Synthesis of Various Schiff Bases Containing Isoxazole Ring and Their Applications with Thioglycollic Acid and Diverse Phosphorus Reagents

Article abstract of DOI:10.1002/jhet.2541

A series of Schiff bases bearing isoxazole and pyrazole rings were synthesized. Application of thioglycollic acid on two selective synthesized Schiff bases afforded the corresponding thiazolidin-4-one derivatives. On the other hand, following the multicomponents one-pot Kabachnik– Fields reaction, the Schiff base generated in situ from 4-chlorobenzaldehyde and 5-methyl isoxazol-3-amine was trapped by phosphorus reagents to produce the corresponding amino phosphonates in moderate yields. However, the latter products could also be obtained in better yields (≥78%) by directly applying the dialkylphosphites to a selective synthesized Schiff base. Similarly, a series of α-aminophosphonates could be obtained from 5-chloro-3-methyl-1H-pyrazol-4-carbaldehyde, 5-methylisoxazol-3-amine, and phosphorus reagents. Moreover, applying hexaalkyl triamido phosphites to the N-(4-chlorobenzylidene)-5-methylisoxazol-3-amine in ethanol afforded methylphosphonic diamide derivatives, whereas N-((5-chloro-3-methyl-1H-pyrazol-4-yl)methylene)-5-methylisoxazol-3-amine underwent dechlorination through reaction with hexaalkyl triamido phosphites to give the respective amine derivatives.

Full text of DOI:10.1002/jhet.2541

Month 2015
Synthesis of Various Schiff Bases Containing Isoxazole Ring and Their
Applications with Thioglycollic Acid and Diverse Phosphorus Reagents
a
b
a
*
Abeer A. Shady, Sherifa M. Abu Bakr, and Maha D. Khidre
aChemical Industries Division, National Research Centre, Elbohouth Street, D-12311, Dokki, Cairo, Egypt
bPharmaceutical Industries Division, National Research Centre, Elbohouth Street, D-12311, Dokki, Cairo, Egypt
*
E-mail: abraouf1234@yahoo.com
Received May 27, 2015
DOI 10.1002/jhet.2541
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A series of Schiff bases bearing isoxazole and pyrazole rings were synthesized. Application of
thioglycollic acid on two selective synthesized Schiff bases afforded the corresponding thiazolidin-4-one de-
rivatives. On the other hand, following the multicomponents one-pot Kabachnik– Fields reaction, the Schiff
base generated in situ from 4-chlorobenzaldehyde and 5-methyl isoxazol-3-amine was trapped by phospho-
rus reagents to produce the corresponding amino phosphonates in moderate yields. However, the latter prod-
ucts could also be obtained in better yields (≥78%) by directly applying the dialkylphosphites to a selective
synthesized Schiff base. Similarly, a series of α-aminophosphonates could be obtained from 5-chloro-3-
methyl-1H-pyrazol-4-carbaldehyde, 5-methylisoxazol-3-amine, and phosphorus reagents. Moreover, apply-
ing hexaalkyl triamido phosphites to the N-(4-chlorobenzylidene)-5-methylisoxazol-3-amine in ethanol
afforded methylphosphonic diamide derivatives, whereas N-((5-chloro-3-methyl-1H-pyrazol-4-yl)methylene)-
5-methylisoxazol-3-amine underwent dechlorination through reaction with hexaalkyl triamido phosphites to
give the respective amine derivatives.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
structural features and diverse applications in biological
systems [14].
Literature survey revealed that isoxazole rings have been
widely used as key building blocks for drugs; their
derivatives are endowed with broad spectrum of pharmaco-
logical properties including hypoglycemic, analgesic, anti-
inflammatory, anti-bacterial, anti-HIVs, and anti-cancer
activities [1–5]. In addition, pyrazole derivatives have re-
ceived considerable attention owing to their diverse chemo-
therapeutic potentials including versatile anti-neoplastic
activities [6–13]. Many of these compounds are demonstrated
as anti-leukemic [6,7], anti-tumor [8,9], and anti-proliferative
[10,11] agents, in addition to their capability to exert remark-
able anti-cancer effects through inhibiting different types of
enzymes that play important roles in cell division [12,13].
The chemistry of substituted heterocyclic phosphor es-
ters has attracted many attention because of their unique
α-Aminophosphonates constitute an important class of
compounds that attract medicinal chemists because of
their wide use in drug development; they can serve as
both hyperglycemic and hypoglycemic agents in differ-
ent concentrations [15,16], anti-tumor agents [17,18],
pharmacogenic agents [19], and as inhibitors of serine
hydrolases [20].
We now report on multicomponent reactions with three
or more reactants combined in a one-pot procedure to
give a single product. Accordingly, efficient synthesis of
α-aminophosphonates from selected amine, aldehyde,
and phosphorus reagents including trialkylphosphites,
dialkylphosphites, or hexaalkyl triamidophosphites could
be achieved following the previously reported method
[21–25] using 10% FeCl3 in tetrahydrofuran (THF)
© 2015 HeteroCorporation

A. A. Shady, S. M. Abu Bakr, and M. D. Khidre
Vol 000
solution to facilitate the Mannich-type reaction of alde-
RESULTS AND DISCUSSION
hyde, amine, and phosphorus reagent.
We adopted the multicomponent reactions in a one-pot
synthesis of the target α-aminophosphonate by mixing stoi-
chiometric amounts of an amine with appropriate alde-
hyde, and the phosphorus reagents trialkylphosphites or
dialkylphosphites as displayed in Scheme 1.
Appling hexaalkyl triamidophosphites to the Schiff ba-
ses in different solvents afforded phosphorylating and
amine- induced dephosphorylating derivatives.
The required carbaldehydes 2a and 2b were obtained in
moderate yields (~43%), via Vilsmeier–Haack reaction of
3-methyl-1H-pyrazole-5(4H)-one or 1-aryl-3-methyl-1H-
pyrazole-5(4H)-one [26].
Scheme 1. General pathway for synthesis of Schiff bases and
phosohonate products.
Condensation of carbaldehydes 2a or 2b with 3-amino-
5-methylisoxazole (1) in the presence of glacial acetic acid,
afforded the corresponding methylisoxazol-amines 3a or
3b as shown in Scheme 2. The structure suggested for 3a
and 3b are in good agreement with their analytical and
spectral data.
When compound 3a or 3b was reacted with thioglycollic
acid in dry benzene, the thiazolidine-4-ones 4a or 4b was
produced (Scheme 3). The 1H nmr spectrum of compound
4a revealed the presence of a broad singlet at δ = 10.90ppm
(NH), D2O exchangeable while ei-ms of compound 4b
showed m/z 464 (M+).
When compound 3a was allowed to react with pipera-
zine 5a in DMF under reflux, the corresponding Schiff
base 6a was produced. Moreover, compound 3b was
allowed to react with piperazine, morpholine, and 2-
aminothiazol 5a–5c under the same reaction conditions to
obtain the corresponding Schiff base 6b–6d as shown in
Scheme 3. The spectroscopic data of compound 6a was
in good agreement with the assigned structure.
Scheme 2. Synthesis of Schiff bases 3a, 3b.
The required aminophosphonates 9a–9c were obtained
as colorless crystals by mixing the amine 1 with aldehyde
8 in THF solution containing 10% FeCl3. TAPs 7a–7c
were then added at r.t, followed by heating under reflux
for ~8h (Scheme 4).
Scheme 3. Synthesis of thiazolidine-4-ones 4a, 4b and Schiff bases 6a–6d.
Journal of Heterocyclic Chemistry
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Synthesis of Various Schiff Bases Containing Isoxazole Ring and Their Applications
with Thioglycollic Acid and Diverse Phosphorus Reagents
Scheme 4. Synthesis of α-aminophosphonates 9a–9c via TAPs.
Scheme 7. Synthesis of α-aminophosphonates 15a–15c via TAPs.
Scheme 5. Synthesis of α-aminophosphonates 9a–9c via DAPs.
Scheme 8. Synthesis of α-aminophosphonates 15a–15c via DAPs.
Structural reasoning for 9 are as follows: compatible el-
ementary and molecular weight determinations (ms) were
gained for 9a–9c. Positive chemical shifts were recorded
for 9a (δ= 23.80 ppm) [31P- nmr spectrum (νs 85%
H3PO4)], confirming the presence of P-C linkage (phos-
phonate group).
The ir spectrum (KBr, cmꢀ1) of dimethyl (4-chlorophenyl)
(5-methylisoxazol-3-ylamino)methylphosphonate (9a) taken
as a representative example showed the P¼O stretching
band at 1226 (P¼O, bonded) cmꢀ1; this could be
explained by a preferred conformation of intramolecular
hydrogen bonding between the NH proton and the
P¼O moiety.
two methoxyl groups diastereotropic, and hence,
anisochronous is resulting in the observed splitting pat-
tern [27].
The possible explanation for the mechanism of the reac-
tion is proposed according to the Kabachnik–Fields reac-
tion [28,29]. The first step may involve condensation
between aldehyde and amine in the presence of FeCl3
Apparently, the asymmetry of the molecule because
of the presence of a stereocenter would render the
Scheme 6. Synthesis of tetraalkylphosphonic diamide derivatives 14a,14b.
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A. A. Shady, S. M. Abu Bakr, and M. D. Khidre
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Scheme 9. Synthesis of dialkylamino derivatives 17a and 17b.
and formation of the intermediate Schiff base 10, followed
by addition of the phosphorus reagent 7a–7c to produce
9a–9c. The formation of dialkyl and not trialkyl adduct is
acceptable since in the presence of acidic medium (FeCl3),
TAPs are hydrolyzed to their DAP counterparts.
In favor of this mechanism compounds 9a–9c were inde-
pendently synthesized in higher yields (~74%) and character-
ized (Scheme 5). Thus, 9a–9c could be obtained by treating
N-(4-chlorobenzylidene)-5-methylisoxazol-3-amine (10) with
DAPs 11a–11c at 100°C in absence of solvent to give color-
less phosphonate 1:1 adducts for which structures 9a–9c are,
respectively, assigned.
On the other hand, when Schiff base 10 was allowed to
react with hexaalkyl triamidophosphites 12a or 12b in
boiling ethanol, the corresponding tetraalkylphosphonic di-
amide derivatives 14a or 14b were isolated in ~62% yield.
Satisfactory elementary analyses and molecular weight de-
terminations confirmed structure 14.
Obviously, compounds 14a or 14b were formed through
an initial addition of the aminophosphine 12a or 12b to the
Schiff base 10 giving rise to the phosphonium dipolar ion in-
termediates 13A. Stabilization of 13A was attained by its re-
action with fortuitous water to give the intermediates 13B
and an extrusion of dialkylamine moiety leading to 14a or
14b [30]; the reaction mechanism is depicted in Scheme 6.
In the same sense, the target α-aminophosphonates
15a–15c could be obtained in moderate yield (≥50%) by
mixing the amine 1 with the aldehyde 2a in THF solution
containing 10% FeCl3. TAPs 7a–7c were then added at r.
t., followed by heating under reflux for ~10 h (Scheme 7).
Similarly, compounds 15a–c were separated in good
yields and identified (mp, mixed m.ps. comparative ir and
ms spectra) by treating 3a with DAPs 11a–11c at 100°C
in absence of solvent (Scheme 8). The structures suggested
for all new compounds are in good agreement with their
analytical and spectral data (refer to experimental section).
The behavior of compound 3a toward hexaalkyl
triamidophosphites 12a and 12b was also investigated.
The reaction proceeded in THF at reflux temperature to
give products devoid of phosphorus 17a and 17b.
The reaction mechanism is depicted in Scheme 9. Initial
nucleophilic attack by the phosphine-phosphorus atom on
3a would produce a betaine of a structure like 16A [31].
By virtue of the great affinity of phosphonium ions to ha-
lides [32] would facilitate formation of transient betaine
of type 16B. The latter in which phosphorus can act as a
good leaving group because of its bulkiness, 16B, decom-
poses to afford 17a or 17b.
Analytical and spectroscopic data recorded for com-
pounds 17a and 17b afford a strong support for the postu-
lated mechanism.
CONCLUSIONS
It was an attractive challenge in this work to synthesize
novel molecules carrying the isoxazole moiety in combina-
tion with different side chains and with pyrazole ring
aiming to obtain potent biological drugs. We also report a
one pot synthesis of aminophosphonates via Kabachnik–
Fields reaction, starting from substituted amines and alde-
hyde derivatives in the presence of phosphorus reagents.
These targeted products were resynthesized in better yields
by directly applying phosphorus reagents on synthesized
Schiff bases.
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Synthesis of Various Schiff Bases Containing Isoxazole Ring and Their Applications
with Thioglycollic Acid and Diverse Phosphorus Reagents
Finally, hexaalkyl triamidophosphites used as aminating
agent and induce chlorine displacement to yield the respec-
tive 5-(dialkylamino)- derivatives.
10.17g, mp 280–283°C (from EtOH); ir (KBr, νmax, cm-1):
1
3100 (CHarom), 1725 (O¼C). H nmr (DMSO-d6): δH 2.59
(3H, s, CH3), 7.27–7.52 (2H, 2d, JHH 7.8Hz, ArH), 8.33
(1H, s, ArH), 10.8 (1H, s, HCO). 13C nmr (DMSO-d6): δC
13.5 (CH3), 113.1, 140.2, 145.2 (C(4), C(5), C(3)), 124.9,
126.8, 134.7, 136.8, 145.1, 146.9 (ArC), 180.6 (CHO).
ei-ms, m/z (%)=310 (M+, 25). Anal. Calcd for
C11H7ClN4O5 (310.65): C, 42.53; H, 2.27; N, 18.04%.
Found: C, 42.68; H, 2.12; N, 17.84%.
EXPERIMENTAL
General. Melting points were determined with an open
capillary tube on an electrothermal (variable heater, Stuart,
UK) melting point apparatus and were uncorrected. The ir
spectra were recorded on a JASCO FT- ir 6100 using KBr
disk (Jasco, Japan). The nmr spectra were measured with a
General procedure for synthesis of compounds 3a and
3b.
A mixture of 3-amino-5-methylisoxazole (1)
(4.90 g, 50mmol) and 5-Chloro-3-methyl-1H-pyrazole-4-
carbaldehyde (2a, 50mmol, 7.20 g), 5-chloro-1-(2,4-
dinitrophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (2b,
50mmol, 15.55 g) in glacial acetic acid (100mL) was
refluxed for 18–20h (TLC). After cooling, the formed
precipitate was filtered, washed with petroleum ether
60–80 and crystallized from ethanol to afford Schiff
1
Jeol E.C.A-500 MHz (13C: 125.4 MHz, H: 500.7 MHz, 31P:
200.7 MHz) spectrometer (Jeol, Japan). 1H and 13C nmr
spectra were recorded with trimethylsilane as internal standard
in CDCl3 and/or DMSO. 31P nmr spectra were recorded with
H3PO4 (85%) as external reference. Chemical shifts (δ) are
given in parts per million. The mass spectra were performed
at 70 eV on an ms-50 Kratos (A.E.I.) spectrometer (Kratos,
UK). The appropriate precautions in handling moisture-
sensitive compounds were observed. The purity of all new
samples was verified by microchemical analysis (C/H/N/S)
and spectroscopy. Solvents were dried by standard
techniques. All chemicals used were purchased from Aldrich.
TLC: Merck 0.2 mm silica gel 60 F154 anal aluminum plates.
Elemental analyses were carried out at the Microanalysis
Laboratory, Cairo University, Cairo, Egypt, using Elemental
Analyessystem GMbH-vario EL III Elemental Analyzer
Germany. The known Schiff base 10 was obtained using the
procedure reported by Rajanarendar et.al. [33].
bases 3a or 3b.
N-[(5-Chloro-3-methyl-1H-pyrazol-4-yl)methylene]-5-
methylisoxazol-3-amine (3a). Yellowish brown solid, yield
40%, 4.45g, mp 158–160°C (from EtOH); ir (KBr, νmax
,
cmꢀ1): 3345 (w, NH), 1624 (N¼CH). H nmr (DMSO-
d6): δH 2.18 (3H, s, CH3-pyrazole), 2.38 (3H, s, CH3-
isoxazole), 6.58 (1H, s, H-isoxazole), 8.41(1H, s,
CH¼N), 10.82 (1H, s(br), NH, D2Oexchangeable). 13C nmr
(DMSO-d6): δC 13.1 (Me-isoxazole), 13.8 (Me-pyrazole),
86.9, 143.1, 165.1 (C(4), C(3), C(5)-isoxazole), 96.8,
145.0, 146.2 [C(4′), C(3′), C(5′)-pyrazole], 153.2
(HC¼N). ei-ms, m/z (%) = 224 (M+, 35). Anal. Calcd for
C9H9ClN4O (224.65): C, 48.12; H, 4.04; N, 24.94%.
1
General procedure for synthesis of carbaldehydes 2a and
Found: C, 48.28; H, 3.88; N, 24.80%.
2b. To ice cold dimethylformamide (400 mmol) was
N-{[5-Chloro-1-(2,4-dinitrophenyl)-3-methyl-1H-pyrazol-4-
added dropwise with stirring phosphorus oxychloride
(400 mmol) over a period of 30 min, stirring was
continued for further 45 min, and the reaction mixture
was kept at 0°C. 3-Methyl-1H-pyrazole-5(4H)-one (7.8 g,
80mmol) or 1-(2,4-dinitrophenyl)-3-methyl-1H-pyrazol-4
(5H)-one (21.1 g, 80 mmol) was then added, and the
reaction mixture was allowed to attain room temperature.
The mixture was then heated at 90°C for 4–6 h (TLC),
allowed to cool and poured onto a mixture of crushed ice
and water. The precipitates obtained were filtered, dried,
and crystallized from ethanol to obtain the required
yl]methylene}-5-methylisoxazol-3-amine (3b).
Yellowish
brown solid, yield 40%, 7.80 g, mp 233–235°C (from
EtOH); ir (KBr, νmax, cmꢀ1): 3100 (CHarom), 1628
(N¼CH). 1H nmr (DMSO-d6): δH 2.19 (3H, s, CH3-
pyrazole), 2.40 (3H, s, CH3-isoxazole), 6.55 (1H, s, H-
isoxazole), 7.30–7.51 (2H, 2d, JHH 7.4Hz, ArH), 8.30 (1H,
s, ArH), 8.49 (1H, s, CH¼N). 13C nmr (DMSO-d6): δC
12.9 (Me-isoxazole), 13.3 (Me-pyrazole), 90.2, 145.9, 164.1
(C(4), C(3), C(5) -isoxazole), 99.8, 144.1, 146.3 (C(4′), C
(3′), C(5′)-pyrazole), 122.8, 125.1, 135.8, 136.1, 144.3,
146.1 (ArC), 153.9 (HC¼N). ei-ms, m/z (%) =390 (M+,
30). Anal. Calcd for C15H11ClN6O5 (390.74): C, 46.11; H,
2.84; N, 21.51%. Found: C, 46.22; H, 2.65; N, 21.39%.
5-chloro -4-carbaldehydes 2a or 2b.
5-Chloro-3-methyl-1H-pyrazole-4-carbaldehyde (2a). Straw
yellow solid, yield 45%, 5.17g, mp 200–202°C (from
1
EtOH); ir (KBr, νmax, cmꢀ1): 3345 (NH), 1725 (O¼C). H
General procedure for synthesis thiazolidinones 4a, 4b.
A
mixture of compound 3a (0.44g, 2mmol) or 3b (0.78g,
2 mmol) and thioglycolic acid (0.2 mL, 2 mmol) in dry
benzene (20 mL) was heated under reflux for 10–20 h.
The solvent was evaporated under reduced pressure, and
the formed residue was treated with diluted solution of
sodium carbonate (10%). The formed precipitate was
filtered, dried, and crystallized from ethanol to give 4a
or 4b.
nmr (DMSO-d6): δH 2.52 (3H, s, CH3), 10.82 (1H, s(br),
NH, D2Oexchangeable), 10.2(1H, s, HCO). 13C nmr (DMSO-
d6): δC 12.8 (CH3), 110.9, 142.8, 147.7 (C(4), C(5), C(3)),
181.2 (CHO). ei-ms, m/z (%)= 144 (M+, 30). Anal. Calcd
for C5H5ClN2O (144.56): C, 41.54; H, 3.49; N, 19.38%.
Found: C, 41.71; H, 3.35; N, 19.21%.
5-chloro-1-(2,4-dinitrophenyl)-3-methyl-1H-pyrazole-4-
carbaldehyde (2b). Yellowish brown solid, yield 41%,
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A. A. Shady, S. M. Abu Bakr, and M. D. Khidre
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2-(5-Chloro-3-methyl-1H-pyrazol-4-yl)-3-(5-methylisoxazol-
3-yl)-1,3-thiazolidin-4-one (4a).
N-((1-(2,4-dinitrophenyl)-3-methyl-5-(piperazin-1-yl)-1H-
pyrazol-4-yl)methylene)-5-methylisoxazol-3-amine (6b).
Straw yellow solid, yield
Pale
50%, 0.27 g, mp 211–213°C (from EtOH); ir (KBr, νmax
,
brown solid, yield 47%, 1.03g, mp >300°C (from acetic
1
cmꢀ1): 3230 (NH), 1725 (CO). H nmr (DMSO-d6): δH
acid); ir (KBr, νmax, cmꢀ1): 3200 (NH), 3100 (CHarom),
1
2.15 (3H, s, CH3-pyrazole), 2.28 (3H, s, CH3-isoxazole),
3.60 (2H, s, CH2-thiazolidine), 5.30 (1H, s, H- thiazolidine),
6.63 (1H, s, H-isoxazole), 10.90 (1H, s(br) NH,
D2Oexchangeable). 13C nmr (DMSO-d6): δC 12.9 (Me-
isoxazole), 13.3 (Me-pyrazole), 36.5 (CH2- thiazolidine),
58.4(CH- thiazolidine), 89.5, 142.3, 165.1 (C(4), C(3), C(5)
-isoxazole), 99.1, 143.1, 145.1 (C(4′), C(3′), C(5′)-pyrazole),
173.5 (C¼O). ei-ms, m/z (%) = 298 (M+, 25). Anal. Calcd
1626 (N¼CH). H nmr (DMSO-d6): δH 2.32 (3H, s, CH3-
pyrazole), 2.56 (3H, s, CH3-isoxazole), 2.94–3.11 (8H, m,
CH2- piperazine), 6.30 (1H, s, H-isoxazole), 7.25,7.48
(2H, 2d, JHH 7.8 Hz, ArH), 8.22 (1H, s, CH¼N), 8.34
(1H, s, ArH), 9.90 (1H, s(br), NH, D2Oexchangeable). 13C
nmr (DMSO-d6): δC 12.5 (Me-isoxazole), 13.6 (Me-
pyrazole), 43.6, 47.4(4C-piperazine ), 89.7, 145.4, 165.9
(C(4), C(3), C(5)-isoxazole), 100.2, 148.3, 150.2 (C(4′), C
(3′), C(5′)-pyrazole), 122.3, 124.7, 135.3, 139.1, 142.8,
144.2 (ArC), 151.7 (HC¼N). ei-ms, m/z (%)=441
(M+ +1, 36). Anal. Calcd for C19H20N8O5 (440.41): C,
for C11H11ClN4O2S (298.75): C, 44.22; H, 3.71; N, 18.75;
S, 10.73%. Found: C, 44.31; H, 3.59; N, 18.65; S, 10.81%.
2-[5-Chloro-1-(2,4-dinitrophenyl)-3-methyl-1H-pyrazol-4-yl]-3-
(5-methylisoxazol-3-yl)-1,3-thiazolidin-4-one (4b).
Yellowish
51.82; H, 4.58; N, 25.44%. Found: C, 52.01; H, 4.37; N,
25.23%.
brown solid, yield 40%, 0.38 g, mp >300°C (from
EtOH); ir (KBr, νmax, cmꢀ1): 3100 (CHarom), 1720 (CO).
1H nmr (DMSO-d6): δH 2.25 (3H, s, CH3-pyrazol), 2.68
(3H, s, CH3-isoxazole), 3.64 (2H, s, CH2-thiazolidine),
5.28 (1H, s, H-thiazolidine), 6.61 (1H, s, H-isoxazole),
7.31–7.49 (2H, 2d, JHH 7.4 Hz, ArH), 8.32 (1H, s, ArH).
13C nmr (DMSO-d6): δC 12.9 (Me-isoxazole), 13.3
(Me-pyrazol), 36.1 (CH2- thiazolidine), 57.4(CH-
thiazolidine), 86.9, 144.3, 165.4 (C(4), C(3), C(5)-
isoxazole), 100.2, 144.2, 145.6 (C(4′), C(3′), C(5′)-
pyrazole), 123.6, 124.8, 135.6, 136.2, 143.1, 145.8
(ArC), 174.2 (C¼O). ei-ms, m/z (%) = 464 (M+, 20).
Anal. Calcd for C17H13ClN6O6S (464.84): C, 43.93; H,
2.82; N, 18.08; S, 6.90%. Found: C, 44.02; H, 2.68; N,
18.01; S, 6.96%.
N-((1-(2,4-dinitrophenyl)-3-methyl-5-morpholino-1H-
pyrazol-4-yl)methylene)-5-methylisoxazol-3-amine (6c).
Beige
color solid, yield 40%, 0.88g, mp 119–121°C (from
EtOH); ir (KBr, νmax, cmꢀ1): 3100 (CHarom), 1620
(N¼CH). 1H nmr (DMSO-d6): δH 2.45 (3H, s, CH3-
pyrazole), 2.55 (3H, s, CH3-isoxazole), 3.24–3.49 (8H, m,
CH2-morpholine), 6.25 (1H, s, H-isoxazole), 7.30, 7.53
(2H, 2d, JHH 7.4Hz, ArH), 8.20 (1H, s, CH¼N), 8.32
(1H, s, ArH). 13C nmr (DMSO-d6): δC 12.8
(Me-isoxazole), 13.3 (Me-pyrazole), 49.3, 64.2(4C-
morpholine), 92.1, 144.2, 166.3 (C(4), C(3),
C
(5)-isoxazole), 101.2, 147.0, 151.1 (C(4′), C(3′), C(5′)-
pyrazole), 123.3, 124.6, 134.8, 136.2, 144.4, 145.6 (ArC),
153.8 (HC¼N). ei-ms, m/z (%)=441 (M+, 20). Anal.
Calcd for C19H19N7O6 (441.40): C, 51.70; H, 4.34; N,
General procedure for synthesis of methylene-isoxazoles
6a–6d. A mixture of 5 mmol of compound 3a (1.12 g)
22.21%. Found: C, 51.82; H, 4.27; N, 22.11%.
N-{[1-(2,4-dinitrophenyl)-3-methyl-5-(1,3-thiazol-2-ylamino)-
1H-pyrazol-4- yl]methylene}-5-methylisoxazol-3-amine (6d).
or 3b (1.95 g) and different amines, namely piperazine,
morpholine, or 2-aminothiazole (5a–5c) (5 mmol) in dry
DMF (20 mL) was refluxed for 36 h. The reaction
mixture followed by TLC. After complete the reaction,
cool and poured onto ice/cold water. The formed
precipitate was filtered, dried, and crystallized from
ethanol to give 6a–6d.
5-Methyl-N-[(3-methyl-5-piperazin-1-yl-1H-pyrazol-4-
yl)methylene]isoxazol-3-amine (6a). Yellowish brown solid,
yield 45%, 0.62g, mp 187–189°C (from EtOH); ir
(KBr, νmax, cmꢀ1): 3440, 3376 (2NH), 1622 (N¼CH).
1H nmr (DMSO-d6): δH 2.35 (3H, s, CH3-pyrazol), 2.58
(3H, s, CH3-isoxazole), 2.95–3.09 (8H, m, CH2-
piperazine), 6.31 (1H, s, H-isoxazole), 8.32 (1H, s,
CH¼N), 9.92, 9.99 (2H, 2s(br), 2NH, D2Oexchangeable).
13C nmr (DMSO-d6): δC 12.9 (Me-isoxazole), 13.4 (Me-
pyrazole), 44.2, 48.1(4C-piperazine ), 90.2, 144.0,
166.2 (C(4), C(3), C(5)-isoxazole), 99.9, 145.1, 146.7
(C(4′), C(3′), C(5′)-pyrazole), 155.5 (HC¼N). ei-ms,
m/z (%) = 274 (M+, 22). Anal. Calcd for C13H18N6O
(274.32): C, 56.92; H, 6.61; N, 30.64%. Found: C,
56.99; H, 6.45; N, 30.54%.
Yellowish brown solid, yield 45%, 1.02g, mp >300°C
(from EtOH); ir (KBr, νmax, cmꢀ1): 3150 (NH), 3095
(CHarom), 1625 (N¼CH). 1H nmr (DMSO-d6): δH 2.51
(3H, s, CH3-pyrazole), 2.56 (3H, s, CH3-isoxazole), 6.58
(1H, s, H-isoxazole), 7.95–8.56 (6H, m, H-thiazole, CH¼N
and ArH), 9.31 (1H, s(br), NH, D2Oexchangeable). 13C nmr
(DMSO-d6): δC 13.0 (Me-isoxazole), 13.3 (Me-pyrazole),
91.2, 147.1, 166.7 (C(4), C(3), C(5)-isoxazole), 99.9, 147.8
150.1 (C(4′), C(3′), C(5′)-pyrazole), 115.2, 132.2, 158.4
(3C- thiazole), 122.6, 125.1, 132.6, 135.7, 145.2, 148.0
(ArC), 154.1 (HC¼N). ei-ms, m/z (%)=454 (M+, 15).
Anal. Calcd for C18H14N8O5S (454.42): C, 47.58; H, 3.11;
N, 24.66, S, 7.06%. Found: C, 47.65; H, 3.02; N, 24.58, S,
7.11%.
General procedure for the one-pot preparation of 9a–9c.
A
stirred mixture of 0.8 g 4-chlorobenzaldehyde (8, 5.6 mmol),
0.55 g 3-amino-5-methylisoxazole (1, 5.6 mmol), and
trimethyl (7a), triethyl (7b), or triisopropylphosphite (7c)
(6 mmol) in 10 mL THF containing 10% FeCl3 was heated
under reflux for 5–8h. After completion of the reaction
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of Various Schiff Bases Containing Isoxazole Ring and Their Applications
with Thioglycollic Acid and Diverse Phosphorus Reagents
(TLC), 10 mL AcOEt was added to the mixture. The organic
phase was separated, washed with 20mL distilled water,
and dried over anhydrous sodium sulfate. Solvents were
evaporated under vacuum, and the residue was crystallized
(M+, 11). Anal. Calcd for C17H24ClN2O4P (386.81): C,
52.79; H, 6.25; N, 7.24%. Found: C, 52.98; H, 6.04; N,
7.15%.
Products 9a–9c were obtained in good yield, 9a (76%,
0.9 g), 9b (72%, 0.93 g), 9c (75%, 1.05 g) when dimethyl
(11a), diethyl (11b), or diisopropyl phosphite (11c) were
heated with Schiff base 10 in the absence of solvent at
100°C for 2–4h. After removing the volatile materials in
vacuo, the residue was triturated with light petroleum and
left to cool. The solid formed was collected and crystal-
lized from a suitable solvent. Compounds 9a–9c were ver-
ified by mps, mixed mps, and comparative ir spectra with
the previous obtained ones.
from the proper solvent to give compounds 9a–9c.
Dimethyl (4-chlorophenyl)(5-methylisoxazol-3-ylamino)
methylphosphonate (9a). White solid, yield 57%, 1.07g,
mp 115–117°C (from cyclohexane); ir (KBr, νmax, cmꢀ1):
1
3340 (NH), 1226 (P¼O, bonded), 1110 (P-O-C). H nmr
3
(CDCl3): δH 2.21 (3H, s, CH3), 3.44, 3.77 (6H, 2d, JPH
2
10.6Hz, 2(H3CO)P), 5.17 (1H, d, JPH 22.9Hz, HCP),
5.54 (1H, s, H-isoxazole), 7.55 and 7.78 (4H, 2d, JHH
8.6Hz, ArH), 8.57(1H, br, NH). 13C nmr (CDCl3): δC
1
12.3 (Me-isoxazole), 52.4 (d, JPC 158.2 Hz, C-P), 53.8
Synthesis of 14a and 14b by reaction of the Schiff base 10
2
(d, JPC 15.8 Hz, (MeO)2P), 88.5, 155.2 (C(4), C(5)-
with hexaalkyltriamidophosphites 12a and 12b.
No
isoxazole), 122.8, 128.8 (C(3′), C(5′), C(4′)-Ar), 129.2(d,
reaction occurred when equimolar amounts of 10 and
phosphine 12a or 12b were heated under reflux in THF
(or benzene) even after 3 days, after which compound 10
was recovered practically unchanged in 87% yield. A
stirred solution of 0.8 g 10 (3.6 mmol) and 3.6 mmol
phosphine 12a or 12b in 25mL ethyl alcohol was boiled
under reflux for 28–30h (TLC). The volatile materials
were evaporated under vacuum; the residue was
collected, washed with light petroleum, and crystallized
2
3JPC 10.6 Hz, C(2′), C(6′)-Ar), 134.7(d, JPC 11.2Hz, C
3
(1′)-Ar), 135.6 (d, JPC 8.6 Hz, C(3)-isoxazole). 31P nmr
(CDCl3): δP 23.80. MS, m/z (%) = 330 (M+, 10). Anal.
Calcd for C13H16ClN2O4P (330.70): C, 47.21; H, 4.88;
N, 8.47%. Found: C, 47.35; H, 4.72; N, 8.35%.
Diethyl
(4-chlorophenyl)(5-methylisoxazol-3-ylamino)
methylphosphonate (9b).
White solid, yield 60%,
1.22 g, mp 148–150°C (from MeCN); ir (KBr, νmax
,
cmꢀ1): 3350 (NH), 1225 (P¼O, bonded), 1129 (P-O-
from the proper solvent to give compounds 14a and 14b.
1
C). H nmr (CDCl3): δH 1.12, 1.29 (6H, 2dt, JHH 7.6,
P-{(4-chlorophenyl)[(5-methylisoxazol-3-yl)amino]methyl}-
4JPH 4.8 Hz, 2(H3CCOP)), 2.26 (3H, s, CH3), 3.75,
N,N,N′,N′-tetramethylphosphonic diamide (14a).
Yellow
3
4.16 (4H, 2dq, JHH 7.6, JPH 8.6 Hz, 2(H2COP)), 5.20
solid, yield 63%, 0.81g, mp 190–192°C (from CH2Cl2); ir
2
(1H, d, JPH 22.9 Hz, HCP), 5.59 (1H, s, H-isoxazole),
(KBr, νmax, cmꢀ1): 3320 (NH), 1229 (P¼O, bonded),
1
7.28 and 7.53 (4H, 2d, JHH 7.6 Hz, ArH), 8.54 (1H, br,
1320, 860 (P-N-Me). H nmr (CDCl3): δH 2.39 (3H, s,
NH). 13C nmr (CDCl3): δC 12.8 (Me-isoxazole), 16.3
CH3), 2.42, 2.48 (12H,2d, 3JPH 10.4Hz, (Me2N)2–P), 5.48
3
1
2
(d, JPC 8.2 Hz, 2(CH3COP)), 54.9 (d, JPC 169.4 Hz,
(1H, d, JPH 20.6Hz, HCP), 6.21 (1H, s, H-isoxazole),
2
C-P), 62.3 (d, JPC 8.9 Hz, 2(CH2OP)), 85.1, 157.1 (C
6.51 (1H, br, NH), 7.39 and 7.53 (4H, 2d, JHH 7.8Hz,
(4), C(5)-isoxazole), 124.1, 130.2 (C(3′), C(5′), C(4′)-
ArH). 13C nmr (CDCl3): δC 13.6 (Me-isoxazole), 43.8
3
2
1
Ar), 128.3 (d, JPC 9.8 Hz, C(2′), C(6′)-Ar), 133.9 (d,
(d, JPC 27.4Hz, CH3NP), 52.4 (d, JPC 170.2Hz, C-P),
84.2, 158.6 (C(4), C(5)-isoxazole), 126.5, 132.5 (C(3′),
3
2JPC 10.4 Hz, C(1′)-Ar), 136.1 (d, JPC 8.2 Hz, C(3)-
isoxazole). 31P nmr (CDCl3): δP 25.6. MS, m/z (%)
= 358 (M+, 10). Anal. Calcd for C15H20ClN2O4P
(358.76): C, 50.22; H, 5.62; N, 7.81%. Found: C,
C(5′), C(4′)-Ar), 131.1(d, JPC 8.8Hz, C(2′), C(6′)-Ar),
3
2
3
134.0 (d, JPC 14.1Hz, C(1′)-Ar), 134.8 (d, JPC 8.4Hz,
C(3)-isoxazole). 31P nmr (CDCl3): δP 33.4. MS, m/z
(%)=356 (M+, 10). Anal. Calcd for C15H22ClN4O2P
(356.79): C, 50.50; H, 6.22; N, 15.70%. Found: C,
50.35; H, 5.49; N, 7.96%.
Diisopropyl(4-chlorophenyl)(5-methylisoxazol-3-ylamino)
methylphosphonate (9c). White solid, yield 55%, 1.21g,
50.66; H, 6.01; N, 15.56%.
mp 170–172°C (from CHCl3); ir (KBr, νmax, cmꢀ1): 3345
(NH), 1224 (P¼O, bonded), 1110 (P-O-C). 1H nmr
P-{(4-chlorophenyl)[(5-methylisoxazol-3-yl)amino]methyl}-
N,N,N′,N′-tetraethylphosphonic diamide (14b).
Yellow
4
(CDCl3): δH 1.11, 1.33 (12H, 2dd, JHH 7.2, JPH 5.8 Hz,
solid, yield 61%, 0.9 g, mp 170–172°C (from CHCl3); ir
(KBr, νmax, cmꢀ1): 3335 (NH), 1230 (P¼O, bonded),
1323, 865 (P-N-Et). 1H nmr (CDCl3): δH 1.09, 1.15
4(H3CCOP)), 2.28 (3H, s, CH3), 4.62, 4.81 (2H, 2m,
2
2HCOP), 5.18 (1H, d, JPH 20.6 Hz, HCP), 5.56 (1H, s,
4
H-isoxazole), 7.56 and 7.77 (4H, 2d, JHH 8.6 Hz, ArH),
(6H, 2dt, JHH 6.6, JPH 4.8 Hz, H3CCNP), 2.41 (3H, s,
8.56 (1H, br, NH). 13C nmr (CDCl3): δC 13.2 (Me-
CH3), 2.89–3.00 (8H, m, (CH2N)2-P), 5.36 (1H, d, JPH
2
3
1
isoxazole), 23.9 (d, JPC 8.4 Hz, CH3COP), 57.4 (d, JPC
22.2 Hz, HCP), 6.29 (1H, s, H-isoxazole), 6.59 (1H, br,
NH), 7.36 and 7.62 (4H, 2d, JHH 7.6 Hz, ArH). 13C nmr
(CDCl3): δC 11.8 (Me-isoxazole), 14.2 (MeCN), 38.8
2
164.4 Hz, C-P), 77.6 (d, JPC 9.8 Hz, CHOP), 86.2, 156.3
(C(4), C(5)-isoxazole), 126.0, 129.3 (C(3′), C(5′), C(4′)-
3
2
1
Ar), 128.9 (d, JPC 10.4Hz, C(2′), C(6′)-Ar), 134.1 (d,
(d, JPC 24.2 Hz, CH2NP), 54.1 (d, JPC 164.8 Hz, C-P),
3
2JPC 11.6Hz, C(1′)-Ar), 135.9 (d, JPC 8.8 Hz, C(3)-
83.7, 159.4 (C(4), C(5)-isoxazole), 127.1, 132.8 (C(3′),
isoxazole). 31P nmr (CDCl3): δP 27.4. MS, m/z (%) = 386
C(5′), C(4′)-Ar), 132.7(d, JPC 9.2 Hz, C(2′), C(6′)-Ar),
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Shady, S. M. Abu Bakr, and M. D. Khidre
Vol 000
2
3
Diisopropyl{(5-chloro-3-methyl-1H-pyrazol-4-yl)[(5-methyl
isoxazol-3-yl)amino]methyl}phosphonate (15c).
133.2 (d, JPC 12.8 Hz, C(1′)-Ar), 134.7 (d, JPC 8.7 Hz,
C(3)-isoxazole). 31P nmr (CDCl3): δP 34.6. MS, m/z
(%) = 412 (M+, 9). Anal. Calcd for C19H30ClN4O2P
(412.89): C, 55.27; H, 7.32; N, 13.57%. Found: C,
55.39; H, 7.20; N, 13.45%.
Yellow
solid, yield 50%, 1.08 g, mp 230–232°C (from acetone);
ir (KBr, νmax, cmꢀ1): 3360, 3300 (2NH), 1224 (P¼O,
1
bonded), 1022 (P-O-C). H nmr (CDCl3): δH 1.09, 1.19
4
(12H, 2dd, JHH 6.9, JPH 6.4 Hz, 4H3CCOP), 2.16 (3H, s,
General procedure for the synthesis of 15a–15c.
A
CH3-pyrazole), 2.49 (3H, s, CH3-isoxazole), 4.58–4.85
mixture of 0.8 g 5-chloro-3-methyl-1H-pyrazole-4-
carbaldehyde (2a, 5.53 mmol), 0.54 g 3-amino-5-
methylisoxazole (1, 5.53mmol), and trimethyl (7a),
triethyl (7b), or triisopropyl phosphite (7c) (6mmol) in
15mL THF containing 10% FeCl3 (or 2 mL glacial acetic
acid) was heated under reflux for 6–8h (TLC). The
product mixture was extracted with 50 mL AcOEt,
washed with 20 mL distilled water, and dried over
anhydrous sodium sulfate. Solvents were evaporated
under vacuum, and the residue was crystallized from the
proper solvent to give the corresponding phosphonates
3
2
(2H, m, JPH 10.8Hz, 2HCOP), 5.52 (1H, d, JPH
20.2 Hz, HCP), 6.01 (1H, s, H-isoxazole), 6.91, 7.72
(2H, 2br, 2NH). 13C nmr (CDCl3): δC 12.1 (Me-
3
isoxazole), 13.2 (Me-pyrazole), 26.1 (d, JPC 10.2 Hz,
CH3COP), 56.8 (d, JPC 170.1 Hz, C-P), 78.1 (d, JPC
1
2
12.4 Hz, CHOP), 83.7, 158.9 (C(4), C(5)-isoxazole),
2
3
109.8 (d, JPC 11.2Hz, C(4′)-pyrazole), 126.7 (d, JPC
3
8.2 Hz, C(3′)-pyrazole), 130.3 (d, JPC 8.4 Hz, C(5′)-
pyrazole), 134.2 (d, JPC 8.2 Hz, C(3)-isoxazole). 31P nmr
3
(CDCl3): δP 28.8. MS, m/z (%)= 390 (M+, 12). Anal.
Calcd for C15H24ClN4O4P (390.80): C, 46.10; H, 6.19;
N, 14.34%. Found: C, 46.22; H, 6.02; N, 14.21%.
Phosphonates 15a–15c were obtained in higher yield,
15a (73%, 0.87 g), 15b (75%, 0.97 g), 15c (70%, 0.97 g)
and characterized by mps, mixed mps, and comparative ir
spectra with the previous obtained ones. That was taken
place by heating Schiff base 3a with dimethyl (11a),
diethyl (11b), or diisopropyl phosphite (11c) in the absence
of solvent at 100°C for 4–6 h (TLC). After the usual work-
ing up, the residue was collected and crystallized from a
proper solvent.
15a–15c.
Dimethyl{(5-chloro-3-methyl-1H-pyrazol-4-yl)[(5-methyl
isoxazol-3-yl)amino]methyl}phosphonate (15a).
Yellow
solid, yield 55%, 1.02g, mp 190–192°C (from EtOH); ir
(KBr, νmax, cmꢀ1): 3340, 3335 (2NH), 1226 (P¼O,
1
bonded), 1050 (P-O-C). H nmr (CDCl3): δH 2.19 (3H, s,
CH3-pyrazole), 2.49 (3H, s, CH3-isoxazole), 3.60, 3.65
3
2
(6H, 2d, JPH 12 Hz, 2(H3CO)P), 5.62 (1H, d, JPH
20.2Hz, HCP), 5.82 (1H, s, H-isoxazole), 6.96, 7.81 (2H,
2br, 2NH). 13C nmr (CDCl3): δC 12.3 (Me-isoxazole),
1
13.2 (Me-pyrazole), 51.8 (d, JPC 160.6 Hz, C-P), 53.8
(d, JPC 18.2 Hz, (MeO)2P), 84.2, 158.8 (C(4), C(5)-
isoxazole), 110.8 (d, JPC 12.2Hz, C(4′)-pyrazole), 126.5
Reaction of 3a with hexaalkyltriamidophosphites 12a and
2
12b.
General procedure: A mixture of 3a (0.8 g,
2
3.56 mmol) and hexamethyl (12a) or hexaethyl
triamidophosphite (12b) (4mmol) in dry THF (50ml) was
refluxed for 4–6 h (TLC). The solid formed was
collected, and then crystallized from suitable solvent to
give 17a or 17b.
N-((5-(dimethylamino)-3-methyl-1H-pyrazol-4-yl)methylene)-5-
methylisoxazol-3-amine (17a). Pale yellow powder, yield
3
3
(d, JPC 8.6Hz, C(3′)-pyrazole), 130.7 (d, JPC 8.2 Hz, C
(5′)-pyrazole), 134.1 (d, JPC 8.4 Hz, C(3)-isoxazole). 31P
3
nmr (CDCl3): δP 29.3. MS, m/z (%)= 334 (M+, 13). Anal.
Calcd for C11H16ClN4O4P (334.70): C, 39.47; H, 4.82;
N, 16.74%. Found: C, 39.52; H, 4.71; N, 16.61%.
Diethyl{(5-chloro-3-methyl-1H-pyrazol-4-yl)[(5-methyl
isoxazol-3-yl)amino]methyl}phosphonate
(15b).
Straw
74%, 0.61g, mp 185–187°C (from cyclohexane); ir (KBr,
yellow solid, yield 53%, 1.06g, mp 224–226°C (from
ν
max, cmꢀ1): 3400 (NH), 2942 (N(CH3)2), 1640 (N¼CH).
MeCN); ir (KBr, νmax, cmꢀ1): 3346, 3338 (2NH), 1228
1H nmr (CDCl3): δH 2.12 (3H, s, CH3-pyrazole), 2.34
(3H, s, CH3-isoxazole), 3.09 (6H, s, Me2N), 6.11 (1H, s,
H-isoxazole), 8.55 (1H, s, CH¼N), 9.02 (1H, br, NH).
13C nmr (CDCl3): δC 12.3 (Me-isoxazole), 13.6 (Me-
pyrazole), 41.7 (2MeN), 96.2, 131.9, 158.4 (C(4), C(3),
C(5)-isoxazole), 108.5, 126.2, 135.6 [C(4′), C(3′), C(5′)-
pyrazole), 154.8 (C¼N). MS, m/z (%) = 233 (M+, 45).
Anal. Calcd for C11H15N5O (233.27): C, 56.64; H, 6.48;
1
(P¼O, bonded), 1066 (P-O-C). H nmr (CDCl3): δH 1.17,
4
1.67 (6H, 2dt, JHH 7.2, JPH 4.6 Hz, 2H3CCOP), 2.18
(3H, s, CH3-pyrazole), 2.51 (3H, s, CH3-isoxazole), 3.89,
4.03 (4H, 2m, 2H2COP), 5.57 (1H, d, JPH 18.6Hz,
2
HCP), 5.65 (1H, s, H-isoxazole), 6.97, 7.79 (2H, 2br,
2NH). 13C nmr (CDCl3): δC 12.5 (Me-isoxazole), 13.6
3
(Me-pyrazole), 16.9 (d, JPC 6.6 Hz, CH3COP), 52.2 (d,
1JPC 168.2 Hz, C-P), 64.4 (d, JPC 8.8 Hz, CH2OP), 84.8,
2
N, 30.02%. Found: C, 56.78; H, 6.32; N, 29.03%.
N-((5-(diethylamino)-3-methyl-1H-pyrazol-4-yl)methylene)-5-
methylisoxazol-3-amine (17b). Pale yellow powder, yield
2
158.1 (C(4), C(5)-isoxazole), 111.9 (d, JPC 10.8 Hz, C
(4′)-pyrazole), 128.1 (d, JPC 8.8 Hz, C(3′)-pyrazole),
3
3
3
128.9 (d, JPC 8.5 Hz, C(5′)-pyrazole), 132.9 (d, JPC
8.6Hz, C(3)-isoxazole).31P nmr (CDCl3): δP 24.5. MS,
m/z (%) =362 (M+, 12). Anal. Calcd for C13H20ClN4O4P
(362.75): C, 43.04; H, 5.56; N, 15.45%. Found: C, 43.18;
H, 5.42; N, 15.31%.
71%, 0.66g, mp 198–200°C (from n-hexane); ir (KBr,
νmax
,
cmꢀ1): 3425 (NH), 2930 (N(C2H5)2), 1635
1
(N¼CH). H nmr (CDCl3): δH 0.09, 1.05 (6H, 2t, JHH
6.8, H3CCN), 2.11 (3H, s, CH3-pyrazole), 2.31 (3H, s,
CH3-isoxazole), 2.79, 2.98 (4H, 2q, JHH 6.8, CH2N), 6.15
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of Various Schiff Bases Containing Isoxazole Ring and Their Applications
with Thioglycollic Acid and Diverse Phosphorus Reagents
[12] Warshakoon, N. C.; Wu, S.; Boyer, A.; Kawamoto, R.;
(1H, s, H-isoxazole), 8.59 (1H, s, CH¼N), 8.99 (1H, br,
NH). 13C nmr (CDCl3): δC 12.1 (2Me-CN), 13.2 (Me-
isoxazole), 13.9 (Me-pyrazole), 46.6 (2CH2-N), 98.0,
129.8, 159.1 (C(4), C(3), C(5)-isoxazole), 111.3, 124.6,
130.9 (C(4′), C(3′), C(5′)-pyrazole), 156.2 (C¼N). MS,
m/z (%)=261 (M+, 42). Anal. Calcd for C13H19N5O
(261.32): C, 59.75; H, 7.33; N, 26.80 %. Found: C,
59.62; H, 7.21; N, 26.69 %.
Renock, S.; Xu, K.; Pokross, M.; Evdokimov, A. G.; Zhou, S.; Winter, C.;
Walter, R.; Mekel, M. Bioorg Med Chem Lett 2006, 16, 5687.
[13] Zhu, G. D.; Gong, J.; Gandhi, V. B.; Woods, K.; Luo, Y.;
Liu, X.; Guan, R.; Klinghofer, V.; Johnson, E. F.; Stoll, V. S.; Mamo, M.;
Li, Q.; Rosenberg, S. H.; Giranda, V. L. Bioorg Med Chem 2007, 15,
2441.
[14] Quin, L. D. A guide to organophosphorus chemistry. Wiley-
Interscience: New York, 2000.
[15] Westheimer, F. H., et al. Science 1987, 235, 1173.
[16] Kafarski, P.; Lejczak, B. Curr Med Chem Anticancer Agents
2001, 1, 301.
[17] Bloemink, M. J.; Diederen, J. J. H.; Dorenbos, J. P. Heetebrij,
R. J.; Keppler, B. K. Eur J inorg chem 1999, 1999, 1655.
[18] Rao, X.; Song, Z.; He, L. Heteroatom Chem 2008, 19, 512.
[19] Makhaeva, G. F.; Malygin, V. V.; Aksinenko, A. Y.; Sokolov,
V. B.; Strakhova, N. N.; Rasdolsky, A. N.; Richardson, R. J.; Martynov,
I. V. Dokl Biochem Biophys 2005, 400, 92.
[20] Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J Chem Soc
Perkin Trans 1984, 1, 2845.
[21] Abdou, W. M.; Salem, M. A. I.; Barghash, R. F. Arkivoc 2007,
15, 45.
REFERENCES AND NOTES
[1] Shin, K. D.; Lee, M. Y.; Shin, D. S.; Lee, S.; Son, K. H.; Koh, S.;
Paik, Y. K.; Kwon, B. M.; Han, D. C. J Biol Chem 2005, 280, 41439.
[2] Simoni, D.; Roberti, M.; Paolo, I. F.; Rondanin, R.;
Baruchello, R.; Malagutti, C.; Mazzali, A.; Rossi, M.; Grimaudo, S.;
Capone, F.; Dusonchet, L.; Meli, M.; Raimondi, M. V.; Landino, M.;
D’Alessandro, N.; Tolomeo, M.; Arindam, D.; Lu, S.; Benbrook, D. M.
J Med Chem 2001, 44, 2308.
[3] Liu, X. H.; Cui, P.; Song, B. A.; Bhadury, P. S.; Zhu, H.,. L.;
Wang, S. F. Bioorg Med Chem 2008, 16, 4075.
[22] Abdou, W. M.; Sediek, A. A.; Khidre, M. D. Monatsh Chem
2008, 139, 617.
[4] Velaparthi, S.; Brunsteiner, M.; Uddin, R.; Wan, B.;
Franzblau, S. G.; Petukhov, P. A. J Med Chem 2008, 51, 1999.
[5] Magedov, I. V.; Manpadi, M.; Van Slambrouck, S.; Steelant,
W. F. A.; Rozhkova, E.; Przhevalískii, N. M.; Rogelj, S.; Kornienko, A.
J Med Chem 2007, 50, 5183.
[23] Abdou, W. M.; Shaddy, A. A. Lett Org Chem 2008, 5, 569.
[24] Abdou, W. M.; Khidre, M. D.; Khidre, R. E. Eur J Med Chem
2009, 44, 526.
[25] Abdou, W. M.; Shaddy, A. A.; Sediek, A. A. J Chem Res
2009, 8.
[6] Chou, L. C.; Huang, L. J.; Yang, J. S.; Lee, F. Y.; Teng, C. M.;
Kuo, S. C. Bioorg Med Chem 2007, 15, 1732.
[26] Xiao, H. Q. Ouyang, G. P. Sun, X. D. Yao, X. D. Bao, G. Q.
Qi, C. Z. Chin J Synth Chem 2005, 13, 600.
[7] Manetti, F.; Brullo, C.; Magnani, M.; Mosci, F.; Chelli, B.;
Crespan, E.; Schenone, S.; Naldini, A.; Bruno, O.; Trincavelli, M. L.;
Maga, G.; Carraro, F.; Martini, C.; Bondavalli, F.; Botta, M. J Med Chem.
2008, 51, 1252.
[8] Xia, Y.; Dong, Z. W.; Zhao, B. X.; Ge, X.; Meng, N.; Shin,
D. S.; Miao, J. Y. Bioorg Med Chem 2007, 15, 6893.
[27] Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Com-
pounds; John Wiley and Sons Inc.: New York, 1994, p 486.
[28] Matveeva, E. D.; Zefirov, N. S. Dokl Chem 2008, 420, 137.
[29] Kaboudin, B. Phosphorus Sulfur Silicon Relat Elem 2002,
177, 1749.
[30] Abdou, W. M.; Barghash, R. F.; Bekheit, M. S. Monatsh Chem
2011, 142, 649.
[9] Xia, Y.; Fan, C. D.; Zhao, B. X.; Zhao, J.; Shin, D. S.; Miao,
J. Y. Eur J Med Chem 2008, 43, 2347.
[31] aArutgunam, A.; Gunar, V. I.; Zav’yalov, S. I. Izv Akad Nauk,
SSSR Serkhim 1969, 12, 2857; Chem Abstr 1970, 72, 78979.
[32] Hudson, R. F. Structure and Mechanism in Organophosphorus
Chemistry; Academic Press: London, 1965, pp 204–249.
[33] Rajanarendar, E.; Afzal, M. d.; Ramu, K. Indian J Chem Sect
B 2003, 42, 927.
[10] Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli, F.; Brullo, C.;
Fossa, P.; Mosti, L.; Menozzi, G.; Carraro, F.; Naldini, A.; Bernini, C.;
Manetti, F.; Botta, M. Bioorg Med Chem Lett 2004, 14, 2511.
[11] Daidone, G.; Raffa, D.; Maggio, B.; Valeria, R. M.; Plescia, F.;
Schillaci, D. Eur J Med Chem 2004, 39, 219.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet