Formation and reductive ring opening reactions of indolyl-isoxazolidines: Access to novel natural product analogs and precursors

Article abstract of DOI:10.1016/j.tet.2015.12.032

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(3-indolyl)-N-phenylnitrone (2) with variedly substituted dipolarophiles were carried out to obtain syn- C4 and C5 substituted indolyl-isoxazolidines 6a-c and 7a-f, respectively. Reduction of obtained isoxazolidines, by employing various reducing agents, causes cleavage of the N-O bond, which is accompanied by concomitant cleavage of C-N bond leading to the formation of a library of novel indole based natural product analogs and precursors.

Full text of DOI:10.1016/j.tet.2015.12.032

Tetrahedron 72 (2016) 900e911
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formation and reductive ring opening reactions of indolyl-
isoxazolidines: access to novel natural product analogs and
precursors
a
b
b
c
d
Gagandeep Singh , Suresh Sharma , Vivek Gupta , Tilak Raj , Palwinder Singh ,
a,
*
Mohan Paul S. Ishar
a
Bio-Organic and Photochemistry Laboratory, Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar-143 005, Punjab, India
Post-Graduate Department of Physics & Electronics, University of Jammu, Jammu Tawi-180 006, India
Post Graduate Department of Chemistry, Dev Samaj College for Women, Ferozepur-152 002, Punjab, India
Department of Chemistry, Guru Nanak Dev University, Amritsar-143 005, Punjab, India
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2015
Received in revised form 9 December 2015
Accepted 13 December 2015
Available online 29 December 2015
Regio- and stereoselective 1,3-dipolar cycloadditions of C-(3-indolyl)-N-phenylnitrone (2) with variedly
substituted dipolarophiles were carried out to obtain syn- C4 and C5 substituted indolyl-isoxazolidines
6aec and 7aef, respectively. Reduction of obtained isoxazolidines, by employing various reducing
agents, causes cleavage of the NeO bond, which is accompanied by concomitant cleavage of CeN bond
leading to the formation of a library of novel indole based natural product analogs and precursors.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dipolar cycloaddition
Indolyl-isoxazolidines
Reductive cleavage
Reduction
NeO and CeN bond cleavage
1. Introduction
1,3-Dipolar cycloaddition is a versatile tool in the hands of
synthetic organic chemists to generate various biologically impor-
1
tant target molecules and their precursors. Notably, substituted
isoxazolidines have been synthesized via 1,3-dipolar cycloadditions
of nitrones with alkenes and are important precursors to b-amino
2
3
4a
4b
acids,
b-lactams, 1,3-amino alcohols, and pyrrolidinones ob-
tained through reductive NeO bond cleavage. Earlier, we have re-
2
,3,3
Scheme 1.
ported the formation of conformationally constrained
b
eamino
alcohols by reductive cleavage of the NeO bond of tricyclic iso-
xazolidines with ammonium formate in the presence of palladium
on charcoal (Pd/C) or zinc-acetic acid (Scheme 1).
There are available various literature reports, where oxazolidi-
nones have been subjected to reductive ring opening to get natural
On the other hand, the indole moiety is a prominent and privileged
structural motif found in numerous natural products, metabolites,
neurotransmitters and various synthetic compounds with in-
teresting biological activities (Fig. 1). A large number of indole al-
kaloids are reported to possess cytotoxic, analgesic, anxiolytic, anti-
5
a
products,
precursors
for
natural
products
and
peptidomimetics.5
beh
inflammatory, and immunomodulating activities.
6a
6
a
Inspired by reported significance of indole based scaffolds and
5
a,6b
in continuation of our previous work,
we have examined 1,3-
dipolar cycloaddition reactions of C-(3-indolyl)-N-phenylnitrone
with various dipolarophiles to obtain variously substituted indolyl-
isoxazolidines; reductive cleavage of NeO bond of the obtained
*
Corresponding author. Tel.: þ91 183 2258802x3321; fax: þ91 183 2258802;
e-mail address: mpsishar@yahoo.com (M.P.S. Ishar).
http://dx.doi.org/10.1016/j.tet.2015.12.032
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

G. Singh et al. / Tetrahedron 72 (2016) 900e911
901
Fig. 1. Structures of some naturally occurring indoles.
constants are always higher than trans in case of isoxazolidines
7
and related heterocycles. Thus, for instance, in the case of 6b,
C3eH appeared as a doublet at
d
5.44 (J¼8.6 Hz); the high value
of J3,4 alluded to cis arrangement. However, in the case of 7aef,
1
H NMR clearly indicated that the methylene hydrogens (C4eHs)
are coupled with both C3eH and C5eH, and is corroborated by
1
3
C chemical shifts of various carbons of isoxazolidine moiety. For
13
Fig. 2. E and Z conformations of nitrone (2).
instance, the C NMR resonance of methylene carbon (C4) in
aef appeared in the range 37e45, clearly indicating that it is
7
d
not attached to oxygen. The assigned stereochemistry in cyclo-
adducts (7aef) is also based on NMR spectral evidence. The syn
relationship between indole moiety at C3 and various sub-
isoxazolidines was anticipated to furnish valuable precursors for
the preparation of pharmaceuticals, natural products and pepti-
domimetic scaffolds.
1
stituents at C5 in 7aef are based on H NMR couplings involving
C3e, C4e and C5eHs and followed from the consistent obser-
6
,7bed,8
1
2
2
. Results and discussion
vation
5e9 Hz) than the trans (0e6 Hz) in case of isoxazolidines. For
instance, in compound 7f the values of coupling constants
that the cis vicinal H coupling are always higher
(
.1. (a) Regio- and stereoselective 1,3-dipolar cycloadditions
of C-(3-indolyl)-N-phenylnitrone (2) with variously
substituted dipolarophiles (3e5)
J
3,4a¼8.2 Hz, J3,4b¼5.4 Hz, J5,4a¼7.5 and J5,4b¼4.2 Hz, indicated that
both C3eH and C5eH shows higher coupling and hence cis re-
lationship with C4eHa, thereby, establishing a cis relationship
between C3eH and C5eH.
The formation of cycloadducts 6aec as minor regioisomer of
addition can be rationalized in terms of the frontier molecular or-
bital controlled cycloaddition involving HOMO (dipole)-LUMO
(dipolarophiles) interaction. To rationalize the effect of 3-indolyl
moiety on the molecular orbitals of 1,3-dipole, the DFT (Density
functional theory) calculations were performed using GGA-DFT
Initially, the reactions of C-(3-indolyl)-N-phenylnitrone (2) with
various monosubstituted and disubstituted dipolarophiles (3aef, 4
and 5) were carried out by irradiating equimolar amount of the
6
addends in a focused monomode microwave reactor. After com-
6
,9
pletion of the reactions (monitored by TLC) the residues obtained
were resolved by column chromatography over silica gel to obtain
the cycloadducts 6e9, which were characterized spectroscopically
1
13
6d,e
(
H NMR, C NMR and HRMS). The results are summarized in
package DMol-3
on C-(3-indolyl)-N-phenylnitrone (2), a,N-
Scheme 2 and Table 1.
diphenyl nitrone (2A) and C-(chrom-4-one-3-yl)-N-phenylnitrone
The assigned regiochemistry of addition in 6aec is based on
(2B) in Z conformation, whose cycloaddition reactions have been
1
6b,c,10
H NMR chemical shift of methylene-Hs (C5eHs) located at
reported by us earlier (Table 2).
The calculations revealed that
1
d
4.55e4.41 and this downfield shifted position in H NMR is
nitrone 2 has high lying HOMO as compared to other nitrones 2A
and 2B. Therefore, formation of 4-substituted regioisomer is ob-
tained even with less electron deficient dipolarophiles. Normally, 4-
substituted isoxazolidines are obtained in reactions involving
indicative of the attachment of methylene carbon to oxygen in
aec. These conclusions are corroborated by the observed proton
6
13
connectivities (couplings) and C NMR chemical shift assign-
ments, which clearly indicated that C4eH is vicinal to both C3eH
and C5eHs. The syn/anti-stereochemistry in 6aec involving in-
dole group at C3 and the ester functionality at C4 of isoxazolidine
ring is based on 1H NMR couplings involving C3eH and C4eH,
9
highly electron deficient dipolarophiles such as nitro-olefins,
wherein HOMO (dipole)-LUMO (dipolarophiles) interaction in-
tervenes, however, in the case of relatively electron rich dipoles
having a high lying HOMO result in obtaining of 4-regioisomers
even with less electron deficient dipolarophile such as acrylates.
1
and follows from the premise that the cis-vicinal H coupling

902
G. Singh et al. / Tetrahedron 72 (2016) 900e911
Scheme 2. Synthesis of variously substituted Indolyl-Isoxazolidines (6e9).
Table 1
Similarly, corresponding syn cycloadducts 7aef (C5-substituted
Reaction time and yields (%) of products 6e9
regio-isomer), can originate from an exo-mode of addition of the
substituent on the dipolarophiles with the nitrone in its Z-form
(approach III) or/and endo-mode of addition of dipolarophiles with
Serial no.
Dipolarophile
Reaction
time (min)
Yield (%)a of various
products 6:7, 8 and 9
10
1
2
3
4
5
6
7
8
3; R¼eO
2
Me
Et
5
5
5
5
5
5
5
5
6a (40%)
6b (45%)
6c (40%)
6d (e)
6e (e)
6f (e)
7a (45%)
nitrone reacting in E form (approach IV) as shown in Fig. 4.
Further, the investigations were extended to disubstituted
dipolarophiles such as ethyl crotonate (4) and -methyl styrene (5).
R¼eCO
R¼eCO
R¼ePh
2
7b (50%)
7c (55%)
7d (90%)
7e (88%)
7f (80%)
2
Bu
a
The reaction of nitrone (2) with ethyl crotonate (4) afforded a single
product, which has been characterized as cycloadduct 8 by com-
parison of the spectroscopic data with the data reported for
cycloadducts derived from addition of some nitrones to croto-
R¼ep-Tolyl
R¼ePyridyl
4
5
8 (88%)
9 (90%)
a
Based on isolated pure products along with, in some cases, 1H NMR spectral
11
nates. The structures of cycloadducts 8 and 9 were established
analysis of mixture fractions from column chromatography.
1
13
spectroscopically ( H NMR, C NMR and HRMS); finally, confirmed
13b,c
by X-ray crystallography (Fig. 5).
Though, the regiochemistry of addition to 4 and 5 was antici-
9
pated in the light of literature reports, however, in the case of
cycloadduct 8, the obtained stereo-selectivity can be rationalized in
terms of addition of nitrone in its Z-form with ester moiety of 4
being exo-oriented and methyl moiety is endo-oriented or nitrone
in its E-form approaches with ester moiety being endo-oriented and
methyl is exo-oriented. Similarly, cycloadduct 9 can originate from
an exo-orientation of the phenyl substituent on the dipolarophile 5
with the nitrone in its Z-form or nitrone in its E-form approaches
with phenyl moiety being endo-oriented.
Formation of mixture of regioisomers in addition of nitrones with
dipolarophiles such as acrylates, nitro-olefins and acrylonitrile has
9
precedents, whereas, the regioselective addition leading to major
products 7aef, is a consequence of LUMO (dipole)-HOMO (dipo-
larophiles) interactions anticipated for 1,3-cycloadditions involving
nitrones.9
,10
The observed syn-selective cycloaddition of the C-(3-indolyl)-N-
phenylnitrone (2) to acrylates (3aec) leading to 6aec, the minor
cycloadducts, can be rationalized in terms exo-mode of addition of
nitrone in Z-form1 (approach 1, Fig. 3). Alternatively, the stable Z-
forms (A) of nitrones are reported to exist in equilibrium with
a small amount of the E-isomer (B) of the nitrone under reaction
conditions (Fig. 2); involvement of nitrone in its more reactive, i.e.,
less stable E-form in cycloaddition leading to major reaction
3a
2.2. (b) Cleavage of NeO bond of obtained isoxazolidines
(6e9)
Earlier, we have reported the formation of conformationally
2
,3,3
constrained
b
eamino alcohols, which are valuable precursors
9
d
products is precedented. Therefore, addition of nitrone (2) in E-
form through an endo-transition state, known to be favored for
a variety of reason,6 can also explain the obtained syn stereo-
chemistry in the case of 6aec (approach II, Fig. 3).
for pharmaceuticals and peptidomimetic scaffolds, via reductive
5
a
cleavage of the NeO bond of tricyclic isoxazolidines. Therefore,
the cleavage of NeO bond of obtained indolyl-isoxazolidines was
,9d
5
a
investigated under reductive conditions as employed earlier.

G. Singh et al. / Tetrahedron 72 (2016) 900e911
903
Table 2
HOMO and LUMO energies and HOMO-LUMO gap energies for nitrones 2, 2A and 2B by DFT calculations
Nitrones Molecular orbital of HOMO-LUMO of nitrones
HOMO-LUMO gap energies
1
.828
1
1
.571
.625
Fig. 3. 1,3-dipolar cycloadditions of nitrone (2) to substituted acrylates (3aec).
Fig. 5. OERTEP diagram of compounds 8 and 9.
Initially, compound 7b was subjected to reduction with HCOONH
4
hydroxy-4-(1H-indol-3-yl) butanoate (12b), derived from cleavage
of NeO bond along with reductive loss of aniline moiety, in 61%
yield. Some unconsumed starting material was also recovered after
(
5 equiv) and 5% Pd/C (5 equiv) in a mixture of solvents (THF:Me-
thanol) at room temperature. The obtained product was charac-
1
13
terized spectroscopically ( H NMR, C NMR and HRMS) as ethyl-2-
Scheme 3. Reductive cleavage of NeO bond of comp. (7b).
Fig. 4. 1,3-dipolar cycloadditions of nitrone (2) to monosubstituted dipolarophiles
(
3def).

904
G. Singh et al. / Tetrahedron 72 (2016) 900e911
6
h (Scheme 3) and no amino alcohol was detected. 1H NMR of
compound 12b showed a doublet at 2.90 ppm (1H), exchangeable
with D O, which was ascribed to OH group. The presence of ester
moiety in 12b is confirmed by quartet (2H) and triplet (3H) at 4.18
and
1.26, respectively with mutual coupling constant of J¼7.0 Hz.
The presence of two methylene (2ꢀCH ) groups were further cor-
(1H, 13C NMR including COSY, HSQC and HRMS). The 1H NMR
spectra of compound 10b clearly indicated the presence of quartet
(2H) and triplet (3H) at 4.18 and 1.24 ppm with coupling con-
stant of J¼7.0 Hz attributed to ester moiety. The broad singlet ob-
served at 2.65 ppm (1H, exchangeable with D O) was assigned to
the OH-proton. Another doublet of two protons was observed at
3.82 ppm, ascribable to the methylene group vicinal to OH and
ester group, and this downfield shift confirms that this methylene
d
2
d
d
d
d
d
2
2
1
13
roborated by H NMR and C NMR spectral evidences. The assigned
structure is also supported by proton-carbon connectivities via
HSQC spectrum. The peak corresponding to the mass of 12b with m/
z 270.1099 (calcd m/z 270.1101 [MþNa]) was observed in the high
resolution mass spectrum (HRMS), which confirmed the assigned
structure.
In order to obtain the desired amino-alcohol product via
cleavage of NeO bond of 7b, a variety of other reductive conditions
were evaluated (Table 3). However, reaction of 7b under various
reductive conditions results in the formation of 12b only, in varied
yields and no desired amino-alcohol product was formed.
d
1
13
group is attached to heteroatom. Other H and C NMR assign-
ments were in agreement with the assigned structure. The peak
corresponding to the mass of 10b with m/z 248.1272 (calcd m/z
þ
248.1281 [MþH] ) was observed in the high resolution mass
spectrum (HRMS), which also confirmed the molecular formula
3
(C14H17NO ) for assigned structure.
On the other hand, in the case of compounds 11aec, the pres-
ence of trans-substituted olefinic moiety, besides ester function,
1
was revealed by appearance of two mutually coupled H resonance
doublets at
d
7.92e7.85 and
d
6.59e6.43 (coupling constant value of
-unsaturated ester
J¼15.9e16.0 Hz); a characteristic feature of
a,b
Table 3
function. The peaks at m/z 224.0675, 216.1011 and 266.1140 in the
HRMS of compounds 11a, 11b, and 11c, respectively, confirmed the
Optimization of reductive ring opening of isoxazolidine 7b: Screening of reducing
agents
þ
assigned structures (calcd m/z 224.0681[MþNa] , 216.1019
þ
þ
Entry
Reducing agent
Solvent
Yield (%)
Time (h)
[
MþH] , 266.1151[MþNa] , respectively); as the obtained indolyl-
1
2
3
Zn (5 equiv)
Zn (10 equiv)
Zn (5 equiv)
AcOH
AcOH
AcOH:H
35
40
36
11
10
12
acrylates (11aec) are known compounds and these were further
confirmed by comparison of melting points with literature data.
Mechanistically, the major transformation of cycloadducts 6aec
and 7aef, leading to the formation of 10aec and 12aef, re-
spectively, involves the reductive cleavage of NeO bond and con-
comitant cleavage of CeN bond of isoxazolidine moiety leading to
loss of aniline moiety (Schemes 6 and 7). The reductive cleavage of
allylic and benzylic CeN bond under drastic conditions has pre-
2
2
O
O
2
:1
AcOH:H
:1
THF:MeOH
:3
THF:MeOH
:3
THF:MeOH
:3
THF:MeOH
:3
THF:MeOH
:3
THF:MeOH
:3
4
5
6
7
8
9
Zn (10 equiv)
42
52
58
61
65
68
85
12
8
2
ZneHCOONH
ZneHCOONH
4
(5 equiv)
1
4
(10 equiv)
8
1
12
5% Pd/CeHCOONH
4
4
(5 equiv)
6
cedents, however, in present study, complete loss of aniline
1
moiety occurs under much milder conditions and no amino alcohol
5% Pd/CeHCOONH
(10 equiv)
4
5a
is formed as reported earlier
.
1
The formation of minor products 11aec, results from the re-
ductive cleavage of NeO bond followed by sequence of retro Aldol
reaction and loss of aniline moiety (Scheme 6). Apparently, com-
pounds 10aec and 11aec have been derived from common in-
termediate [C] and compounds 12aef and 13 are derived from an
analogous intermediate [D] as shown in Schemes 6 and 7, however,
it is not clear whether retro-aldol triggers eliminative loss of aniline
moiety or cleavage of CeN bond triggers retro-aldol reaction. Ap-
parently, the differing behavior of isoxazolidines (6e9) on re-
ductive cleavage, leading to loss of aniline moiety as compared to
10% Pd/CeHCOONH
4
(5 equiv)
2
1
1
0
10% Pd/CeHCOONH
4
(10 equiv)
0.5
1
It was observed that the use of an excess (10 equiv) of ammo-
nium formate and 10% Pd/C in THF-MeOH solvent, efficiently
cleaved the NeO and CeN bonds of compound 7b at RT to furnish
compound 12b in good yield and in less time than Zn/acetic acid
and Zn/HCOONH
and clean.
5
a
formation of amino alcohols reported by us earlier, is a conse-
quence of contiguous position of aniline moiety to electron rich C3
of indole nucleus.
4
(entry 10, Table 3); the reaction is also very neat
Further, to investigate the substrate influence on reductive
cleavage of NeO bond of isoxazolidines and to examine whether
the obtained reductive loss of aniline moiety is a general behavior
of 3-(1H-Indol-3-yl)-isoxazolidine derivatives (6e9); these were
subjected to the optimized reductive conditions (entry 10, Table 3).
As observed, when compounds 6aec (bearing ester moiety at C4)
were subjected to reduction, these afforded compounds 10aec in
good yields along with indolyl acrylates (11aec) as minor products
To establish the general behavior of such C3 indolyl-
isoxazolidines, isoxazolidine (16a) was synthesized by addition of
nitrone (15) to 4-methylstyrene (3e, Scheme 8). The compound 16
was isolated chromatographically and characterized spectroscopi-
1
13
cally ( H NMR, C NMR and HRMS). Isoxazolidine 16a was sub-
jected to reductive cleavage under optimized conditions, which led
to the formation of compound 17 (Scheme 8); isolated chromato-
1
13
graphically and characterized spectroscopically ( H NMR, C NMR
and HRMS). This clearly indicates the general applicability of the
developed procedure to synthesize substituted indole derivatives
(10e13 and 17).
(Scheme 4), whereas, reductive NeO bond cleavage of iso-
xazolidines 7aef (C5-substituted regioisomer) and cycloadduct 9
led to the formation of compounds 12aef and 13 (Scheme 5); the
formation of compounds 10e13 revealed that the concomitant re-
ductive cleavage of CeN bond leads to loss of aniline moiety is
general behavior of the indolyl-isoxazolidines, under optimized
reductive conditions.
All the products were isolated and purified by column chro-
matography (silica gel 60e120 mesh, eluted with ethyl acetate:
Hexane (4:6)) and the assigned structures of adducts (10aec,
To further establish that the loss of aniline moiety is a specific
feature of indol-3-yl substituted isoxazolidines, pyridyl-
isoxazolidine derivative (20a) was synthesized by addition of
7
a
nitrone (19) to 4-methylstyrene (3e, Scheme 9). The compound
20 was isolated chromatographically and characterized spectro-
1
13
scopically ( H NMR, C NMR and HRMS). However, when com-
pound 20a was subjected to reductive cleavage under optimized
conditions, it led to the formation of amino alcohol derivative (21,
11aec, 12aef and 13) are based on rigorous spectroscopic analysis

G. Singh et al. / Tetrahedron 72 (2016) 900e911
905
Scheme 4
Scheme 5
Schemes 4 and 5. Reductive ring opening of Indolyl-isoxazolidines 6e9; Reaction conditions: 1.5 mmol of substrate (6e9), 10 equiv of 10% Pd/C, 10 equiv of HCOONH
4
, THF/MeOH
(
1:3), RT.
Scheme 9), which was isolated chromatographically and charac-
to syn- C4 and C5 substituted indolyl-isoxazolidines 6aec and
7aef, respectively. The obtained isoxazolidines were subjected
to reduction under variety of conditions, however, with am-
monium formate and 10% Pd/C at RT, results in the formation
of a novel compounds (10aec, 12aef and 13) along with
indolyl-acrylates (11aec) via reductive ring opening of iso-
xazolidine moiety and concomitant cleavage of CeN bond
leading to loss of aniline moiety; the observed facile concom-
itant cleavage of CeN bond under milder conditions is a new
1
13
terized spectroscopically ( H NMR, C NMR and HRMS). These
experiments firmly confirmed our earlier observation that the loss
of aniline moiety during reductive cleavage is a consequence of its
contiguous position to the electron rich C3-position of indole
nucleus.
3
. Conclusions
Regio- and stereoselective 1,3-dipolar cycloadditions of
nitrone (2) with variously substituted dipolarophiles (3e5) lead
characteristic
xazolidines.
feature
not
observed
in
related
iso-
4
b,5,6
That the loss of aniline moiety is

906
G. Singh et al. / Tetrahedron 72 (2016) 900e911
Scheme 6.
a consequences of its contiguous position to electron rich C3
atom of indole nucleus has been established by carrying out
further experiments with methoxy-indolyl-isoxazolidine (16a)
and pyridyl-isoxazolidine (20a). Moreover, due to the structural
occurring and pharmacologically active a-hydroxy ketones
kurasoins and sattazolin, the obtained chemistry has lots of
potential; therefore, these findings should be of considerable
interest for the construction of novel bio-active molecules,
natural product precursors and peptidomimetic scaffolds.
resemblance of
a-hydroxy ketones 12aec with the naturally
Scheme 7.
Scheme 8.

G. Singh et al. / Tetrahedron 72 (2016) 900e911
907
Scheme 9.
4
4
. Experimental section
which was placed in the cavity of the microwave reactor. After
closing the cavity of the reactor with the cavity lid, the contents
were irradiated (150 W, 100 C) for 5 min (1 min hold time and
ꢁ
.1. Materials and equipments
4
min running time) till all the nitrones (2) was consumed (moni-
Starting materials and reagents were purchased from commer-
tored by TLC). After completion of the reaction, the residues were
loaded onto silica gel column (60e120 mesh, column packed in
hexane); elution of column using hexaneechloroform (gradient)
afforded 6e9. The reported yields were based on isolated pure
products and relative proportions determined in the mixtures by
cial suppliers and used after further purification (crystallization/
1
13
distillation). H and C NMR spectra were recorded on a Bruker
Avance 500 MHz NMR spectrometer using CDCl and DMSO-d as
3
6
a solvent. Chemical shifts are given in ppm with TMS as an internal
reference. J values are given in Hertz. Mass spectra were recorded
on a Bruker micrOTOF Q II Mass spectrometer (LC MS/MS). The
CEM-Discover Focused Monomode Microwave reactor (2450 MHz,
1
H NMR spectroscopy.
4.2.2.1. 3-(1H-Indol-3-yl)-2-phenyl-isoxazolidine-4-carboxylic
3
00 W) was used for microwave irradiation. Reactions were mon-
acid ethyl ester (6b). R
f
0.54 (CHCl
3
/hexane 8:2); Brownish viscous
itored by thin layer chromatography (TLC) on glass plates coated
with silica gel GF-254. Column chromatography was performed
with 60e120 mesh silica. All melting points are uncorrected and
measured in open glass-capillaries using Veego Precision Digital
Melting Point Apparatus.
oil, Yield (225 mg, 45%).
1
H NMR (CDCl
3
, 500 MHz):
d
8.22 (br s, 1H, NH), 7.73 (d, 1H,
0
0
0
J¼6.9 Hz, C4 eH), 7.67 (d, 1H, J¼7.2 Hz, C7 eH), 7.27 (s, 1H, C2 eH),
0
0
7.12e7.01 (m, 6H, arom.-Hs & C6 , C5 eHs), 6.89 (t, 1H, J¼6.8 Hz,
arom.-H), 5.44 (d, 1H, J¼8.6 Hz, C3eH), 4.57 (dd, 1H, J¼11.2 Hz &
7
.6 Hz, C5eHa), 4.41 (dd, 1H, J¼11.2 Hz & 5.6 Hz, C5-Hb), 3.92 (q, 2H,
J¼7 Hz, OCH
2
), 3.79 (unresolved ddd, 1H, J¼8.6 Hz & 7.6 Hz, C4eH),
) ppm.
C NMR (CDCl , 125 MHz):
22.9, 121.9, 119.5, 118.5, 116.4, 115.3, 112.1, 111.3, 68.2, 65.6, 61.8,
4
.2. Synthesis
1
.27 (t, 3H, CH
3
13
3
d 171.1, 152.3, 134.6, 129.8, 123.8,
4.2.1. General procedure for synthesis of C-(3-indolyl)-N-phenyl-
1
nitrone (2). 3-Formylindole (2.8 mmol) was dissolved in dry
ethanol (30 ml) and to the clear solution N- phenylhyroxyl-
amine hydrochloride (2.8 mmol) was added, and the contents
were allowed to stand at room temperature for overnight.
Then, solvent was evaporated under vacuum to obtain the
viscous yellow oil, which was crystallized in chloroformeether
56.4, 15.2.
HRMS (ESI, m/z): calcd for C20
found 359.1358.
H
20
N
2
O
3
[MþNa]þ, 359.1366,
4
.2.2.2. 3-(1H-Indol-3-yl)-2-phenyl-isoxazolidine-4-carboxylic
acid butyl ester (6c). R 0.56 (CHCl /hexane 8:2); Brownish viscous
oil, Yield (200 mg, 40%).
f
3
(
1:2) to obtain nitrones (2) as light yellow powder (yield 90%).
The nitrone was dried under vacuum and stored under
refrigeration.
1
H NMR (CDCl
3
, 500 MHz):
d
8.24 (br s, 1H, NH), 7.76 (d, 1H,
0
0
0
J¼6.8 Hz, C4 eH), 7.69 (d, 1H, J¼7.4 Hz, C7 eH), 7.28 (s, 1H, C2 eH),
0
0
7
.21e7.12 (m, 6H, arom.-Hs & C6 , C5 eHs), 6.86 (t, 1H, J¼7 Hz,
4.2.2. General procedure for the reaction of C-(3-indolyl)-N-phenyl-
arom.-H), 5.43 (d, 1H, J¼8 Hz, C3eH), 4.52 (dd, 1H, J¼11.8 Hz &
nitrone (2) with various dipolarophiles (3aef, 4 and 5) under mon-
omode microwave irradiation. C-(3-indolyl)-N-phenylnitrone (2,
8
2
(
.9 Hz, C5eHa), 4.43 (dd, 1H, J¼11.8 Hz & 5.4 Hz, C5-Hb), 4.19 (m,
H, OCH
), 3.77 (unresolved ddd, 1H, J¼8.9 Hz & 8 Hz, C4eH), 1.56
), 1.33 (m, 2H, CH ), 1.10 (t, 3H, CH ).
2
1.28 mmol) and dipolarophiles (3aef, 4 and 5; 1.0 equiv) were
m, 2H, CH
2
2
3
added in the 150 ml round bottom flask, fitted with a condenser,

908
G. Singh et al. / Tetrahedron 72 (2016) 900e911
13C NMR (CDCl
23.2, 122.5, 121.9, 119.4, 118.7, 115.2, 111.1, 110.3, 69.2, 66.6, 65.8,
, 125 MHz): d 172.4, 150.7, 135.7, 128.9, 125.7,
4.2.2.7. 3-(1H-indol-3-yl)-2-phenyl-5-p-tolylisoxazolidine
(7e). R 0.58 (CHCl /hexane 8:2); Colorless semisolid, Yield
3
1
5
f
3
4.4, 33.2, 21.2, 14.3.
HRMS (ESI, m/z): calcd for C22
found 365.1862.
(440 mg, 88%).
1
H N
24 2
O
3
[MþH]þ, 365.1859,
H NMR (CDCl
3
, 500 MHz):
d
8.14 (br s, 1H, NH), 7.80 (d, 1H,
0
J¼8 Hz, C4 eH), 7.42e7.16 (m, 12H, arom.-Hs), 6.99 (t, 1H, J¼7.5 Hz,
arom.-H), 5.24 (m, 2H, C3eH and C5eH), 3.23 (ddd, 1H,
4
.2.2.3. 3-(1H-Indol-3-yl)-2-phenyl-isoxazolidine-5-carboxylic
acid methyl ester (7a). R 0.55 (CHCl /hexane 8:2); Brownish vis-
cous oil, Yield (225 mg, 45%).
J
gem¼12.8 Hz & J¼7.0, 4.5 Hz, C4-Ha), 2.68 (ddd, 1H, Jgem¼12.8 Hz &
J¼6.75, 2.5 Hz, C4-Hb), 2.38 (s, 3H, CH ).
152.9, 138.1, 136.9, 134.9, 129.2,
f
3
3
13
3
C NMR (CDCl , 125 MHz): d
1
H NMR (CDCl
3
, 500 MHz):
d
8.26 (br s, 1H, NH), 7.78 (d, 1H,
128.9, 127.0, 125.4, 122.3, 121.6, 121.3, 119.7, 119.3, 117.9, 114.2, 111.4,
80.5, 65.8, 46.5, 21.2.
0
0
0
J¼6.6 Hz, C4 eH), 7.69 (d, 1H, J¼7.5 Hz, C7 eH), 7.26 (s, 1H, C2 eH),
0
0
7
.16e7.04 (m, 6H, arom.-Hs & C6 , C5 eHs), 6.97 (t, 1H, J¼6.2 Hz,
arom.-H), 5.21 (dd, 1H, J¼7.5, 3 Hz, C5eH), 4.65 (dist dd, 1H,
J¼8.0 Hz, C3eH), 3.11(s, 3H, OCH ), 2.95 (dt, 1H, Jgem¼12.8 & J¼8 Hz,
C4-Ha), 2.67 (ddd, 1H, Jgem¼12.8 Hz & J¼7.5, 3 Hz, C4-Hb).
HRMS (ESI, m/z): calcd for C24
22
H N
2
O [MþNa]þ, 377.1624, found
377.1618.
3
4.2.2.8. 3-(1H-indol-3-yl)-2-phenyl-5-(pyridin-4-yl)isoxazolidine
13
C NMR (CDCl
23.9, 122.5, 121.9, 119.5, 118.5, 115.3, 112.1, 111.3, 67.2, 64.6, 51.8,
0.2.
HRMS (ESI, m/z): calcd for C19
found 345.1201.
3
, 125 MHz):
d
170.1, 150.3, 135.7, 128.9, 125.9,
(7f). R
f
0.55 (CHCl
3
/hexane 8:2); Light yellow solid, mp
ꢁ
1
4
137e139 C; yield (400 mg, 80%).
1
3
H NMR (CDCl , 500 MHz): d 8.29 (br s, 1H, NH), 7.51e7.25 (m,
H
18
N
2
O
3
[MþNa]þ, 345.1209,
14H, arom.-Hs), 5.42 (dd, 1H, J¼8.2, 5.4 Hz, C3eH), 5.02 (dd, 1H,
J¼7.5, 4.2 Hz, C5eH), 2.97 (ddd, 1H, Jgem¼13.5 Hz & J¼8.2, 4.2 Hz,
C4-Ha), 2.72 (ddd, 1H, Jgem¼13.5 Hz & J¼7.5, 5.4 Hz, C4-Hb).
13
4
.2.2.4. 3-(1H-Indol-3-yl)-2-phenyl-isoxazolidine-5-carboxylic
acid ethyl ester (7b). R 0.57 (CHCl /hexane 8:2); Brownish viscous
oil, Yield (250 mg, 50%).
3
C NMR (CDCl , 125 MHz): d 151.7, 149.8, 149.0, 136.8, 128.9,
f
3
128.5, 125.3, 122.6, 122.4, 122.1, 121.2, 119.8, 116.7, 114.9, 111.4, 78.1,
65.2, 44.8.
HRMS (ESI, m/z): calcd for C22
342.1588.
1
H NMR (CDCl
3
, 500 MHz):
d
8.27 (br s, 1H, NH), 7.78 (d, 1H,
H
19
N
3
O [MþH]þ, 342.1600, found
0
0
0
J¼6.6 Hz, C4 eH), 7.69 (d, 1H, J¼7.5 Hz, C7 eH), 7.26 (s, 1H, C2 eH),
0
0
7
.16e7.04 (m, 6H, arom.-Hs & C6 , C5 eHs), 6.97 (t, 1H, J¼7.2 Hz,
arom.-H), 5.48 (dd, 1H, J¼7.5, 3 Hz, C5eH), 4.65 (dist dd, 1H,
J¼8.0 Hz, C3eH), 4.19 (q, 2H, J¼7 Hz, OCH ), 3.65 (dt, 1H,
gem¼12.8 Hz & J¼8 Hz, C4-Ha), 3.45 (ddd, 1H, Jgem¼12.8 Hz & J¼7.5,
Hz, C4-Hb), 1.23 (t, 3H, CH ).
, 125 MHz):
23.2, 122.2, 119.7, 118.8, 115.9, 115.3, 112.3, 111.2, 69.2, 65.4, 61.6,
4.2.2.9. 3-(1H-Indol-3-yl)-5-methyl-2-phenyl-isoxazolidine-4-
2
carboxylic acid ethyl ester (8). R
solid, Yield (440 mg, 88%).
f
3
0.59 (CHCl /hexane 8:2); Colorless
J
1
3
3
H NMR (CDCl
3
, 500 MHz):
d
8.16 (br s, 1H, NH), 7.80 (d, 1H,
13
0
0
C NMR (CDCl
3
d
170.1, 151.7, 135.1, 130.1, 123.9,
J¼7.8 Hz, C4 eH), 7.72 (d, 1H, J¼8 Hz, C7 eH), 7.27e7.03 (m, 5H,
0
0
0
1
3
arom.-Hs & C6 eH, C2 eH), 7.02e6.96 (m, 3H, arom.-Hs & C5 eHs),
5.29 (d, 1H, J¼10.0 Hz, C3eH), 4.89 (dq, 1H, J¼9.5 Hz & 6.0 Hz,
8.4, 14.9.
HRMS (ESI, m/z): calcd for C20
37.1539.
H
20
N
2
O
3
[MþH]þ, 337.1546, found
C5eH), 4.25 (q, 2H, J¼7.5 Hz, OCH ), 3.63 (dd, 1H, J¼10.0 Hz &
2
3
9.5 Hz, C4eH), 1.94 (d, 3H, J¼6.0 Hz, C5e CH
3
), 1.30 (t, 3H, J¼7.5 Hz,
3C NMR (CDCl
, 125 MHz): d 170.7, 151.7, 136.7, 128.8, 125.9,
3
CH ) ppm.
3
1
4
.2.2.5. 3-(1H-Indol-3-yl)-2-phenyl-isoxazolidine-5-carboxylic
acid butyl ester (7c). R
oil, Yield (275 mg, 60%).
f
0.54 (CHCl
3
/hexane 8:2); Brownish viscous
123.7, 122.8, 121.7, 120.5, 118.2, 114.4, 111.2, 109.7, 77.7, 68.1, 63.8,
59.3, 18.1, 14.1 ppm.
1
H NMR (CDCl
3
, 500 MHz):
d
8.24 (br s, 1H, NH), 7.79 (d, 1H,
HRMS (ESI, m/z): calcd for C21
351.1700.
22
H N
2
O
3
[MþH]þ, 351.1703, found
0
0
0
J¼6.5 Hz, C4 eH), 7.72 (d, 1H, J¼7 Hz, C7 eH), 7.29 (s, 1H, C2 eH),
7
(
4
2
.16e7.04 (m, 8H, arom.-Hs), 6.89 (t, 1H, J¼7.2 Hz, arom.-H), 5.26
dd, 1H, J¼8.0, 4.0 Hz, C5eH), 4.85 (dist dd, 1H, J¼7.5 Hz, C3eH),
4.2.2.10. 3-(1H-indol-3-yl)-5-methyl-2,5-diphenyl-isoxazolidine
ꢁ
.23 (m, 2H, OCH
.59 (ddd, 1H, Jgem¼13.8 Hz & J¼7.5, 4.0 Hz, C4-Hb), 1.52 (m, 2H,
), 1.34 (m, 2H, CH ), 0.82 (t, 3H, CH ).
, 125 MHz): 171.4, 151.3, 134.7, 129.2, 125.9,
22.8, 122.2, 121.5, 119.8, 117.9, 115.2, 112.1, 110.8, 68.9, 67.6, 65.8,
7.1, 34.2, 21.4, 14.8.
2
), 3.02 (dt, 1H, Jgem¼13.8 Hz & J¼8.0 Hz, C4-Ha),
(9). R
f
0.58 (CHCl
3
/hexane 8:2); Colorless solid, mp 133e135 C;
Yield (450 mg, 90%).
1
CH
2
2
3
H NMR (CDCl
3
, 500 MHz): d 8.17 (br s, 1H, NH), 7.62e6.84 (m,
1
3
C NMR (CDCl
3
d
15H, arom.-Hs), 4.83 (dist dd, 1H, J¼8.0 Hz, C3eH), 3.20 (dd, 1H,
1
3
J
gem¼12.5 Hz & J¼7.5 Hz, C4-Ha), 2.86 (dd, 1H, Jgem¼12.5 Hz &
J¼5.4 Hz, C4-Hb), 2.21 (s, 3H, CH
3
).
151.9, 137.7, 136.6, 134.8, 129.2,
1
3
HRMS (ESI, m/z): calcd for C22
found 365.1836.
H N
24 2
O
3
[MþH]þ, 365.1859,
C NMR (CDCl
3
, 125 MHz):
d
128.9, 127.0, 124.7, 122.9, 121.6, 121.3, 119.7, 119.3, 117.9, 113.8, 112.4,
79.1, 65.82, 47.1, 22.1.
4
.2.2.6. 3-(1H-indol-3-yl)-2,5-diphenyl-isoxazolidine
(7d). R
f
HRMS (ESI, m/z): calcd for C24
377.1619.
22
H N
2
O [MþNa]þ, 377.1624, found
ꢁ
0
.61 (CHCl
3
/hexane 8:2); Light brown solid, mp 123e125 C; Yield
(
450 mg, 90%).
1
H NMR (CDCl
3
, 500 MHz):
d
8.04 (br s, 1H, NH), 7.71 (d, 1H,
4.2.2.11. 3-(5-Methoxy-1H-indol-3-yl)-2-phenyl-5-p-tolylisox-
0
J¼8.2 Hz, C4 eH), 7.41e6.86 (m, 14H, arom.-Hs), 5.23e5.18 (m, 2H,
C3eH and C5eH), 3.21 (ddd, 1H, Jgem¼11.4 Hz & J¼7.2, 3.5 Hz, C4-
Ha), 2.64 (ddd, 1H, Jgem¼11.4 Hz & J¼6.0, 4.5 Hz, C4-Hb).
azolidine (16a). R
f
0.58 (CHCl
3
/EtOAc 8:2); Cream white solid, Yield
(450 mg, 90%).
1
H NMR (CDCl
3
, 500 MHz): d
8.00 (br s, 1H, NH), 7.40 (m, 2H,
13
C NMR (CDCl
3
, 125 MHz):
d
151.7, 138.5, 136.7, 134.4, 128.9,
arom.-Hs), 7.31 (m, 4H, arom.-Hs), 7.23 (m, 6H, arom-Hs), 6.98 (t,
1H, J¼7.0 Hz, arom.-H), 5.24 (dd, 1H, J¼6.0 Hz, 3.5 Hz, C5eH), 5.18
(dd, 1H, J¼7.5 Hz, 4.0 Hz, C3eH), 3.84 (s, 3H, OCH3), 3.23 (ddd, 1H,
1
8
28.2, 126.8, 125.3, 122.4, 121.9, 121.2, 118.7, 118.1, 116.9, 114.4, 110.8,
0.5, 65.8, 44.9.
HRMS (ESI, m/z): calcd for C23
41.1644.
H
20
N
2
O [MþH]þ, 341.1648, found
J
gem¼13.1 Hz & J¼7.5, 3.5 Hz, C4-Ha), 2.67 (ddd, 1H, Jgem¼13.1 Hz &
3
J¼6.0, 4.0 Hz, C4-Hb), 2.37 (s, 3H, CH
3
).

G. Singh et al. / Tetrahedron 72 (2016) 900e911
909
13C NMR (CDCl
28.8,128.4,126.8,125.7,123.2,122.4,121.3, 117.5,116.2,114.3,112.5,
, 125 MHz):
d
152.8, 138.0, 135.2, 132.7, 129.2,
HRMS (ESI, m/z): calcd for C14
248.1272.
H17NO
[MþH] , 248.1281, found
þ
3
3
1
8
0.3, 65.8, 55.8, 46.3, 21.1.
HRMS (ESI, m/z): calcd for C25
þ
H N
24 2
O
2
[MþnNa] , 407.1730,
4.2.3.3. Butyl-2-((1H-indol-3-yl)-methyl)-3-hydroxypropanoate
(10c). R 0.53 (CHCl /EtOAc 7:3); Light brown semisolid, Yield
275 mg, 55%).
found 407.1736.
f
3
(
1
4
.2.2.12. 3-(2-Phenyl-5-p-tolylisoxazolidin-3-yl)pyridine
H NMR (CDCl
3
, 500 MHz):
d
8.35 (br s, 1H, NH), 7.64 (d, 1H,
0
0
(
9
20a). R
f
0.58 (CHCl
3
/EtOAc 8:2); Cream white solid, Yield (450 mg,
J¼7.5 Hz, C4 eH), 7.35 (d, 1H, J¼7.5 Hz, C7 -H), 7.22 (t, 1H, J¼7.5 Hz,
0
0
0
0%).
C5 -H), 7.14 (t, 1H, J¼7.5 Hz, C6 -H), 6.99 (s, 1H, C2 -H), 4.31 (m, 2H,
1
0
H NMR (CDCl
3
, 500 MHz):
d
8.77 (br s, 1H, 2 -H), 8.59 (d, 1H,
OCH
2
), 3.81 (d, 2H, J¼5.0 Hz, CH OH), 3.20 (dd, 1H, Jgem¼13.5 Hz &
2
0
0
J¼4.5 Hz, 6 -H), 7.97 (d, 1H, J¼8.0 Hz, 4 -H), 7.37e7.28 (m, 6H,
AreHs), 7.21 (d, 2H, J¼8.0 Hz, arom-Hs), 7.08 (d, 1H, J¼8.5 Hz,
arom.-H), 7.00 (m, 1H, arom-H), 5.21 (dd, 1H, J¼6.0 Hz, 4.0 Hz,
C5eH), 5.01 (t, 1H, J¼7.5 Hz, C3eH), 3.23 (ddd, 1H, Jgem¼12.0 Hz &
J¼6.5, 5.0 Hz, C4eHa), 2.46 (ddd, 1H, Jgem¼12.0 Hz & J¼7.0, 3.0 Hz,
J¼5.4 Hz, C3-Ha), 3.10 (dd, 1H, Jgem¼13.5 Hz & J¼8.2 Hz, C3-Hb),
3.06e3.01 (m, 1H, C2eH), 2.60 (bs, 1H, OH), 1.43e1.35 (m, 4H,
2ꢀCH
2
), 0.99 (t, 3H, CH
C NMR (CDCl
3
).
1
3
3
, 125 MHz): d 173.3, 134.3, 126.3, 123.7, 120.9,
119.4, 118.3, 112.2, 111.5, 82.1, 64.5, 62.8, 48.1, 36.8, 22.1, 14.8.
HRMS (ESI, m/z): calcd for C16
276.1596.
þ
C4eHb), 2.38 (s, 3H, CH
3
).
, 125 MHz):
34.3, 134.1, 129.3, 129.1, 126.8, 123.8, 121.7, 113.9, 80.5, 69.0, 48.1,
H
21NO
3
[MþH] , 276.1594, found
13
C NMR (CDCl
3
d 152.0, 148.8, 148.1, 138.6, 138.3,
1
2
1.1.
HRMS (ESI, m/z): calcd for C21
found 339.1460.
4.2.3.4. Methyl -3-(1H-indol-3-yl)acrylate (11a). Off white solid,
þ
ꢁ
20
H N
2
O [MþnNa] , 339.1467,
mp 91e93 C; Yield (125 mg, 25%).
1
3
H NMR (CDCl , 500 MHz): d 8.49 (br s, 1H, NH), 7.92 (d, 1H,
J¼15.9 Hz), 7.49e7.26 (m, 5H, arom.-Hs), 6.46 (d, 1H, J¼15.9 Hz),
3.29 (s, 3H, OCH ).
C NMR (CDCl
123.3, 121.5120.5, 113.5, 111.7, 14.4.
HRMS (ESI, m/z): calcd for C12
224.0675.
4
.2.3. General procedure for the reaction of (6e9) with Pd/C,
HOOCNH to synthesize (10e13). A solution of (6e9, 16a and 20a
.5 mmol) in Ammonium formate (10 equiv), methanol (15 ml) and
3
13
4
3
, 125 MHz):
d
168.2, 138.1, 137.0, 128.7, 125.3,
1
ꢁ
þ
THF (5 ml) was stirred at room temperature (25e28 C). Activated
0% palladium on charcoal (10 equiv) was added to the above so-
H
11NO
2
[MþNa] , 224.0681, found
1
lution and stirred the mixture for 30 min (monitored by TLC). The
reaction mixture was filtered and the filtrate extracted with ether
4.2.3.5. Ethyl- 3-(1H-indol-3-yl)acrylate (11b). Off white solid,
ꢁ
(
30 ml). The aqueous phase was basified with aqueous sodium
hydroxide (10%) and extracted with dichloromethane (3ꢀ 50 ml).
The combined organic layer was dried over Na SO and concen-
mp 97e99 C; Yield (100 mg, 20%).
1
3
H NMR (CDCl , 500 MHz): d 8.33 (br s, 1H, NH), 7.88 (d, 1H,
2
4
J¼15.9 Hz), 7.57e7.18 (m, 5H, arom.-Hs), 6.43 (d, 1H, J¼15.9 Hz),
4.27 (q, 2H, J¼7.2 Hz, OCH ), 1.35 (t, 3H, J¼7.2 Hz, CH ).
, 125 MHz): 167.8, 137.7, 137.2, 130.6, 125.5,
123.4, 122.7120.8, 113.6, 111.4, 60.1, 14.1.
HRMS (ESI, m/z): calcd for C13
216.1011.
trated under reduced pressure and vacuum. Purification by column
chromatography (70% ethyl acetate in hexane) afforded (10e13, 17
and 21).
2
3
13
C NMR (CDCl
3
d
þ
H13NO
2
[MþH] , 216.1019, found
4.2.3.1. Methyl-2-((1H-indol-3-yl)-methyl)-3-hydroxypropanoate
(
10a). R 0.51 (CHCl /EtOAc 7:3); Light brown semisolid, Yield
f
3
(
300 mg, 60%).
4.2.3.6. Butyl -3-(1H-indol-3-yl)acrylate (11c). Light brown vis-
1
H NMR (CDCl
3
, 500 MHz):
d
8.30 (br s, 1H, NH), 7.62 (d, 1H,
cous oil, Yield (150 mg, 30%).
0
0
1
J¼7.5 Hz, C4 eH), 7.30 (d, 1H, J¼7.5 Hz, C7 -H), 7.23 (t, 1H, J¼7.5 Hz,
3
H NMR (CDCl , 500 MHz): d 8.37 (br s, 1H, NH), 7.85 (d, 1H,
0
0
0
C5 -H), 7.15 (t, 1H, J¼7.5 Hz, C6 -H), 7.01 (s, 1H, C2 -H), 3.79 (d, 2H,
J¼5.4 Hz, CH OH), 3.71 (s, 1H, OCH ), 3.20 (dd, 1H, Jgem¼13.8 Hz &
J¼5.4 Hz, C3-Ha), 3.06 (dd, 1H, Jgem¼13.8 Hz & J¼7.5 Hz, C3-Hb),
.02e2.97 (m, 1H, C2eH), 2.61 (bs, 1H, OH).
J¼16.0 Hz), 7.52e7.28 (m, 5H, arom.-Hs), 6.59 (d, 1H, J¼16.0 Hz),
2
3
4.31 (m, 2H, OCH
2
), 1.43e1.35 (m, 4H, 2ꢀCH
2 3
), 0.89 (t, 3H, CH ).
, 125 MHz): 168.3, 137.9, 137.1, 130.7, 125.3,
13
C NMR (CDCl
3
d
3
123.8, 122.5, 120.9, 112.6, 111.7, 67.3, 40.1, 20.3, 15.3.
13
þ
C NMR (CDCl
3
, 125 MHz):
d
174.8, 135.9, 127.5, 123.1, 122.2,
HRMS (ESI, m/z): calcd for C15
266.1140.
H17NO
2
[MþNa] , 266.1151, found
1
18.9, 118.2, 112.8, 110.7, 62.9, 61.1, 47.9, 23.8.
HRMS (ESI, m/z): calcd for C13
34.1118.
þ
H
15NO
3
[MþH] , 234.1124, found
2
4.2.3.7. Methyl-2-hydroxy-4-(1H-indol-3-yl)butanoate (12a). R
.48 (CHCl /EtOAc 7:3); Light brown semisolid, Yield (440 mg, 88%).
f
0
3
1
4
.2.3.2. Ethyl-2-((1H-indol-3-yl)-methyl)-3-hydroxypropanoate
H NMR (CDCl
3
, 500 MHz):
d
8.02 (br s, 1H, NH), 7.64 (d, 1H,
0
0
(10b). R 0.54 (CHCl /EtOAc 7:3); Light brown semisolid, Yield
f
3
J¼8.0 Hz, C4 -H), 7.38 (d, 1H, J¼8.0 Hz, C7 -H), 7.21 (t, 1H, J¼7.5 Hz,
0
0
0
(
325 mg, 65%).
C5 -H), 7.14 (t, 1H, J¼7.5 Hz, C6 -H), 7.03 (s, 1H, C2 -H), 4.29 (m, 1H,
C2eH), 3.72 (s, 3H, OCH
), 3.04 (d, 1H, J¼5 Hz, OH), 2.95 (m, 2H,
CH ), 2.20 (m, 2H, CH ).
, 125 MHz):
119.2, 118.8, 115.4, 111.1, 69.8, 52.4, 34.5, 29.7.
HRMS (ESI, m/z): calcd for C13
[MþH] , 234.1124, found
234.1114.
1
H NMR (CDCl
3
, 500 MHz):
d
8.35 (br s, 1H, NH), 7.64 (d, 1H,
3
0
0
J¼7.5 Hz, C4 eH), 7.35 (d, 1H, J¼7.5 Hz, C7 -H), 7.22 (t, 1H, J¼7.5 Hz,
2
2
0
0
0
13
C5 -H), 7.14 (t, 1H, J¼7.5 Hz, C6 -H), 6.99 (s, 1H, C2 -H), 4.18 (q, 2H,
J¼7.0 Hz, OCH ), 3.82 (d, 2H, J¼5.4 Hz, CH OH), 3.20 (dd, 1H,
gem¼14.5 Hz & J¼6.0 Hz, C3-Ha), 3.06 (dd, 1H, Jgem¼14.5 Hz &
J¼8.0 Hz, C3-Hb), 3.02e2.97 (m, 1H, C2eH), 2.65 (bs, 1H, OH), 1.24
t, 3H, J¼7.0 Hz, CH ).
, 125 MHz):
19.3, 118.6, 112.4, 111.3, 62.5, 60.8, 48.2, 24.0, 14.1.
C NMR (CDCl
3
d 175.8, 136.3, 127.4, 121.9, 121.6,
2
2
þ
J
H15NO
3
(
3
13
C NMR (CDCl
3
d
175.3, 136.3, 127.3, 122.7, 121.9,
4.2.3.8. Ethyl-2-hydroxy-4-(1H-indol-3-yl)butanoate
(12b). R
f
1
0.46 (CHCl /EtOAc 7:3); Light brown semisolid, Yield (425 mg, 85%).
3

910
G. Singh et al. / Tetrahedron 72 (2016) 900e911
1
13C NMR (CDCl
, 125 MHz): d 142.7, 136.4, 128.5, 127.6, 127.4,
3
H NMR (CDCl
3
, 500 MHz):
d
8.00 (br s, 1H, NH), 7.65 (d, 1H,
0
0
J¼8.0 Hz, C4 -H), 7.38 (d, 1H, J¼8.0 Hz, C7 -H), 7.22 (t, 1H, J¼7.5 Hz,
126.2, 122.9, 121.7, 119.9, 118.7, 115.8, 111.2, 65.8, 38.2, 21.8, 14.7.
0
0
0
þ
C5 -H), 7.14 (t, 1H, J¼7.5 Hz, C6 -H), 7.03 (s, 1H, C2 -H), 4.26 (m, 1H,
C2eH), 4.18 (q, 2H, J¼7 Hz, OCH ), 2.96 (m, 2H, CH ), 2.90 (d, 1H,
J¼5 Hz, OH), 2.23 (m, 1H, CH ), 2.10 (m, 1H, CH ) 1.26 (t, 3H,
J¼7.0 Hz, CH ).
C NMR (CDCl
19.2, 118.9, 115.2, 111.0, 69.8, 61.7, 34.6, 20.3, 14.1.
HRMS (ESI, m/z): calcd for C18
266.1524.
H
19NO [MþH] , 266.1539, found
2
2
2
2
3
4.2.3.14. 3-(5-Methoxy-1H-indol-3-yl)-1-p-tolylpropan-1-ol
(17). R 0.33 (CHCl /EtOAc 7:3); Yellow-brown semisolid, Yield
13
3
, 125 MHz):
d
175.4, 136.3, 127.4, 121.9, 121.6,
f
3
1
(440 mg, 88%).
þ
1
HRMS (ESI, m/z): calcd for C14
70.1099.
H
17NO
3
[MþNa] , 270.1101, found
H NMR (CDCl
3
, 500 MHz):
d
7.88 (br s, 1H, NH), 7.29 (m, 5H,
0
0
2
arom.-Hs), 7.02 (s, 1H, C4 -H), 6.98 (s, 1H, C2 eH), 6.88 (m, 1H,
arom-H), 4.75 (t, 1H, J¼6.5 Hz, C1eH), 3.87 (s, 3H, OCH3), 2.88 (m,
4
.2.3.9. Butyl-2-hydroxy-4-(1H-indol-3-yl)butanoate
(12c). R
f
2H, C2eH), 2.38 (s, 3H, CH
3
), 2.24 (dt, 1H, Jgem¼13.5 Hz & J¼7.5 Hz,
0
.44 (CHCl
3
/EtOAc 7:3); Light brown semisolid, Yield (415 mg, 83%).
C3eH), 2.14 (dt, 1H, Jgem¼13.5 Hz & J¼6.5 Hz, C3-Hb), 1.99 (bs, 1H,
1
H NMR (CDCl
3
, 500 MHz):
d
8.06 (br s, 1H, NH), 7.68 (d, 1H,
OH).
0
0
13C NMR (CDCl
J¼8.0 Hz, C4 -H), 7.42 (d, 1H, J¼8.0 Hz, C7 -H), 7.25 (t, 1H, J¼7.5 Hz,
3
, 125 MHz): d 153.8, 141.7, 137.2, 131.5, 129.1,
0
0
0
C5 -H), 7.11 (t, 1H, J¼7.5 Hz, C6 -H), 7.09 (s, 1H, C2 -H), 4.37 (m, 1H,
C2eH), 4.21 (m, 2H, OCH ), 2.88 (m, 2H, CH
), 2.83 (d, 1H, J¼4.5 Hz,
OH), 2.28 (m, 1H, CH ), 2.18 (m, 1H, CH ),
), 1.49e1.38 (m, 4H, 2ꢀCH
.99 (t, 3H, CH ).
C NMR (CDCl 174.7, 135.8, 126.8, 121.7, 121.7,
127.8, 125.9,122.0,115.7,112.1,111.7,100.8, 74.0, 55.9, 38.9, 21.4, 21.1.
þ
2
2
HRMS (ESI, m/z): calcd for C19
found 318.1458.
H21NO
2
[MþnNa] , 318.1464,
2
2
2
0
3
13
3
, 125 MHz):
d
4.2.3.15. 3-(Phenylamino)-3-(pyridin-3-yl)-1-p-tolylpropan-1-ol
1
19.1, 118.6, 114.9, 110.7, 68.8, 62.7, 42.6, 34.6, 22.3, 20.4, 14.5.
(21). R
f
0.33 (CHCl
3
/EtOAc 7:3); Yellow-brown semisolid, Yield
þ
HRMS (ESI, m/z): calcd for C16
H
21NO
3
[MþH] , 276.1594, found
(450 mg, 90%).
1
0
0
276.1580.
H NMR (CDCl
3
, 500 MHz):
d
8.58 (s, 1H, 2 -H), 8.37 (s, 1H, 6 -H),
0
7
.73 (d, 1H, J¼8.0 Hz, 4 -H), 7.24e7.11 (m, 7H, arom.-Hs), 6.71 (t, 1H,
4.2.3.10. 3-(1H-indol-3-yl)-1-phenylpropan-1-ol (12d). R
f
0.51
J¼7.5 Hz, AreH), 6.51 (t, 2H, J¼8.0 Hz, AreHs), 4.76 (dd, 1H, J¼6.0 &
(
CHCl /EtOAc 7:3); Light brown semisolid, Yield (450 mg, 90%).
3
3.0 Hz, C1eH), 4.61 (dd, 1H, J¼5.5 & 3.0 Hz, C3eH), 4.25 (br s, 2H,
1
H NMR (CDCl
3
, 500 MHz):
d
8.00 (br s, 1H, NH), 7.63 (d, 1H,
NH & OH), 2.36 (s, 3H, CH
(m, 1H, C2-Hb).
3
), 2.32e2.27 (m, 1H, C2-Ha) 2.00e1.96
0
0
J¼8 Hz, C4 eH), 7.41e7.15 (m, 8H, arom.-Hs), 6.97 (s, 1H, C2 -H),
1
3
4
(
.79 (t, 1H, J¼6.5 Hz, C1eH), 2.96e2.83 (m, 2H, C2eH), 2.30e2.18
m, 3H, CH & OH).
C NMR (CDCl
3
C NMR (CDCl , 125 MHz): d 148.1, 147.9, 146.9, 141.6, 139.8,
2
137.4, 134.3, 129.2, 129.1, 125.6, 123.9, 117.9, 113.9, 72.6, 55.4, 47.3,
21.1.
HRMS (ESI, m/z): calcd for C21
found 341.1617.
13
3
, 125 MHz):
d
144.7, 136.4, 128.5, 127.6, 127.5,
þ
126.0, 121.9, 121.3, 119.2, 118.9, 115.9, 111.1, 74.2, 39.1, 21.5.
22
H N
2
O [MþnNa] , 341.1624,
þ
HRMS (ESI, m/z): calcd for C17
74.1191.
H
17NO [MþNa] , 274.1202, found
2
Acknowledgements
4.2.3.11. 3-(1H-indol-3-yl)-1-p-tolylpropan-1-ol (12e). R
f
0.54
(
CHCl /EtOAc 7:3); Off white semisolid, Yield (460 mg, 92%).
3
Financial assistance in the form of sponsored research project
02(0082)/12/EMR-II) by Council of Scientific and Industrial Re-
search (CSIR), New Delhi is gratefully acknowledged. GS acknowl-
edges CSIR, New Delhi for SRF. University Grants Commission, New
Delhi is acknowledged for grant under University with Potential for
Excellence to Guru Nanak Dev University.
1
H NMR (CDCl
3
, 500 MHz):
d
8.00 (br s, 1H, NH), 7.62 (d,
(
0
0
1
(
H, J¼8 Hz, C4 eH), 7.37 (d, 1H, J¼8.0 Hz, C7 -H), 7.30e7.19
m, 5H, arom.-Hs), 7.14 (t, 1H, J¼7.5 Hz, arom.-H), 6.99 (s, 1H,
0
C2 -H), 4.76 (t, 1H, J¼6.5 Hz, C1eH), 2.94e2.81 (m, 2H, C2eH),
2
.39 (s, 3H, CH
3
), 2.26 (dt, 1H, Jgem¼13.7 Hz & J¼8.0 Hz,
C3eH), 2.16 (dt, 1H, Jgem¼13.7 Hz & J¼6.0 Hz, C3-Hb), 1.98 (bs,
1
H, OH).
13C NMR (CDCl
Supplementary data
3
, 125 MHz): d 141.7, 137.2, 136.3, 129.1, 127.5,
1
25.9, 121.9, 121.2, 119.1, 118.9, 116.0, 111.1, 74.0, 39.0, 21.5, 21.1.
þ
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.12.032.
HRMS (ESI, m/z): calcd for C18
H19NO
3
[MþH] , 266.1539, found
2
66.1520.
References and notes
4.2.3.12. 3-(1H-indol-3-yl)-1-(pyridin-4-yl)propan-1-ol (12f). R
f
0
.52 (CHCl
3
/EtOAc 7:3); Light brown semisolid, Yield (425 mg, 85%).
1
1. (a) Caruthers, W. R. Cycloadditions in Organic Synthesis; Pergamon: London,
H NMR (CDCl
3
, 500 MHz):
d
8.02 (br s, 1H, NH), 7.61 (d, 1H,
1990, Chapter 6, p 269; (b) Gothelf, K. V.; Jorgenson, K. A. Chem. Rev. 1998, 98,
0
0
J¼8 Hz, C4 eH), 7.43e7.13 (m, 7H, arom.-Hs), 6.98 (s, 1H, C2 -H),
863.
2
. (a) Martin, J. N.; Jones, R. C. F. In Synthetic Applications of 1,3- Dipolar Cycload-
dition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson,
W. H., Eds.; Wiley and Sons: Hoboken, NJ, 2003, Chapter 1, p 1; (b) Gothelf, K. V.
In Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jørgensen, K. A.,
Eds.; Wiley-VCH: Weinheim, Germany, 2002, Chapter 6, p 211.
4
(
.75 (t, 1H, J¼7.0 Hz, C1eH), 2.92e2.82 (m, 2H, C2eH), 2.32e2.19
m, 3H, CH & OH).
C NMR (CDCl
2
13
3
, 125 MHz): d 156.1, 147.7, 147.3, 136.4, 128.5,
127.6, 126.0, 121.3, 118.9, 115.9, 111.1, 73.1, 40.1, 22.1.
þ
3. Hanselmann, R.; Zhou, J.; Ma, P.; Confalone, P. N. J. Org. Chem. 2003, 68, 8739.
HRMS (ESI, m/z): calcd for C16
75.1137.
H
16
N
2
O [MþNa] , 275.1154, found
4
. (a) For a review, see: Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107,
767; (b) Argyropoulou, E. C.; Xenikaki, E. M.; Stampelos, X. N.; Alexopoulou, I. N.
Tetrahedron 1997, 53, 707.
2
5
. (a) Bhella, S. S.; Ishar, M. P. S.; Singh, G.; Singh, R.; Singh, G.; Raj, T. Can. J. Chem.
4
.2.3.13. 4-(1H-indol-3-yl)-2-phenylbutan-2-ol (13). R
f
0.48
2008, 86, 451; (b) Bensa, D.; Coldham, I.; Feinaugle, P.; Pathak, R. B.; Butlin, R. J.
(
CHCl
3
/EtOAc 7:3); Light brown semisolid, Yield (400 mg, 80%).
Org. Biomol. Chem. 2008, 6, 1410e1415; (c) Katz, S. J.; Bergmeier, S. C. Tetrahe-
dron Lett. 2002, 43, 557e559; (d) Coe, D. M.; Perciaccante, R.; Procopiou, P. A.
Org. Biomol. Chem. 2003, 1, 1106e1111; (e) Martın, R.; Murruzzu, C.; Pericas, M.
A.; Riera, A. J. Org. Chem. 2005, 70, 2325e2328; (f) Lin, C.; Pan, Y.; Patkar, L. N.;
Lin, H.; Tzou, D. M.; Subramanian, T.; Lin, C. Bioorg. & Med. Chem. 2004, 12,
3259e3267; (g) Matsushima, Y.; Nakayama, T.; Tohyama, S.; Eguchi, T.;
1
H NMR (CDCl
3
, 500 MHz):
d
8.01 (br s, 1H, NH), 7.62 (d, 1H,
0
0
J¼8 Hz, C4 eH), 7.43e7.17 (m, 8H, arom.-Hs), 6.99 (s, 1H, C2 -H),
4
(
.77 (t, 1H, J¼6.5 Hz, C1eH), 2.97e2.85 (m, 2H, C2eH), 2.31e2.16
m, 3H, CH & OH).
2

G. Singh et al. / Tetrahedron 72 (2016) 900e911
911
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B.; Jarosinski, M. A. J. Org. Chem. 1997, 62, 5615e5618.
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Strozier, R. W.; George, J. K. J. Am. Chem. Soc. 1973, 95, 7287; (g) Houk, K. N.;
Sims, J.; Watts, C. R.; Luskus, L. J. Am. Chem. Soc. 1973, 95, 7301; (h) Sims, J.;
Houk, K. N. J. Am. Chem. Soc. 1973, 95, 5800.
6
. (a) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi,
E. H. Molecules 2013, 18, 6620e6662; (b) Bhella, S. S.; Pannu, A. P. S.; Elango, M.;
Kapoor, A.; Hundal, M. S.; Ishar, M. P. S. Tetrahedron 2009, 65, 5928; (c) Singh,
R.; Bhella, S. S.; Saxena, A. K.; Shanmugavel, M.; Faruk, A.; Ishar, M. P. S. Tet-
rahedron 2007, 63, 2283; (d) Fang, X.; Huo, Y.; Wei, Z.; Yuan, G.; Huang, B.; Zhu,
S. Tetrahedron 2013, 69, 10052; (e) Wang, Li; Jiao, S.; Zhang, W.; Liu, Y.; Yu, G.
Chin. Sci. Bull. 2013, 58, 2733.
10. (a) Singh, G.; Kaur, A.; Sharma, V.; Suri, N.; Sharma, P. R.; Saxena, A. K.; Ishar, M.
P. S. RSC Med. Chem. Commun. 2013, 4, 972.
7
. (a) Singh, G.; Ishar, M. P. S.; Girdhar, N. K.; Singh, L. J. Heterocycl. Chem. 2005, 42,
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therein; (b) Huisgen, R.; Seidel, H.; Brunning, I. Chem. Ber. 1969, 102, 7702.
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5671; (b) Sato, M.; Gunji, Y.; Ikeno, T.; Yamada, T. Synthesis 2004, 1434.
13. (a) The X-ray crystallographic data for compound 2 has been submitted to
Cambridge crystallography Data Center (CCDC No. 1410260); (b) The X-ray
crystallographic data for compound 8 has been submitted to Cambridge crys-
tallography Data Center (CCDC No. 1410259); (c) The X-ray crystallographic
data for compound 9 has been submitted to Cambridge crystallography Data
Center (CCDC No. 1410471).
1047; (b) Huisgen, R.; Gashey, R.; Seidl, H. Chem. Ber. 1968, 101, 2548; (c)
Huisgen, R.; Seidl, H.; Gashey, R. Chem. Ber. 1968, 101, 2559; (d) Huisgen, R.;
Hauck, H.; Gashey, R.; Seidl, H. Chem. Ber. 1968, 101, 2568.
8
. (a) Griffiths, P. J. F.; Ellis, G. P. Spectrochim. Acta 1972, 28A, 707; (b) Breitmaier,
E.; Voelter, W. Carbon-13 NMR Spectroscopy; VCH: New York, 1987; p 279; (c)
Ishar, M. P. S.; Singh, G.; Kumar, K.; Singh, R. Tetrahedron 2000, 56, 7817.
. (a) Gilchrist, T. L.; Storr, R. C. Organic Reactions and Orbital Symmetry; Cam-
bridge Univ.: Cambridge, 1972; p 132; (b) Fleming, I. Frontier Orbitals and Or-
9
ganic Chemical Reactions; John Wiley
& Sons: London, 1976; p 148; (c)