From 4,5,6,7-tetrahydroindoles to 3- or 5-(4,5,6,7-tetrahydroindol-2-yl) isoxazoles in two steps: A regioselective switch between 3- and 5-isomers

Article abstract of DOI:10.1016/j.tet.2014.05.099

(4,5,6,7-Tetrahydroindol-2-yl)alkynes, synthesized by cross-coupling of 4,5,6,7-tetrahydroindoles with aroyl(hetaroyl)bromoalkynes or ethyl bromopropynoate in the presence of K₂CO₃, regioselectively cyclize with hydroxylamine to eith

Full text of DOI:10.1016/j.tet.2014.05.099

Accepted Manuscript
From 4,5,6,7-tetrahydroindoles to 3- or 5-(4,5,6,7-tetrahydroindol-2-yl)isoxazoles in
two steps: a regioselective switch between 3- and 5-isomers
Lyubov N. Sobenina , Denis N. Tomilin , Maxim D. Gotsko , Igor A. Ushakov , Albina
I. Mikhaleva , Boris A. Trofimov
PII:
S0040-4020(14)00805-9
10.1016/j.tet.2014.05.099
TET 25648
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 March 2014
Revised Date: 15 May 2014
Accepted Date: 27 May 2014
Please cite this article as: Sobenina LN, Tomilin DN, Gotsko MD, Ushakov IA, Mikhaleva AI, Trofimov
BA, From 4,5,6,7-tetrahydroindoles to 3- or 5-(4,5,6,7-tetrahydroindol-2-yl)isoxazoles in two steps: a
regioselective switch between 3- and 5-isomers, Tetrahedron (2014), doi: 10.1016/j.tet.2014.05.099.
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From 4,5,6,7-tetrahydroindoles to 3- or 5-
(4,5,6,7-tetrahydroindol-2-yl)isoxazoles in
two steps: a regioselective switch between 3-
and 5-isomers
Leave this area blank for abstract info.
Lyubov N. Sobenina, Denis N. Tomilin, Maxim D. Gotsko, Igor A. Ushakov, Albina I. Mikhaleva, Boris A.
Trofimov
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Science, 1 Favorsky Str.,
664033 Irkutsk, Russian Federation

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1
Tetrahedron
journal homepage: www.elsevier.com
>From 4,5,6,7-tetrahydroindoles to 3- or 5-(4,5,6,7-tetrahydroindol-2-yl)isoxazoles in
two steps: a regioselective switch between 3- and 5-isomers
Lyubov N. Sobenina, Denis N. Tomilin, Maxim D. Gotsko, Igor A. Ushakov, Albina I. Mikhaleva, Boris
A. Trofimov*
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Science, 1 Favorsky Str., 664033 Irkutsk, Russian Federation, tel/fax: + 7
(3952) 41-93-46 e-mail: boris_trofimov@irioch.irk.ru
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
(4,5,6,7-Tetrahydroindol-2-yl)alkynes, synthesized by cross-coupling of 4,5,6,7-
tetrahydroindoles with aroyl(hetaroyl)bromoalkynes or ethyl bromopropynoate in the presence
of K2CO3, regioselectively cyclize with hydroxylamine to either 3- or 5-(4,5,6,7-tetrahydroindol-
2-yl)isoxazoles depending on the acidity of the reaction mixture: in the presence of acetic acid 3-
isomers are formed (ca. 100% selectivity), while under neutral conditions the reaction is
switched to 5-isomers (94-97% selectivity).
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
4,5,6,7-tetrahydroindoles
aroyl(hetaroyl)bromoalkynes
3-(4,5,6,7-tetrahydroindol-2-yl)-2-propynones
3-(4,5,6,7-tetrahydroindol-2-yl)-2-propynoates
hydroxylamine
isoxazoles
used as fatty acid amide hydrolase inhibitors,21 and agonists of α7
nicotinic acetylcholine receptors,22 have anticancer,23
antimicrobial24 and anti-inflammatory25 activities.
1. Introduction
Isoxazoles and their derivatives are important scaffolds for the
synthesis of various natural compounds and their congeners.1 The
interest in isoxazoles is steadily growing as they are potent,
selective agonists for human cloned dopamine D4 receptors,2
GABAA receptor antagonist,3 COX-2,4 tyrosine kinase5 and HIV-
1 replication6 inhibitors, exhibit analgesic,7 antiinflammatory,5
Among the known methods of isoxazole synthesis, [2+3]-
cycloaddition of 1,3-dipoles to alkynes and the reaction of
hydroxylamine with 1,3-diketone or an α,β-unsaturated ketones
are the most important.26 Although frequently used, majority of
the above routes lead to mixtures of regioisomers.26,27 However,
in some cases, the reactions can be directed to selective formation
of a single isomer by changing either the process conditions or
the substrate structure. For example, ethynyl ketones bearing
amino acid moieties react with hydroxylamine in the presence of
pyridine to form a mixture of regioisomers,27 while without
pyridine, selective oximation of the carbonyl group with
following cyclization occurs.27 On the contrary, for the selective
oximation of the carbonyl group in diphenylpropynones, pyridine
is required, whereas other isomer is formed with sodium
anticancer,8
antimicrobial9
(including
antitubercular10),
antifungal,11 antiviral,12 antipsychotic,13 and hypoglycemic14
activities. Many known drugs (sulfisoxazoles,15 antibiotics:
oxacillin, cloxacillin and dicloxacillin,16 isocarboxazide,
a
monoaminoxidase inhibitor used in psychotherapy,17 and agarin,
which acts on the central nervous system18) contain isoxazole
rings. Fused isoxazoles are present in the structure of anabolic
steroids15 and compounds possessing antimetastatic activity.19
The high potential of isoxazoles as protecting functions and
their tendency to be converted into other functionalities ensure
their wide spread use in organic synthesis.1
carbonate.28
Gemdifluoroethynyl
ketones
give
with
hydroxylamine both the expected isomers of isoxazoles, with or
without pyridine.29
As important areas of isoxazole application intensify, the
search for shorter and simpler routes to their novel derivatives,
including their ensembles with other heterocycles, particularly
with pyrrole or indole rings increases. The latter may additionally
improve pharmaceutically targeted properties of these ensembles.
This is supported for instance by the fact that pyrrolyl- and
indolylisoxazoles are selective inhibitors of protein kinase C,20
In spite of that, the control of regioselectivity of the isoxazole
synthesis remains a challenge for organic chemistry.
A few known regioselective syntheses of isoxazoles comprise
of the addition of hydroxylamine to α-benzotriazolyl-α,β-
unsaturated ketones30 and β-dimethylaminovinyl ketones,31 the

ACCEPTED MANUSCRIPT
2
Tetrahedron
Table 2
reactions of chalcones with hydroxylamine hydrochloride using
K2CO3 as solid support under microwave conditions,32
Cyclocondensation of 3-(4,5,6,7-tetrahydroindol-2-yl)-2-propynones 3a-i
with NH2OH
cyclization of α,β-unsaturated aldehydes/ketones with N-
hydroxyl-4-toluenesulfonamide,33
a
ruthenium (II)-,34 or
copper(I)-35 catalyzed cycloaddition reaction between nitrile
oxides and acetylenes, and also four-component interaction of a
terminal alkyne, hydroxylamine, carbon monoxide, and an aryl
iodide in the presence of a palladium catalyst.36
2. Result and discussion
Here we report an efficient regioselective synthesis of (4,5,6,7-
tetrahydroindol-2-yl)isoxazoles that allows the preparation of
either 3- or 5-isomers from the same starting materials depending
on media acidity.
Isoxazoles 4-16
Yield, %
85
Isoxazoles 4-16
Yield, %
91
O
The method consists of the cyclization of (4,5,6,7-
tetrahydroindol-2-yl)alkynes 3a-j with hydroxylamine. The
former have been synthesized by cross-coupling of 4,5,6,7-
tetrahydroindoles 1a-d with aroyl(hetaroyl)bromoalkynes 2a-c
N
N
Ph
Ph
11
37
(Table 1) or ethyl bromopropynoate in the presence of K2CO3
90
91
88
Table 1
The
cross-coupling
of
4,5,6,7-tetrahydroindoles
1a-d
with
aroyl(hetaroyl)bromoalkynes 2a-c
N
N
O
90
80
OH
Ph
6
76 (1H
NMR)
O
N
N
Ethynylpyrrole 3
Yield, % Ethynylpyrrole 3
Yield, %
O
14
5437
52
44
48
67
41
87
80
90
6837
7137
7037
43
85
86
Noteworthy, with the excess NaOH (in the system
NH2OH·HCl/NaOH, 1:1.5 molar ratio), 4,5-dihydroisoxazol-5-
ols are not detected in the reaction mixture at all.
Apparently, in the presence of acetic acid, the attack of the
NH2OH nucleophile at the β-acethylenic carbon of ketones
3a,b,d-f is electrophilically assisted by the simultaneous
protonation of the carbonyl group (and finally 1,4-addition takes
place to deliver isoxazoles 4-8), (Scheme 1).
3-(4,5,6,7-Tetrahydroindol-2-yl)-2-propynones 3a-i readily
cyclize with hydroxylamine (10-fold excess) to give
regioselectively
either
3-(4,5,6,7-tetrahydroindol-2-yl)-4,5-
dihydroisoxazol-5-ols 4-8 or 5-(4,5,6,7-tetrahydroindol-2-
yl)isoxazoles 9-16 (Table 2). The cyclization can be easily
switched from the direction leading exclusively to isoxazoles 4-8
to the formation of isoxazoles 9-16 by simple changing of the
proton concentration in the reaction mixture. When the reaction
is carried out in the presence of acetic acid (NH2OH·HCl/NaOAc,
1:1 system), only isoxazoles 4-8 are formed, whereas under
neutral or basic conditions (NH2OH·HCl/NaOH (1:1 or 1:1.5
system), the cyclization takes another pathway to produce
preferably (94-97% or entirely) isoxazoles 9-16.
Scheme 1.

ACCEPTED MANUSCRIPT
3
The switch to the formation of isoxazoles 9-16 occurs when
the system NH2OH·HCl/NaOAc is replaced by the
NH2OH·HCl/NaOH system, which is unable to exert the
electrophilic assistance and hence the common oximation of the
carbonyl group prevails. Interestingly, some other ethynyl
ketones react with hydroxylamine hydrochloride in the presence
of КОН to selectively yield 4,5-dihydroisoxazol-5-ols, i.e. the
reaction proceeds across the triple bond.38
In some cases (e.g., with R2 = 2-thienyl) the aromatization
of 4,5-dihydroisoxazol-5-ol occurs during the synthesis
(compound 23, Table 3).
Table 3.
The isoxazoles 19-23, synthesized by dehydration of 3-(4,5,6,7-
tetrahydroindol-2-yl)-4,5-dihydroisoxazol-5-ols
Isoxazoles 8
Yield, % Isoxazoles 8
Yield, %
49
In the case of 3-(4,5,6,7-tetrahydroindol-2-yl)-2-propynoates
17a-c, easily available from 4,5,6,7-tetrahydroindoles 1a-c and
ethyl bromopropynoate,39 the cyclization with hydroxylamine
results in isoxazolinones 18a-c only (Scheme 2, Table 3).
89
Scheme 2.
91
73
79
4,5-Dihydroisoxazol-5-ols 4, 5, 7 undergo easy aromatization
when refluxing (benzene, 1 h) in the presence of TsOH·H2O to
isoxazoles 19-21 in 73-92% yield (Scheme 3).
The cyclization of propynone 3g in the presence of
NH2OH·HCl/NaOH is accompanied by the cleavage (under the
action of hydroxide ion) of the acyl-acetylene bond to give
terminal acetylene (Scheme 6) that agrees with earlier reports.41
Scheme 3.
Scheme 6.
Under the same conditions dehydration of N-vinylisoxazole 6
is accompanied by devinylation to afford NH-isoxazole 19 in
58% yield (Scheme 4). Apparently this is a result of the
electrophilic addition of water to the vinyl group of isoxazole 22
and subsequently decomposition of the hemiaminal 23 (Scheme
4).
3. Conclusion
In conclusion, we have developed regioselective route to
functionalized tetrahydroindole-isoxazole ensembles using
nucleophilic addition of hydroxylamine to the triple bond or the
carbonyl group of (4,5,6,7-tetrahydroindol-2-yl)alkynes, the
products of cross-coupling of 4,5,6,7-tetrahydroindoles with
aroyl(hetaroyl)bromoalkynes or ethyl bromopropynoate in the
presence of K2CO3 The synthesized compounds represent a new
family of promising precursors for the drug design, potent
building blocks for heterocyclic synthesis.
Scheme 4.
TsOH·H2O
N
H2O
N
O
O
N
N
- H2O
OH
Ph
Ph
6
22
N
N
O
4. Experimental section
O
N
N
H
19
- MeCHO
OH
Ph
Ph
4.1. General information
23
IR spectra were obtained on a Bruker IFS-25 spectrometer
(400-4000 cm-1, KBr pellets or thin films). 1Н (400.13 MHz), 13
С
N-Vinyl-derivative 6 has been dehydrated with retention of N-
vinyl group (Scheme 5) in boiling aqueous methanol in the
presence of Na2CO3 according to the published procedure.40
(100.61 MHz) NMR spectra were recorded on a Bruker Avance
1
400 instrument in СDСl3. The assignment of signals in the Н
NMR spectra was made using COSY and NOESY experiments.
1
Scheme 5.
Resonance signals of carbon atoms were assigned based on H-
13C HSQC and 1H-13C HMBC experiments. The 1H and 13C
chemical shifts were referenced to HMDS. The chemical shifts
were recorded in ppm.
1-Phenyl-3-(4,5,6,7-tetrahydro-1H-indol-2-yl)-2-propynone
3a was prepared according to the procedure reported.42 1-Phenyl-
3-(1-methyl- (3b) and 1-phenyl-3-(1-benzyl-(3c)-4,5,6,7-

ACCEPTED MANUSCRIPT
4
Tetrahedron
tetrahydro-1H-indol-2-yl)-2-propynones
were
prepared
5); δC (100.6 MHz, CDCl3) 168.7, 144.9, 135.6, 133.4, 132.9,
127.7, 119.5, 119.0, 110.3, 95.5, 88.2, 30.8, 22.8, 22.5, 22.3,
22.1.
according to the published procedure43 and 1-phenyl-3-(1-vinyl-
4,5,6,7-tetrahydro-1H-indol-2-yl)-2-propynone 3d was prepared
according to the literature procedure.44
4.2.5. 3-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-
yl)-1-(thiophen-2-yl)prop-2-yn-1-one (3i).
4.2. General procedure of 1-hetaryl-3-(4,5,6,7-tetrahydro-1H-
indol-2-yl)-2-propynones 3e-j preparation
о
Yield 67%; yellow crystals, mp 120 С; [Found: C, 76.60; H,
5.45; N, 4.20; S, 9.19. C22H19NOS requires C, 76.49; H, 5.54; N,
4.05; S, 9.28%]; νmax(KBr) 2157 (С≡С), 1603 (C=O) cm-1; δH
(400.13 MHz, CDCl3) 7.64 (1 H, dd, J 3.7, 1.2 Hz, H-5 of
thiophene), 7.58 (1 H, dd, J 4.9, 1.2 Hz, H-3 of thiophene), 7.32-
7.29 (2 H, m, Hm Ph), 7.26-7.23 (1 H, m, Hp Ph), 7.09-7.07 (2 H,
m, Ho Ph), 7.03 (1 H, dd, J 4.9, 3.7 Hz, H-4 of thiophene), 6.68
(1 H, s, Н-3), 5.22 (2 H, s, CH2), 2.52-2.49 (2 H, m, CH2-7),
2.45-2.42 (2 H, m, CH2-4), 1.77-1.75 (2 H, m, CH2-6), 1.71-1.69
(2 H, m, CH2-5); δC (100.6 MHz, CDCl3) 169.1, 145.2, 137.2,
135.9, 133.8, 133.4, 128.8, 128.0, 127.5, 126.5, 120.4, 119.9,
110.9, 95.5, 88.3, 48.2, 23.1, 22.9, 22.8, 22.7.
Equimolar
amounts
(0.5-1.0
mmol)
of
4,5,6,7-
tetrahydroindole 1b-d and hetaroylbromoalkyne 2b,c were
ground at room temperature with a 10-fold amount (by weight) of
K2CO3 in a china mortar for 10 min. The reaction mixture self-
heated (5-8°C) and within 10 min turned from yellow to orange-
brown. After 60 min the reaction mixture was placed on the
column with Al2O3 and eluted with n-hexane to afford pure 1-
hetaryl-3-(4,5,6,7-tetrahydro-1H-indol-2-yl)-2-propynone 3e-j.
4.2.1. 1-(Furan-2-yl)-3-(1-methyl-4,5,6,7-
tetrahydro-1H-indol-2-yl)prop-2-yn-1-one (3e).
о
Yield 43%; yellow crystals; mp 138 С; [Found: C, 75.92; H,
4.2.6. 1-(Thiophen-2-yl)-3-(1-vinyl-4,5,6,7-
5.90; N, 5.39. C16H15NO2 requires C, 75.87; H, 5.97; N, 5.53%];
νmax(KBr) 2170 (С≡С), 1610 (C=O) cm-1; δH (400.13 MHz,
CDCl3) 7.62 (1 H, dd, J 1.7, 0.8 Hz, Н-5 of furan), 7.27 (1 H, dd,
J 3.6, 0.8 Hz, Н-3 of furan), 6.57 (1 H, s, Н-3), 6.55 (1 H, dd, J
3.6, 1.7 Hz, Н-4 of furan), 3.60 (3 H, s, NMe), 2.55-2.52 (2 H, m,
CH2-7), 2.49-2.46 (2 H, m, CH2-4), 1.84-1.81 (2 H, m, CH2-6),
1.72-1.69 (2 H, m, CH2-5); δC (100.6 MHz, CDCl3) 164.2, 153.1,
146.6, 135.7, 119.5, 118.9, 118.2, 112.0, 110.3, 95.4, 88.7, 30.7,
22.8, 22.5, 22.3. 22.1.
tetrahydro-1H-indol-2-yl)prop-2-yn-1-one (3j).
о
Yield 41%; yellow crystals, mp 97 С; [Found: C, 72.41; H,
5.41; N, 4.86; S, 11.36. C17H15NOS requires C, 72.57; H, 5.37;
N, 4.98; S, 11.40%]; νmax(KBr) 2164 (С≡С), 1645 (N-CH=CH2),
1593 (C=O) cm-1; δH (400.13 MHz, CDCl3) 7.87 (1 H, dd, J 3.7,
1.2 Hz, H-5 of thiophene), 7.65 (1 H, dd, J 4.9, 1.2 Hz, H-3 of
thiophene), 7.14 (1 H, dd, J 4.9, 3.7 Hz, H-4 of thiophene), 6.99
(1 H, dd, J 16.0, 9.0 Hz, HХ), 6.68 (1 H, s, Н-3), 5.44 (1 H, d, J
16.0 Hz, HВ), 5.04 (1 H, d, J 9.0 Hz, HА), 2.67-2.65 (2 H, m,
CH2-7), 2.51-2.48 (2 H, m, CH2-4), 1.84-1.80 (2 H, m, CH2-6),
1.75-1.71 (2 H, m, CH2-5); δC (100.6 MHz, CDCl3) 169.2, 145.2,
135.1, 134.1, 133.7, 129.8, 128.1, 122.1, 121.3, 110.2, 105.1,
95.2, 87.6, 24.0, 22.9, 22.8, 22.7.
4.2.2. 3-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-
yl)-1-(furan-2-yl)prop-2-yn-1-one (3f).
Yield 52%; yellow crystals, mp 115 оС; [Found: 80.34; H,
5.89; N, 4.24. C22H19NO2 requires C, 80.22; H, 5.81; N, 4.22%];
νmax(KBr) 2163 (С≡С), 1610 (C=O) cm-1; δH (400.13 MHz,
CDCl3) 7.52 (1 H, dd, J 1.7, 0.8 Hz, Н-5 of furan), 7.34-7.30 (2
H, m, Hm Ph), 7.28-7.26 (1 H, m, Hp Ph), 7.12-7.10 (3 H, m, Ho
Ph, Н-3 of furan), 6.66 (1 H, s, Н-3), 6.47 (1 H, dd, J 3.6, 1.7 Hz,
Н-4 of furan), 5.21 (2 H, s, CH2), 2.51-2.48 (2 H, m, CH2-7),
2.45-2.42 (2 H, m, CH2-4), 1.77-1.73 (2 H, m, CH2-6), 1.71-1.67
(2 H, m, CH2-5); δC (100.6 MHz, CDCl3) 164.1, 153.0, 146.6,
136.9, 135.6, 128.4, 127.1, 126.2, 120.0, 119.5, 118.2, 111.9,
110.5, 95.1, 88.5, 47.8, 22.7, 22.5, 22.4, 22.3.
4.3. Synthesis of 5-aryl-3-(4,5,6,7-tetrahydro-1H-indol-2-yl)-
4,5-dihydroisoxazol-5-ols 4-8 (general procedure)
A solution of NH2OH·HCl (2.088 g, 30 mmol) in H2O (5 mL)
was added to a solution of NaOAc·3H2O (4.082 g, 30 mmol) in
H2O (5 mL). The resulting solution was added to a solution of 1-
aryl(hetaryl)-3-(4,5,6,7-tetrahydro-1H-indol-2-yl)-2-propynone
3a,b,d-f (2.95 mmol) in DMSO (50 mL) and the reaction mixture
was stirred at 45-50оС for 4 h. The reaction mixture was cooled
to room temperature, diluted with water (100 mL) and extracted
with diethyl ether (5 х 30 mL). Ether extracts were washed with
water and dried over Na2SO4. The residue, after removing
solvent, was fractionated by column chromatography (Al2O3, n-
hexane : diethyl ether, 4 : 1) to afford target the 5-aryl-3-(4,5,6,7-
tetrahydroindol-2-yl)-5-aryl-4,5-dihydroisoxazol-5-ol 4-8 as
yellow, very viscous oil, which transforms to a yellow powder on
keeping. In the case of 1-(thiophen-2-yl)-3-(1-vinyl-4,5,6,7-
tetrahydro-1H-indol-2-yl)prop-2-yn-1-one (3j) the product of the
reaction is 2-(5-(thiophen-2-yl)isoxazol-3-yl)-1-vinyl-4,5,6,7-
tetrahydro-1H-indole (23).
4.2.3. 1-(Furan-2-yl)-3-(1-vinyl-4,5,6,7-tetrahydro-
1H-indol-2-yl)prop-2-yn-1-one (3g).
о
Yield 44%; yellow crystals, mp 114 С; [Found: C, 77.11; H,
5.65; N, 5.30. C17H15NO2 requires C, 76.96; H, 5.70; N, 5.28%];
νmax(KBr) 2167 (С≡С), 1642 (NCH=CH2), 1608 (C=O) cm-1; δH
(400.13 MHz, CDCl3) 7.61 (1 H, dd, J 1.7, 0.8 Hz, Н-5 of furan),
7.26 (1 H, dd, J 3.6, 0.8 Hz, Н-3 of furan), 6.98 (1 H, dd, J 16.1,
9.1 Hz, Hx), 6.66 (1 H, s, Н-3), 6.55 (1 H, dd, J 3.6, 1.7 Hz, Н-4
of furan), 5.47 (1 H, d, J 16.1 Hz, HВ), 5.01 (1 H, d, J 9.1 Hz,
HA), 2.66-2.63 (2 H, m, CH2-7), 2.49-2.46 (2 H, m, CH2-4), 1.83-
1.79 (2 H, m, CH2-6), 1.74-1.70 (2 H, m, CH2-5); δC (100.6 MHz,
CDCl3) 164.5, 153.3, 147.2, 135.2, 129.8, 122.1, 121.3, 119.1,
112.4, 110.1, 104.7, 95.1, 88.1, 24.0, 22.9, 22.8, 22.7.
4.3.1. 5-Phenyl-3-(4,5,6,7-tetrahydro-1H-indol-2-
yl)-4,5-dihydroisoxazol-5-ol (4).
4.2.4. 3-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-
yl)-1-(thiophen-2-yl)prop-2-yn-1-one (3h).
Yield 85%; yellow very viscous oil; [Found: C, 72.06; H,
6.51; N, 9.90. C17H18N2O2 requires C, 72.32; H, 6.43; N, 9.92%];
νmax(KBr) 3444 (OH), 3249 (NH), 1608 (C=N) cm-1; δH (400.13
MHz, CDCl3) 8.81 (1 H, br s, NH), 7.62-7.60 (2 H, m, Hо Ph),
7.39-7.34 (3 H, m, Hm,p Ph), 6.11 (1 H, s, H-3), 3.53 (1 H, d, J
16.9 Hz, CH2 of isoxazole), 3.39 (1 H, d, J 16.9 Hz, CH2 of
isoxazole), 2.97 (1 H, br s, OH), 2.60-2.57 (2 H, m, CH2-7), 2.47-
2.45 (2 H, m, CH2-4), 1.80-1.78 (2 H, m, CH2-5), 1.73-1.72 (2 H,
m, CH2-6); δC (400 MHz, CDCl3) 151.1, 140.7, 132.7, 128.5,
о
Yield 48%; yellow crystals, mp 140 С; [Found: C, 71.40; H,
5.57; N, 5.11; S, 11.68%. C16H15NOS requires C, 71.34; H, 5.61;
N, 5.20; S, 11.90%]; νmax(KBr) 2163 (С≡С), 1598 (C=O) cm-1; δH
(400.13 MHz, CDCl3) 7.87 (1 H, dd, J 3.7, 1.2 Hz, H-5 of
thiophene), 7.63 (1 Н, dd, J 4.9, 1.2 Hz, H-3 of thiophene), 7.14
(1 H, dd, J 4.9, 3.7 Hz, H-4 of thiophene), 6.59 (1 H, s, Н-3),
3.61 (3 H, s, NMe), 2.56-2.53 (2 H, m, CH2-7), 2.50-2.47 (2 H,
m, CH2-4), 1.85-1.80 (2 H, m, CH2-6), 1.74-1.70 (2 H, m, CH2-

ACCEPTED MANUSCRIPT
5
128.3, 125.7, 118.8, 118.6, 124.5, 106.8, 49.4, 23.5, 23.0, 22.8,
22.6.
N, 9.45; S, 10.82%]; νmax(KBr) 1612 (C=N) cm-1; δH (400.13
MHz, CDCl3) 7.50-7.49 (1 H, m, H-5 of thiophene), 7.43-7.41 (1
H, m, H-3 of thiophene), 7.40 (1 H, dd, J 16.0, 9.0 Hz, HХ), 7.11-
7.09 (1 H, m, H-4 of thiophene), 6.47 (1 H, s, Н-3), 6.42 (1 H, s,
H of isoxazole), 5.08 (1 H, d, J 16.0 Hz, HВ), 5.02 (1 H, d, J 9.0
Hz, HА), 2.72-2.69 (2 H, m, CH2-7), 2.55-2.52 (2 H, m, CH2-4),
1.84-1.78 (2 H, m, CH2-6), 1.77-1.73 (2 H, m, CH2-5); δC (100.6
MHz, CDCl3) 163.7, 156.9, 132.6, 132.5, 129.3, 128.0, 127.8,
126.9, 120.4, 120.3, 112.5, 105.7, 98.6, 24.7, 22.6, 23.1, 23.0.
4.3.2. 3-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-
yl)-5-phenyl-4,5-dihydroisoxazol-5-ol (5).
Yield 90%; yellow very viscous oil; [Found: C, 72.86; H,
6.96; N, 9.23. C18H20N2O2 requires C, 72.95; H, 6.80; N, 9.45%];
νmax(KBr) 3432 (OH), 1595 (C=N) cm-1; δH (400.13 MHz,
CDCl3) 7.64-7.62 (2 H, m, Hо Ph), 7.40-7.34 (3 H, m, Hm,p Ph),
6.11 (1 H, s, H-3), 3.79 (3 H, s, NMe), 3.58 (1 H, d, J 16.9 Hz,
CH2 of isoxazole), 3.46 (1 H, d, J 16.9 Hz, CH2 of isoxazole),
2.97 (1 H, br s, OH), 2.56-2.53 (2 H, m, CH2-7), 2.48-2.45 (2 H,
m, CH2-4), 1.86-1.80 (2 H, m, CH2-5), 1.73-1.68 (2 H, m, CH2-
6); δC (100.6 MHz, CDCl3) 152.0, 140.9, 134.9, 128.7, 128.5,
125.8, 120.4, 118.3, 113.0, 105.5, 51.2, 33.2, 23.5, 23.1, 23.0,
22.2.
4.4. Synthesis of 3-aryl(hetaryl)-5-(4,5,6,7-tetrahydro-1H-
indol-2-yl)isoxazoles 9-16 (general procedure)
A solution of NH2OH·HCl (2.088 g, 30 mmol) in H2O (5 mL)
was added to a solution of NaOH (1.8 g, 45 mmol) in H2O (5
mL). This was added to a solution of 1-aryl(hetaryl)-3-(4,5,6,7-
tetrahydro-1H-indol-2-yl)-2-propynones 3a-i (2.95 mmol) in
DMSO (50 mL) and the reaction mixture was stirred at 45-50 оС
for 4 h. The reaction mixture was cooled to room temperature,
diluted with water (100 mL) and extracted with diethyl ether (5 х
30 mL). Ether extracts were washed with water and dried over
Na2SO4. The residue, after removal of solvent, was crystallized
from acetone / H2O (1:1) to afford target 3-aryl(hetaryl)-5-
(4,5,6,7-tetrahydro-1H-indol-2-yl)isoxazol 9-16 as light yellow
crystals.
4.3.3. 5-Phenyl-3-(1-vinyl-4,5,6,7-tetrahydro-1H-
indol-2-yl)-4,5-dihydroisoxazol-5-ol (6).
Yield 90%; yellow very viscous oil; [Found: C 73.86; H, 6.60;
N, 9.18. C19H20N2O2 requires C, 74.00; H, 6.54; N, 9.08%];
νmax(KBr) 3414 (OH), 1642 (N-CH=CH2), 1595 (C=N) cm-1. δH
(400.13 MHz, CDCl3) 7.63-7.61 (2 H, m, Hо Ph), 7.53 (1 H, dd,
J 16.0, 9.0 Hz, HX), 7.38-7.36 (3 H, m, Hm,p Ph), 6.18 (1 H, s,
H-3), 5.09 (1 H, d, J 16.0 Hz, HB), 5.05 (1 H, d, J 9.0 Hz, HA),
3.58 (1 H, d, J 16.8 Hz, CH2 of isoxazole), 3.45 (1 H, d, J 16.8
Hz, CH2 of isoxazole), 2.99 (1 H, br s, OH), 2.70-2.68 (2 H, m,
CH2-7), 2.50-2.47 (2 H, m, CH2-4), 1.81-1.77 (2 H, m, CH2-5),
1.75-1.70 (2 H, m, CH2-6); δC (100.6 MHz, CDCl3) 151.5, 140.6,
134.1, 133.1, 128.6, 128.4, 125.6, 120.5, 120.3, 114.6, 105.6,
105.5, 51.0, 24.8, 23.4, 23.3, 22.8.
4.4.1. 3-Phenyl-5-(4,5,6,7-tetrahydro-1H-indol-2-
yl)isoxazole (9).
o
Yield 85%; light yellow crystals, mp 146-148 C; [Found: C
76.89; H, 6.13; N, 10.79. C17H16N2O requires C, 77.25; H, 6.10;
N, 10.60%]; νmax(KBr) 1620 (C=N) cm-1; δH (400.13 MHz,
CDCl3) 8.42 (1 H, br s, NH), 7.82-7.80 (2 H, m, Ho Ph), 7.44-
7.42 (3 H, m, Hm,p Ph), 6.45 (1 H, d, J 2.3 Hz, H-3), 6.43 (1 H,
s, H of isoxazole), 2.64-2.61 (2 H, m, CH2-7), 2.54-2.51 (2 H, m,
CH2-4), 1.86-1.80 (2 H, m, CH2-6), 1.78-1.73 (2 H, m, CH2-5);
δC (100.6 MHz, CDCl3) 164.5, 162.8, 131.3, 129.9, 129.3, 128.9,
126.9, 119.6, 118.2, 109.2, 93.5, 23.6, 23.1, 22.9, 22.8.
4.3.4. 5-(Furan-2-yl)-3-(1-methyl-4,5,6,7-
tetrahydro-1H-indol-2-yl)-4,5-dihydroisoxazol-5-ol
(7).
о
Yield 80%, yellow crystals, mp 97 С; [Found: C, 67.30; H,
6.39; N, 9.66. C16H18N2O3 requires C, 67.12; H, 6.34; N, 9.78%];
νmax(KBr) 3393 (OH), 1595 (C=N) cm-1. δH (400.13 MHz,
CDCl3) 7.42-7.41 (1 H, m, Н-5 of furan), 6.53-6.52 (1 H, m, Н-3
of furan), 6.37-6.36 (1 H, m, Н-4 of furan), 6.15 (1 H, s, H-3),
3.75 (3 H, s, NMe), 3.72 (1 H, d, J 16.8 Hz, CH2 of isoxazole),
3.50 (1 H, d, J 16.8 Hz, CH2 of isoxazole), 3.40 (1 H, br s, OH),
2.56-2.53 (2 H, m, CH2-7), 2.49-2.46 (2 H, m, CH2-4), 1.86-1.80
(2 H, m, CH2-5), 1.73-1.68 (2 H, m, CH2-6); δC (100.6 MHz,
CDCl3) 152.3, 151.9, 143.7, 135.6, 120.7, 119.0, 113.7, 111.1,
108.6, 102.1, 48.8, 33.7, 24.0, 23.6, 23.5, 22.8.
4.4.2. 5-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-
yl)-3-phenylisoxazole (10).
Yield 86%; light yellow crystals, mp 116-118 oC; [Found: C,
77.67; H, 6.61; N, 9.71. C18H18N2O requires C, 77.67; H, 6.52; N,
10.06%]; νmax(KBr) 1617 (C=N) cm-1; δH (400.13 MHz, CDCl3)
7.83-7.82 (2 H, m, Ho Ph), 7.45-7.43 (3 H, m, Hm,p Ph), 6.48 (1
H, s, H-3), 6.45 (1 H, s, H of isoxazole), 3.71 (3 H, s, NMe),
2.59-2.56 (2 H, m, CH2-7), 2.54-2.51 (2H, m, CH2-4), 1.89-1.83
(2 H, m, CH2-6), 1.76-1.71 (2 H, m, CH2-5); δH (100.6 MHz,
CDCl3) 165.0, 162.4, 133.3, 129.9, 129.4, 128.9, 126.8, 119.8,
118.7, 110.4, 95.7, 32.0, 23.4, 23.1, 23.0, 22.2; MS (relative
intensity), m/z: 278 (100) – M+., 250 (32), 249 (21), 162 (17), 91
(9), 77 (21), 51 (6).
4.3.5. 3-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-
yl)-5-(furan-2-yl)-4,5-dihydroisoxazol-5-ol (8).
Yield 87%; yellow crystals, mp 114-116 оС; [Found: C, 73.03;
H, 6.19; N, 13.39. C22H22N2O3 requires C, 72.91; H, 6.12; N,
13.24%]; νmax(KBr) 3376 (OH), 1596 (C=N) cm-1. δH (400.13
MHz, CDCl3) 7.42-7.41 (1 H, m, Н-5 of furan), 7.26-7.24 (2 H,
m, Hm Ph), 7.21-7.17 (1 H, m, Hp Ph), 7.00-6.98 (2 H, m, Ho
Ph), 6.50-6.49 (1 H, m, Н-3 of furan), 6.37-6.36 (1 H, m, Н-4 of
furan), 6.23 (1 H, s, H-3), 5.57 (1 H, d, J 16.4 Hz, CH2Ph), 5.52
(1 H, d, J 16.4 Hz, CH2Ph), 3.75 (1 H, d, J 16.9 Hz, CH2 of
isoxazole), 3.63 (1 H, d, J 16.9 Hz, CH2 of isoxazole), 3.23 (1 H,
br s, OH), 2.53-2.50 (2 H, m, CH2-7), 2.46-2.43 (2 H, m, CH2-4),
1.79-1.74 (2 H, m, CH2-5), 1.73-1.69 (2 H, m, CH2-6); δC (100.6
MHz, CDCl3) 151.5, 151.3, 143.2, 138.6, 135.6, 128.6, 127.0,
126.5, 120.3, 119.1, 113.9, 110.7, 108.1, 101.6, 49.1, 48.4, 23.5,
23.2, 23.1, 22.3.
4.4.3. 5-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-
yl)-3-phenylisoxazole (11).
o
Yield 91%; light yellow crystals, mp 144-146 C; [Found: C,
80.93; H, 6.30; N, 7.67. C24H22N2O requires C, 81.33; H, 6.26; N,
7.90%]; νmax(KBr) 1613 (C=N) cm-1; δH (400.13 MHz, CDCl3)
7.72-7.71 (2 H, m, Ho Ph), 7.40-7.39 (3 H, m, Hm,p Ph), 7.30-
7.26 (2 H, m, Hm CH2Ph), 7.22-7.19 (1 H, m, Hp CH2Ph), 6.99-
6.97 (2 H, m, Ho CH2Ph), 6.57 (1 H, s, H-3), 6.29 (1 H, s, H of
isoxazole), 5.33 (2 H, s, CH2Ph), 2.58-2.55 (2 H, m, CH2-4),
2.49-2.47 (2 H, m, CH2-7), 1.83-1.78 (2 H, m, CH2-6), 1.76-1.72
(2 H, m, CH2-5); δC (100.6 MHz, CDCl3) 164.7 (O-C=), 162.3
(C=N), 138.0 (Ci CH2Ph), 133.4 (C-5 of pyrrole), 129.7 (Cp Ph),
129.2 (Ci Ph), 128.7 (Cm Ph, Cm CH2Ph), 127.2 (Cp Ph), 126.7
(Co Ph), 125.8 (Co CH2Ph), 119.7 (C-2 of pyrrole), 119.2 (C-4 of
pyrrole), 111.1 (J 170.3 Hz, C-3 of pyrrole), 95.9 (J 95.9 Hz, CH
4.3.6. 2-(5-(Thiophen-2-yl)isoxazol-3-yl)-1-vinyl-
4,5,6,7-tetrahydro-1H-indole (23).
Yield 79%; light yellow solid, mp 97 оС; [Found: C, 69.05; H,
5.41; N, 9.22; S, 11.06. C17H16N2OS requires: C, 68.89; H, 5.44;

ACCEPTED MANUSCRIPT
6
Tetrahedron
of isoxazole), 48.1 (CH2Ph), 23.4 (CH2-5), 23.1 (CH2-7), 22.9
5); δC (100.6 MHz, CDCl3) 164.6, 157.5, 152.8, 137.9, 133.6,
(CH2-6), 22.1 (CH2-4).
131.0, 128.8, 127.5, 127.2, 127.1, 125.8, 119.5, 119.3, 111.3,
95.8, 48.1, 23.3, 23.0, 22.9, 22.1.
4.4.4. 2-(3-Furan-2-yl)isoxazol-5-yl)-1-methyl-
4,5,6,7-tetrahydro-1H-indole (12).
4.5. Synthesis of 2-(5-arylisoxazol-3-yl)-4,5,6,7-tetrahydro-
1H-indoles 19-21 (general procedure)
o
Yield 91%; light yellow crystals, mp 120-122 C; [Found: C,
71.71; H, 6.35; N, 10.20. C16H16N2O2 requires C, 71.62; H, 6.01;
N, 10.44%]; νmax(KBr) 1622 (C=N) cm-1; δH (400.13 MHz,
CDCl3) 7.53-7.52 (1 H, m, H-5 of furan), 6.90-6.89 (1 H, m, H-3
of furan), 6.51-6.50 (1 H, m, H-4 of furan), 6.48 (1 H, s, H-3 of
pyrrole), 6.40 (1 H, s, H of isoxazole), 3.69 (3 H, s, NMe), 2.57-
2.56 (2 H, m, CH2-7), 2.51-2.50 (2 H, m, CH2-4), 1.85-1.84 (2 H,
m, CH2-6), 1.73-1.72 (2 H, m, CH2-5); δC (100.6 MHz, CDCl3)
164.7, 154.9, 144.7, 143.7, 133.5, 119.5, 118.8, 110.7, 110.6,
109.9, 95.1, 32.0, 23.4, 23.1, 23.0, 22.2.
A
solution of 3-(4,5,6,7-tetrahydroindol-2-yl)-5-aryl-4,5-
dihydroisoxazol-5-ol 4, 5, 7 (1 mmol) in benzene (10 mL) was
refluxed in the presence of p-TsOH·H2O (0.009 g, 0.05 mmol)
and Na2SO4 (0.284 g, 1 mmol) for 1 h. The cooled reaction
mixture was poured into diethyl ether (30 mL) and washed twice
with solution of NaHCO3, NaCl and finally with H2O, dried over
MgSO4. After removal of solvent, the residue was purified by
column chromatography (Al2O3, n-hexane : diethyl ether, 10:1) to
afford 2-(5-arylisoxazol-3-yl)-4,5,6,7-tetrahydro-1H-indole 19-
21.
4.4.5. 1-Benzyl-2-(3-furan-2-yl)isoxazol-5-yl)-
4,5,6,7-tetrahydro-1H-indole (13).
4.5.1. 2-(5-Phenylisoxazol-3-yl)-4,5,6,7-tetrahydro-
1H-indole (19).
Yield 88%; light yellow crystals, mp 144-146 oC; [Found: C,
76.41; H, 6.04; N, 7.92. C22H20N2O2 requires C, 76.72; H, 5.85;
N, 8.13%]; νmax(KBr) 1613 (C=N) cm-1; δH (400.13 MHz, CDCl3)
7.48 (1 H, dd, J 1.8, 0.7 Hz, H-5 of furan), 7.29-7.25 (2 H, m,
Hm Ph), 7.22-7.18 (1 H, m, Hp Ph), 6.97-6.95 (2 H, m, Ho Ph),
6.81 (1 H, d, J 3.4, 0.7 Hz, H-3 of furan), 6.57 (1 H, s, H-3 of
pyrrole), 6.47 (1 H, dd, J 3.4, 1.8 Hz, H-4 of furan), 6.24 (1 H, s,
H of isoxazole), 5.31 (2 H, s, CH2), 2.57-2.54 (2 H, m, CH2-7),
2.49-2.46 (2 H, m, CH2-4), 1.81-1.77 (2 H, m, CH2-6), 1.76-1.70
(2 H, m, CH2-5); δC (100.6 MHz, CDCl3) 164.3, 154.7, 144.4,
143.5, 137.8, 133.6, 128.7, 127.2, 125.7, 119.4, 119.2, 111.5,
111.3, 109.7, 95.1, 48.0, 23.3, 23.0, 22.9, 22.1.
Yield 89%; light yellow solid, mp 208-210 oC; [Found: C,
77.11; H, 5.98; N, 10.49. C17H16N2O requires C, 77.25; H, 6.10;
N, 10.60%]; νmax(KBr) 1620 (C=N) cm-1; δH (400.13 MHz,
CDCl3) 8.77 (1 H, br s, NH), 7.79-7.77 (2 H, m, Hо Ph), 7.47-
7.41 (3 H, m, Hm,p Ph), 6.61 (1 H, s, H of isoxazole), 6.37 (1 H,
s, H-3 of pyrrole), 2.64-2.61 (2 H, m, CH2-7), 2.55-2.52 (2 H, m,
CH2-4), 1.85-1.80 (2 H, m, CH2-5), 1.79-1.74 (2 H, m, CH2-6);
δC (100.6 MHz, DMSO-d6) δ 169.6, 158.1, 132.1, 131.7, 130.7,
128.4, 126.9, 119.3, 118.9, 110.6, 99.0, 24.8, 24.3, 23.9, 23.7.
4.5.2. 1-Methyl-2-(5-phenylisoxazol-3-yl)-4,5,6,7-
tetrahydro-1H-indole (20).
Yield 91%; light yellow solid, mp 98-100 C; [Found: C, 77.38;
4.4.6. 2-(3-(Furan-2-yl)isoxazol-5-yl)-1-vinyl-
4,5,6,7-tetrahydro-1H-indole (14).
o
H, 6.36; N, 10.21. C18H18N2O requires C, 77.67; H, 6.52; N,
10.06%]; νmax(KBr) 1616 (C=N) cm-1; δH (400.13 MHz, CDCl3)
7.80-7.78 (2 H, m, Hо Ph), 7.47-7.41 (3 H, m, Hm,p Ph), 6.62 (1
H, s, H of isoxazole), 6.38 (1 H, s, H-3 of pyrrole), 3.82 (3 H, s,
NMe), 2.59-2.56 (2 H, m, CH2-7), 2.55-2.52 (2 H, m, CH2-4),
1.89-1.83 (2 H, m, CH2-5), 1.76-1.71 (2 H, m, CH2-6); δC (100.6
MHz, CDCl3) 168.1, 157.3, 133.1, 129.9, 128.9, 127.5, 125.8,
120.5, 118.1, 110.4, 98.4, 32.7, 23.4, 23.1, 22.9, 22.2; MS
(relative intensity), m/z: 278 (100) – M+., 274 (16), 250 (34), 249
(10), 176 (23), 173 (31), 148 (20), 105 (36), 91 (8), 77 (36), 51
(8).
This compound is isolated as mixture with 2-ethynyl-1-vinyl-
4,5,6,7-tetrahydroindole. Yield 76% (1H NMR); δH (400 MHz,
CDCl3) 7.46 (1 H, dd, J 3.6, 1.0 Hz, H-5 of furan), 7.39 (1 H, dd,
J 5.0, 1.0 Hz, H-3 of furan), 7.10 (1 H, dd, J 5.0, 3.6 Hz, H-4 of
furan), 7.02 (1 H, dd, J 15.9, 8.8 Hz, HX), 6.54 (1 H, s, H-3 of
pyrrole), 6.39 (1 H, s, H of isoxazole), 5.16 (1 H, d, J 15.9 Hz,
HВ), 5.13 (1 H, d, J 8.8 Hz, HА), 2.67-2.64 (2 H, m, CH2-7), 2.55-
2.52 (2 H, m, CH2-4), 1.85-1.79 (2 H, m, CH2-6), 1.77-1.72 (2 H,
m, CH2-5).
4.4.7. 1-Methyl-2-(3-thiophen-2-yl)isoxazol-5-yl)-
4,5,6,7-tetrahydro-1H-indole (15).
o
Yield 80%; light yellow crystals, mp 74-76 C; [Found: C,
4.5.3. 2-(5-(Furan-2-yl)isoxazol-3-yl)-1-methyl-
4,5,6,7-tetrahydro-1H-indole (21).
67.29; H, 6.00; N, 9.69; S, 11.33. C16H16N2OS requires C, 67.58;
H, 5.67; N, 9.85; S, 11.28%]; νmax(KBr) 1616 (C=N) cm-1; δH
(400.13 MHz, CDCl3) 7.47 (1 H, dd, J 3.6, 1.0 Hz, H-5 of
thiophene), 7.39 (1 H, dd, J 5.0, 1.0 Hz, H-3 of thiophene), 7.10
(1 H, dd, J 5.0, 3.6 Hz, H-4 of thiophene), 6.46 (1 H, s, H-3 of
pyrrole), 6.37 (1 H, s, H of isoxazole), 3.69 (3 H, s, NMe), 2.59-
2.55 (2 H, m, CH2-7), 2.53-2.50 (2 H, m, CH2-4), 1.88-1.82 (2 H,
m, CH2-6), 1.76-1.70 (2 H, m, CH2-5); δC (100.6 MHz, CDCl3)
165.5, 158.1, 134.0, 131.7, 128.1, 127.8, 127.6, 120.0, 119.3,
111.1, 96.1, 32.5, 23.9, 23.6, 23.4, 22.7.
Yield 73%; light yellow solid, mp 80 oC; [Found: C, 71.71; H,
6.35; N, 10.04. C16H16N2O2 requires C, 71.62; H, 6.01; N,
10.44%]; νmax(KBr) 1651 (C=N) cm-1; δH (400.13 MHz, CDCl3)
7.52-7.51 (1 H, m, H-5 of furan), 6.88-6.87 (1 H, m, H-3 of
furan), 6.54 (1 H, s, H-4 of isoxazole), 6.52-6.51 (1H, m, H-4 of
furan), 6.37 (1 H, s, H-3 of pyrrole), 3.80 (3 H, s, NMe), 2.59-
2.57 (2 H, m, CH2-4), 2.54-2.51 (2 H, m, CH2-7), 1.89-1.83 (2 H,
m, CH2-5), 1.76-1.70 (2 H, m, CH2-6); δC (100.6 MHz, CDCl3)
160.1, 157.1, 144.0, 143.6, 133.4, 120.3, 118.3, 111.9, 110.8,
110.2, 98.3, 32.8, 23.5, 23.2, 23.1, 22.3.
4.4.8. 1-Benzyl-2-(3-(thiophen-2-yl)isoxazol-5-yl)-
4,5,6,7-tetrahydro-1H-indole (16).
4.6. 2-(5-Phenylisoxazol-3-yl)-1-vinyl-4,5,6,7-tetrahydro-1H-
indole (22).
о
Yield 90%; light yellow crystals, mp 112-114 С; [Found: C,
73.51; H, 5.40; N, 7.80; S, 9.09. C22H20N2OS requires C, 73.30;
H, 5.59; N, 7.77; S, 8.90%]; νmax(KBr) 1612 (C=N) cm-1; δH
(400.13 MHz, CDCl3) 7.36-7.35 (2 H, m, H-5, H-3 of
thiophene), 7.30-7.26 (2 H, m, Hm Ph), 7.23-7.19 (1 H, m, Hp
Ph), 7.07-7.04 (1 H, m, H-4 of thiophene), 6.98-6.96 (2 H, m, Ho
Ph), 6.56 (1 H, s, Н-3 of pyrrole), 6.21 (1 H, s, H of isoxazole),
5.32 (2 H, s, CH2Ph), 2.58-2.55 (2 H, m, CH2-7), 2.49-2.46 (2 H,
m, CH2-4), 1.84-1.78 (2 H, m, CH2-6), 1.76-1.71 (2 H, m, CH2-
A solution of Na2CO3 (1.0 g, 9.43 mmol) in H2O (5 mL) was
added to a solution of 3-(1-vinyl-4,5,6,7-tetrahydroindol-2-yl)-5-
aryl-4,5-dihydroisoxazol-5-ol 6 (1.151 g, 4.66 mmol) in MeOH
(24 mL). The reaction mixture was refluxed for 3 h. The MeOH
was evaporated under reduced pressure, and the aqueous layer
was extracted with CH2Cl2 (3 x 15 mL). The combined organic
extracts were dried over anhydrous Na2SO4, and the solvent was

ACCEPTED MANUSCRIPT
7
evaporated under reduced pressure. Column chromatography
Russian Fund for Basic Research (Grant No. 13-03-91150
(SiO2, n-hexane/Et2O, 10:1) of the residue afforded isoxazole 8c
(0.663 g, 49%) as light yellow solid, mp 102-104 C; [Found: C,
NNSFC).
o
References and notes
78.57; H, 6.24; N, 9.55. C19H18N2O requires C, 78.59; H, 6.25; N,
9.65%]; νmax(KBr) 1615 (C=N) cm-1; δH (400.13 MHz, CDCl3)
7.79-7.77 (2 H, m, Ho Ph), 7.47-7.41 (4 H, m, Hm,p Ph, HX),
6.62 (1 H, s, H of isoxazole), 6.45 (1 H, s, H-3 of pyrrole), 5.09
(1 H, d, J 16.0 Hz, HB), 5.03 (1 H, d, J 8.9 Hz, HA), 2.73-2.70 (2
H, m, CH2-7), 2.57-2.54 (2 H, m, CH2-4), 1.83-1.76 (4 H, m,
CH2-5,6); δC (100.6 MHz, CDCl3) 169.1, 157.5, 133.0, 130.6,
129.5, 128.0, 126.3, 121.2, 120.7, 112.8, 106.1, 106.0, 99.4, 22.3,
24.1, 23.5, 23.4.
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A solution of NH2OH·HCl (2.088 g, 30 mmol) in H2O (5 mL)
was added to a solution of NaOH (1.2 g, 30 mmol) in H2O (5
mL). This solution was added to ethyl 3-(4,5,6,7-tetrahydro-1H-
indol-2-yl)propynoate 17a-c (2.95 mmol) in DMSO (50 mL) and
о
reaction mixture was stirred at 45-50 С for 4 h, then cooled to
room temperature, diluted with water (100 mL) and extracted
with diethyl ether (1 х 30 mL), then with CH2Cl2 (8 x 30 mL).
Dichloromethane extracts were washed with water and dried over
Na2SO4. The residue, after removal of solvent, was recrystallized
from acetone / H2O (1:1) to afford target 3-(4,5,6,7-tetrahydro-
1H-indol-2-yl)isoxazol-5(4H)-one 18a-c as light yellow solid.
4.7.1. 3-(4,5,6,7-Tetrahydro-1H-indol-2-
yl)isoxazol-5(4H)-one (18a).
o
Yield 84%; yellow solid, mp 180-182 C; [Found: C, 64.83;
H, 5.56; N, 13.40. C11H12N2O2 requires C, 64.69; H, 5.92; N,
13.72%]; νmax(KBr) 3279 (NH), 1806, 1793 (C=O), 1602 (C=N)
cm-1; δH (400.13 MHz, CDCl3) 9.07 (1 H, br s, NH), 6.23 (1 H, s,
H-3 of pyrrole), 3.69 (2 H, s, CH2 of isoxazole), 2.60-2.58 (2 H,
m, CH2-7), 2.48-2.45 (2 H, m, CH2-4), 1.82-1.77 (2 H, m, CH2-
5), 1.75-1.69 (2 H, m, CH2-6); δC (100.6 MHz, CDCl3) 174.7,
155.4, 134.3, 119.9, 117.1, 114.5, 34.0, 23.2, 22.8, 22.7, 22.5.
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4.7.2. 3-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-
yl)isoxazol-5(4H)-one (18b).
o
Yield 87%; yellow solid, mp 160 C; [Found: C, 66.25; H,
6.61; N, 13.05. C12H14N2O2 requires C, 66.04; H, 6.47; N,
12.84%]; νmax(KBr) 1794 (C=O), 1602 (C=N) cm-1; δH (400.13
MHz, CDCl3) 6.19 (1 H, s, H-3 of pyrrole), 3.72 (3 H, s, N-Me),
3.71 (2 H, s, CH2 of isoxazole), 2.55-2.52 (2 H, m, CH2-7), 2.48-
2.45 (2 H, m, CH2-4), 1.86-1.80 (2 H, m, CH2-5), 1.73-1.67 (2 H,
m, CH2-6); δC (100.6 MHz, CDCl3) 174.6, 156.4, 137.0, 119.5,
118.3, 114.9, 35.1, 33.3, 23.0, 22.7, 22.6, 22.0.
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yl)isoxazol-5(4H)-one (18c).
o
Yield 83%; yellow solid, mp 148 C; [Found: C, 68.12; H,
19. Tontini, A.; Diamantini, G.; Balsamini, C.; Tarzia, G.; Perissini, L.;
6.32; N, 12.18. C13H14N2O2 requires: C, 67.81; H, 6.13; N,
12.17%]; νmax(KBr) 1799 (C=O), 1642 (NCH=CH2) cm-1; δH
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CH2-7), 2.50-2.47 (2 H, m, CH2-4), 1.82-1.76 (2 H, m, CH2-5),
1.75-1.69 (2 H, m, CH2-6); δC (100.6 MHz, CDCl3) 174.4, 156.1,
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22.6.
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This work was supported by leading scientific schools by the
President of the Russian Federation (Grant NSh-1550.2012.3),

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