A green synthesis of new 3-aryl-4-phenylsulfonyl-5-aminoisoxazoles

Article abstract of DOI:10.1016/j.tet.2014.03.106

The present work describes a new protocol for the synthesis of 5-aminoisoxazoles using α-chlorooximes and 2-phenylsulfonyl acetonitrile via green chemistry routes. The titled 5-aminoisoxazoles 3 were further reacted with 4-nitrobenzoyl chloride to obtain

Full text of DOI:10.1016/j.tet.2014.03.106

Tetrahedron 70 (2014) 3590e3594
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A green synthesis of new 3-aryl-4-phenylsulfonyl-5-
aminoisoxazoles
,
a
a
b
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Cevher Altug , Muhammet Buyukbayram , Ozge Kavas , Muhsine Zeynep Yavuz
a
_
Department of Chemistry, Abant Izzet Baysal University, TR-14280 Bolu, Turkey
Department of Medical Pharmacology, Faculty of Medicine, Abant Izzet Baysal University, TR-14280 Bolu, Turkey
b
_
a r t i c l e i n f o
a b s t r a c t
Article history:
The present work describes a new protocol for the synthesis of 5-aminoisoxazoles using a-chlorooximes
Received 5 February 2014
Received in revised form 19 March 2014
Accepted 31 March 2014
Available online 4 April 2014
and 2-phenylsulfonyl acetonitrile via green chemistry routes. The titled 5-aminoisoxazoles 3 were fur-
ther reacted with 4-nitrobenzoyl chloride to obtain 5-amidoisoxazoles with moderate yields. These
heterocyclic compounds were tested in vitro MTT study to investigate inhibitive abilities to some cancer
cell lines (C3a, L929, T98g and Mcf-7) and compounds 3a, 3c, 3e and 3h showed noticeable cytotoxic
property against four cancer cell lines.
Keywords:
Green chemistry
Ó 2014 Elsevier Ltd. All rights reserved.
a
-Chlorooximes
5-Aminoisoxazoles
MTT
1. Introduction
cyanoisoxazole,15 condensation of
a-cyanoketones with hydroxyl-
amine.9 Reaction of arylnitrile oxides with sodium enolates16 and
multicomponent reactions of arylisocyanides with nitrostyrenes in
water.17 Becalli et al. reacted active methylene containing nitriles
Heterocyclic compounds have an important place in the life
cycle. They have a very wide range of applications from industrial
products to all living organisms.1 Therefore, synthesising hetero-
cyclic molecules in an environmentally friendly way is very im-
portant. Green chemistry is a method related with minimizing
environmental pollution by designing new processes to increase
atom economy and decrease the use of solvent, reaction time, and
the number of steps in reactions.2
Many isoxazole containing heterocyclic motifs exhibit a broad
range of biological activities and uses in industry.3 Thus, it is critical
to develop new routes to these heterocyclic molecules. Among
them, isoxazoles, particularly 5-amino and 5-amido isoxazoles
possess antioxidant,4 anti-inflammatory,5 antibacterial,6 fungi-
cidal,7 antiprotozoal,8 cytotoxic9 activities, and suppressive effects
against influenza viruses A (H3N2) and B.10 Generally, methods for
preparing tri-substituted isoxazoles rely on the cycloaddition of
nitrile oxides with appropriate alkenes or alkynes. Depending on
the substitution pattern of the nitrile oxide and dipolarophile cy-
cloaddition results the 4- or 5-regioisomers.11 Synthesis and re-
actions of aminoisoxazoles been reviewed.12,13 The most important
syntheses of 5-aminoisoxazoles resulted from the addition of
lithiated nitrile anions to nitrile oxides,14 reduction of 5-
with
a-chlorooximes to obtain 5-aminoisoxazoles, which were
isolated but not purified and characterised, but diazotised
with sodium nitrite to give alkyne derivatives.18 5-Aminoisoxazoles
show many biological activities, and we believe the investigation
of novel green synthetic routes to 4-phenylsulfonyl-5-amino
isoxazoles, their synthetic conversion to 4-phenylsulfonyl-5-
amido isoxazoles, and anti-tumour activity studies would be very
beneficial to the development of new drug candidates.
a
-Chlorooximes have a dual character, they can be considered as
in situ formed nitrile oxide precursors or ready to nucleophilic/
electrophilic attacks on an iminic carbon.19,20 We have previously
investigated C-acylation21 and nucleophilic substitution reactions22
of a-chlorooximes with heterocyclic enamines and primary amines
to give isoxazoles and N-substituted amidoximes, respectively. In
continuation of our work related with the investigation of green
synthesis,23 we have modified reaction conditions to obtain 5-
aminoisoxazoles with moderate to good yields.
2. Results and discussion
The reactions were performed in a mortar by grinding the re-
agents without use of any solvent. When these reactions were
conducted in the presence of a solvent (DCM), reaction yields are
increased. (Table 1). The products were simply isolated by
* Corresponding author. Tel.: þ90 3742541000x1252; fax: þ90 3742534642;
ꢀ
e-mail address: altug_c@ibu.edu.tr (C. Altug).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.106

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C. Altug et al. / Tetrahedron 70 (2014) 3590e3594
3591
Table 1
This might be explained by the attack of in situ formed nitrile oxide
to carbonyl part of benzoyl chloride.27
Reactions of a-chlorooximes with 2-phenylsulfonyl acetonitrile
The structures of the compounds were investigated utilizing IR,
1H and 13C NMR, and HRMS. Distinctive SO2 stretching frequencies
appeared around 1350 cmꢀ1 and 1145 cmꢀ1 for both 5-amino and
5-amido isoxazoles in the IR spectra. The vibrational frequency of
the C]O group of the 5-amido isoxazoles was observed around
1645 cmꢀ1. The 1H NMR spectra of the 5-aminoisoxazoles showed
a broad singlet for the NH2 protons between 8.23e8.40 ppm in
DMSO-d6 due to hydrogen bonding. When CDCl3 was used as
a solvent, for 3i and 3j, the NH2 protons resonated at 6.25 and
6.29 ppm, respectively. NH protons gave resonances between
10.79e13.11 ppm for the 5-amido isoxazoles in DMSO-d6. The 13C
NMR spectra of 5-aminoisoxazoles displayed the C-5 carbons at
169e170 ppm, iminic carbon resonances at 158e164 ppm, and the
C-4 carbons resonance at 91e93 ppm. 5-Amido isoxazoles showed
carbonyl carbons at 164e171 ppm, C-5 carbons at 158e161 ppm,
iminic carbons at around 148e151 ppm, and C-4 carbons at
106 ppm. Due to hindered rotation for compound 3i, each carbon
atom of the benzene ring can be seen separately.
Compound
Ar
Yield/%
60 (66)a
54
Mp ꢁC
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
4-FC6H4
4-ClC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
2,6-DiClC6H3
2,4-DiClC6H3
3,4-DiMeOC6H3
2-Thienyl
123e124
147e148
142e143
212e214
173e174
177e178
185e187
195e196
166e167
155e157
45
62 (78)a
34 (40)a
52
84
79
66
50
3j
a
Reaction was performed in DCM.
Although there are examples28e30 of reactions between sulfonyl
chlorides and 5-aminoisoxazoles, our attempts to synthesize 5-
recrystallization. The
a-chlorooximes were synthesized from the
corresponding aldoximes by chlorination with N-chlor-
osuccinimide.24 They were then reacted with 2-phenylsulfonyl
acetonitrile to afford 5-aminoisoxazoles. The scope and generality
of this work was investigated by electron releasing and with-
sulfonamido
isoxazoles
from
3-aryl-4-benzenesulfonyl-5-
aminoisoxazoles in the presence of various bases have been un-
successful. 5-Aminoisoxazoles were reacted with benzenesulfonyl
chloride derivatives or aliphatic sulfonyl chlorides, i.e., meth-
anesulfonyl chloride in the presence of Et3N, pyridine, NaOH, NaH,
n-BuLi or K2CO3 to provide sulfonamide substituted isoxazoles, but
no product was found. The difference in reactivity was ascribed
to the presence of the sterically hindered 4-benzenesulfonyl
substituent.
A proposed reaction mechanism for the formation of the 5-
aminoisoxazoles is shown below (Scheme 1). The active methy-
lene proton is firstly deprotonated by the base. Subsequently, in-
termolecular nucleophilic attack of resulting anion to in situ formed
nitrile oxide 7 produces compound 8. Furthermore, intramolecular
attack of oxygen to nitrile results in cyclization compound 10. Fi-
nally, tautomerization of this compound gives 5-aminoisoxazole 4.
drawing substituent on aryl and heteroaryl substitue
chlorooximes.
a
-
When electron neutral alkyl groups were substituted at the
a
-
position of the nitriles, a strong base was required25 or prolonged
reaction time was applied for 1 or 2 days under conventional
heating26 to obtain 5-aminoisoxazoles at room temperature in air.
However, in our case the electron withdrawing effect of phenyl-
sulfonyl group was sufficient enough to initiate the reaction with
a weak base, EtN3, under solvent free conditions. The strongly
electron withdrawing phenylsulfonyl group might stabilize the
anion, and allow the formation of the desired 5-aminoisoxazoles 3
(Table 1).
The formation of 5-amido-4-phenylsulfonyl isoxazoles 5 was
carried out by reacting 5-aminoisoxazoles 3 with p-nitrobenzoyl
chloride in the presence of Et3N in DCM with moderate yields.
(Table 2). Attempts to carry out a one-pot formation of 5-amido-4-
phenylsulfonyl isoxazoles
5
from
a-chlorooximes 1, 2-
phenylsulfonyl acetonitrile and benzoyl chloride were unsuccess-
ful, with inseparable mixtures being obtained (monitored by TLC).
Table 2
Reaction of 5-aminoisoxazoles with p-nitrobenzoyl chloride to furnish 3-aryl-4-
phenylsulfonyl-5-amido isoxazoles
Scheme 1. Proposed reaction mechanism.
3. Biological assessment
Compound
Ar
Yield/%
Mp ꢁC
The synthesized compounds have been assayed against four
cancer cell lines. Since compounds having low GI values are more
toxic on cells and they cause cell death at lower doses. However,
such compounds have higher activities in the treatment of diseases
such as cancer.31 Compounds 3a, 3c, 3e and 3h showed cytotoxic
activities against C3a, L929, T98g and Mcf-7 cell lines (Table 3). The
structureeactivity relationship revealed that free amino containing
5-aminoisoxazoles 3 showed higher activities than the 5-amido
isoxazoles 5.
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
4-FC6H4
4-ClC6H4
4-NO2C6H4
2-NO2C6H4
2,6-DiClC6H3
2,4-DiClC6H3
3,4-DiMeOC6H3
2-Thienyl
60
56
54
55
59
42
52
50
45
169e170
191e192
149e150
215e216
154e155
197e198
90 decomp.
178e180
164e165

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C. Altug et al. / Tetrahedron 70 (2014) 3590e3594
3592
Table 3
5.2.1. 3-Phenyl-4-(phenylsulfonyl)isoxazol-5-amine 3a. Obtained as
brown crystals (180 mg, 60%), mp 123e124 ꢁC nmax. (KBr) 3392
(NH2), 1300 (SO2), 1145 (SO2) and 1639 (C]C) cmꢀ1. HRMS: re-
quires for C15H13N2O3S [MþH]þ 301.0647, found, 301.0647. 1H NMR
Cytotoxic activities of compounds 3aej and 5aei against cancer cell linesa
GI values (
m
M)b in cell linesc
C3a
L929
T98g
Mcf-7
(400 MHz, DMSO) d 8.23 (broad s, 2H, NH2), 7.64e7.59 (m, 2H), 7.58
3a
3b
3c
3d
3e
3f
3g
3h
3i
31
22
29
16
10
17
>100
98
>100
14
14
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
(t, J 1.8, 1H), 7.54e7.49 (m, 3H), 7.49e7.43 (m, 2H), 7.43e7.38 (m,
32
52
35
35
>100
25
2H). 13C NMR (100 MHz, DMSO)
d 170.5, 160.9, 143.4, 133.7, 130.7,
129.8, 129.4, 128.7, 127.8, 126.2, 91.5. m/z (TOF EIþ) 301 (MþH,
71
50
>100
80
>100
34
100%), 252 (8).
74
>100
30
30
>100
29
>100
>100
75
5.2.2. 3-(4-Fluorophenyl)-4-(phenylsulfonyl)isoxazol-5-amine
3b. Obtained as brown crystals (170 mg, 54%), mp 147e148 ꢁC nmax.
(KBr) 3410 (NH2), 3300 (NH2), 1640 (C]C), 1300 (SO2) and 1140
(SO2) cmꢀ1. HRMS: requires for C15H10N2O3FS [MꢀH]ꢀ 317.0396,
85
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
3j
>100
>100
>100
41
5a
5b
5c
5d
5e
5f
5g
5h
5i
found, 317.0384. 1H NMR (400 MHz, CDCl3)
d 7.58 (d, J 2.2, 1H), 7.56
(dd, J 2.2, 1.4, 1H), 7.56e7.54 (m, 1H), 7.53 (d, J 1.2, 1H), 7.51 (t, J 4.6,
64
1H), 7.36 (dd, J 8.1, 7.4, 1H), 7.10 (t, J 8.7, 1H), 6.24 (br s, 2H, NH2). 13
C
>100
>100
>100
69
1
NMR (100 MHz, CDCl3)
d
169.4, 164.1 (d, JCeF 249.4, CeF), 160.2,
142.1, 133.3, 131.4 (d, 3JCeF 8.6, CH meta to F), 128.9, 126.5, 123.0 (d,
4JCeF 3.3, C para to F), 115.5 (d, JCeF 21.7, CH ortho to F), 93.7. m/z
2
>100
(TOF ESꢀ) 317 (MꢀH, 100%).
a
Determined by MTT assay (24 h drug exposure), see Biological experimental for
details.
b
c
5.2.3. 3-(4-Chlorophenyl)-4-(phenylsulfonyl)isoxazol-5-amine
3c. Obtained as pale brown solid (151 mg, 45%), mp 142e143 ꢁC
nmax. (KBr) 3450 (NH2), 3345 (NH2), 1640 (C]C) and 1300e1140
(SO2) cmꢀ1. HRMS: requires for C15H10N2O3SCl [MeH]ꢀ 333.0101,
Compounds tested in triplicate, data expressed as mean values.
Cancer cell line origin: MCF-7 (human breast adenocarcinoma cell), T98g (hu-
man glioblastoma cells), L929 (mouse fibroblast cell), c3a (human hepatocellular
carcinoma cell).
found, 333.0103. 1H NMR (400 MHz, DMSO)
d
8.28 (br s, 2H, NH2),
7.68e7.62 (m, 2H), 7.59e7.50 (m, 5H), 7.46e7.40 (m, 1H), 7.28e7.23
4. Conclusion
(m, 1H). 13C NMR (100 MHz, DMSO)
d 169.7, 158.9, 143.1, 133.8,
133.6, 132.2, 129.7, 127.2, 127.1, 126.4, 92.7. m/z (TOF ESꢀ) 333 (MeH,
In conclusion, we have developed a method for the synthesis
of 3-aryl-4-phenylsulfonyl 5-aminoisoxazoles with complete
regioselectivity in a solvent free medium with moderate yields.
Transformation of these 5-aminoisoxazoles to novel 5-
benzamidoisoxazoles was also investigated. Structure of com-
pounds was investigated by means of IR, 1H, 13C NMR and HRMS. A
reaction mechanism was proposed. Four of nineteen compounds
showed high activity against human cancer cell lines.
100%).
5.2.4. 3-(4-Nitrophenyl)-4-(phenylsulfonyl)isoxazol-5-amine
3d. Obtained as yellow solid (218 mg, 62%), mp 212e214 ꢁC. nmax.
(KBr) 3440 (NH2), 3330 (NH2), 1640 (C]C) and 1300e1140 (SO2)
cmꢀ1. HRMS: requires for C15H10N3O5S [MeH]ꢀ, 344.0341 found,
344.0347. 1H NMR (400 MHz, DMSO)
d
8.38 (br s, 2H), 8.31 (d, J 8.8,
2H), 7.72 (d, J 4.4, 2H), 7.69e7.59 (m, 3H), 7.54 (d, J 8.8, 2H). 13C NMR
(100 MHz, DMSO)
d 170.5, 159.5, 149.0, 143.2, 134.1, 133.9, 131.0,
5. Experimental section
5.1. General
129.9, 126.3, 123.8, 91.9. m/z (TOF ESꢀ) 344 (MeH, 100%).
5.2.5. 3-(3-Nitrophenyl)-4-(phenylsulfonyl)isoxazol-5-amine
3e. Obtained as yellow solid (117 mg, 34%), mp 173e174 ꢁC nmax.
(KBr) 3430 (NH2), 3330 (NH2), 1640 (C]C) and 1300e1135 (SO2)
cmꢀ1. HRMS: requires for C15H10N3O5S [MeH]ꢀ 344.0341, found,
The IR spectra were recorded on a SHIMADZU FTIR-8400S in-
strument with KBr discs. The NMR spectra were recorded on
a Bruker Avance III (400 and 500 MHz for 1H NMR and 100 and
125 MHz for 13C) either using DMSO-d6 or CDCl3. All chemical shifts
were reported in parts per million downfield from TMS. Coupling
constants (J) were reported in Hertz. 2-Phenylsulfonyl acetonitrile
was purchased from SigmaeAldrich. Melting points were de-
termined on a MELTEMP apparatus and uncorrected. The reactions
were monitored by TLC on Merck (5735) plates. Mass spectra
measurements were performed using a Micromass LCT Premier XE
(Waters MS Technologies) orthogonal acceleration Time-of-Flight
mass spectrometer operation in both positive and negative ion
mode with electrospray ionization.
344.0329. 1H NMR (400 MHz, DMSO)
d 8.40e8.38 (m, NH2
and aromatic CH 3H), 8.23 (s, 1H), 7.90 (d, J 6.7, 1H), 7.83e7.74 (m,
1H), 7.72e7.62 (m, 3H), 7.58e7.50 (m, 2H). 13C NMR
(100 MHz, DMSO)
d 170.0, 158.5, 147.2, 142.6, 135.1, 133.3, 130.0,
129.4, 128.2, 125.6, 124.9, 123.5, 91.0. m/z (TOF ESꢀ) 344 (MeH,
100%).
5.2.6. 3-(2-Nitrophenyl)-4-(phenylsulfonyl)isoxazol-5-amine
3f. Obtained as yellow solid (180 mg, 52%), mp 177e178 ꢁC. nmax.
(KBr) 3430 (NH2), 3330 (NH2), 1640 (C]C) and 1300e1135 (SO2)
cmꢀ1. HRMS: requires for C15H10N3O5S [MeH]ꢀ 344.0341, found,
344.0334. 1H NMR (400 MHz, DMSO)
d 8.40e8.37 (m, NH2 and
5.2. Typical procedure for preparation of 3-aryl-4-(phenyl-
sulfonyl)isoxazol-5-amines
aromatic CH, 3H), 8.22 (d, J 1.5, 1H), 7.90 (d, J 7.7, 1H), 7.77 (t, J 8.0,
1H), 7.69e7.62 (m, 3H), 7.53 (t, J 7.7, 2H). 13C NMR (100 MHz, DMSO)
d
170.0, 158.5, 147.3, 142.6, 135.2, 133.4, 130.1, 129.4, 128.6, 125.7,
2-Phenylsulfonylacetonitrile (1 mmol, 181 mg, 1 equiv), the
appropriate a-chlorooxime (1 mmol, 1 equiv) and Et3N (1,1 mmol,
125.0, 123.6, 91.0. m/z (TOF ESꢀ) 344 (MeH, 100%).
222 mg, 2.2 equiv.) were mixed in a mortar and grinded for 5 min.
After completion of the reaction, as judged by TLC, H2O (5 mL) was
added and the resulting precipitate was filtered. Filtrated solids
were dried and recrystallized from EtOAc/Hexane.
5.2.7. 3-(2,6-Dichlorophenyl)-4-(phenylsulfonyl)isoxazol-5-amine
3g. Obtained as greyish brown crystals (310 mg, 84%), mp
185e187 ꢁC. nmax. (KBr) 3430 (NH2), 3315 (NH2), 1640 (C]C) and
1300-1145 (SO2) cmꢀ1. HRMS: requires for C15H9N2O3SCl2 [MeH]ꢀ

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C. Altug et al. / Tetrahedron 70 (2014) 3590e3594
3593
366.9711, found, 366.9722. 1H NMR (400 MHz, DMSO)
NH2, 1H), 7.69e7.62 (m, 3H), 7.60e7.58 (m, 3H), 7.55 (t, J 7.6, 2H). 13
d
8.37 (s,
1H), 8.34 (d, J 8.8, 2H), 8.27e8.19 (m, 3H), 7.60 (d, J 7.4, 1H),
7.58e7.50 (m, 4H), 7.32 (t, J 8.9, 1H), 6.97 (d, J 7.6, 2H). 13C NMR
C
NMR (100 MHz, DMSO)
d
169.2, 156.4, 142.1, 134.7, 133.2, 132.5,
(100 MHz, DMSO)
d
165.8, 161.9, 160.87 (d, 1JCeF 281.6, CeF), 156.8,
129.1, 128.0, 126.0, 125.9, 91.7. m/z (TOF ESꢀ) 366 (MeH, 100%),
148.9, 139.0, 133.0, 131.6 (d, JC-F 8.8, CH meta to F), 131.0, 129.8,
128.8,126.8,123.2,115.1 (d, 2JCeF 21.9, CH ortho to F), 114.8,106.9. m/
z (TOF ESꢀ) 466 (MeH, 100%).
3
180(5).
5.2.8. 3-(2,4-Dichlorophenyl)-4-(phenylsulfonyl)isoxazol-5-amine
3h. Obtained as grey crystals (292 mg, 79%), mp 195e196 ꢁC nmax.
5.3.3. N-(3-(4-Chlorophenyl)-4-(phenylsulfonyl)isoxazol-5-yl)-4-
nitrobenzamide 5c. Obtained as yellow solid (260 mg, 54%), mp
149e151 ꢁC. nmax. (KBr) 1649 (C]O), 1535 (C]N) and 1344e1149
(SO2) cmꢀ1. HRMS: requires for C22H13N3O6SCl [MeH]ꢀ 482.0214,
(KBr) 3440e3335 (NH2), 1640 (C]C) and 1300e1140 (SO2) cmꢀ1
.
HRMS: requires for
366.9728. 1H NMR (400 MHz, DMSO)
(app. d, J 2.0, 1H), 7.71e7.64 (m, 2H), 7.63e7.59 (m, 2H), 7.57e7.53
(m, 2H), 7.32 (d, J 8.3, 1H). 13C NMR (100 MHz, DMSO)
169.1, 157.5,
C
15H9N2O3SCl2 [MeH]ꢀ 366.9711, found,
8.33 (br s, NH2, 2H), 7.76
d
found Mꢀ, 482.0214. 1H NMR (500 MHz, DMSO)
d
10.76 (br s, NH,
1H), 8.44 (d, J 8.7, 2H), 8.23 (d, J 8.7, 2H), 7.60 (t, J 7.4, 1H), 7.47e7.40
(m, 3H), 7.37 (d, J 7.9, 2H), 7.34 (d, J 7.9, 2H), 7.27 (t, J 3.3, 1H). 13
NMR (125 MHz, DMSO) 166.5, 158.1, 148.2, 145.4, 143.1, 139.1,
d
142.4, 135.5, 134.1, 133.2, 132.7, 129.2, 128.8, 127.0, 125.7, 125.6, 92.1.
C
m/z (TOF ESꢀ) 366 (MeH, 100%).
d
133.1, 132.3, 131.3, 130.6, 129.7, 128.8, 128.4, 126.8, 122.8, 106.8. m/z
5.2.9. 3-(3,4-Dimethoxyphenyl)-4-(phenylsulfonyl)isoxazol-5-amine
(TOF ESꢀ) 482 (MeH, 100%).
3i. Obtained as white solid (238 mg, 66%), mp 166e167 ꢁC nmax.
(KBr) 3400e3320 (NH2), 1640 (C]C) and 1300e1140 (SO2) cmꢀ1
.
5.3.4. N-(3-(4-Nitrophenyl)-4-(phenylsulfonyl)isoxazol-5-yl)-4-
nitrobenzamide 5d. Obtained as yellow solid (272 mg, 55%), mp
215e216 ꢁC. nmax. (KBr) 1647 (C]O), 1525 (C]N) and 1340e1145
(SO2) cmꢀ1. HRMS: requires for C22H13N4O8S [MeH]ꢀ 493.0454,
HRMS: requires for
C
17H17N2O5S [MþH]þ 361.0858, found,
361.0852. 1H NMR (400 MHz, CDCl3)
d 7.59e7.54 (m, 2H), 7.52e7.47
(m, 1H), 7.40e7.34 (m, 2H), 7.21 (d, J 2.0, 1H), 7.19 (s, 1H), 6.89 (d, J
8.6, 1H), 6.25 (br s, NH2, 2H), 3.94 (s, OCH3, 3H), 3.88 (s, OCH3, 3H).
found Mꢀ, 493.0447. 1H NMR (500 MHz, DMSO)
d
13.02 (br s, NH,
1H), 8.35 (d, J 8.8, 2H), 8.28 (d, J 8.8, 2H), 8.24e8.18 (m, 4H), 7.84 (d, J
8.8, 2H), 7.67e7.52 (m, 3H). 13C NMR (125 MHz, DMSO)
166.8,
13C NMR (100 MHz, CDCl3)
d 169.4, 160.6, 150.6, 148.5, 142.2, 133.1,
128.8,126.7,126.3,122.1,119.2,112.1, 112.0,110.6, 93.2, 55.9, 55.8. m/
d
z (TOF EIþ) 361 (MþH, 100%).
158.8, 148.3, 147.9, 145.5, 143.2, 139.9, 139.4, 139.0, 136.6, 132.5,
130.8, 129.8, 128.7, 128.3, 126.8, 122.9, 106.9. m/z (TOF ESꢀ) 493
(MeH, 100%).
5.2.10. 4-(Phenylsulfonyl)-3-(thiophen-2-yl)isoxazol-5-amine
3j. Obtained as grey solid (153 mg, 50%), mp 155e157 ꢁC nmax. (KBr)
3450e3320 (NH2), 1640 (C]C) and 1300e1140 (SO2) cmꢀ1. HRMS:
requires for C13H11N2O3S2 [MþH]þ 307.0211, found Mþ, 307.0203.
5.3.5. N-(3-(2-Nitrophenyl)-4-(phenylsulfonyl)isoxazol-5-yl)-4-
nitrobenzamide 5e. Obtained as yellow solid (292 mg, 59%), mp
154e155 ꢁC nmax. (KBr) 1649 (C]O), 1535 (C]N) and 1334e1157
(SO2) cmꢀ1. HRMS: requires for C22H13N4O8S [MeH]ꢀ 493.0454,
1H NMR (500 MHz, CDCl3)
d 7.87 (dd, J 3.7, 1.1, 1H), 7.72 (dd, J 8.5,1.2,
2H), 7.52 (ddd, J 8.6, 3.0, 1.8, 1H), 7.42e7.39 (m, 3H), 7.11 (dd, J 5.1,
3.8, 1H), 6.29 (br s, NH2, 2H). 13C NMR (125 MHz, CDCl3)
d
169.9,
found Mꢀ, 493.0430. 1H NMR (500 MHz, DMSO)
d 11.98 (broad s,
155.1, 142.1, 133.5, 131.4, 129.2, 129.0, 128.1, 127.6, 126.4, 92.4. m/z
(TOF EIþ) 361 (MþH, 100%), 255 (10), 214 (20).
NH, 1H), 8.40 (d, J 8.8, 2H), 8.36 (ddd, J 8.3, 2.1, 0.9, 1H), 8.19e8.17
(m, 3H), 7.86 (d, J 7.8, 1H), 7.73 (t, J 8.0, 1H), 7.63 (d, J 7.5, 2H),
7.56 (t, J 7.5, 1H), 7.41 (t, J 7.8, 2H). 13C NMR (125 MHz, DMSO)
5.3. Typical reaction procedure for preparation of 5-
benzamidoisoxazoles
d 164.5, 159.4, 149.9, 147.4, 139.9, 135.4, 134.3, 130.4, 129.9, 129.3,
127.8, 127.1, 125.5, 123.9, 123.8, 106.9. m/z (TOF ESꢀ) 493 (MeH,
100%).
4-Nitrobenzoyl chloride (1 mmol, 1.0 equiv) and 5-
aminoisoxazole (1 mmol, 1 equiv) were mixed in DCM (25 mL) in
a round-bottomed flask and the reaction mixture was stirred at
room temperature until all reactants dissolved. Triethylamine
(3 mmol, 3.0 equiv) was then added dropwise and the reaction
stirred room temperature for 1e3 h. The reaction mixture was
washed with water (3ꢂ15 mL), dried (Na2SO4) and the solvent
evaporated. The resulting solid was recrystallized from hexane/
benzene to give the pure products with data given below.
5.3.6. N-(3-(2,6-Dichlorophenyl)-4-(phenylsulfonyl)isoxazol-5-yl)-4-
nitrobenzamide 5f. Obtained as yellow solid (218 mg, 42%), mp
197e198 ꢁC nmax. (KBr) 1647 (C]O), 1529 (C]N) and 1344e1145
(SO2) cmꢀ1. HRMS: requires for C22H12N3O6SCl2 [MeH]ꢀ 515.9824,
found Mꢀ, 515.9807. 1H NMR (500 MHz, DMSO)
d 10.79 (broad s,
NH, 1H), 8.46 (d, J 8.7, 2H), 8.25 (d, J 8.8, 2H), 7.64 (t, J 7.4, 2H), 7.49
(d, J 7.6, 1H), 7.41 (t, J 7.5, 3H), 7.34 (d, J 7.7, 2H). 13C NMR (125 MHz,
DMSO)
d 166.7, 156.9, 156.0, 148.4, 145.6, 142.9, 139.2, 134.7, 132.5,
131.6, 129.8, 128.4, 127.9, 127.1, 122.9, 106.9. m/z (TOF ESꢀ) 515
(MeH, 100%).
5.3.1. N-(3-Phenyl-4-(phenylsulfonyl)isoxazol-5-yl)-4-
nitrobenzamide 5a. Obtained as light yellow powder (270 mg, 60%),
mp 169e170 ꢁC. nmax. (KBr) 1647 (C]O), 1530 (C]N) and
1344e1145 (SO2) cmꢀ1. HRMS: requires for C22H14N3O6S [MeH]ꢀ
5.3.7. N-(3-(2,4-Dichlorophenyl)-4-(phenylsulfonyl)isoxazol-5-yl)-4-
nitrobenzamide 5g. Obtained as dark yellow solid (270 mg, 52%),
mp 90 ꢁC (decomp.) nmax. (KBr) 1641 (C]O), 1535 (C]N) and
448.0603, found Mꢀ, 448.0590. 1H NMR (500 MHz, DMSO)
d
12.95
(br s, NH, 1H), 8.28 (d, J 9.0, 2H), 8.25e8.22 (m, 2H), 8.20 (d, J 7.4,
2H), 7.62e7.54 (m, 3H), 7.53e7.51 (m, 2H), 7.50e7.45 (m, 3H). 13
NMR (125 MHz, DMSO) 171.7, 166.4, 160.1, 156.6, 148.1, 145.5,
1344e1147 (SO2) cmꢀ1
.
HRMS: requires for C22H12N3O6SCl2
[MeH]ꢀ 515.9824, found Mꢀ, 515.9808. 1H NMR (500 MHz, DMSO)
13.11 (broad s, NH, 1H), 8.32e8.23 (m, 4H), 7.81e7.73 (m, 1H),
7.65e7.52 (m, 5H), 7.48 (d, J 7.5,1H), 6.95 (s,1H). 13C NMR (125 MHz,
DMSO) 166.8, 157.4, 148.3, 145.6, 143.1, 134.6, 134.4, 132.6, 132.4,
C
d
d
143.4, 139.2, 132.1, 129.6, 129.1, 128.5, 127.5, 126.5, 122.7, 106.7. m/z
(TOF ESꢀ) 448 (MeH, 100%).
d
129.8, 128.9, 128.7, 128.6, 128.5, 126.9, 125.9, 122.9, 106.9. m/z (TOF
ESꢀ) 515 (MeH, 100%).
5.3.2. N-(3-(4-Fluorophenyl)-4-(phenylsulfonyl)isoxazol-5-yl)-4-
nitrobenzamide 5b. Obtained as yellow solid (262 mg, 56%), mp
191e192 ꢁC. nmax. (KBr) 1647 (C]O), 1518 (C]N) and 1342e1147
(SO2) cmꢀ1. HRMS: requires for C22H13N3O6FS [MeH]ꢀ 466.0509,
5.3.8. N-(3-(3,4-Dimethoxyphenyl)-4-(phenylsulfonyl)isoxazol-5-yl)-
4-nitrobenzamide 5h. Obtained as yellow solid (245 mg, 50%), mp
178e180 ꢁC nmax. (KBr) 1647 (C]O), 1521 (C]N) and 1340e1138
found Mꢀ, 466.0528. 1H NMR (500 MHz, DMSO)
d 12.78 (br s, NH,

ꢀ
C. Altug et al. / Tetrahedron 70 (2014) 3590e3594
3594
(SO2) cmꢀ1. HRMS: requires for C24H18N3O8S [MeH]ꢀ 508.0815,
found Mꢀ, 508.0814. 1H NMR (500 MHz, DMSO)
11.96 (broad s,
Supplementary data
d
NH, 1H), 8.44 (d, J 8.9, 2H), 8.23 (d, J 8.9, 2H), 7.70 (d, J 8.4, 2H), 7.62
(t, J 6.4, 1H), 7.49 (t, J 7.9 Hz, 2H), 7.09e6.95 (m, 3H), 3.82 (s, 3H),
Copies of 1H and 13C NMR spectra of all new compounds. Sup-
plementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.106.
3.70 (s, 3H). 13C NMR (125 MHz, DMSO)
d 164.7, 160.8, 150.5, 149.8,
148.2, 140.6, 139.1, 133.9, 129.8, 129.1, 126.9, 123.8, 121.9, 118.7,
114.0, 112.2, 111.4, 106.9, 55.6, 55.4. m/z (TOF ESꢀ) 508 (MeH,
100%).
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Acknowledgements
31. Carmichael, J.; Mitchell, J. B.; Degraff, W. G.; Gamson, J.; Gazdar, A. F.; Johnson,
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ꢀ
nancial support and to Pınar C¸ aglar (YTU) for NMR measurements.