.4 (C-(CH ) ), 24.6 (C4-Ind), 24.5
3 3 3 3
1
9
1
(
C6-Ind), 23.8 (C3-Alk), 23.1 (C7-Ind). F{ H} NMR (376.5 MHz, CDCl ): δ 113.5 (F).
3
Ethyl 1-(5-bromopentyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5j.
O
OCH CH
2
3
4
2
3
3
a
3
5
6
2
1
4
Ind
Ar
F
a N1
7
6
5
7
2
1
4
5
3
Alk
Br

1
6
ACCEPTED MANUSCRIPT
Yellow oil; yield 1.02 g, 78% (5j); 60 mg, 12% (6a); R (hexane/EtOAc 2:1) 0.60; [Found: C, 60.1; H,
f
6
.4; N, 3.0. C H BrFNO requires C, 60.55; H, 6.24; Br, 18.31; F, 4.35; N, 3.21]. ν
(thin film)
max
2
2
27
2
-1
2
936, 2857, 1732, 1697, 1600, 1509, 1489, 1459, 1414, 1255, 1158, 1117, 1094, 1038, 838, 523 cm .
1
H NMR (500 MHz, CDCl ): δ 1.06 (3H, t, J 7.1, OCH CH ), 1.22-1.28 (2H, m, СH -Alk3), 1.44-
3
H
2
3
2
1
.50 (2H, m, СH -Alk2), 1.65-1.71 (2H, m, СH -Alk4), 1.77-1.81 (2H, m, СH -Ind5), 1.85-1.89 (2H,
2 2 2
m, СH -Ind6), 2.55 (2H, br t, J 5.9 Hz, СH -Ind7), 2.78 (2H, br t, J 5.9 Hz, СH -Ind4), 3.28 (2H, t, J
2
2
2
6
.6 Hz, СH -Alk5), 3.60 (2H, t, J 7.7 Hz, СH -Alk1), 4.04 (2H, q, J 7.1 Hz, OCH CH ), 7.10 (2H, dd,
2 2 2 3
1
3
1
JHH 8.6 Hz, JHF 8.6 Hz, H2,H6-Ar), 7.28 (2H, dd, JHH 8.6 Hz, JHF 3.0 Hz, H3,H5-Ar). C{ H} NMR
1
3
(
125.7 MHz, CDCl ): δ 165.3 (C=O), 162.5 (d, J = 247.1 Hz, C4-Ar), 136.1 (C2-Ind), 132.5 (d, J
3 CF CF
2
2
=
8.2 Hz, C2-Ar), 129.0 (d, J = 3.4 Hz, C1-Ar), 128.4 (C7a-Ind), 119.2 (C3a-Ind), 114.9 (d, J =
CF CF
2
1.6 Hz, C3-Ar), 111.2 (C3-Ind), 58.8 (OCH CH ), 43.4 (C1-Alk), 33.1 (C5-Alk), 31.8 (C4-Alk), 29.9
2 3
(C2-Alk), 25.1 (C3-Alk), 23.4 (C5-Ind), 23.3 (C4-Ind), 23.0 (C6-Ind), 22.2 (C7-Ind), 14.1
19
1
(
OCH CH ). F{ H} NMR (470.5 MHz, CDCl ): δ -113.8 (F).
2
3
3
Methyl 1-(5-chloropentyl)-2-hexyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5k.
Colorless oil; yield 0.75 g, 68% (5j); 50 mg, 14% (6a); R (hexane/EtOAc 2:1) 0.60; [Found: C, 68.4;
f
H, 9.6; N, 3.6. C H ClNO requires C, 68.55; H, 9.31; Cl, 9.64; N, 3.81]. ν (thin film) 2931, 2856,
21
24
2
max
-1 1
1
695, 1518, 1441, 1422, 1328, 1259, 1237, 1187, 1155, 1113, 1032, 786, 732, 653 cm . H NMR (500
MHz, CDCl ): δ 0.89 (3H, t, J 6.8 Hz, СH -Alk2-6), 1.26-1.34 (4H, m, СH -Alk2-4, CH -Alk2-5),
3
H
2
2
2
1
.37-1.43 (2H, m, СH -Alk2-3), 1.47-1.56 (4H, m, СH -Alk2-2, СH -Alk1-3), 1.61-1.67 (2H, m, СH -
2 2 2 2
Alk1-2), 1.71-1.74 (2H, m, СH -Ind5), 1.77-1.83 (4H, m, СH -Ind6, СH -Alk1-4), 2.47 (2H, br t, J 5.8
2
2
2
Hz, СH -Ind7), 2.68 (2H, br t, J 5.9 Hz, СH -Ind4), 2.87 (2H, br t, J 8.0 Hz, СH -Alk2-1), 3.54 (2H, t,
2
2
2
13
1
J 6.5 Hz, СH -Alk1-5), 3.71 (2H, t, J 7.8 Hz, СH -Alk1-1), 3.76 (3H, s, OCH ). C{ H} NMR (125.7
2
2
3
MHz, CDCl ): δ 166.4 (C=O), 139.4 (C2-Ind), 126.9 (C7a-Ind), 118.5 (C3a-Ind), 108.6 (C3-Ind), 50.1
3
(
OCH ), 44.5 (C5-Alk1), 42.9 (C1-Alk1), 32.1 (C4-Alk1), 31.6 (C4-Alk2), 30.6 (C2-Alk1), 30.5 (C2-
3
Alk2), 29.5 (C3-Alk2), 25.5 (C1-Alk2), 24.2 (C3-Alk1), 23.5 (C4-Ind+C5-Ind), 23.1 (C6-Ind), 22.6
1
5
(
C5-Alk2), 22.1 (C7-Ind), 14.0 (C6-Alk2). N NMR (50.6 MHz, CDCl ): δ 163.7 (N). HRMS
3
+
(
MALDI) calcd. for C H ClNO [M+Cs] 500.1327, found 500.1354.
2
1
34
2

1
7
ACCEPTED MANUSCRIPT
Methyl 5-tert-butyl-1-(5-chloropentyl)-2-phenyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5l.
Maize yellow oil; yield 0.99 g, 79% (5l); 54 mg, 15% (6a); R (hexane/EtOAc 2:1) 0.60; [Found: C,
f
7
1.9; H, 8.5; N, 3.2. C H ClNO requires C, 72.18; H, 8.24; Cl, 8.52; N, 3.37]. ν (thin film) 2953,
25 34 2 max
-1 1
2
926, 2855, 1703, 1480, 1444, 1407, 1366, 1310, 1207, 1165, 1124, 1098, 761, 702 cm . H NMR
(
500 MHz, CDCl ): δ 1.00 (9H, s, (CH ) ), 1.22-1.30 (2H, m, СH -Alk3), 1.42-1.51 (4H, m, СH -
3 H 3 3 2 2
Alk2, CH -Ind5, СH -Ind6), 1.55-1.60 (2H, m, СH -Alk4), 2.09-2.12 (1H, m, СH -Ind6), 2.40-2.43
X
A
2
B
(
1H, m, СH -Ind4), 2.51-2.54 (1H, m, СH -Ind7), 2.65-2.68 (1H, m, СH -Ind7), 3.00-3.03 (1H, m,
A A B
СH -Ind4), 3.39 (2H, t, J 6.6 Hz, СH -Alk5), 3.57 (3H, s, OCH ), 3.63 (2H, t, J 7.7 Hz, СH -Alk1),
B
2
3
2
1
3
1
7
.31 (2H, dd, J 8.0, 1.7 Hz, H2,H6-Ar), 7.38-7.43 (3H, m, H3,H4,H5-Ar). C{ H} NMR (125.7 MHz,
CDCl ): δ 165.9 (C=O), 137.7 (C2-Ind), 133.0 (C1-Ar), 130.7 (C2-Ar), 128.4 (C7a-Ind), 127.9 (C4-
3
Ar), 127.8 (C3-Ar), 119.6 (C3a-Ind), 110.6 (C3-Ind), 50.2 (OCH ), 45.4 (C5-Ind), 44.4 (C5-Alk), 43.5
3
(
C1-Alk), 32.5 (C(CH ) ), 31.7 (C4-Alk), 30.0 (C2-Alk), 27.5 (C(CH ) ), 24.7 (C4-Ind), 24.5 (C6-
3 3 3 3
+
Ind), 23.8 (C3-Alk), 23.1 (C7-Ind). HRMS (MALDI) calcd. for C H ClNO [M+Cs] 548.1327,
2
5
34
2
found 548.1320.
Ethyl 1-(5-bromopentyl)-2-phenyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 5m.
Yellow oil; yield 0.83 g, 66% (5l); 0.11 g, 22% (6a); R (hexane/EtOAc 2:1) 0.50; [Found: C, 63.0; H,
f
7
1
.0; N, 3.2. C H ClNO requires C, 63.16; H, 6.75; Br, 19.10; N, 3.35]. ν
(thin film) 2935, 1752,
max
25
34
2
-1 1
695, 1484, 1454, 1264, 1202, 1158, 1115, 754, 700 cm . H NMR (500 MHz, CDCl ): δ 1.00 (3H,
3
H
t, J 7.1 Hz, OCH CH ), 1.23-1.27 (2H, m, СH -Alk3), 1.44-1.50 (2H, m, СH -Alk2), 1.62-1.68 (2H,
2
3
2
2
m, СH -Alk4), 1.78-1.82 (2H, m, СH -Ind5), 1.85-1.90 (2H, m, СH -Ind6), 2.56 (2H, br t, J 6.1 Hz,
2
2
2

1
8
ACCEPTED MANUSCRIPT
СH -Ind7), 2.80 (2H, br t, J 6.0 Hz, СH -Ind4), 3.25 (2H, t, J 6.7 Hz, СH -Alk5), 3.62 (2H, t, J 7.7 Hz,
2
2
2
СH -Alk1), 4.03 (2H, q, J 7.1 Hz, OCH CH ), 7.30 (2H, dd, J 7.9, 2.1 Hz, H2,H6-Ar), 7.37-7.40 (3H,
2
2
3
1
3
1
m, H3,H4,H5-Ar). C{ H} NMR (125.7 MHz, CDCl ): δ 165.4 (C=O), 137.4 (C2-Ind), 133.1 (C1-
3
Ar), 130.8 (C2-Ar), 128.2 (C7a-Ind), 127.9 (C4-Ar), 127.8 (C3-Ar), 119.2 (C3a-Ind), 110.9 (C3-Ind),
5
8.8 (OCH CH ), 43.4 (C1-Alk), 33.1 (C5-Alk), 31.9 (C4-Alk), 29.9 (C2-Alk), 25.1 (C3-Alk), 23.5
2 3
1
5
(
C4-Ind), 23.3 (C5-Ind), 23.1 (C6-Ind), 22.3 (C7-Ind), 14.0 (OCH CH ). N NMR (50.6 MHz,
2 3
CDCl ): δ 164.4 (N).
3
Piperidinium chloride 6a.
о
Off-white powder, m.p. 247-248 С; [Found: C, 49.3; H, 10.0; N, 11.3. C H ClN: C, 49.38; H, 9.95;
5
12
Cl, 29.15; N, 11.52]. νmax (thin film) 2950, 2842, 2809, 2763, 2735, 2527, 2428, 1593, 1462, 1437,
-1 1
1
032, 943, 557 cm . H NMR (400 MHz, CDCl ): δ 1.51-1.57 (2H, m, СH -4), 1.65-1.70 (4H, m,
3
H
2
1
3
1
СH -3,СH -5), 2.95 (4H, t, J 5.7 Hz, СH -2,СH -6), 9.15 (2H, br s, NH ). C{ H} NMR (100.6 MHz,
2
2
2
2
2
1
5
DMSO-d ): δ 43.3 (C2, С6), 21.9 (C3, С5), 21.7 (C4). N NMR (50.6 MHz, DMSO-d ): δ 41.5 (N).
6
6
Piperidinium bromide 6b.
о
Off-white powder, m.p. 334-336 С; [Found: C, 36.0; H, 7.5; N, 8.3. C H BrN: C, 36.16; H, 7.28; Br,
5
12
4
1
3
8.12; N, 8.43]. νmax (thin film) 3177, 2949, 2840, 2808, 2738, 2627, 2513, 2413, 1586, 1462, 1434,
-1 1
030, 551 cm . H NMR (400 MHz, CDCl ): δ δ 1.51-1.57 (2H, m, СH -4), 1.63-1.68 (4H, m, СH -
3
H
2
2
13
1
,СH -5), 3.00 (4H, t, J 5.0 Hz, СH -2,СH -6), 8.42 (2H, br s, NH ). C{ H} NMR (100.6 MHz,
2
2
2
2
DMSO-d ): δ 43.8 (C2, С6), 22.1 (C3, С5), 21.6 (C4).
6
2
-Phenyl-1-(piperidin-1-yl)ethanone 7a.

1
9
ACCEPTED MANUSCRIPT
Colorless oil; yield 24 mg, 4%; R (hexane/EtOAc 2:1) 0.60; [Found: C, 76.5; H, 8.6; N, 6.7.
f
C H NO requires C, 76.81; H, 8.43; N, 6.89]. ν (thin film) 3028, 3005, 2937, 2856, 1738, 1640,
max
13
17
-1 1
1
444, 1368, 1256, 1225, 1136, 1123, 1022, 726, 698 cm . H NMR (600 MHz, CDCl ): δ 1.29-1.33
3 H
(
2H, m, СH -3), 1.37-1.41 (2H, m, СH -5), 1.51-1.55 (2H, m, СH -4), 3.40 (2H, t, J 5.6 Hz, СH -2),
2 2 2 2
3
.43 (2H, t, J 5.6 Hz, СH -6), 3.68 (2H, s, CH ), 7.21 (1H, t, J 7.4 Hz, H4′), 7.22 (2H, d, J 7.7 Hz, H2′,
2 2
1
3
1
H6′), 7.30 (2H, dd, J 7.4, 7.7 Hz, H3′, H5′). C{ H} NMR (125.7 MHz, DMSO-d ): δ 168.3 (C=O),
6
1
36.0 (C1-Ar), 128.7 (C2-Ar), 128.2 (C3-Ar), 126.2 (C4-Ar), 46.4 (C2), 42.0 (C6), 39.7 (CH ), 25.8
2
1
5
(
C3), 25.2 (C5), 23.9 (C4). N NMR (50.6 MHz, DMSO-d ): δ 121.1 (N1). HRMS (MALDI) calcd.
6
+
for C H NO [M+Cs] 336.0359, found 336.0330.
1
3
17
2
-(4-nitrophenyl)-1-(piperidin-1-yl)ethanone 7b.
4
5
6
3
2
N
O
1'
6
'
2'
3'
5'
4'
NO2
Yellow oil; yield 45 mg, 6%; R (hexane/EtOAc 2:1) 0.60; Found: C, 62.8; H, 6.7; N, 11.1.
f
C H N O requires C, 62.89; H, 6.50; N, 11.28. ν (thin film) 2932, 1923, 2854, 1736, 1632, 1606,
13
16
2
3
max
-1 1
1
517, 1443, 1423, 1346, 1250, 1225, 1135, 1109, 1013, 857, 820, 734 cm . H NMR (600 MHz,
CDCl ): δ 1.44-1.46 (2H, m, СH -3), 1.53-1.55 (2H, m, СH -5), 1.60-1.63 (2H, m, СH -4), 3.40 (2H,
3
H
2
2
2
t, J 5.3 Hz, СH -2), 3.58 (2H, t, J 5.3 Hz, СH -6), 3.81 (2H, s, CH ), 7.42 (2H, d, J 8.8 Hz, H2′, H6′),
2
2
2
1
3
1
8
1
2
.17 (2H, d, J 8.8 Hz, H3′, H5′). C{ H} NMR (125.7 MHz, CDCl ): δ 167.7 (C=O), 147.0 (C4-Ar),
3
43.0 (C1-Ar), 129.8 (C2-Ar), 123.7 (C3-Ar), 47.2 (C2), 43.1 (C6), 40.4 (CH ), 26.4 (C3), 25.4 (C5),
2
1
5
4.3 (C4). N NMR (50.6 MHz, CDCl ) δ 124.5 (N1), 370.0 (NO ). HRMS (MALDI) calcd. for
3
2
+
C H N O [M+Cs] 381.0210, found 381.0240.
13
16
2
3
4
.4. General procedure for the synthesis of 3.

2
0
ACCEPTED MANUSCRIPT
A solution of pyrrolidine (5 mmol) and cyclohexanone а (5 mmol) in benzene (25 mL) was heated to
reflux with the Dean-Stark apparatus for 1 h, then cooled to room temperature and methyl 3-chloro-2-
oxo-3-arylpropanoate 2 (5 mL) in benzene was added then heated to reflux for another 2 h. The
solvent was removed to give a slightly yellow crude product 3, which was purified on column
chromatography with silica gel (eluent – hexane/EtOAc).
Methyl 1-(4-chlorobutyl)-2-phenyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 3a.
Colorless oil; yield 1.69 g, 98%; R (hexane/EtOAc 2:1) 0.53; [Found: C, 69.1; H, 6.8; N, 3.9.
f
C H ClNO requires C, 69.45; H, 6.99; Cl, 10.25; N, 4.05]. ν (thin film) 2933, 2853, 1702, 1527,
max
20
24
2
-1 1
1
481, 1459, 1441, 1406, 1370, 1276, 1250, 1204, 1154, 1120, 1086, 1025, 757, 702 cm . H NMR
(
500 MHz, CDCl ): δ 1.52-1.58 (2H, m, СH -Alk3), 1.58-1.64 (2H, m, СH -Alk2), 1.78-1.82 (2H, m,
3
H
2
2
СH -Ind5), 1.86-1.90 (2H, m, СH -Ind6), 2.58 (2H, br t, J 6.0 Hz, СH -Ind7), 2.79 (2H, br t, J 6.1 Hz,
2
2
2
СH -Ind4), 3.32 (2H, t, J 6.3 Hz, СH -Alk4), 3.58 (3H, s, OCH ), 3.66 (2H, t, J 7.4 Hz, СH -Alk1),
2
2
3
2
1
3
1
7
.30-7.32 (2H, m, H2,H6-Ar), 7.38-7.43 (3H, m, H3,H4,H5-Ar). C{ H} NMR (125.7 MHz, CDCl ):
3
δ 165.8 (C=O), 137.5 (C2-Ind), 132.8 (C1-Ind), 130.7 (C2-Ar), 128.2 (C7a-Ind), 128.0 (C4-Ar), 127.9
(
C3-Ar), 119.2 (C3a-Ind), 110.7 (C3-Ind), 50.2 (OCH ), 44.0 (C4-Alk), 42.8 (C1-Alk), 29.3 (C3-Alk),
3
1
5
2
7.9 (C2-Alk), 23.4 (C5-Ind), 23.3 (C4-Ind), 23.0 (C6-Ind), 22.2 (C7-Ind). N NMR (50.6 MHz,
CDCl ): δ 163.9 (N).
3
Methyl 1-(4-chlorobutyl)-2-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 3b.
Maize yellow oil; yield 1.56 g, 82%; R (hexane/EtOAc 2:1) 0.51; [Found: C, 63.0; H, 6.3; N, 3.5.
f
C H Cl NO requires C, 63.16; H, 6.10; Cl, 18.64; N, 3.68]. ν (thin film) 2922, 2850, 1701, 1525,
20
23
2
2
max

2
1
ACCEPTED MANUSCRIPT
1
7
479, 1449, 1440, 1400, 1368, 1276, 1265, 1233, 1200, 1152, 1124, 1085, 1010, 965, 824, 786, 750,
-1 1
34 cm . H NMR (400 MHz, CDCl ): δ 1.54-1.64 (4H, m, СH -Alk2, СH -Alk3), 1.76-1.82 (2H, m,
3
H
2
2
СH -Ind5), 1.84-1.90 (2H, m, СH -Ind6), 2.56 (2H, br t, J 6.1 Hz, СH -Ind7), 2.77 (2H, br t, J 6.1 Hz,
2
2
2
СH -Ind4), 3.36 (2H, t, J 6.2 Hz, СH -Alk4), 3.60 (3H, s, OCH ), 3.65 (2H, t, J 7.3 Hz, СH -Alk1),
2
2
3
2
1
3
1
7
.25 (2H, d, J 8.5 Hz, H3,H5-Ar), 7.40 (2H, d, J 8.5 Hz, H2,H6-Ar). C{ H} NMR (125.7 MHz,
CDCl ): δ 165.7 (C=O), 136.1 (C2-Ind), 134.2 (C4-Ar), 132.1 (C2-Ar), 131.3 (C1-Ar), 128.7 (C7a-
3
Ind), 128.2 (C3-Ar), 119.4 (C3a-Ind), 111.1 (C3-Ind), 50.3 (OCH ), 44.0 (C4-Alk), 42.9 (C1-Alk),
3
1
5
2
9.4 (C3-Alk), 28.0 (C2-Alk), 23.4 (C5-Ind+C4-Ind), 23.0 (C6-Ind), 22.3 (C7-Ind). N NMR (50.6
MHz, CDCl ): δ 163.8 (N1).
3
Methyl 1-(4-chlorobutyl)-2-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 3c.
Yellow oil; yield 1.87 g, 88%; R (hexane/EtOAc 2:1) 0.73; [Found: C, 56.3; H, 5.6; N, 3.2.
f
C H BrClNO requires C, 56.55; H, 5.46; Br, 18.81; Cl, 8.35; N, 3.30]. ν (thin film) 2935, 2853,
max
20
23
2
-1 1
1
699, 1520, 1480, 1440, 1406, 1266, 1274, 1210, 1204, 1128, 1120, 1075, 1021, 757, 735 cm . H
NMR (600 MHz, CDCl ): δ 1.54-1.58 (2H, m, СH -Alk3), 1.59-1.63 (2H, m, СH -Alk2), 1.78-1.80
3
H
2
2
(
2H, m, СH -Ind5), 1.86-1.88 (2H, m, СH -Ind6), 2.56 (2H, br t, J 6.1 Hz, СH -Ind7), 2.76 (2H, br t, J
2 2 2
6
.1 Hz, СH -Ind4), 3.36 (2H, t, J 6.2 Hz, СH -Alk4), 3.59 (3H, s, OCH ), 3.64 (2H, t, J 7.3 Hz, СH -
2 2 3 2
1
3
1
Alk1), 7.18 (2H, d, J 8.4 Hz, H3,H5-Ar), 7.55 (2H, d, J 8.4 Hz, H2,H6-Ar). C{ H} NMR (150.9
MHz, CDCl ): δ 165.7 (C=O), 136.0 (C2-Ind), 132.4 (C1-Ar), 132.4 (C2-Ar), 131.2 (C3-Ar), 128.7
3
(
C7a-Ind), 122.4 (C4-Ar), 119.5 (C3a-Ind), 111.2 (C3-Ind), 50.3 (OCH ), 44.0 (C4-Alk), 42.9 (C1-
3
Alk), 29.4 (C3-Alk), 28.1 (C2-Alk), 23.4 (C4-Ind+C5-Ind), 23.1 (C6-Ind), 22.3 (C7-Ind).
Methyl 1-(4-chlorobutyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 3d.

2
2
ACCEPTED MANUSCRIPT
Colorless oil; yield 1.67 g, 92%; R (hexane/EtOAc 2:1) 0.59; [Found: C, 65.9; H, 6.6; N, 3.7.
f
C H ClFNO requires C, 66.02; H, 6.37; Cl, 9.74; F, 5.22; N, 3.85]. ν (thin film) 2924, 2850,
max
20
23
2
1
7
1
704, 1600, 1527, 1480, 1459, 1441, 1406, 1370, 1276, 1250, 1204, 1154, 1122, 1090, 1025, 757, 732,
-1 1
02, 646, 592, 521 cm . H NMR (500 MHz, CDCl ): δ 1.55-1.61 (4H, m, СH -Alk2, СH -Alk3),
3
H
2
2
.78-1.81 (2H, m, СH -Ind5), 1.85-1.88 (2H, m, СH -Alk6), 2.56 (2H, br t, J 6.0 Hz, СH -Ind7), 2.77
2
2
2
(
2H, br t, J 6.0 Hz, СH -Ind4), 3.35 (2H, t, J 6.1 Hz, СH -Alk4), 3.59 (3H, s, OCH ), 3.64 (2H, t, J 7.4
2 2 3
Hz, СH -Alk1), 7.11 (2H, dd, J 8.7 Hz, JHF 8.7 Hz, H2,H6-Ar), 7.28 (2H, dd, JHH 8.7 Hz, JHF 3.0
2
HH
1
3
1
1
Hz, H3,H5-Ar). C{ H} NMR (125.7 MHz, CDCl ): δ 165.8 (C=O), 162.6 (d, J 247.9 Hz, C4-Ar),
3
CF
3
4
1
36.4 (C2-Ind), 132.5 (d, J 8.2 Hz, C2-Ar), 128.8 (d, J 3.1 Hz, C1-Ar), 128.5 (C7a-Ind), 119.3
CF CF
2
(
C3a-Ind), 115.0 (d, J 21.4 Hz, C3-Ar), 111.1 (C3-Ind), 50.3 (OCH ), 44.0 (C4-Alk), 42.9 (C1-
CF 3
1
9
1
Alk), 29.7 (C3-Alk), 28.0 (C2-Alk), 23.4 (C4-Ind+C5-Ind), 23.1 (C6-Ind), 22.3 (C7-Ind). F{ H}
+
NMR (470.5 MHz, CDCl ): δ 113.6 (F). HRMS (MALDI) calcd. for C H ClFNO [M + Cs]
3
20 23
2
4
96.0450, found 496.0414.
General procedure for the synthesis of 10.
.5. A solution of 3 or 5 (0.5 mmol) and 0.61 g of chloranil (2.5 mmol) in p-xylene (20 mL) was
4
heated at reflux for 17 h, cooled, filtered and the solid residue was washed with ether (3×5 mL). The
solvent was evaporated in vacuo and the residue was chromatographed (hexane : EtOAc) to give a
pure indole derivative 10.
Methyl 1-(5-chloropentyl)-2-phenyl-1H-indole-3-carboxylate 10a.
Colorless oil; yield 1.45 g, 85%; R (hexane/EtOAc 2:1) 0.40; [Found: C, 70.1; H, 6.0; N, 3.9.
f
C H ClNO requires C, 70.27; H, 5.90; Cl, 10.37; F, 5.22; N, 4.10]. ν (thin film) 2951, 2927,
max
20
20
2
-1 1
1
694, 1541, 1483, 1460, 1406, 1234, 1190, 1146, 1117, 1092. 1026, 791, 753, 701, 646 cm . H NMR
(
500 MHz, CDCl ): δ 1.48-1.54 (2H, m, СH -Alk3), 1.63-1.69 (2H, m, СH -Alk2), 3.44 (2H, t, J 6.5,
3
H
2
2
СH -Alk4), 3.60 (3H, s, OCH ), 4.05 (2H, t, J 7.3 Hz, СH -Alk1), 7.26 (1H, ddd, J 7.5, 7.4, 1.1 Hz,
2
3
2
H5-Ind), 7.31 (1H, ddd, J 7.0, 6.8, 1.3 Hz, H6-Ind), 7.43-7.46 (2H, m, H3,H5-Ar), 7.51-7.53 (3H, m,

2
3
ACCEPTED MANUSCRIPT
1
3
1
H2,H4, H6-Ar), 7.75 (1H, br d, J 8.2 Hz, H7-Ind), 8.09 (1H, br d, J 6.3 Hz, H4-Ind). C{ H} NMR
125.7 MHz, CDCl ): δ 164.3 (C=O), 146.1 (C2-Ind), 135.6 (C7a-Ind), 131.0 (C1-Ar), 130.1 (C2-Ar),
(
3
1
28.8 (C4-Ar), 128.0 (C3-Ar), 126.0 (C3a-Ind), 122.7 (C6-Ind), 121.8 (C5-Ind), 121.2 (C4-Ind), 110.9
(
C7-Ind), 104.2 (C3-Ind), 50.3 (OCH ), 44.5 (C4-Alk), 42.6 (C1-Alk), 29.0 (C3-Alk), 26.5 (C2-Alk).
3
1
5
+
N NMR (50.6 MHz, CDCl ): δ 150.8 (N1). HRMS (MALDI) calcd. for C H ClNO [M+Cs]
3
20 20
2
4
74.0232, found 474.0249.
Methyl 2-(4-bromophenyl)-1-(4-chlorobutyl)-1H-indole-3-carboxylate 10c.
Sallow oil; yield 1.72 g, 82%; R (hexane/EtOAc 2:1) 0.63; [Found: C, 56.9; H, 5.0; N, 3.2.
f
C H BrClNO requires C, 57.09; H, 4.55; Br, 18.99; Cl, 8.43; N, 3.33]. ν (thin film) 3598, 3160,
max
20
19
2
-1 1
2
142, 1660, 1040, 1014, 968, 889, 756, 656 cm . H NMR (500 MHz, CDCl ): δ 1.50-1.56 (2H, m,
3 H
СH -Alk3), 1.62-1.68 (2H, m, СH -Alk2), 3.47 (2H, t, J 6.5 Hz, СH -Alk4), 3.63 (3H, s, OCH ), 4.06
2
2
2
3
(
2H, t, J 7.3 Hz, СH -Alk1), 7.26 (1H, ddd, J 8.1, 7.2, 1.1 Hz, H5-Ind), 7.32 (1H, ddd, J 8.0, 7.2, 1.3
2
Hz, H6-Ind), 7.41 (2H, d, J 8.5 Hz, H3,H5-Ar), 7.66 (1H, br d, J 8.0 Hz, H7-Ind), 7.72 (2H, d, J 8.5
1
3
1
Hz, H2,H6-Ar), 8.09 (1H, dd, J 8.0, 1.0 Hz, H4-Ind). C{ H} NMR (100.6 MHz, DMSO-d ): δ 164.2
6
(
C=O), 144.7 (C2-Ind), 135.7 (C7a-Ind), 132.3 (C2-Ar), 131.0 (C3-Ar), 130.3 (C1-Ar), 125.9 (C3a-
Ind), 122.8 C6-Ind), 122.5 (C4-Ar), 121.9 (C5-Ind), 121.2 (C4-Ind), 111.0 (C7-Ind), 104.5 (C3-Ind),
0.4 (OCH ), 44.5 (C4-Alk), 42.7 (C1-Alk), 29.0 (C3-Alk), 26.5 (C2-Alk).
5
3
Methyl 2-(4-fluorophenyl)-1-(4-chlorobutyl)-1H-indole-3-carboxylate 10d.
Reddish-brown oil; yield 1.55 g, 86%; R (hexane/EtOAc 2:1) 0.51; [Found: C, 66.7; H, 5.5; N, 3.7.
f
C H ClFNO requires C, 66.76; H, 5.32; Cl, 9.85; F, 5.28; N, 3.89]. ν (thin film) 3580, 3176,
max
20
19
2

2
4
ACCEPTED MANUSCRIPT
-1 1
2
262, 1650, 1038, 1022, 988, 860, 781, 744, 720, 662, 635 cm . H NMR (400 MHz, CDCl ): δ
3 H
1
.49-1.56 (2H, m, СH -Alk3), 1.62-1.69 (2H, m, СH -Alk2), 3.46 (2H, t, J 6.4 Hz, СH -Alk4), 3.62
2
2
2
(
3H, s, OCH ), 4.05 (2H, t, J 7.3 Hz, СH -Alk1), 7.24-7.31 (2H, m, H5,H6-Ind), 7.35 (2H, dd, J 8.7
3 2 HH
Hz, JHF 8.7 Hz, H2,H6-Ar), 7.51 (2H, dd, JHH 8.7 Hz, JHF 3.0 Hz, H3,H5-Ar), 7.66 (1H, d, J 8.0 Hz,
1
3
1
H7-Ind), 8.09 (1H, d, J 8.1 Hz, H4-Ind). C{ H} NMR (100.6 MHz, DMSO-d ): δ 164.3 (C=O),
6
1
3
1
1
62.4 (d, J = 245.7 Hz, C4-Ar), 145.0 (C2-Ind), 135.7 (C7a-Ind), 132.5 (d, J 8.4 Hz, C2-Ar),
CF CF
4
27.4 (d, J 3.2 Hz, C1-Ar), 125.9 (C3a-Ind), 122.8 (C6-Ind), 121.8 (C5-Ind), 121.2 (C4-Ind), 115.0
CF
2
(
d, J 21.7 Hz, C3-Ar), 111.0 (C7-Ind), 104.5 (C3-Ind), 50.4 (OCH ), 44.5 (C4-Alk), 42.6 (C1-Alk),
CF
3
1
9
1
2
9.0 (C3-Alk), 26.5 (C2-Alk). F{ H} NMR (376.5 MHz, DMSO-d ): δ 112.6 (F). HRMS (MALDI)
6
+
calcd. for C H FClNO [M+H] 360.1161, found 360.1132.
2
0
19
2
Methyl 2-(4-nitrophenyl)-1-(4-chlorobutyl)-1H-indole-3-carboxylate 10g.
Brown oil; yield 1.78 g, 92%; R (hexane/EtOAc 2:1) 0.50; [Found: C, 61.9; H, 5.2; N, 7.1.
f
C H ClN O requires C, 62.10; H, 4.95; Cl, 9.17; N, 7.24]. ν (thin film) 2498, 2864, 1688, 1603,
max
20
19
2
4
-1 1
1
520, 1485, 1457, 1439, 1389, 1348, 1194, 1160, 1145, 1119, 1017, 860, 790, 754, 710 cm . H NMR
(
600 MHz, CDCl ): δ 1.50-1.55 (2H, m, СH -Alk3), 1.62-1.67 (2H, m, СH -Alk2), 3.47 (2H, t, J 6.6
3
H
2
2
Hz, СH -Alk4), 3.63 (3H, s, OCH ), 4.09 (2H, t, J 7.5 Hz, СH -Alk1), 7.30 (1H, dd, J 7.0, 7.9 Hz, H5-
2
3
2
Ind), 7.35 (1H, ddd, J 7.0, 7.9, 0.9 Hz, H6-Ind), 7.71 (1H, br d, J 7.9 Hz, H7-Ind), 7.79 (2H, d, J 8.8
1
3
1
Hz, H2,6-Ind), 8.11 (1H, br d, J 7.9 Hz, H4-Ind), 8.36 (2H, d, J 8.8 Hz, H3,5-Ar). C{ H} NMR
150.9 MHz, DMSO-d ): δ 164.1 (C=O), 147.7 (C4-Ar), 143.5 (C2-Ind), 138.0 (C1-Ar), 136.0 (C7a-
(
6
Ind), 131.9 (C2-Ar), 125.7 (C3a-Ind), 123.1 (C6-Ind), 123.0 (C3-Ar), 122.1 (C5-Ind), 121.3 (C4-Ind),
11.1 (C7-Ind), 105.0 (C3-Ind), 50.5 (OCH ), 44.5 (C4-Alk), 42.8 (C1-Alk), 28.9 (C3-Alk), 26.5 (C2-
1
3
1
5
Alk). N NMR (50.6 MHz, DMSO-d ): δ 150.2 (N1), 370.4 (NO ).
6
2
Methyl 1-(5-chloropentyl)-2-(4-chlorophenyl)-1H-indole-3-carboxylate 11b.

2
5
ACCEPTED MANUSCRIPT
Maize yellow oil; yield 1.39 g, 71%; R (hexane/EtOAc 2:1) 0.56; [Found: C, 64.5; H, 5.5; N, 3.4.
f
C H Cl NO requires C, 64.62; H, 5.42; Cl, 18.17; N, 3.59]. ν (thin film) 3622, 3154, 2257, 2130,
21
21
2
2
max
-1 1
1
665, 1153, 1053, 1041, 1016, 979, 828, 772, 669 cm . H NMR (400 MHz, CDCl ): δ 1.14-1.22
3 H
(2H, m, СH -Alk3), 1.48-1.59 (4H, m, СH -Alk2, СH -Alk4), 4.02 (2H, t, J 7.5 Hz, СH -Alk5), 3.62
2 2 2 2
(
3H, s, OCH ), 4.02 (2H, t, J 7.5 Hz, СH -Alk1), 7.26 (1H, ddd, J 7.2, 7.7, 1.2 Hz, H5-Ind), 7.31 (1H,
3
2
ddd, J 7.2, 7.9, 1.3 Hz, H6-Ind), 7.48 (2H, d, J 8.6 Hz, H3,H5-Ar), 7.58 (2H, d, J 8.6 Hz, H2,H6-Ind),
1
3
1
7
.64 (1H, br d, J 7.9 Hz, H7-Ind), 8.09 (1H, dd, J 7.7, 1.3 Hz, H4-Ind). C{ H} NMR (150.9 MHz,
DMSO-d ): δ 164.3 (C=O), 144.7 (C2-Ind), 135.7 (C7a-Ind), 133.8 (C4-Ar), 132.1 (C2-Ar), 130.0
6
(C1-Ar), 128.1 (C3-Ar), 125.9 (C3a-Ind), 122.8 (C6-Ind), 121.8 (C5-Ind), 121.2 (C4-Ind), 111.0 (C7-
Ind), 104.4 (C3-Ind), 50.4 (OCH ), 44.9 (C5-Alk), 43.2 (C1-Alk), 31.2 (C4-Alk), 28.3 (C2-Alk), 23.3
3
+
(
C3-Alk). HRMS (MALDI) calcd. for C H Cl NO [M+Cs] 521.9998, found 522.0021.
2
1
21
2
2
Methyl 1-(5-chloropentyl)-2-(4-bromophenyl)-1H-indole-3-carboxylate 11c.
Yellow oil; yield 1.50 g, 69%; R (hexane/EtOAc 2:1) 0.58; [Found: C, 57.7; H, 5.0; N, 3.1.
f
C H BrClNO requires C, 58.02; H, 4.87; Br, 18.38; Cl, 8.15; N, 3.22]. ν (thin film) 3603, 3175,
max
21
21
2
-1 1
2
257, 2130, 1666, 1649, 1041, 1014, 979, 827, 754 cm . H NMR (500 MHz, CDCl ): δ 1.14-1.21
3 H
(2H, m, СH -Alk3), 1.48-1.59 (4H, m, СH -Alk2, СH -Alk4), 3.48 (2H, t, J 6.7 Hz, СH -Alk5), 3.63
2 2 2 2
(
3H, s, OCH ), 4.02 (2H, t, J 7.5 Hz, СH -Alk1), 7.26 (1H, ddd, J 7.6, 7.8, 1.1 Hz, H5-Ind), 7.31 (1H,
3
2
ddd, J 7.6, 8.1, 1.3 Hz, H6-Ind), 7.42 (2H, d, J 8.5 Hz, H3,H5-Ar), 7.65 (1H, br d, J 8.1 Hz, H7-Ind),
1
3
1
7
.72 (2H, d, J 8.5 Hz, H2,H6-Ar), 8.08 (1H, ddd, J 7.8, 1.3, 0.7 Hz, H4-Ind). C{ H} NMR (125.7
MHz, DMSO-d ): δ 164.3 (C=O), 144.8 (C2-Ind), 135.7 (C7a-Ind), 132.4 (C2-Ar), 131.0 (C3-Ar),
6
1
30.4 (C1-Ar), 125.9 (C3a-Ind), 122.8 (C6-Ind), 122.5 (C4-Ar), 121.8 (C5-Ind), 121.2 (C4-Ind), 111.0

2
6
ACCEPTED MANUSCRIPT
(
C7-Ind), 104.4 (C3-Ind), 50.4 (OCH ), 44.9 (C5-Alk), 43.2 (C1-Alk), 31.3 (C4-Alk), 28.3 (C2-Alk),
3
+
2
3.3 (C3-Alk). HRMS (MALDI) calcd. for C H ClBrNO [M+Cs] 567.9472, found 567.9493.
2
1
21
2
Methyl 1-(5-chloropentyl)-2-(4-fluorophenyl)-1H-indole-3-carboxylate 11d.
O
OCH
2
3
4
Ind
7
3
5
3
a
3
5
6
2 1
4
Ar
F
a N1
7
6
2
1
4
5
3
Alk
Cl
Reddish-brown oil; yield 1.40 g, 75%; R (hexane/EtOAc 2:1) 0.56; [Found: C, 67.3; H, 5.9; N, 3.7.
f
C H ClFNO requires C, 67.47; H, 5.66; Cl, 9.48; F, 5.08; N, 3.75]. ν (thin film) 3447, 2258,
max
21
21
2
-1 1
2
130, 1654, 1045, 1026, 997, 828, 767, 651 cm . H NMR (500 MHz, CDCl ): δ 1.15-1.21 (2H, m,
3 H
СH -Alk3), 1.48-1.58 (4H, m, СH -Alk2, СH -Alk4), 2.50 (2H, t, J 6.6 Hz, СH -Alk5), 3.62 (3H, s,
2
2
2
2
OCH ), 4.01 (2H, t, J 7.5 Hz, СH -Alk1), 7.26 (1H, ddd, J 7.2, 7.6, 1.0 Hz, H5-Ind), 7.30 (1H, ddd, J
3
2
7
.6, 8.1, 1.2 Hz, H6-Ind), 7.35 (2H, dd, JHH 8.8 Hz, JHF 8.8 Hz, H2,H6-Ar), 7.51 (2H, dd, JHH 8.8 Hz,
JHF 3.3 Hz, H3,H5-Ar), 7.64 (1H, br d, J 8.1 Hz, H7-Ind), 8.09 (1H, ddd, J 7.2, 1.2, 0.7 Hz, H4-Ind).
1
3
1
1
C{ H} NMR (125.7 MHz, DMSO-d ): δ 164.3 (C=O), 162.3 (d, J = 246.1 Hz, C4-Ar), 145.0 (C2-
6
CF
3
4
Ind), 135.6 (C7a-Ind), 132.5 (d, J = 8.6 Hz, C2-Ar), 127.5 (d, J = 3.2 Hz, C1-Ar), 125.9 (C3a-
CF
CF
2
Ind), 122.7 (C6-Ind), 121.8 (C5-Ind), 121.2 (C4-Ind), 115.0 (d, J = 21.7 Hz, C3-Ar), 111.0 (C7-
CF
Ind), 104.4 (C3-Ind), 50.4 (OCH ), 44.9 (C5-Alk), 43.1 (C1-Alk), 31.2 (C4-Alk), 28.3 (C2-Alk), 23.3
3
1
9
1
(
C3-Alk). F{ H} NMR (470.5 MHz, DMSO-d ): δ 112.6 (F). HRMS (MALDI) calcd. for
6
+
C H ClFNO [M+Cs] 506.0294, found 506.0267.
21
21
2
Methyl 1-(5-chloropentyl)-2-(3-bromophenyl)-1H-indole-3-carboxylate 11f.
O
OCH
3
Br
3
4
Ind
7
2
3
a
3
5
6
2 1
Ar
4
a N1
7
6
5
2
1
4
5
3
Alk
Cl
Yellow oil; yield 1.43 g, 66%; R (hexane/EtOAc 2:1) 0.51; [Found: C, 57.9; H, 5.0; N, 3.0.
f
C H BrClNO requires C, 58.02; H, 4.87; Br, 18.38; Cl, 5.15; N, 3.22]. ν (thin film) 3440, 2256,
max
21
21
2
-1
1
2
130, 1654, 1044, 1028, 997, 964, 888, 780, 745, 716, 700, 655, 545 cm . H NMR (500 MHz,

2
7
ACCEPTED MANUSCRIPT
CDCl ): δ 1.15-1.21 (2H, m, СH -Alk3), 1.48-1.54 (2H, m, СH -Alk4), 1.54-1.60 (2H, m, СH -
3
H
2
2
2
Alk2), 3.47 (2H, t, J 6.6 Hz, СH -Alk5), 3.64 (3H, s, OCH ), 4.01 (2H, t, J 7.5 Hz, СH -Alk1), 7.26
2
3
2
(1H, ddd, J 8.0, 7.9, 1.1 Hz, H5-Ind), 7.31 (1H, ddd, J 8.0, 8.1, 1.4 Hz, H6-Ind), 7.46-7.50 (2H, m,
H5,H6-Ar), 7.64 (1H, br d, J 8.1 Hz, H7-Ind), 7.68-7.69 (1H, m, H2-Ar), 7.71-7.74 (1H, ddd, J 6.9,
1
3
1
2
.2, 2.1 Hz, H4-Ar), 8.08 (1H, ddd, J 7.9, 1.4, 1.2 Hz, H4-Ind). C{ H} NMR (125.7 MHz, DMSO-
d6): δ 164.2 (C=O), 144.3 (C2-Ind), 135.7 (C7a-Ind), 133.5 (C1-Ar), 132.8 (C2-Ar), 131.8 (C4-Ar),
30.0 (C5-Ar), 129.4 (C6-Ar), 125.8 (C3a-Ind), 122.9 (C6-Ind), 121.9 (C5-Ind), 121.3 (C4-Ind), 121.1
1
(
C3-Ar), 111.0 (C7-Ind), 104.5 (C3-Ind), 50.5 (OCH ), 44.9 (C5-Alk), 43.2 (C1-Alk), 31.2 (C4-Alk),
3
+
2
8.3 (C2-Alk), 23.3 (C3-Alk). HRMS (MALDI) calcd. for C H ClBrNO [M+Na]
21 21 2
4
56.0336;458.0316, found 456.0348;458.0332.
Methyl 1-(5-chloropentyl)-2-(4-nitrophenyl)-1H-indole-3-carboxylate 11g.
O
OCH
3
4
Ind
7
2
3
5
3
a
3
5
6
2 1
4
Ar
NO2
a N1
7
6
2
1
4
5
3
Alk
Cl
Yellow oil; yield 1.80 g, 90%; R (hexane/EtOAc 2:1) 0.48; [Found: C, 62.8; H, 5.5; N, 7.2.
f
C H ClN O requires C, 62.92; H, 5.28; Cl, 8.84; N, 6.99]. ν (thin film) 3500, 2861, 1696, 1602,
max
21
21
2
4
-
1 1
1
1
047, 1021, 995, 858, 758, 702 cm . H NMR (600 MHz, CDCl ): δ 1.15-1.20 (2H, m, СH -Alk3),
3 H 2
.47-1.52 (2H, m, СH -Alk4), 1.53-1.58 (2H, m, СH -Alk2), 3.46 (2H, t, J 6.6 Hz, СH -Alk5), 3.63
2
2
2
(
3H, s, OCH ), 4.05 (2H, t, J 7.4 Hz, СH -Alk1), 7.29 (1H, dd, J 7.1, 7.9 Hz, H5-Ind), 7.34 (1H, ddd, J
3
2
7
.1, 8.2, 1.3 Hz, H6-Ind), 7.69 (1H, br d, J 8.2 Hz, H7-Ind), 7.79 (2H, d, J 8.7 Hz, H2,H6-Ar), 8.10
1
3
1
(
1H, br d, J 7.9 Hz, H4-Ind), 8.37 (2H, d, J 8.7 Hz, H3,H5-Ar). C{ H} NMR (150.9 MHz, DMSO-
d6): δ 164.2 (C=O), 147.7 (C4-Ar), 143.6 (C2-Ind), 138.1 (C1-Ar), 136.0 (C7a-Ind), 132.0 (C2-Ar),
1
1
25.8 (C3a-Ind), 123.2 (C6-Ind), 123.0 (C3-Ar), 122.1 (C5-Ind), 121.3 (C4-Ind), 111.2 (C7-Ind),
04.9 (C3-Ind), 50.6 (OCH ), 44.9 (C5-Alk), 43.3 (C1-Alk), 31.2 (C4-Alk), 28.3 (C2-Alk), 23.2 (C3-
3
Alk).
Methyl 5-tert-butyl-1-(5-chloropentyl)-2-(4-fluorophenyl)-1H-indole-3-carboxylate 11i.

2
8
ACCEPTED MANUSCRIPT
Yellow oil; yield 1.68 g, 78%; R (hexane/EtOAc 2:1) 0.58; [Found: C, 69.6; H, 7.0; N, 3.1.
f
C H ClFNO requires C, 69.84; H, 6.80; Cl, 8.25; F, 4.42; N, 3.26]. ν (thin film) 3593, 3182,
max
25
29
2
-1 1
2
260, 2131, 1644, 1046, 1024, 983, 830, 772, 742, 721, 669, 649 cm . H NMR (500 MHz, CDCl ):
3
δ 1.15-1.21 (2H, m, СH -Alk3), 1.37 (9H, s, (CH ) ), 1.48-1.57 (4H, m, СH -Alk2, СH -Alk4), 3.48
H
2
3 3
2
2
(
2H, t, J 6.6 Hz, СH -Alk5), 3.59 (3H, s, OCH ), 3.97 (2H, t, J 7.5 Hz, СH -Alk1), 7.34 (2H, dd, J
2 3 2 HH
8
.9 Hz, JHF 8.9 Hz, H2,H6-Ar), 7.38 (1H, dd, J 8.7, 2.0 Hz, H6-Ind), 7.47 (2H, dd, JHH 8.9 Hz, JHF 3.3
1
3
1
Hz, H3,H5-Ar), 7.53 (1H, dd, J 8.7, 0.4 Hz, H7-Ind), 8.11 (1H, dd, J 2.0, 0.4 Hz, H4-Ind). C{ H}
1
NMR (125.7 MHz, DMSO-d ): δ 164.5 (C=O), 162.3 (d, J = 245.8 Hz, C4-Ar), 144.9 (C2-Ind),
6
CF
3
4
1
1
1
44.3 (C5-Ind), 133.9 (C7a-Ind), 132.5 (d, J = 8.4 Hz, C2-Ar), 127.7 (d, J = 3.2 Hz, C1-Ar),
CF CF
2
25.8 (C3a-Ind), 120.8 (C6-Ind), 116.8 (C4-Ind), 115.0 (d, J = 21.7 Hz, C3-Ar), 110.4 (C7-Ind),
CF
04.3 (C3-Ind), 50.3 (OCH ), 44.9 (C5-Alk), 43.1 (C1-Alk), 34.4 (C(CH ) ), 31.6 (C(CH ) ), 31.2
3
3 3
3 3
1
9
1
(
C4-Alk), 28.3 (C2-Alk), 23.3 (C3-Alk). F{ H} NMR (470.5 MHz, DMSO-d ): δ 112.7 (F). HRMS
6
+
(
MALDI) calcd. for C H ClFNO [M+H] 430.1944, found 430.1953.
2
5
29
2
ACKNOWLEDGMENT
This work was supported by the Russian scientific foundation (grant № 14-23-00073).
SUPPLEMENTARY DATA
1
D and 2D NMR spectra for all compounds. Supplementary data related to this article can be
found at …
REFERENCES AND NOTES
1
. (a) Hesse, M. Alkaloids, Nature’s Curse or Blessing?, Wiley-VCH, Weinheim, Germany,
2
002, p. 316; (b) Seigler, D. S. Plant Secondary Metabolism, Springer, Berlin, 2001, pp. 628–
7
76.
2
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