An eco-friendly synthesis of novel 3,5-disubstituted-1,2-isoxazoles in PEG-400, employing the Et3N-promoted hydroamination of symmetric and unsymmetric 1,3-diyne-indole derivatives

Article abstract of DOI:10.1039/c4ra11571f

A facile, efficient and atom-economic synthesis of 3,5-disubstituted 1,2-isoxazoles bearing indole moieties, is reported. The synthesis of these isoxazoles was carried out by the triethylamine-promoted reaction of symmetric and unsymmetric 1,3-diyne indole derivatives with hydroxylamine in PEG-400, as an eco-friendly solvent, under relatively mild conditions. The synthesis of the starting 1,3-diyne indole derivatives was performed by the aerobic self-coupling of diversely functionalized N-propargyl indoles and N-propargyl carbazole under copper catalysis, or by the reaction of the propargyl derivatives with phenyl- or p-tolyl-acetylene under combined nickel and copper catalysis. The isoxazolation reaction was optimized, its scope and limitations were studied and a detailed reaction mechanism was proposed.

Full text of DOI:10.1039/c4ra11571f

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DOI: 10.1039/C4RA11571F
R2
An eco-friendly synthesis of novel 3,5-disubstituted-1,2-
NH2OH.HCl
PEG-400
Et3N, 80-100ºC
R3
isoxazoles in PEG-400, employing the Et3N-promoted
hydroamination of symmetric and unsymmetric 1,3-diyne-
indole derivatives
R1
N
R4
R3
R2
Mariana M. Bassaco, Margiani P. Fortes, Davi F. Back, Teodoro
S. Kaufman* and Claudio C. Silveira*
R1
R1= H, Me; R2= H;
R1-R2= CH=CH-CH=CH
N
PEG-400 proved to be a useful solvent for the mild and efficient
synthesis of 3,5-disubstituted 1,2-isoxazoles derived from 1,3-diyne
indoles. The scope and limitations of the reaction were also studied.
R3= H, OMe, Br, 4-Me-C6H4
R4= Ph, 4-Me-C6H4, CH2N-Carbazolyl,
CH2N-indolyl(R1,R2,R3-substituted)
R4
N
O

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DOI: 10.1039/C4RA11571F
Cite this: DOI: 10.1039/c0xx00000x
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PAPER
An eco-friendly synthesis of novel 3,5-disubstituted-1,2-isoxazoles in
PEG-400, employing the Et3N-promoted hydroamination of symmetric
and unsymmetric 1,3-diyne-indole derivatives
Mariana M. Bassaco,a Margiani P. Fortes,a Davi F. Back,a Teodoro S. Kaufmanb* and Claudio C.
5
Silveiraa*
Received (in XXX, XXX) Xth XXXXXXXXX 201X, Accepted Xth XXXXXXXXX 201X
DOI: 10.1039/b000000x
A facile, efficient and atom-economic synthesis of 3,5-disubstituted 1,2-isoxazoles bearing indole
moieties, is reported. The synthesis of these isoxazoles was carried out by the triethylamine-promoted
10 reaction of symmetric and unsymmetric 1,3-diyne indole derivatives with hydroxylamine in PEG-400, as
an eco-friendly solvent, under relatively mild conditions. The synthesis of the starting 1,3-diyne indole
derivatives was performed by the aerobic self-coupling of diversely functionalized N-propargyl indoles
and N-propargyl carbazole under copper catalysis, or by the reaction of the propargyl derivatives with
phenyl- or p-tolyl-acetylene under combined nickel and copper catalysis. The isoxazolation reaction was
15 optimized, its scope and limitations were studied and a detailed reaction mechanism was proposed.
Introduction
OH
RHNO2S
F3C
O
Organic chemists are placing increasing research efforts toward
the development of new, efficient, sustainable and atom-
economic synthetic methodologies, with the aim of rapidly
20 achieving high molecular complexity from simple building
blocks, under convenient conditions.
The development of new protocols suitable for the synthesis of
1,2-isoxazoles is of current interest1 because this structural motif
is found in some natural products, such as the neurotoxin ibotenic
25 acid and the CNS depressant muscimol.2 This heterocyclic ring is
also part of many pharmaceutically relevant compounds,3 such as
the non-steroidal anti-inflammatory agent valdecoxib, its prodrug
parecoxib and the semisynthetic -lactam antibiotics cloxacillin
and dicloxacillin, being also found in the antibacterial
30 sulfamethoxazole, the antiinflammatory isoxicam, and the
antirheumatic and antiarthritic drug leflunomide.4
N
HO
O
NH2
Ibotenic acid
N
H
O
N
OH
Me
R= H, Valdecoxib
O
N
H2N
N
R= MeCH2CO, Parecoxib
Me
O
O
Leflunomide
HO2C
Muscimol
O
O
O
Me
Me
N
H
R
O
Me
O
S
S
H
N
N
N
H
Cl
N
O
OH
N
O
Me
Me
Isoxicam
R= H, Cloxacillin
R= Cl, Dicloxacillin
H
N
Therefore, the 1,2-isoxazole moiety is highly regarded in
Medicinal and Organic Chemistry, as a privileged heterocycle, a
useful building block and a masked 1,3-dicarbonyl (an important
35 synthetic functionality) scaffold,5 due to the easy cleavage of its
N-O bond.6
O
S
Br
O
NH2
N
O
Me
H
Sulfamethoxazole
H
R
a
HO
Departamento de Química, Universidade Federal de Santa Maria
H
97105-900, Santa Maria, RS, Brazil, Tel/Fax: +55-55-3220-8754; E-
40 mail: silveira@quimica.ufsm.br; mariquimica@gmail.com;
margiani.fortes@ufsm.br; daviback@gmail.com
R1
OH
b
Me
Instituto de Química Rosario (CONICET-UNR), Suipacha 531,
Dipline D
H
H
S2002LRK, Rosario, SF, Argentina. Tel/Fax: +54-341-4370477; E-
mail: kaufman@iquir-conicet.gov.ar
Falcarinol, R= OH, R1= H; Falcaridiol, R=R1= OH
45 † Electronic Supplementary Information (ESI) available: selected spectra
of intermediates and final product. See DOI: 10.1039/b000000x/
Figure 1. Some relevant natural products containing 1,2-isoxazole and
1,3-diyne moieties, and pharmaceutical compounds bearing the 1,2-
50 isoxazole ring.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, vol, 00–00 | 1

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The 1,2-isoxazole ring is generally constructed employing two
1,2-isoxazoles, and in order to circumvent the limitations of the
main alternative methodologies, namely the condensation of 55 previous methods, here we report a convenient synthesis of 3,5-
hydroxylamine with 1,3-dicarbonyl derivatives and related
compounds such as -unsaturated ketones and nitriles, or their
synthetic equivalents, and the [3+2] cycloaddition of alkynes with
nitrile oxides.7
disubstituted 1,2-isoxazoles from indole-derived V1ie,w3-AdrtiicyleneOsnline
employing polyethyleneglycol 400 (PEG-400) as solvent.
The proposed 1,2-isoxazole synthesis is part of our continuing
interest in developing new synthetic methodologies toward
DOI: 10.1039/C4RA11571F
5
On the other hand, the 1,3-diynes are very interesting 60 indole-based heterocyclic compounds under mild and eco-
compounds, because they can participate in various reactions
leading to heterocyclic compounds, including intramolecular
friendly conditions,20 which include the use of sustainable, less
conventional solvents such as PEG-400, as reaction medium.20d
10 cyclization, 1,3-dipolar addition and cyclization via two-fold
attack at the acetylene bond, among others.8 Therefore, this
structural moiety is an important building block, being found in
synthetic intermediates and different products of biomedical9 or
technological interest.10
Results and discussion
The precursor N-propargyl indole (2a-e) and carbazole (2f)
65 derivatives were synthesized, in 70-80% yield (Table 1), by
conventional propargylation of different indoles (1a-e) and
carbazole (1f) with propargyl bromide and KOH in DMF.21
15
Complex structures containing conjugated triple bonds are also
found as natural products, often embodied with relevant
biological activities.11 Examples of these are dipline D (Figure 1),
isolated from the sponge Diplastrella sp.,11a which exhibits potent
anti-HIV activity, as well as falcarinol and falcarindiol, obtained
Table 1. Synthesis of symmetric 1,3-diynes 3a-f. N-Propargylation of
indoles 1a-e and carbazole (1f), and their CuCl-catalyzed aerobic
70 homocoupling.
R2
R2
20 from Daucus carota (carrots) and Panax ginseng (red ginseng),
which feature antibacterial, antifungal, anti-inflammatory and
platelet anti-aggregation properties.12
Br
R3
R3
R1
R1
KOH, DMF, r.t., 6h
N
N
Alkynes are usually considered carbonyl surrogates;13 this can
be exemplified by the preparation of acetophenone oxime from
25 phenylacetylene and hydroxylamine.14 In addition, in recent times
-acetylenic oximes and oxime ethers have been used as
precursors of 3,5-disubstituted 1,2-isoxazoles, accessed by
copper, silver or gold-catalyzed cycloisomerization,15 and
electrophilic cyclization.16
H
1
2
CuCl(cat.)
,
R2
R2
R3
R3
air, DMSO,
90ºC, 4h
R1
R1
N
N
30
The related gold- or palladium-based annulations of aryl-
propargyl hydroxylamines and the K2CO3-mediated cyclization
of propargyl oximes have also been employed for that purpose.17
Generally, however, these transformations involving alkynes
have some drawbacks; they require either costly catalysts,
3
Entry
Nº
Prod. Nº
(Yield, %) (Yield, %)
Prod. Nº
R1
R2
R3
1
2
3
4
5
6
H
H
H
Me
H
H
H
H
H
H
H
OMe
Br
H
4-MeC6H4
H
2a (76)
2b (71)
2c (70)
2d (72)
2e (80)
2f (78)
3a (83)
3b (72)
3c (76)
3d (83)
3e (72)
3f (60)
35 stoichiometric amounts of special promoters and long reaction
times, or proceed in moderate yields.
Despite these precedents, the use of 1,3-diynes as precursors
for the synthesis of 3,5-disubstituted 1,2-isoxazole derivatives has
only few and scattered precedents.18 Furthermore, several 1,3-
40 diynes derived from different N-propargyl heterocycles have been
synthesized for potential pharmaceutical and technological
applications;19 however, their transformation into more complex
structures has remained virtually unexplored.
We envisioned that 1,3-diynes, available through copper-
45 catalyzed homo- and heterocoupling of terminal alkynes, could
be regarded as synthetic equivalents of 1,3-dicarbonyl moieties.
In this capacity, we speculated that 1,4-disubstituted 1,3-diynes
could be suitable starting materials toward polyfunctionalized
1,2-isoxazoles (Scheme 1).
CH=CH-CH=CHa
a Carbazole (1f) was used as starting material.
In turn, the N-propargyl indoles and carbazole were subjected
Glaser type coupling to afford the corresponding
to
a
75 homodimerized 1,3-diynes 3a-f, employing 5 mol% CuCl as
catalyst in DMSO (1 mL/mmol) and air (atmospheric O2) as the
stoichiometric oxidant.22 The product yields were satisfactory,
ranging from 60 to 83%, when the reaction was performed by
heating 4 h at 90°C.
Cu-Catalyzed Aerobic
+
R1
R2
Homocoupling/Heterocoupling
R2
R1
R2
3
4
NH2OH.HCl
R1
N2
5
O 1
PEG-400
50
Scheme 1. Proposed synthesis of symmetric and unsymmetric 1,3-diynes
and their conversion into 3,5-disubstituted 1,2-isoxazoles.
80
Figure 2. ORTEP view of 1,3-diyne compound 3a, as determined by X-
ray crystallography.
Therefore, in view of the importance of the polysubstituted
2
|
RSC Adv., 2014, vol, 00–00
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Page 4 of 13
Single crystal X-ray analysis of 3a (CCDC number is 1027013)
The symmetric 1,4-diphenyl- and 1,4-di-p-tolyl- 1,3-
confirmed the proposed structure and revealed some interesting
features (Figure 2). The 1,3-diyne unit is not linear and was
found to be bent, with C2-C3-C4 and C3-C4-C5 angles of 177.2
± 0.1º, and a torsion angle C2-C3-C4-C5 of 10.1º;18d on the other
hand, the indole moieties are located on opposite sides of the
plane drawn by the propargylic hydrogens, and exhibit a small
torsion, with a N1-C1-C6-N2 dihedral angle of 146.9º.
butadiynes were concomitantly formed, but these were easily
View Article Online
separated from their more polar nitrogen-containing congeners
DOI: 10.1039/C4RA11571F
during the chromatographic purification stage.
5
45
Interestingly, except for 1,6-di(9H-carbazol-9-yl)hexa-2,4-
diyne (3f),25 both the symmetric and unsymmetric 1,3-diynes (3a-
e and 5a-f) are novel, and their structures were unequivocally
1
elucidated after exhaustive spectroscopic analyses (FTIR, H and
In addition, their homocyclic rings are situated in the same
13C NMR and MS).
10 hemispace, with observed C14-N1-C1-C2 and C22-N2-C6-C5
dihedral angles of -79.0º and -65.3º, respectively, whereas the
N1-C1-C2 and N2-C6-C5 angles are of similar values (112.8º and
112.6º, respectively). As a consequence, the indole moieties are
not contained in parallel planes, but in ones tilted towards each
15 other.
Next, in order to broaden the scope of the transformation, the
synthesis of unsymmetric 1,3-diynes was approached. However,
the Glaser-synthesis of these compounds mets with the problem
of affording mixtures of homo- and hetero-coupled products,
50
With the set of required precursor 1,3-diynes in hands, the
study of their transformation into 3,5-disubstituted 1,2-isoxazoles
6 was initiated, employing 1,6-di-(1H-indol-1-yl)hexa-2,4-diyne
(3a, 0.3 mmol) as the starting material.
In the presence of Et3N (4 equiv.), it was observed that the
55 reaction with NH2OH.HCl (2.5 equiv.) was incomplete after
heating 20 h in DMSO at 60°C (Table 3, entry 1),18c affording
only 43% yield of the expected 1,2-isoxazole 6a. Therefore, the
transformation was tested at 80 ºC, and 59% of the product was
isolated (entry 2). Increasing the temperature to 110 ºC resulted in
20 which often follow
a
statistical distribution. Therefore, 60 a moderate decrease of the yield to 50% of 6a (entry 3), which
unsymmetric 1,3-diynes are usually prepared by the copper-
catalyzed Cadiot-Chodkiewicz cross-coupling between terminal
alkynes and haloalkynes, and its modifications.23
was further reduced to 45% when the reaction was carried out at
120 ºC (entry 4).
Consequently, aiming to attain better yields, the reaction was
tested under different conditions. Initially, and in order to reduce
An advantageous alternative has been recently reported by the
25 group of Lei, as a variation of the Glaser-Hay coupling, and 65 the use of poorly friendly organic solvents, the performance of
entails the addition of NiCl2.6H2O as a co-catalyst to promote the
oxidative heterocoupling process between aryl and propargyl
acetylenes. The reaction is run under CuI catalysis in THF, with
added TMEDA as ligand, and air (atmospheric oxygen) is used as
30 the stoichiometric oxidant.24 The transformation, which proceeds
at ambient temperature, requires a sacrificial excess of one of the
starting alkynes.
Therefore, the propargyl derivatives 2a-c and 2f were coupled
with excess phenylacetylene (4a) and p-tolylacetylene (4b),
35 affording the corresponding unsymmetric 1,3-diynes (5a-f) in 60-
85% yield, as shown in Table 2.
alternative reaction media was explored. However, the starting
material was fully recovered and no product was observed when
the reaction was carried out in glycerol (entry 5).
Table 3. Isoxazolation of the symmetric 1,3-diyne 3a. Optimization of the
70 synthesis of the 3,5-disubstituted 1,2-isoxazole 6a.a
NH2OH.HCl
N
N
Conditions
3a
N
O
N
N
Table 2. NiCl2.6H2O and CuI co-catalyzed aerobic synthesis of
unsymmetric 1,3-diynes 5a-f.
6a
R2
Run
Nº
1
2
3
4
5
6
7
H2NOH.HCl
(equiv.)
2.5
Et3N
(equiv.)
Temp. Time Yield
(°C)
60
80
110
120
80
80
80
80
80
80
80
80
80
80
R3
Solvent
(h)
20
20
20
20
12
12
12
12
20
8
(%)
43
59
50
45
R1
+
R4
DMSO
DMSO
DMSO
4
4
4
N
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
4a R= H
4b R= Me
2
DMSO
4
b
Glycerol
2.5
2.5
2.5
4
4
4
-
R2
R3
NiCl2.6H2O(cat.)
,
tBuOH
75
72
89
91
72
65
89
73
61
CuI(cat.), air,
TMEDA, THF,
r.t., 6h
2-PrOH
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
R1
8
9
N
R4
10
11
12
13
14
4
1c
5
2.5
12
12
12
Entry
Nº
Prod. Nº
(Yield, %)
5a (76)
5b (70)
5c (83)
5d (60)
5e (80)
5f (85)
d
R1
R2
R3
R4
-
1.5
1.5
1
2
3
4
5
6
H
H
H
H
H
H
H
H
H
H
OMe
Br
H
H
H
Me
H
Me
H
a Reaction conditions: 1,3-diyne (3a, 0.3 mmol); solvent (0.5 mL).
b Starting material was recovered.
CH=CH-CH=CHa
CH=CH-CH=CHa
c The reaction was carried out under microwave irradiation.
Me
75 d The reaction was carried out in the presence of 2.5 equiv. K2CO3 as base.
40 a N-propargylcarbazole (2f) was used as starting material.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, vol, 00–00 | 3

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RSC Advances
On the other hand, the transformation took place satisfactorily
in monohydric alcohols such as BuOH (75% yield, entry 6) and 60 f), the reaction conditions for the synthesis of 3,5-disubstituted
2-PrOH (72%, entry 7). This was in marked contrast with
previous observations on an analogous transformation (10-15%
yield).18c
of the transformation to the use of unsymmetrical 1,3-diynes (5a-
t
View Article Online
DOI: 10.1039/C4RA11571F
1,2-isoxazoles 7 were optimized (Table 4).
Employing 1-(5-phenylpenta-2,4-diynyl)-1H-indole (5a) as
model unsymmetric 1,3-diyne, it was observed that under the
previously optimized conditions, the reaction took place rather
5
Continuing along this line and running the isoxazolation in
PEG-400 afforded 6a in 89% yield (entry 8); however, the 65 sluggishly, providing 7a in only 52% yield even after 24 h (entry
1
reaction performance remained essentially unmodified when the
heating period was extended to 20 h (entry 9).
This was considered a very interesting result because PEG-
400, a polymeric, non-toxic, biodegradable, strongly hydrophilic
1). In addition, careful H NMR analysis of the products of this
initial test revealed the generation of two regioisomers (7a and
7’a) resulting from attack at both ends of the 1,3-diyne moiety.
The structures of the products were unequivocally established
10
and non-volatile solvent, qualifies as an eco-friendly reaction 70 after a detailed NMR analysis, which confirmed a Markovnikov
medium.26 Furthermore, use of PEG-400 represented a substantial
improvement, since this solvent allowed the reaction to be
15 advantageously carried out with great success under considerably
milder conditions (80ºC vs. 110ºC). In addition, similar results
selectivity for the major product (7a).14 The outcome of the
reaction forced to also evaluate the regioselectivity of the
transformation under each new condition.
In order to speed up the reaction, its performance was tested at
were achieved with less solvent consumption and in reaction 75 100°C; this condition increased the regioselectivity, keeping the
times shorter (12 h vs. 20 h) than those reported for analogous
processes,18c,d run in the more environmentally problematic
20 DMSO.26b
overall yield almost unaltered (entry 2). Therefore, the focus was
placed on the study of the effect of the amounts of base and
NH2OH.HCl. Very good yields were attained in the presence of
4.0 equiv. Et3N and 2.5 equiv. NH2OH.HCl (entry 3); however,
Therefore, the optimization of the transformation was pursued
in PEG-400. Reducing the reaction time to 8 h afforded 72% of 80 the yield remained almost unchanged when the excess of
6a, a significantly lower yield (entry 10), whereas when the
reaction was carried out under microwave irradiation, incomplete
25 consumption of the starting material was observed after 1 h,
resulting in a less satisfactory 65% yield of 6a (entry 11).
NH2OH.HCl was raised to 4.0 equiv. (entry 4). In both cases, the
same good (7a:7’a = 10:1) selectivity was observed.
Table 4. Isoxazolation of the unsymmetric 1,3-diyne 5a in PEG-400.
Optimization of the synthesis of 3,5-disubstituted 1,2-isoxazoles 7.a
The nature and amount of base were next optimized, observing
that reduction to 2.5 equivalents of Et3N did not affect the
performance of the reaction (entry 12), while employing K2CO3
30 instead of Et3N resulted in diminished product yields (entry 13).
Finally, simultaneous reduction of the amounts of Et3N and
NH2OH.HCl to 1.5 equiv. each caused a substantial deterioration
of the performance of the reaction (entry 14), suggesting that both
play significative roles in the transformation. Therefore, it was
35 considered that the optimum conditions were those of entry 12,
which entail a lower consuimption of added base.
The identity of 6a, which confirmed the Markovnikov
selectivity of the reaction,14 was established after an exhaustive
NMR analysis of the heterocyclic product. This included a
40 revealing HMBC experiment, which exhibited a correlation
between the protons of the methylene group attached to one of
the indolyl moieties ( 5.18, s, 2H) and the carbon atom attached
to the isoxazolic nitrogen ( 160.8) and two additional cross-
peaks between the protons of both methylene groups associated
45 to the other indolyl moiety [3.05 (t, J = 7.0, 2H) and 4.28 (t, J
= 7.0, 2H)] and the carbon atom attached to the oxygen atom of
the isoxazole ring ( 170.2).
The group of Bao has found that DMSO was the best
performing solvent in a similar transformation with 1,3-diaryl-
50 1,3-diynes, lacking a clear explanation for this serendipitous
finding.18c In our hands, DMSO was clearly outperformed by
PEG-400. Notwithstanding, however, 1,4-diphenyl-1,3-butadiyne
was refractory to undergo efficient isoxazolation in PEG-400,
suggesting that the solvent should be playing some crucial role
55 during the reaction and that different kinds of substrates may
require different solvents for a proper reaction. In this way, PEG-
400 and DMSO may be complementary realtion media.
N
5a
NH2OH.HCl,
PEG-400,
Conditions
O
N
N
O
+
N
N
7'a
7a
85
Run
Nº
1
2
3
4
5
6
7
Base
(equiv.)
Et3N (2.5)
Et3N (2.5)
Et3N (4.0)
Et3N (4.0)
H2NOH.HCl
(equiv.)
Temp. Time Yield Ratio
(°C)
80 °C
(h)
24
24
12
12
12
12
12
12
(%) 7a:7’a
2.5
2.5
2.5
4.0
2.5
2.5
2.5
2.5
52
53
85
84
50
85
85
72
7:1
10:1
10:1
10:1
7:1
11:1
8:1
11:1
100° C
100° C
100° C
100° C
100° C
100° C
100° C
K2CO3 (4.0)
DIPEA (4.0)
iPr2NH (4.0)
Et2NH (4.0)
8
a Reaction conditions: 1,3-diyne (5a, 0.3 mmol) and PEG-400 (0.5 mL).
Speculating that the nature of the base may have impact on the
yields of 7a and the selectivity of the reaction, various bases were
tested. The use of K2CO3 was helpless, since lower yields and
90 product regioselectivity were observed (entry 5), while
employing the more hindered N,N-diisopropylethylamine
(DIPEA) furnished only subtle improvements in both, reaction
yield and regioselectivity (entry 6).
On the other side, the use of secondary amines such as iPr2NH
After this successful outcome, and in order to expand the scope
4
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Page 6 of 13
and Et2NH caused either diminished regioselectivity (entry 7) or
In addition, in the case of the products resulting from
lower yields (entry 8), respectively. These results underscored the
role of the added base on the reaction outcome. Being the
isoxazolation of 5a-f, mixtures of 1,2-isoxazoles (7 and 7’) were
View Article Online
invariably observed, being always 7’ their minor component. The
DOI: 10.1039/C4RA11571F
improvements induced by DIPEA minor in nature, the conditions 25 latter resulted from attack of the hydroxylamine nitrogen to the
5
of entry 3 were taken as optimal. These were still milder and
more time-efficient conditions than those previously found for
similar transformations.18c,d
more hindered benzylic position of the starting 1,3-diynes 5.
Interestingly, however, the use of PEG-400 seemed to afford
highly selective reactions, resulting in mixtures with significantly
lower amounts (< 12.5%) of the minor regioisomers 7’a-f than in
The two sets of optimized conditions were employed for the
synthesis of 3,5-disubstituted 1,2-isoxazole derivatives 6 and 7 30 a similar transformation employing DMSO (up to 42.6%).18c
10 (Table 5). Under these conditions, the isoxazoles were isolated in
moderate to excellent yields. The average yields of the products
derived from unsymmetric 1,3-diynes (7a-f) were slightly higher
and more consistent (75-89%) than those arising from 6a-f, their
The structures of the isoxazoles 6a-f were also ascertained by
NMR analysis, interpreting the effect of the heteroatoms of the
1,2-isoxazole ring on the shieldings of the hydrogens of the
neighboring methylene groups. These were observed as a pair of
symmetric counterparts (58-89%). However, they could not be 35 coupled triplets resonating, at approximately  3.0 and 4.2
15 correlated with structural or electronic features of the starting
heterocyles among both series of products.
(attached to the indolic nitrogen atom) and a singlet at
approximately 5.2 ppm (displaced downfield to  5.6 in the case
of the carbazole derivatives). The latter was assigned to the
protons of the methylene moiety attached to both, the indole
40 nitrogen and the carbon of the isoxazole ring attached to the
isoxazolic nitrogen.
Table 5. Synthesis of 3,5-disubstituted 1,2-isoxazoles 6a-f and 7a-f from
symmetric (3a-f) and unsymmetric (5a-f) 1,3-diynes, in PEG-400.
R2
R2
R3
R3
The structures of the compounds 7a-f were easily
differentiated from those of their 7’a-f congeners. The former
exhibited the resonances of their methylene protons as two
45 singlets, at approximately  3.9 and 5.2. The latter resonance was
assigned to the methylene moiety attached to the indolic nitrogen
atom; analogously to the cases of 6a-f, this signal appears
deshielded at  5.67 in the carbazole derivatives.
On the other side, compounds 7’a-f displayed the pair of
50 coupled methylene protons as triplets resonating at approximately
 3.3 and 4.5 ppm, the latter signal being attributed to the
methylene group attached to the indole nitrogen.
R1
R1
R3
N
N
R2
R1
3
R2
N
R3
NH2OH.HCl,
Et3N (2.5 equiv.),
N
O
R1
PEG-400, 80ºC, 12h
N
R2
6
R3
R1
Based on literature precedents, including the conclusions of a
recently disclosed theoretical study of the isoxazolation of
N
55 symmetric 1,4-diphenyl-1,3-butadiyne,27
mechanism (Scheme 2) can be proposed.
a detailed reaction
R4
5
R4
Hydroxylamine is known to add efficiently to alkynes to give
oximes, with the Markovnikov-type reactivity of this process
being at the hearth of the selectivity of the transformation.14,28
60 Accordingly, it can be proposed that the reaction is initiated when
one of the triple bonds of the 1,3-diyne conjugated system (5a)
suffers a Cope-type intermolecular hydroamination (aza-protio
transfer) reaction mediated by the hydroxylamine nitrogen, which
is analogous to the reverse of the Cope elimination.29
NH2OH.HCl, Et3N (4 equiv.),
PEG-400, 100ºC, 12h
R4
R2
R2
R1
R3
O
N
O
N
R1
+
N
R3
N
7'
7
65
Interestingly, unlike the copper-catalyzed 1,3-dipolar
cycloaddition between nitrile oxides and alkynes to afford 1,2-
isoxazoles,30 there is a mounting body of evidence that this non-
catalyzed reaction, which should lead to the ene-N-oxide
intermediate i, is a concerted process when carried out under
Entry
Nº
1
2
3
4
5
6
7
Prod. Nº
Ratio
7:7’
-
-
-
-
-
-
10:1
8:1
10:1
9.5:1
9:1
7:1
R1
R2
R3
R4
(Yield, %)
6a (89)
6b (71)
6c (83)
6d (58)
6e (63)
6f (89)
7a (85)
7b (84)
7c (75)
7d (76)
7e (84)
7f (89)
H
H
H
Me
H
H
H
H
H
H
H
OMe
Br
H
-
-
-
-
-
-
H
Me
H
Me
H
70 thermal and metal-free conditions.31
In turn, this intermediate should experience a proton transfer
reaction from the nitrogen atom to the oxygen, furnishing the
ene-hydroxylamine intermediate ii. Theoretical calculations have
pointed out to this as the rate-determining step of the reaction;28
75 therefore, carrying out the transformation in the presence of an
hydroxylic solvent like PEG-400 may be crucial for its success,
since it can mediate a facile, bimolecular proton transfer within
the generated amine oxide intermediate, through a 5-membered
transition state, speeding up the process (Scheme 2). This
4-MeC6H4
CH=CH-CH=CHa
-
H
H
OMe
Br
H
H
H
H
H
H
H
H
H
8
9
10
11
12
CH=CH-CH=CHa
CH=CH-CH=CHa
H
Me
a
20
1,6-Di(9H-carbazol-9-yl)hexa-2,4-diyne (3f) was used as starting
material.
This journal is © The Royal Society of Chemistry 2014
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RSC Advances
proposal is supported by DFT studies.32
cyclization, which takes place with Markovnikov-type selectivity
Subsequent base-assisted N-oxide-oxime tautomerization of 35 in both, symmetric and unsymmetric 1,3-diynes.
View Article Online
the intermediate ii, also involving the conjugated alkyne,33 could
afford the allenic oxime iii.14 Rotation across the single bond
would then place the oxime and allene moieties in position and
have them with the correct geometry,34 suitable for undergoing an
In conclusion, a regioselective, convenientDaOndI: a10to.1m03-9ec/Co4nRoAm11ic571F
synthesis of 3,5-disubstituted 1,2-isoxazoles bearing
5
functionalized indolyl, aryl and carbazolyl substituents, is
reported. The synthesis of the starting symmetric 1,3-diyne indole
intramolecular electrophilic addition toward the final product 40 derivatives was performed employing an aerobic self-coupling
(7a).35
reaction of differently functionalized N-propargyl indoles and N-
propargyl carbazole under copper catalysis. Analogously, the
unsymmetric 1,3-diyne derivatives were synthesized by reaction
of N-propargyl indoles and N-propargyl carbazole with
45 phenylacetylene or p-tolylacetylene under combined NiII/CuI
catalysis and aerobic conditions.
HOCH2(CH2OCH2)nCH2
O
H
H
O -
H
O
H
N+
H
N
H
..
H
N
N
The isoxazolation of the symmetric and unsymmetric 1,3-
diyne indole derivatives was carried out by reaction with
hydroxylamine in PEG-400, as a superior and eco-friendly
50 solvent, under relatively mild conditions and without the addition
of acids or metal catalysts. The transformation was optimized
relative to reaction temperature and time, as well as regarding the
amounts of base and NH2OH.HCl; its scope and limitations were
studied and a reaction mechanism was proposed.
Cope-type
Hydroamination
5a
i
(Solvent Assisted)
Proton Transfer
H
º
O
H
Et3N:
OH
55
The operational simplicity of the described isoxazolation and
the easy availability of the starting N-propargyl derivatives as
well as their symmetric and unsymmetric 1,3-diynes should
encourage the use of this approach in synthetic and medicinal
chemistry.
N
H
N
N
H
Et3N+H
N
H
Tautomerization
Rotation
60
iii
ii
Experimental section
Electrophilic
Addition
O
N
General information
The solvents for the chemical reactions were purified according
to the literature. Commercial reagents were used without further
N
7a
65 purification. In the conventional purification procedure, the crude
material was submitted to flash column chromatography with
silica gel 60 H (particle size 40-63 m, 230-400 mesh), eluting
isocratically with hexane or mixtures of hexane:EtOAc and
hexane:EtOAc:CH2Cl2.
10 Scheme 2. Proposed reaction mechanism for the synthesis of the 3,5-
disubstituted 1,2-isoxazoles.
This 5-exo-dig cyclization would be formally arising from
simple addition of the hydroxyl group across the distal double
bond of the allene (iii). Theoretical studies have suggested that
15 this step may involve a zwitterionic intermediate that undergoes a
proton transfer reaction.28
Short and Ziegler demonstrated that K2CO3 is able to drive
cyclization of homopropargyl oximes towards isoxazole
derivatives. Interestingly, it seems likely that this process may
20 involve the same kind of allenic intermediates and reaction
mechanism.17a
The group of Bao has recently proposed an analogous but less
detailed mechanism for a similar transformation.18c However, in
their proposal, the roles of the solvent, the added base and the
25 rotation step are ignored, whereas no discussion about the
reaction selectivity is included.
70
All new compounds gave single spots when run on TLC plates
of Kieselgel 60 GF254, employing different hexane:EtOAc and
hexane:EtOAc:CH2Cl2 solvent systems. Chromatographic spots
were detected by irradiation of the plates with UV light (254 nm),
followed by exposure to iodine vapors of by spraying with
75 ethanolic vanillin/sulfuric acid reagent and careful heating.
Apparatus
The melting points were measured on an MQAPF-301 instrument
(Microquímica) and are reported uncorrected. The infrared
80 spectra were acquired on a Shimadzu Prestige-21 spectrometer,
with the samples prepared as KBr pellets or thin films.
The NMR spectra (1H and 13C) were recorded in CDCl3 unless
otherwise stated, on Bruker DPX-200 and Bruker DPX-400
spectrometers (200 and 400 MHz for 1H, respectively). Chemical
85 shift data are reported in ppm downfield from TMS, employed as
internal standard. Coupling constants (J) are informed in Hertz.
Elemental analyses were recorded on a Perkin-Elmer CHN
2400 analyzer. Low resolution mass spectra were acquired on a
As an hydroxylic solvent, PEG-400 is here proposed to be
involved in the formation of intermediate ii, while it is evident
that the added base is useful for freeing the hydroxylamine base
30 from its hydrochloride and plays
a crucial role in the
tautomerization of ii into iii. On the other hand, geometric
considerations should not be mechanistically neglected, since
they turn mandatory the rotation stage for
a successful
6
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Page 8 of 13
Shimadzu QP2010 Plus CG-MS instrument. High-resolution
mass spectral data were obtained in a Bruker microTOF-Q II
instrument. Detection of the ions was performed with
electrospray ionization in positive ion mode.
1-(Prop-2-ynyl)-5-p-tolyl-1H-indole (2e)
View Article Online
DOI: 10.1039/C4RA11571F
1
White crystalline solid, m.p.: 118-119 °C; yield: 80%. H NMR
(400 MHz, DMSO-d6) : 2.37 (s, 3H), 3.39 (t, J = 2.4, 1H), 5.11
60 (d, J = 2.4, 2H), 6.59 (d, J = 3.1, 1H), 7.27 (d, J = 7.9, 2H), 7.46
(d, J = 3.1, 1H), 7.51 (dd, J = 8.5 and 1.5, 1H), 7.59-7.63 (m,
3H) and 7.87 (d, J = 1.5, 1H). 13C NMR (100 MHz, DMSO-d6)
: 20.4, 35.1, 75.2, 78.9, 101.6, 110.1, 118.2, 120.5, 126.4,
128.7, 128.8, 129.2, 131.9, 134.9, 135.2 and 138.6. MS (m/z, rel.
65 int., %): 246 [20, (M+1)+], 245 (100, M+), 230 (16), 206 (26),
204 (12), 84 (10) and 66 (13).
5
General procedure for the synthesis of N-propargyl
heterocycles (2a-f)21b
A solution of the indole or carbazole (1a-f, 15 mmol) in DMF (30
mL) was cooled to 0 ºC. Solid KOH (1.12 g, 20 mmol) was added
10 and the reaction mixture was stirred for 15 minutes, when was
treated with 80% propargyl bromide solution (2.22 mL, 20
mmol). After further stirring for 6 h at room temperature, water
(50 mL) was added, and the organic phase was extracted with
EtOAc (4 × 30 mL). The combined organic layers were dried
15 over MgSO4 and the solvent was evaporated under reduced
pressure. The product was purified by column chromatography,
eluting with hexane.
9-(Prop-2-ynyl)-9H-carbazole (2f)
White crystalline solid, m.p.: 104-105 °C (Lit.:36e 104-107 ºC);
1
70 yield: 78%. H NMR (400 MHz, DMSO-d6) : 3.24 (t, J = 2.4,
1H), 5.31 (d, J = 2.4, 2H), 7.24-7.28 (m, 2H), 7.48-7.52 (m,
2H), 7.69 (d, J = 8.2, 2H) and 8.17 (d, J = 7.8, 2H). 13C NMR
(100 MHz, DMSO-d6) : 31.7, 74.2, 78.9, 109.3, 119.2, 120.1,
122.3, 125.7 and 139.5. MS (m/z, rel. int., %): 206 [11, (M+1)+],
75 205 (71, M+), 204 (100), 166 (47), 140 (23) and 139 (13).
1-(Prop-2-ynyl)-1H-indole (2a)
20 Yellowish crystalline solid, m.p.: 38-40 °C (Lit.:36a 36-37 ºC);
1
yield: 76%. H NMR (200 MHz) : 2.33 (t, J = 2.5, 1H), 4.76
(d, J = 2.5, 2H), 6.51 (d, J = 3.1, 1H), 7.08-7.26 (m, 3H), 7.35
(d, J = 8.1, 1H) and 7.62 (d, J = 7.6, 1H). 13C NMR (50 MHz)
: 35.6, 73.4, 77.7, 102.0, 109.3, 119.8, 121.0, 121.8, 127.2,
25 128.8 and 135.7. MS (m/z, rel. int., %): 155 (66, M+), 154 (100),
116 (30), 89 (32) and 63 (17).
General procedure for the synthesis of the symmetric 1,3-
diynes (3a-f)22c
A stirred mixture of the heterocyclic N-propargyl derivative (2, 5
80 mmol) and CuCl (25 mg, 0.25 mmol, 5 mol%) in DMSO (5 mL)
was heated to 90 ºC for 4 h. Then, the reaction was cooled to
room temperature and filtered through Celite. The filtrate was
diluted with water (15 mL) and extracted with EtOAc (4 × 25
mL). The combined extracts were successively washed with
5-Methoxy-1-(prop-2-ynyl)-1H-indole (2b)
1
White solid, m.p.: 66-67 °C (Lit.:36b 65-69 °C); yield: 71%. H
30 NMR (400 MHz) : 2.35 (t, J = 2.5, 1H), 3.81 (s, 3H), 4.75 (d, 85 water (1 × 10 mL) and brine (1 × 10 mL). The organic layer was
J = 2.5, 2H), 6.42 (d, J = 3.1, 1H), 6.88 (dd, J = 8.9 and 2.4,
1H), 7.07 (d, J = 2.4, 1H), 7.12 (d, J = 3.1, 1H) and 7.25 (d, J =
8.9, 1H). 13C NMR (100 MHz) : 35.8, 55.8, 73.4, 77.8,
101.6, 102.9, 110.0, 112.1, 127.8, 129.3, 131.1 and 154.3. MS
35 (m/z, rel. int., %): 186 [14, (M+1)+], 185 (100, M+), 171 (11),
170 (83), 146 (18), 142 (28), 115 (24), 103 (18) and 76 (16).
dried over MgSO4, and concentrated under reduced pressure. The
product was purified by column chromatography using an
hexane: EtOAc:CH2Cl2 (80:10:10) solvent mixture as eluent.
90 1,6-Bis(1H-indol-1-yl)hexa-2,4-diyne (3a)
1
Light brown solid, m.p.: 147-149 °C; yield: 83%. H NMR (400
MHz) : 4.84 (s, 4H), 6.49 (d, J = 3.1, 2H), 7.07 (d, J = 3.1,
2H), 7.10-7.13 (m, 2H), 7.19-7.23 (m, 2H), 7.31 (d, J = 8.2, 2H)
and 7.60 (d, J = 7.9, 2H). 13C NMR (100 MHz) : 36.3, 69.0,
5-Bromo-1-(prop-2-ynyl)-1H-indole (2c)36c
1
Brown oil; yield: 70%. H NMR (400 MHz) : 2.38 (t, J = 2.5,
40 1H), 4.80 (d, J = 2.5, 2H), 6.44 (dd, J = 3.2 and 0.8, 1H), 7.16 95 73.3, 102.5, 109.2, 120.0, 121.1, 122.1, 127.2, 128.9 and 135.8.
(d, J = 3.2, 1H), 7.23 (d, J = 8.5, 1H), 7.30 (dd, J = 8.7 and 1.8,
1H) and 7.73 (d, J = 1.8, 1H). 13C NMR (100 MHz) : 36.0,
73.9, 77.3, 101.7, 110.8, 113.3, 123.6, 124.8, 128.4, 130.7 and
IR (KBr, ν): 3104, 2904, 1614, 1463, 1333, 1315, 1185, 739
and 719 cm-1. MS (m/z, rel. int., %): 309 [12, (M+1)+], 308 (51,
M+), 281 (28), 253 (17), 209 (14), 208 (21), 207 (100), 191
(100), 133 (15), 117 (38), 89 (24) and 73 (27). HRMS (ESI–
134.5. MS (m/z, rel. int., %): 235 [51, (M+2)+], 234 [21,
+
45 (M+1)+], 233 (50, M+), 154 (100), 153 (22), 127 (26), 126 (15), 100 TOF, m/z): Obsd. 331.1208; C22H16N2Na [(M+Na)+] requires
115 (44), 114 (15), 88 (16) and 62 (14).
331.1211.
2-Methyl-1-(prop-2-ynyl)-1H-indole (2d)36d
1,6-Bis(5-methoxy-1H-indol-1-yl)hexa-2,4-diyne (3b)
1
White solid, m.p.: 71-72 °C; yield: 72%. 1H NMR (400 MHz) :
50 2.21 (t, J = 2.5, 1H), 2.44 (s, 3H), 4.73 (d, J = 2.5, 2H), 7.05-
Beige solid, m.p.: 166-168 °C; yield: 72%. H NMR (400 MHz)
105 : 3.82 (s, 6H), 4.84 (s, 4H), 6.42 (dd, J = 3.2 and 0.8, 2H),
6.88 (dd, J = 8.9 and 2.4, 2H), 7.06 (d, J = 3.2, 2H), 7.07 (d, J
= 2.4, 2H) and 7.21 (d, J = 8.9, 2H). 13C NMR (100 MHz) :
36.5, 55.9, 69.0, 73.3, 102.1, 103.0, 109.9, 112.3, 127.8,
129.3, 131.1 and 154.5. IR (KBr, ν): 3102, 2956, 2935, 2832,
110 1728, 1616, 1576, 1482, 1432, 1397, 1243, 1152, 1030, 802
7.18 (m, 3H), 7.30 (d, J = 8.1, 1H) and 7.50 (d, J = 7.8, 1H). 13
C
NMR (100 MHz) : 12.4, 32.3, 72.1, 78.3, 100.9, 108.8,
119.8, 119.8, 120.9, 128.3, 135.9 and 136.5. MS (m/z, rel. int.,
%): 170 [12, (M+1)+], 169 (87, M+), 168 (100), 167 (40), 154
55 (22), 130 (31), 128 (13), 103 (27), 102 (13), 77 (28) and 63 (14).
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, vol, 00–00 | 7

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RSC Advances
and 726 cm-1. MS (m/z, rel. int., %): 368 (3, M+), 78 (99), 63
(100), 62 (13) and 61 (36). Anal. Calc.: C, 78.24; H, 5.47; N,
7.60. Found: C, 77.86; H, 5.54; N, 7.25.
Solid CuI (10 mg, 0.05 mmol, 5 mol%) and NiCl2.6H2O (12 mg,
0.05 mmol, 5 mol%) were added to a stirred solution of TMEDA
(30 μL, 0.2 mmol, 20 mol%) in THF (4 mL)D. OThI:e10a.1ry0l39a/cCe4tyRlAe1n1e571F
View Article Online
(4a,b, 5 mmol) and the N-propargyl indole or carbazole (1 mmol)
60 were successively added and the system was allowed to stir at
room temperature for 6 h. Then, the volatiles were evaporated
under reduced pressure and the residue was chromatographically
purified, eluting with hexane.
5
1,6-Bis(5-bromo-1H-indol-1-yl)hexa-2,4-diyne (3c)
1
Beige solid, m.p.: 157-159 °C; yield: 76%. H NMR (400 MHz,
DMSO-d6) : 5.26 (s, 4H), 6.46 (dd, J = 3.2 and 0.7, 2H), 7.29
(dd, J = 8.7 and 1.9, 2H), 7.42 (d, J = 3.2, 2H), 7.47 (d, J = 8.7,
2H) and 7.75 (d, J = 1.9, 2H). 13C NMR (100 MHz, DMSO-d6)
65 1-(5-Phenylpenta-2,4-diynyl)-1H-indole (5a)
10 : 35.6, 67.5, 75.0, 101.3, 111.8, 112.2, 122.7, 123.9, 129.8,
130.0 and 134.1. IR (KBr, ν): 3106, 1705, 1604, 1562, 1507,
1463, 1333, 1208, 793, 754 and 581 cm-1. MS (m/z, rel. int., %):
468 [2, (M+2)+], 466 (4, M+), 235 (27), 233 (28), 197 (55),
195 (55), 154 (60), 127 (15), 116 (78) and 89 (39). Anal. Calc.:
15 C, 56.68; H, 3.03; N, 6.01. Found: C, 57.07; H, 3.13; N, 5.87.
1
Light brown solid, m.p.: 68-70 °C; yield: 76%. H NMR (400
MHz) : 4.97 (s, 2H), 6.53 (dd, J = 3.2 and 0.6, 1H), 7.12-7.19
(m, 2H), 7.23-7.34 (m, 4H), 7.38 (d, J = 8.2, 1H), 7.43-7.45
(m, 2H) and 7.63 (d, J = 7.8, 1H). 13C NMR (100 MHz) :
70 36.6, 69.9, 73.2, 76.4, 78.2, 102.4, 109.3, 120.0, 121.1, 121.2,
122.0, 127.2, 128.4, 128.9, 129.4, 132.6 and 135.8. IR (KBr, ν):
3045, 2942, 2240, 1609, 1573, 1513, 1483, 1355, 1304,
1254, 1192, 752, 732 and 686 cm-1. MS (m/z, rel. int., %): 256
[15, (M+1)+], 255 (73, M+), 254 (44), 140 (12), 139 (100), 113
75 (9) and 89 (14). HRMS (ESI–TOF, m/z): Obsd. 278.0948;
1,6-Bis(2-methyl-1H-indol-1-yl)hexa-2,4-diyne (3d)
Brown solid, m.p.: 218 °C (dec); yield: 83%. 1H NMR (400
MHz, DMSO-d6) : 2.39 (s, 6H), 5.13 (s, 4H), 6.22 (s, 2H),
20 6.98-7.09 (m, 4H) and 7.40-7.43 (m, 4H). 13C NMR (100 MHz,
DMSO-d6) : 12.1, 32.4, 66.7, 75.3, 100.5, 109.3, 119.3, 119.5,
120.6, 127.7, 136.2 and 136.3. IR (KBr, ν): 2916, 1614, 1552,
1462, 1337, 787 and 745 cm-1. MS (m/z, rel. int., %): 337 [17,
(M+1)+], 336 (60, M+), 205 (100), 204 (88), 191 (28), 167
C19H13NNa [(M+Na)+] requires 278.0946
.
1-(5-p-Tolylpenta-2,4-diynyl)-1H-indole (5b)
Light brown solid, m.p.: 83-85 °C; yield: 70%. H NMR (400
1
25 (18), 149 (12), 130 (44), 97 (18), 81 (26) and 69 (47). HRMS 80 MHz) : 2.33 (s, 3H), 4.99 (s, 2H), 6.54 (dd, J = 3.2 and 0.5,
(ESI–TOF, m/z): Obsd. 359.1507; C24H20N2Na [(M+Na)+]
requires 359.1519.
1H), 7.09 (d, J = 8.0, 2H), 7.12-7.16 (m, 1H), 7.18 (d, J =
3.2, 1H), 7.24-7.27 (m, 1H), 7.35 (d, J = 8.1, 2H), 7.40 (d, J =
8.3, 1H) and 7.64 (d, J = 7.9, 1H). 13C NMR (100 MHz) :
21.5, 36.7, 70.1, 72.7, 76.1, 78.6, 102.4, 109.3, 118.2, 120.0,
85 121.1, 122.0, 127.2, 129.0, 129.2, 132.5, 135.9 and 139.8. IR
(KBr, ν): 3028, 2951, 2239, 1604, 1508, 1462, 1336, 1314,
1257, 1182, 811, 742 and 720 cm-1. MS (m/z, rel. int., %): 270
[14, (M+1)+], 269 (63, M+), 268 (25), 207 (13), 154 (14), 153
(100) and 152 (23). HRMS (ESI–TOF, m/z): Obsd. 270.1255;
90 C20H16N [(M+H)+] requires 270.1283.
1,6-Bis(5-p-tolyl-1H-indol-1-yl)hexa-2,4-diyne (3e)
30 Brown solid, m.p.: 175-177 °C; yield: 72%. 1H NMR (400 MHz,
DMSO-d6) : 2.33 (s, 6H), 5.27 (s, 4H), 6.50 (d, J = 3.1, 2H),
7.23 (d, J = 7.9, 4H), 7.38 (d, J = 3.1, 2H), 7.44 (dd, J = 8.6
and 1.6, 2H), 7.53-7.55 (m, 6H) and 7.79-7.80 (m, 2H). 13C
NMR (100 MHz, DMSO-d6) : 20.6, 35.6, 67.4, 75.4, 102.1,
35 110.3, 118.3, 120.8, 126.5, 128.9, 129.1, 129.4, 132.1, 134.9,
135.5 and 138.5. IR (KBr, ν): 2915, 1616, 1476, 1335, 799 and
720 cm-1. MS (m/z, rel. int., %): 489 [20, (M+1)+], 488 (50, M+),
282 (22), 281 (32), 267 (28), 266 (20), 244 (17), 208 (20), 207
(100), 206 (64), 204 (25), 97 (23) and 57 (46). HRMS (ESI–
5-Methoxy-1-(5-phenylpenta-2,4-diynyl)-1H-indole (5c)
1
Beige solid, m.p: 105-107 °C; yield: 83%. H NMR (400 MHz)
: 3.84 (s, 3H), 4.95 (s, 2H), 6.45 (d, J = 3.0, 1H), 6.91 (dd, J =
40 TOF, m/z): Obsd. 511.2129; C36H28N2Na [(M+Na)+] requires 95 8.8 and 2.3, 1H), 7.09 (d, J = 2.3, 1H), 7.14 (d, J = 3.0, 1H),
511.2145.
7.26-7.35 (m, 4H) and 7.44-7.46 (m, 2H). 13C NMR (100 MHz)
: 36.8, 55.9, 69.8, 73.2, 76.5, 78.2, 102.0, 103.0, 110.0,
112.3, 121.2, 127.9, 128.4, 129.4, 131.2, 132.6 and 154.5. IR
(KBr, ν): 2943, 2901, 2244, 1619, 1574, 1486, 1451,
100 1423, 1347, 1237, 1152, 1026, 801, 757, 722 and 687
cm-1. MS (m/z, rel. int., %): 286 [16, (M+1)+], 285 (69, M+),
281 (11), 254 (11), 207 (29), 140 (13) and 139 (100). HRMS
(ESI–TOF, m/z): Obsd. 308.1039; C20H15NNaO [(M+Na)+]
1,6-Bis(9H-carbazol-9-yl)hexa-2,4-diyne (3f)
White crystalline solid, m.p.: 204 °C (dec); yield: 60%. 1H NMR
45 (400 MHz, DMSO-d6) : 5.39 (s, 4H), 7.20-7.24 (m, 4H),
7.42-7.46 (m, 4H), 7.59 (d, J = 8.1, 4H) and 8.12 (d, J = 7.6,
4H). 13C NMR (100 MHz, DMSO-d6) : 32.2, 66.5, 74.8,
109.2, 119.4, 120.1, 122.4, 125.7 and 139.3. IR (KBr, ν): 3050,
2910, 1625, 1599, 1485, 1454, 1325, 747 and 720 cm-1. MS (m/z,
50 rel. int., %): 409 [16, (M+1)+], 408 (50, M+), 242 (36), 241
(100), 167 (18), 166 (29) and 140 (16). HRMS (ESI–TOF, m/z):
Obsd. 431.1521; C30H20N2Na [(M+Na)+] requires 431.1524.
requires 308.1046
.
105
5-Bromo-1-(5-p-tolylpenta-2,4-diynyl)-1H-indole (5d)
1
White solid, m.p.: 120-122 °C; yield: 60%. H NMR (400 MHz)
: 2.33 (s, 3H), 4.96 (s, 2H), 6.46 (d, J = 3.1, 1H), 7.09 (d, J =
8.0, 2H), 7.17 (d, J = 3.1, 1H), 7.26 (d, J = 8.7, 1H), 7.31-7.36
General procedure for the preparation of unsymmetric 1,3-
110 (m, 3H) and 7.74 (d, J = 1.6, 1H). 13C NMR (100 MHz) : 21.6,
55 diynes (5a-f)24
8
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RSC Adv., 2014, vol, 00–00
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RSC Advances
Page 10 of 13
36.9, 70.5, 72.5, 75.4, 78.9, 102.0, 110.8, 113.4, 118.0, 123.6,
170.2. IR (KBr, ν): 3099, 3051, 2924, 1709, 1610, 1513, 1477,
124.9, 128.5, 129.2, 130.7, 132.6, 134.6 and 140.0. IR (KBr, ν):
2916, 2891, 2247, 1650, 1560, 1508, 1463, 1433, 1400,
1344, 1268, 1242, 1210, 823, 794, 755 and 723 cm-1. MS
1461, 1429, 1338, 1314, 1257, 1213, 1180, 1011 and 739 cm-1.
View Article Online
MS (m/z, rel. int., %): 341 (14, M+), 131 (1D0O),I:11300.10(1309/0C)4aRnAd11150713F
(10). HRMS (ESI–TOF, m/z): Obsd. 364.1425; C22H19N3NaO
5
(m/z, rel. int., %): 349 [8, (M+2)+], 347 (9, M+), 209 (12), 208 60 [(M+Na)+] requires 364.1426
(21), 207 (100), 153 (44), 133 (15), 96 (17) and 73 (33). HRMS
.
(ESI–TOF, m/z): Obsd. 370.0190; C20H14BrNNa [(M+Na)+]
5-(2-(5-Methoxy-1H-indol-1-yl)ethyl)-3-((5-methoxy-1H-indol-
1-yl)methyl)-1,2-isoxazole (6b)
requires 370.0202.
Beige solid, m.p.: 94-95 °C; yield: 71%. 1H NMR (400 MHz) :
65 3.09 (t, J = 7.0, 2H), 3.82 (s, 6H), 4.30 (t, J = 7.0, 2H), 5.19
(s, 2H), 5.46 (s, 1H), 6.29 (d, J = 3.0, 1H), 6.42 (d, J = 3.0,
1H), 6.81-6.87 (m, 3H), 6.98 (d, J = 3.0, 1H), 7.04 (d, J = 2.4,
1H), 7.07-7.09 (m, 2H) and 7.15 (d, J = 8.9, 1H). 13C NMR (100
MHz) : 28.0, 42.0, 44.1, 55.9, 101.4, 101.5, 102.1, 103.1,
70 103.1, 109.5, 110.1, 112.1, 112.4, 127.9, 128.2, 129.1,
129.3, 131.0, 131.5, 154.3, 154.5, 161.0 and 170.2. IR (KBr,
ν): 3123, 2948, 2829, 1715, 1612, 1484, 1445, 1245, 1237, 1147,
1030, 802, 757 and 730 cm-1. MS (m/z, rel. int., %): 401 (33,
M+), 281 (36), 208 (18), 207 (83), 161 (11), 160 (100) and 117
75 (44). Anal. Calc.: C, 71.80; H, 5.77; N, 10.47. Found: C, 71.53;
H, 5.55; N, 10.06.
10 9-(5-Phenylpenta-2,4-diynyl)-9H-carbazole (5e)
1
White crystalline solid, m.p: 154-155 °C; yield: 80%. H NMR
(400 MHz, DMSO-d6) : 5.58 (s, 2H), 7.25-7.28 (m, 2H),
7.34-7.44 (m, 3H), 7.47-7.53 (m, 4H), 7.72 (d, J = 8.2, 2H) and
13
8.18 (d, J = 7.8, 2H). C NMR (100 MHz, DMSO-d6) : 32.6,
15 67.0, 72.9, 77.2, 79.4, 109.4, 119.5, 119.9, 120.3, 122.5, 125.9,
128.6, 129.8, 132.3 and 139.5. IR (KBr, ν): 3053, 2914, 2244,
1626, 1597, 1487, 1456, 1329, 748, 720 and 684 cm-1.
MS (m/z, rel. int., %): 305 (32, M+), 304 (24), 166 (10), 140 (21)
and 139 (100). Anal. Calc.: C, 90.46; H, 4.95; N, 4.59. Found: C,
20 90.10; H, 4.91; N, 4.29.
9-(5-p-Tolylpenta-2,4-diynyl)-9H-carbazole (5f)
5-(2-(5-Bromo-1H-indol-1-yl)ethyl)-3-((5-bromo-1H-indol-1-
yl) methyl)-1,2-isoxazole (6c)
1
White crystalline solid, m.p: 155-156 °C; yield: 85%. H NMR
(400 MHz, DMSO-d6) : 2.27 (s, 3H), 5.57 (s, 2H), 7.15 (d, J
25 = 7.9, 2H), 7.24-7.28 (m, 2H), 7.36 (d, J = 7.9, 2H), 7.49-7.53
(m, 2H), 7.72 (d, J = 8.2, 2H) and 8.17 (d, J = 7.7, 2H). 13C
NMR (100 MHz, DMSO-d6) : 20.9, 32.6, 67.2, 72.4, 77.5,
78.9, 109.4, 116.8, 119.5, 120.2, 122.5, 125.8, 129.2, 132.2,
139.5 and 139.9. IR (KBr, ν): 3052, 2912, 2242, 1627, 1603,
30 1489, 1455, 1332, 812, 746 and 719 cm-1. MS (m/z, rel. int., %):
319 (5, M+), 170 (65), 150 (12), 135 (22), 133 (57), 103 (21),
102 (29), 86 (100), 84 (100) and 66 (80). HRMS (ESI–TOF,
m/z): Obsd. 320.1420; C24H18N [(M+H)+] requires 320.1434.
80 Beige solid, m.p.: 99-101 °C; yield: 83%. 1H NMR (400 MHz) :
3.07 (t, J = 6.8, 2H), 4.30 (t, J = 6.8, 2H), 5.16 (s, 2H), 5.36 (s,
1H), 6.27 (d, J = 3.1, 1H), 6.43 (d, J = 3.1, 1H), 6.80 (d, J =
2.3, 1H), 6.97- 7.00 (m, 2H), 7.09 (d, J = 8.7, 1H), 7.18 (d, J =
8.7, 1H), 7.24 (d, J = 8.7, 1H), 7.67 (s, 1H) and 7.72 (s, 1H).
85 13C NMR (100 MHz) : 27.8, 41.9, 44.0, 101.4, 101.4, 102.0,
110.2, 110.7, 112.8, 113.2, 123.5, 123.5, 124.5, 124.8, 128.4,
128.8, 130.1, 130.4, 134.1, 134.5, 160.4 and 170.0. IR (KBr,
ν): 3125, 3099, 2932, 1712, 1601, 1510, 1467, 1329, 1276, 1192,
1049, 870, 794, 754, and 718 cm-1. MS (m/z, rel. int., %): 501
90 [11, (M+2)+], 499 (17, M+), 420 (36), 419 (15), 418 (37), 250
(11), 248 (11), 210 (97), 208 (100) and 129 (72). HRMS (ESI–
TOF, m/z): Obsd. 499.9775; C22H18Br2N3O [(M+H)+] requires
35 General procedure for the synthesis of 3,5-disubstituted 1,2-
isoxazoles (6a-f) from the symmetric 1,3-diynes (3a-f)
499.9796
.
A stirred mixture of the symmetric diyne (3, 0.3 mmol),
H2NOH.HCl (48 mg, 0.75 mmol, 2.5 equiv.) and Et3N (0.1 mL,
0.75 mmol, 2.5 equiv.) in PEG-400 (0.5 mL) was heated at 80 ºC
40 for 12 h. After the reaction was completed, water (10 mL) was
added and the products were extracted with EtOAc (3 × 15 mL).
The combined extracts were dried over MgSO4; the solvent was
evaporated under reduced pressure and the oily residue was
chromatographed using hexane: EtOAc (85:15) as eluent.
45
95 5-(2-(2-Methyl-1H-indol-1-yl)ethyl)-3-((2-methyl-1H-indol-1-
yl) methyl)-1,2-isoxazole (6d)
1
Brown solid, m.p: 112-114 °C; yield: 58%. H NMR (400 MHz)
: 2.11 (s, 3H), 2.33 (s, 3H), 2.96 (t, J = 7.1, 2H), 4.18 (t, J =
7.1, 2H), 5.14 (s, 2H), 5.30 (s, 1H), 6.07 (s, 1H), 6.24 (s, 1H),
100 7.00-7.19 (m, 6H), 7.44 (d, J = 7.7, 1H) and 7.49 (d, J = 7.7,
1H). 13C NMR (100 MHz) : 12.2, 12.5, 27.2, 38.4, 40.7,
100.5, 101.1, 101.3, 108.4, 108.7, 119.5, 119.8, 119.8, 119.8,
120.6, 121.0, 128.2, 128.3, 135.9, 136.1, 136.1, 136.7, 161.1
and 170.1. IR (KBr, ν): 3050, 2916, 1603, 1553, 1462, 1397,
105 1341, 1312, 1166, 777, 777 and 743 cm-1. MS (m/z, rel. int., %):
369 (28, M+), 206 (22), 145 (12), 144 (100), 143 (11) and 115
(12). HRMS (ESI–TOF, m/z): Obsd. 392.1720; C24H23N3NaO
5-(2-(1H-Indol-1-yl)ethyl)-3-((1H-indol-1-yl)methyl)-1,2-
isoxazole (6a)
1
Beige solid, m.p.: 90-92 °C; yield: 89%. H NMR (400 MHz) :
3.05 (t, J = 7.0, 2H), 4.28 (t, J = 7.0, 2H), 5.18 (s, 2H), 5.42 (s,
50 1H), 6.35 (d, J = 3.1, 1H), 6.49 (d, J = 3.1, 1H), 6.80 (d, J = 3.1,
1H), 6.98 (d, J = 3.1, 1H), 7.04-7.19 (m, 5H), 7.26 (d, J = 8.2,
1H), 7.56 (dd, J = 7.9 and 0.6, 1H) and 7.60 (dd, J = 7.9 and
0.6, 1H). 13C NMR (100 MHz) : 27.7, 41.7, 43.8, 101.3,
101.9, 102.5, 108.8, 109.3, 119.6, 119.9, 121.1, 121.1, 121.7,
55 122.0, 127.3, 127.6, 128.7, 128.8, 135.6, 136.1, 160.8 and
[(M+Na)+] requires 392.1733
.
110 5-(2-(5-p-Tolyl-1H-indol-1-yl)ethyl)-3-((5-p-tolyl-1H-indol-1-
yl) methyl)-1,2-isoxazole (6e)
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RSC Advances
1
(7b)
Light brown solid, m.p.: 55-56 °C; yield: 63%. H NMR (400
MHz) : 2.34 (s, 6H), 2.97 (t, J = 6.7, 2H), 4.19 (t, J = 6.7,
2H), 5.11 (s, 2H), 5.38 (s, 1H), 6.36 (d, J = 3.0, 1H), 6.48 (d,
J = 3.0, 1H), 6.76 (d, J = 3.1, 1H), 6.92 (d, J = 3.1, 1H), 7.13
(d, J = 8.5, 1H), 7.18 (d, J = 7.9, 4H), 7.23 (d, J = 8.5, 1H),
7.34-7.39 (m, 2H), 7.48 (d, J = 7.9, 4H), 7.74 (s, 1H) and 7.77 (s,
1H). 13C NMR (100 MHz) : 20.9, 27.7, 41.7, 43.8, 101.4,
102.2, 102.8, 109.0. 109.5, 119.2, 121.4, 121.7, 127.1, 127.9,
128.2, 129.1, 129.3, 129.3, 133.0, 133.4, 134.9, 135.4, 135.9,
1
Beige waxy solid; yield: 84%; H NMR (400 MHz) Vie:w2A.r2ti7cle(Osn,line
3H), 3.88 (s, 2H), 5.24 (s, 2H), 5.59 (s, 1HD),O6I:.1500.10(d3,9/JC4=RA31.105,71F
60 1H), 7.00-7.11 (m, 6H), 7.17 (d, J = 8.1, 1H), 7.33 (d, J = 8.1,
1H) and 7.60 (d, J = 7.8, 1H). 13C NMR (100 MHz) : 20.9,
32.7, 41.8, 100.5, 102.4, 109.3, 119.8, 121.0, 122.0, 127.6,
128.6, 128.7, 129.4, 132.4, 136.1, 136.7, 160.7 and 173.3. IR
(KBr, ν): 2924, 2860, 1728, 1603, 1468, 1460, 1268, 1226 and
65 751 cm-1. MS (m/z, rel. int., %): 303 [15, (M+1)+], 302 (60, M+),
207 (14), 197 (29), 170 (40), 169 (53), 131 (13) and 130 (100).
HRMS (ESI–TOF, m/z): Obsd. 303.1543; C20H19N2O [(M+H)+]
5
10 135.9, 139.3, 139.3, 160.7 and 170.1. IR (KBr, ν): 3098, 3020,
2919, 1602, 1516, 1477, 1450, 1335, 1260, 1181, 886, 798, 762
and 722 cm-1. MS (m/z, rel. int., %): 521 (22, M+), 260 (13), 221
(21), 220 (100), 207 (12) and 204 (15). HRMS (ESI–TOF, m/z):
requires 303.1492
.
Obsd. 544.2350; C36H31N3NaO [(M+Na)+] requires 544.2359
.
70 5-Benzyl-3-((5-methoxy-1H-indol-1-yl)methyl)-1,2-isoxazole
15
(7c)
5-(2-(9H-Carbazol-9-yl)ethyl)-3-((9H-carbazol-9-yl) methyl)-
Brown oil; yield: 75%. 1H NMR (400 MHz) : 3.81 (s, 3H), 3.93
(s, 2H), 5.20 (s, 2H), 5.60 (s, 1H), 6.42 (d, J = 3.0, 1H), 6.85
(dd, J = 8.9 and 2.4, 1H), 7.03 (d, J = 3.0, 1H), 7.06 (d, J = 2.4,
75 1H), 7.12-7.14 (m, 2H) and 7.19-7.28 (m, 4H). 13C NMR (100
MHz) : 33.0, 42.0, 55.7, 110.6, 101.9, 102.8, 110.1, 112.2,
127.1, 128.2, 128.6, 128.7, 129.1, 131.3, 135.5, 154.3, 160.7
and 172.9. IR (film, ν): 2939, 2833, 1599, 1484, 1443, 1341,
1243, 1144, 1032, 801 and 715 cm-1. MS (m/z, rel. int., %): 319
80 [24, (M+1)+], 318 (100, M+), 303 (17), 227 (31), 160 (74), 117
(46) and 91 (32). HRMS (ESI–TOF, m/z): Obsd. 341.1260;
1,2-isoxazole (6f)
1
White solid, m.p.: 167-168 °C; yield: 89%. H NMR (400 MHz,
DMSO-d6) : 3.13 (t, J = 7.0, 2H), 4.59 (t, J = 7.0, 2H), 5.60
20 (s, 2H), 6.01 (s, 1H), 7.14-7.18 (m, 2H), 7.23-7.26 (m, 2H), 7.29-
7.33 (m, 2H), 7.43 (d, J = 8.2, 2H), 7.45-7.49 (m, 2H), 7.59 (d, J
= 8.2, 2H), 8.08 (d, J = 7.7, 2H) and 8.16 (d, J = 7.7, 2H). 13C
NMR (100 MHz, DMSO-d6) : 25.5, 37.7, 40.2, 101.4, 108.9,
109.2, 118.8, 119.1, 120.0, 120.1, 122.0, 122.2, 125.5, 125.7,
25 139.5, 139.7, 160.1 and 170.6. IR (KBr, ν): 3051, 1599, 1486,
1456, 1329, 1232, 750 and 722. MS (m/z, rel. int., %): 441 (17,
M+), 181 (19), 180 (100), 167 (77), 149 (40) and 105 (39). Anal.
Calc.: C, 81.61; H, 5.25; N, 9.52. Found: C, 81.58; H, 5.23; N,
9.25.
C20H18N2NaO2 [(M+Na)+] requires 341.1260
.
3-((5-Bromo-1H-indol-1-yl)methyl)-5-(4-methylbenzyl)-1,2-
85 isoxazole (7d)
30
Brown oil; yield: 76%. 1H NMR (400 MHz) : 2.29 (s, 3H), 3.90
(s, 2H), 5.23 (s, 2H), 5.58 (s, 1H), 6.44 (dd, J = 3.2 and 0.7,
1H), 7.02-7.08 (m, 5H), 7.19-7.25 (m, 2H) and 7.72 (d, J = 1.8,
1H). 13C NMR (100 MHz) : 21.0, 32.7, 42.1, 100.4, 102.0,
90 110.8, 113.2, 123.5, 124.8, 128.6, 128.9, 129.4, 130.4, 132.3,
134.7, 136.8, 160.2 and 173.5. IR (film, ν): 2922, 1600, 1514,
1467, 1434, 1334, 1278, 1187, 792, 762 and 719 cm-1. MS (m/z,
rel. int., %): 382 [84, (M+2)+], 380 (85, M+), 277 (26), 275
(26), 210 (70), 208 (74), 196 (64), 130 (18), 129 (100), 128 (22)
95 and 105 (31). HRMS (ESI–TOF, m/z): Obsd. 403.0402;
C20H17BrN2NaO [(M+Na)+] requires 403.0416.
General procedure for the synthesis of 3,5-disubstituted-1,2-
isoxazoles (7a-f) from the unsymmetric 1,3-diynes (5a-f)
A stirred mixture of the unsymmetrical diyne (5, 0.3 mmol),
H2NOH.HCl (48 mg, 0.75 mmol, 2.5 equiv.) and Et3N (0.17 mL,
35 1.2 mmol, 4.0 equiv.) in PEG-400 (0.5 mL) was heated at 100 ºC
for 12 h. After the reaction was completed, water (10 mL) was
added and the products were extracted with EtOAc (3 × 15 mL).
The combined extracts were dried over MgSO4; the solvent was
evaporated under reduced pressure and the oily residue was
40 chromatographed using hexane:EtOAc (90:10) as eluent.
3-((1H-Indol-1-yl)methyl)-5-benzyl-1,2-isoxazole (7a)
1
3-((9H-Carbazol-9-yl)methyl)-5-benzyl-1,2-isoxazole (7e)
Beige waxy solid; yield: 85%. H NMR (400 MHz) : 3.92 (s,
White solid, m.p.: 103-104 °C; yield: 84%. 1H NMR (400 MHz,
100 DMSO-d6) : 4.02 (s, 2H), 5.67 (s, 2H), 5.93 (s, 1H), 7.18-
7.29 (m, 6H), 7.43-7.47 (m, 3H), 7.66 (d, J = 8.2, 2H) and 8.15
(d, J = 7.4, 2H). 13C NMR (100 MHz, DMSO-d6) : 31.7,
37.7, 100.7, 109.1, 119.1, 120.0, 122.2, 125.6, 126.6, 128.3,
128.4, 135.9, 139.7, 160.2 and 172.3. IR (KBr, ν): 3113, 3050,
105 3030, 2927, 1598, 1487, 1456, 1425, 1329, 1261, 1207, 751,
725 and 705 cm-1. MS (m/z, rel. int., %): 339 [11, (M+1)+], 338
(46, M+), 281 (17), 247 (17), 207 (56), 180 (100) and 91 (31).
Anal. Calc.: C, 81.63; H, 5.36; N, 8.28. Found: C, 81.17; H, 5.28;
N, 7.89.
2H), 5.24 (s, 2H), 5.60 (s, 1H), 6.51 (d, J = 3.1, 1H), 7.06 (d, J
45 = 3.1, 1H), 7.08-7.13 (m, 3H), 7.16-7.27 (m, 4H), 7.33 (d, J
= 8.2, 1H) and 7.60 (d, J = 7.8, 1H). 13C NMR (100 MHz) :
33.1, 41.8, 100.6, 102.4, 109.3, 119.8, 121.0, 122.0, 127.1,
127.7, 128.7, 128.7, 128.8, 135.5, 136.1, 160.7 and 172.9. IR
(KBr, ν): 3111, 3027, 2924, 2860, 1724, 1598, 1468, 1420,
50 1327, 1260, 1186, 1131, 996, 822, 746, 743 and 709. MS (m/z,
rel. int., %): 289 [10, (M+1)+], 288 (49, M+), 197 (54), 169
(17), 131 (12), 130 (100), 103 (23) and 91 (17). HRMS (ESI–
TOF, m/z): Obsd. 311.1170; C19H16N2NaO [(M+Na)+] requires
311.1160.
55
110
3-((1H-Indol-1-yl)methyl)-5-(4-methylbenzyl)-1,2-isoxazole
3-((9H-Carbazol-9-yl)methyl)-5-(4-methylbenzyl)-1,2-
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isoxazole (7f)
8. a) W. Shi and A. Lei, Tetrahedron Lett., 2014, 55, 2763–2772; b) I.
A. Maretina and B. A. Trofimov, Adv. Heterocyclic Chem., 2002, 82,
1
White solid, m.p.: 108-110 °C; yield: 89%. H NMR (400 MHz,
DMSO-d6) : 2.22 (s, 3H), 3.95 (s, 2H), 5.67 (s, 2H), 5.90 (s,
1H), 7.06 (s, 4H), 7.20-7.24 (m, 2H), 7.43-7.47 (m, 2H), 7.67
(d, J = 8.2, 2H) and 8.15 (d, J = 7.7, 2H). 13C NMR (100 MHz,
DMSO-d6) : 20.4, 31.4, 37.8, 100.6, 109.2, 119.1, 120.1,
122.2, 125.7, 128.4, 129.0, 132.9, 135.8, 139.7, 160.2 and 172.7.
IR (KBr, ν): 3052, 2954, 2924, 2856, 1730, 1598, 1515, 1483,
1455, 1326, 1206, 1154, 775, 751 and 726 cm-1. MS (m/z, rel.
View Article Online
157–259.
DOI: 10.1039/C4RA11571F
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852–860; b) X. Liang, C.-J. Lee, J. Zhao, E. J. Toone and P. Zhou, J.
Med. Chem., 2013, 56, 6954–6966; c) S. Kyi, N. Wongkattiya, A. C.
Warden, M. S. O'Shea, M. Deighton, I. Macreadie and F. H. M.
Graichen, Bioorg. Med. Chem. Lett., 2010, 20, 4555–4557; d) L.
Manzoni, L. Belvisi, A. Bianchi, A. Conti, C. Drago, M. De Matteo,
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Med. Chem., 2012, 20, 6687–6708.
5
10 int., %): 352 (18, M+), 180 (34), 84 (63) and 78 (100). HRMS
(ESI–TOF, m/z): Obsd. 353.1635; C24H21N2O [(M+H)+] requires
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Acknowledgements
15 The authors are thankful to MCT/CNPq and CAPES, for financial
support. TSK also thanks CONICET and ANPCyT.
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