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Monthly
Phthalimide-N-oxyl salts: Efficient organocatalysts for facile synthesis of (Z)-3methyl-4-arylmethylene isoxazole-5(4H)-one derivatives in water
Mohammad G. Dekamin ● S. Zahra Peyman
Pharmaceutical and Biologically-Active Compounds Research Laboratory, Department of Chemistry,
Iran University of Science & Technology, Tehran 16846-13114, Iran. E-Mail:mdekamin@iust.ac.ir
Contents
Page
1. Experimental section
S2
1.1. Materials and methods
S2
1.2. General procedure for synthesis of POPINO and TBAPINO salts (1a-b)
S2
1.3. Chemical characterization of N-hydroxyphthalimide and TBAPINO (1a-b)
S3
1.4. General procedure for synthesis of isoxazol-5(4H)-ones (5a-l) catalyzed by POPINO
S9
or TBAPINO (1a-b)
Table 1. Synthesis of (Z)-3-methyl-4-arylmethylene-isoxazole-5(4H)-ones (5a-l)
catalyzed by POPINO (1a) and TBAPINO (1b) in water at ambient temperature
Chemical characterization of (Z)-4-(4-hydroxy-3-methoxybenzylidene)-3-methylisoxazol-
S9
5(4H)-one (5a)
S11
Chemical characterization of (Z)-3-methyl-4-(thiophen-2-ylmethylene)isoxazol-5(4H)-one
S15
(5j)
Chemical characterization of (Z)-3-methyl-4-(3-phenylallylidene)isoxazol-5(4H)-one (5l)
S1
S18
1. Experimental section
1.1. Materials and methods
All commercially available chemicals were obtained from Merck and Aldrich, and used without further
purifications, except for benzaldehyde, which was used as a fresh distilled sample. Analytical thin layer chromatography
(TLC) for monitoring reactions was performed using Merck 0.2 mm silica gel 60 F-254 Al-plates. Melting points were
determined using an Electrothermal 9100 apparatus and are uncorrected. Infrared (IR) spectra were acquired on a
Shimadzu FT IR -8400S spectrometer. 1H NMR (500 MHz) Spectra were obtained using a Bruker DRX-500 AVANCE
spectrometer. NMR spectra were determined in CDCl3 or DMSO at ambient temperature. All yields refer to the isolated
products.
1.2. General procedure for synthesis of PINO and TBAPINO salts (1a-b)
1.2.1. General procedure for preparation of Potassium phthalimide-N-oxyl (POPINO, 1a)
A mixture of N-hydroxyphthalimide (1.63 g, 10 mmol) and an equivalent amount of the KOH in EtOH (20 mL) was
refluxed. After completion the reaction, the obtained deep red solid was filtered, washed with cold EtOH and dried prior
to use [45].
1.2.2. General procedure for preparation of tetrabutylammonium phthalimide-N-oxyl (TBAPINO,
1b)
A mixture of 3.78 mmol (0.617 g) of N-hydroxyphthalimide and 3.78 mmol of tetrabutylammonium hydroxide
(F.W. = 259.48 g/mol, 20% w/w in water, d = 0.98 g/mL, 5.0 mL) was stirred at room temperature for 5 min. After that,
10 mL of absolute EtOH was added and the mixture was refluxed 20 min and then allow to cool. The red solid was collected
using vacuum filtration through a Büchner funnel, washed with cold EtOH, and air-dried [37].
S2
1.3. Chemical characterization of N-hydroxyphthalimide and TBAPINO (1b)
Fig. 1. FT IR spectrum of the commercial N-hydroxyphthalimide.
S3
Fig. 2. 1H NMR spectrum of N-hydroxyphthalimide in DMSO-d6.
Fig. 3. 1H NMR spectrum of N-hydroxyphthalimide in DMSO-d6 (Expanded aromatic region).
S4
Fig. 4. FT IR spectrum of tetrabutylammonium phthalimide-N-oxyl (1b).
S5
Fig. 5. 1H NMR spectrum of tetrabutylammonium phthalimide-N-oxyl (1b) in DMSO-d6.
Fig. 6. 1H NMR spectrum of tetrabutylammonium phthalimide-N-oxyl (1b) in DMSO-d6 (Expanded aliphatic
region).
S6
Fig. 7. 1H NMR spectrum of tetrabutylammonium phthalimide-N-oxyl (1b) in DMSO-d6 (Expanded aromatic
region).
S7
Fig. 8. 13C NMR spectrum of tetrabutylammonium phthalimide-N-oxyl (1b) in DMSO-d6.
Fig. 9. 13C NMR spectrum of tetrabutylammonium phthalimide-N-oxyl (1b) in DMSO-d6 (Expanded).
S8
1.4. General procedure for synthesis of isoxazol-5(4H)-ones (5a-l) catalyzed by POPINO or
TBAPINO (1a-b)
A mixture of,
hydroxylamine hydrochloride
(2, 1 mmol),
ethylacetoacetate (3,
1 mmol),
aromatic
aldehyde (4, 1 mmol), and POPINO or TBAPINO (1a-b, 10 mol %) in 4 mL of distilled water was stirred at
room temperature for the time mentioned in Table 2. The reaction progress was monitored by TLC along
with precipitating out of the products from the reaction mixture. After completion of the reaction (monitored
by TLC), pure products were simply isolated by filtration of the reaction mixture and washing the solid with
cold distilled water. The solid products were recrystallized from EtOH if necessary. All products are known
compounds and were characterized on the basis of IR and 1H NMR spectroscopic data and melting points.
Table 1. Synthesis of (Z)-3-methyl-4-arylmethylene-isoxazole-5(4H)-ones (5a-l) catalyzed by TBAPINO (1a) and
POPINO (1b) in water at room temperaturea
Time (h)
Entry
RCOH (4)
Yieldc (%)
M.P(obsd) (°C)
Productb (5)
M.P (°C)
1a
1b
1a
1b
1a
1b
1
Vanillin (4a)
5a
1
0.75
94
97
215-217
213-215
213-215
2
2,4-dimethoxybenzaldehyde
(4b)
5b
1.5
1.1
89
90
204-205
203-205
191
3
4-methylbenzaldehyde (4c)
5c
1.5
1.5
94
97
130-131
129-130
130-132
4
4-methoxybenzaldehyde (4d)
5d
1.1
1
90
93
173-175
172-173
173-175
5
4-hydroxybenzaldehyde (4e)
5e
1.25
1.25
93
95
216-218
215-216
214-216
6
3-hydroxybenzaldehyde (4f)
5f
1.1
1
90
93
203-204
206-208
202-203
7
2-hydroxybenzaldehyde (4g)
5g
2
2
88
91
198-200
195-196
198-201
8
4-dimethylaminobanzaldehyde
(4h)
5h
1
0.75
93
96
206-208
205-207
207-208
9
Benzaldehyde (4i)
5i
1.1
1
92
95
139-140
141-142
140-142
10
2-Thiophenecarboxaldehyde
(4j)
5j
1.25
1
89
94
143-145
142-143
143-145
11
Furfural (4k)
5k
1.25
1
90
93
242-244
241-243
239-241
12
Cinnamaldehyde (4l)
5l
1.3
1.1
85
90
173-175
172-174
171-173
13
4-Chlorobenzaldehyde (4m)
5m
3
3
Trace
trace
-
-
-
14
4-Nitrobenzaldehyde (4n)
5n
3
3
NRd
NR
-
-
-
15
3-Nitrobenzaldehyde (4o)
5o
3
3
NR
NR
-
-
-
16
4-Cyanobenzaldehyde (4p)
5p
3
3
NR
NR
-
-
-
a
Reaction conditions: hydroxylamine hydrochloride (1 mmol), ethyl acetoacetate (1 mmol), and aldehyes (1 mmol), water (2 mL, rt.), POPINO or
TBAPINO (10 mol %).
b
All compounds are known and their structures were established from their spectral data and melting points as compared with literature values.
c
The yields refer to isolated products.
S9
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34.
35.
36.
37.
38.
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40.
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44.
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S10
Chemical Chemical characterization of (Z)-4-(4-hydroxy-3-methoxybenzylidene)-3-methylisoxazol5(4H)-one (5a)
Yellow solid, mp 218-220 °C, Yield: 95%; IR (KBr) cm-1: 3274-3224, 3004, 2925, 1731,1620 1562, 1510,
1440, 1313, 1284, 1184, 1107, 999, 889, 750, 563, 1H NMR (500 MHz, DMSO-d6): δ (ppm): 2.2 (s, 3H), 3.8
(s, 3H), 6.92 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.87 (dd, 3J = 8.4 Hz, 4J = 1.9 Hz, 1H), 8.47 (d, 4J = 1.9 Hz,
1H), 10.72 (s, 1H).
Fig. 10. FT IR spectrum of (Z)-4-(4-hydroxy-3-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (5a).
.
S11
Fig. 11. 1H NMR spectrum of (Z)-3-methyl-4-(4-hydroxy-3-methoxybenzylidene)-3-methylisoxazol-5(4H)-one
(5a) in DMSO-d6.
S12
Fig. 12. 1H NMR spectrum of (Z)-4-(4-hydroxy-3-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (5a) in
DMSO-d6 (Expanded aliphatic region).
S13
Fig. 13. 1H NMR spectrum of (Z)-4-(4-hydroxy-3-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (5a)
in DMSO-d6 (Expanded aromatic region).
S14
Chemical characterization of (Z)-4-(2,4-dimethoxybenzylidene)-3-methylisoxazol-5(4H)-one (5b)
Yellow solid, mp: 203-205 °C, Yield: 90%; 1H NMR (500 MHz, CDCl3): δ (ppm): 2.2 (s, 3H), 3.83 (s, 6H),
6.33 (d, 4J = 2.3 Hz, 1H), 6.53 (dd, 3J = 9.0 Hz, 4J = 2.3 Hz, 1H), 7.87 (s, 1H), 9.12 (d, J = 9.0 Hz, 1H) [33].
Chemical characterization of (Z)-3-methyl-4-(4-methylbenzylidene) isoxazol-5 (4H)-one (5c)
Yellow solid, mp: 129-130 °C, Yield: 97%; 1H NMR (500 MHz, CDC13): δ (ppm): 2.13 (s, 3H), 2.38 (s, 3H),
7.16 (d, J = 8.0 Hz, 2H), 7.32 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H) [15].
Chemical characterization of (Z)-4-(4-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (5d)
Yellow solid, mp: 172-173 °C, Yield: 93%; 1H NMR (500 MHz, DMSO-d6): δ (ppm): 2.21 (s, 3H), 3.86 (s,
3H), 7.01 (d, J = 8.9 Hz, 2H), 7.31 (s, 1H), 8.35 (d, J = 8.9 Hz, 2H) [35].
Chemical characterization of (Z)-4-(4-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (5e)
Yellow solid, mp: 215-216 °C, Yield: 95%; 1H NMR (500 MHz, DMSO-d6): δ (ppm): 2.23 (s, 3H), 6.85 (d, J
= 9.2 Hz, 2H), 7.64 (s, 1H), 8.55 (d, J = 9.2 Hz, 2H), 11.03 (s, 1H) [35].
Chemical characterization of (Z)-4-(3-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (5f)
Yellow solid, mp: 206-208 °C, Yield: 93%; 1H NMR (500 MHz, DMSO-d6): δ (ppm): 2.18 (s, 3H), 7.08 (d, J
= 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.75 (s, 1H), 7.85 (s, 1H), 9.80 (s,1H) [15].
S15
Chemical characterization of (Z)-4-(2-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (5g)
Yellow solid, mp: 195-196 °C, Yield: 91%; 1H NMR (500 MHz, DMSO-d6): δ (ppm): 2.23 (s, 3H), 6.79 (d, J
＝6.8 Hz, 1H), 7.01 (t, J ＝6.8 Hz, 1H), 7.36 (t, J ＝7.4 Hz, 1H), 8.01 (s, 1H), 8.62 (d, J ＝7.4 Hz, 1H), 11.02
(s, 1H) [35].
Chemical characterization of (Z)-4-(4-(dimethylamino) benzylidene)-3-methylisoxazol-5(4H)-one (5h)
Red solid, mp: 205-207 °C, Yield: 96%; 1H NMR (500 MHz, CDC13): δ (ppm): 2.32 (s, 3H), 3.20 (s, 6H), 6.85
(dd, 3J = 8.4, 4J = 1.2 Hz, 2H), 7.34 (s, 1H), 8.53 (d, 3J = 8.4, 4J = 1.2 Hz, 2H) [27].
Chemical characterization of (Z)-4-benzylidene-3-methylisoxazol-5(4H)-one (5i)
Yellow solid, mp: 141-142 °C, Yield: 95%; 1H NMR (500 MHz, CDC13): δ (ppm): 2.24 (s, 3H), 7.35 (s, 1H),
7.43 (t, J = 7.8 Hz, 2H), 7.51 – 7.54 (m, 1H), 8.29 (dd, 3J = 7.4, 4J = 1.3 Hz, 2H) [15].
S16
Chemical characterization of (Z)-3-methyl-4-(thiophen-2-ylmethylene) isoxazol-5(4H)-one (5j)
Yellow solid, mp: 143-145 °C, Yield: 97%; IR (KBr) cm-1: 3078, 2972, 1735, 1608, 1409, 1305, 1217, 1128,
997, 869, 742, 572, 1H NMR (500 MHz, DMSO-d6) δ (ppm): 2.23 (s, 3H), 7.36 (t, J = 4.4 Hz, 1H), 8.19 – 8.20
(d, J = 3.8 Hz, 1H), 8.24 (s, 1H), 8.29 – 8.30 (d, J = 5.4 Hz, 1H).
Fig. 14. FT IR spectrum of (Z)-3-methyl-4-(thiophen-2-ylmethylene) isoxazol-5(4H)-one (5j).
S17
Fig. 15. 1H NMR spectrum of (Z)-3-methyl-4-(thiophen-2-ylmethylene) isoxazol-5(4H)-one (5j) in DMSO-d6.
Fig. 16. 1H NMR spectrum of (Z)-3-methyl-4-(thiophen-2-ylmethylene) isoxazol-5(4H)-one (5j) in DMSO-d6
(Expanded aliphatic region).
S18
Fig. 17. 1H NMR spectrum of (Z)-3-methyl-4-(thiophen-2-ylmethylene) isoxazol-5(4H)-one (5j) in DMSO-d6
(Expanded aromatic region).
S19
Chemical characterization of (Z)-3-methyl-4-(3-phenylallylidene) isoxazol-5(4H)-one (4l)
Yellow solid, mp: 173-175 °C, Yield: 90%; IR (KBr) cm-1: 3020, 2970, 1747, 1614, 1587, 1450, 1303, 1147,
1108, 995, 850, 756, 541, 1H NMR (500 MHz, DMSO- d6): δ (ppm): 2.18 (s, 3H), 7.20 (d, J = 4.0 Hz, 1H), 7.29
– 7.33 (m, 3H), 7.61– 7.65 (m, 2H), 7.79 (d, J =11.7 Hz, 1H), 8.07 – 8.12 (dd, J = 11.7 Hz, J = 4.0 Hz, 1H).
Fig. 18. FT IR spectrum of (Z)-3-methyl-4-(3-phenylallylidene) isoxazol-5(4H)-one (4l).
S20
Fig. 19. 1H NMR spectrum of (Z)-3-methyl-4-(3-phenylallylidene) isoxazol-5(4H)-one (4l) in DMSO-d6.
Fig. 20. 1H NMR spectrum of (Z)-3-methyl-4-(3-phenylallylidene) isoxazol-5(4H)-one (4l) in DMSO-d6
(Expanded aliphatic region).
S21
Fig. 21. 1H NMR spectrum of (Z)-3-methyl-4-(3-phenylallylidene) isoxazol-5(4H)-one (4l) in DMSO-d6
(Expanded aromatic region).
S22