5-Isoxazolecarboxaldehyde: A novel substrate for fast Baylis-Hillman reaction

Article abstract of DOI:10.1055/s-2001-10815

3-Aryl-5-isoxazolecarboxaldehyde undergoes fast Baylis-Hillman reaction with a variety of activated alkenes to yield the corresponding adducts in excellent yields. Some of the Baylis-Hillman adducts reported herein have been subsequently modified to obtai

Full text of DOI:10.1055/s-2001-10815

276
PAPER
5-Isoxazolecarboxaldehyde: A Novel Substrate for Fast Baylis-Hillman
Reaction1
Arundhati Patra,a Sanjay Batra,a* Bijoy Kundu,a Bhawani Shankar Joshi,b Raja Roy,b Amiya Prasad Bhaduria
aMedicinal Chemistry Division, bRSIC Division, Central Drug Research Institute, Lucknow 226 001, India
Fax +91(522)223405, +91(522)223938, E-mail: batra_san@yahoo.co.uk, root@cscdri.ren.nic.in
Received 16 August 2000; revised 5 October 2000
reaction conditions, both physical and chemical, have
been attempted with excellent results.4 On the other hand,
the search for fast reacting electrophiles has led to the
identification of diethyl ketomalonate, furfuraldehyde,
Abstract: 3-Aryl-5-isoxazolecarboxaldehyde undergoes fast Bayl-
is-Hillman reaction with a variety of activated alkenes to yield the
corresponding adducts in excellent yields. Some of the Baylis-Hill-
man adducts reported herein have been subsequently modified to
obtain isoxazole substituted pyrazolin-3-ones and g-butyrolactones. glyoxalate, 2-cycloalkene-1-ones, etc. as substrates,
which all undergo a fast Baylis-Hillman reaction. Indeed,
it has also been reported that even simple aldehydes can
react very fast either with excess of a,b-unsaturated cy-
cloketones in the presence of TiCl4 or with activated alk-
enes in presence of DABCO at low temperatures to
furnish Baylis-Hillman adducts.4c,e
Key words: 5-isoxazolecarboxaldehyde, Baylis-Hillman reaction,
pyrazolin-3-ones, HTIB, g-butyrolactones
The Baylis-Hillman reaction and its synthetic utility is
one of the most attractive and extensively studied subject
of recent times.2 Its importance in solution and solid phase
synthetic organic chemistry is enormous as it leads to syn-
thetically useful multifunctional molecules.2a,3 However,
the inherent drawbacks associated with this reaction are
the slow reaction rates and limited scope of substrate. To
circumvent these shortcomings various alterations in the
In our efforts directed towards studying the chemical
transformations of 3-aryl-5-isoxazolecarboxaldehyde, we
observed that these molecules undergo extremely fast
Baylis-Hillman reactions under ordinary conditions.
Substituted isoxazoles are considered to be one of the
most versatile heteroaromatic synthons because they can
Reagents and conditions: (a) CH2=CHR’, DABCO, r.t.; (b) AcCl, pyridine, DMAP (cat.), CH2Cl2, r.t.; (c) NH2NH2.H2O, MeOH, r.t.;
(d) (CH3CO)2CH2, K2CO3, EtOH, reflux; (e) 20% TFA in CH2Cl2, r.t.; (f) HTIB, CH2Cl2, r.t.
Scheme
Synthesis 2001, No. 2, 276–280 ISSN 0039-7881 © Thieme Stuttgart · New York

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5-Isoxazolecarboxaldehyde
277
Table 1 Physical Data, Yieldsa and Reaction Timesb,c of the New Compounds Preparedd
Compound
R
R¢
Reaction time
Yield (%)
Mp (oC)
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8c
8d
9a
9b
9c
9d
10a
10b
10c
10d
(E)-11a
(E)-11b
(E)-11c
(E)-11d
(Z)-11a
(Z)-11b
(Z)-11c
(Z)-11d
(E)-12a
(E)-12b
(E)-12c
(E)-12d
(Z)-12c
(E)-13a
(E)-13b
(E)-13c
(E)-13d
(Z)-13c
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Bu-n
CO2Bu-n
CO2Bu-n
CO2Bu-n
CO2Bu-n
CO2Bu-t
CO2Bu-t
CO2Bu-t
CO2Bu-t
CO2Bu-t
CN
CN
CN
CN
CN
COMe
COMe
COMe
COMe
COMe
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
15 min
10 min
20 min
30 min
25 min
15 min
15 min
15 min
30 min
20 min
20 min
15 min
20 min
20 min
25 min
20 min
15 min
30 min
25 min
30 min
15 min
15 min
10 min
30 min
30 min
15 min
15 min
15 min
35 min
30 min
5 h
56 h
5 h
7 h
5 h
5 h
5 h
7 h
10 min
10 min
15 min
25 min
2 h
2 h
2 h
2 h
–
80
81
73
95
43
73
93
71
85
45
68
84
73
87
53
61
65
70
75
43
78
87
94
54
49
65
64
55
60
41
70
69
85
72
75
78
89
60
63
91
84
57
67
71
70
79
2
64−65
72−74
oil
108−110
oil
oil
95−96
oil
70−2
90−92
oil
88−90
oil
90−92
101−102
78−80
155−156
oil
79−80
110−112
74−76
54−56
oil
110−111
oil
oil
oil
oil
95−97
oil
68−70
oil
oil
94−96
oil
38−40
108−110
82−84
172−174
203−205
197−199
179−180
105−107
69−70
oil
4-Me
2-Cl
4-OBn
3-NO2
H
4-Me
2-Cl
4-OBn
3-NO2
H
4-Me
2-Cl
4-OBn
3-NO2
H
4-Me
2-Cl
4-OBn
3-NO2
H
4-Me
2-Cl
4-OBn
3-NO2
H
4-Me
2-Cl
4-OBn
3-NO2
H
4-Me
2-Cl
4-OBn
H
4-Me
2-Cl
4-OBn
H
4-Me
2-Cl
4-OBn
H
4-Me
2-Cl
4-OBn
H
4-Me
2-Cl
4-OBn
H
4-Me
2-Cl
4-OBn
2-Cl
H
112−114
oil
oil
oil
–
–
–
4 h
4 h
5 h
6 h
22 h
20 h
21 h
16 h
18 h
3
10
2
oil
91
92
95
90
68
48
64
45
54
36
139−140
174−176
158−160
157−158 (dec)
oil
153−154
160−162
140−142
168−170
oil
4-Me
2-Cl
4-OBn
2-Cl
26 h
a The reported yields are as obtained after column chromatography.
b The reaction time was determined after the addition of aldehyde and reaction carried out as neat.
c All data on the basis of 5 mol % of DABCO.
d All compounds gave satisfactory chemical analyses; C 0.40, H 0.22, N 0.34.
Synthesis 2001, No. 2, 276–280 ISSN 0039-7881 © Thieme Stuttgart · New York

278
A. Patra et al.
PAPER
be efficiently prepared and can be conveniently modified In another synthetic strategy, it was envisaged that the re-
to useful synthetic intermediates.5 Therefore, in order to action of compounds 9a-d with acetyl acetone could lead
explore the synthetic utility of these Baylis-Hillman ad- to Michael adducts as reported earlier,6 which could be
ducts some of them have been chemically transformed to subsequently cyclized to produce lactones. Accordingly,
obtain isoxazole substituted pyrazolin-3-ones and g-buty- we carried out reaction of compounds 9a-d with acetyl
rolactones. The results of this study are presented here.
acetone in the presence of potassium carbonate in 95%
ethanol. This resulted in the formation of products 11a-d,
which were obtained as mixture of E- and Z- isomers as
evidenced on the basis of 1H NMR data.7 These were sep-
arated using column chromatography. The major E-iso-
mer was then subjected to acid hydrolysis in presence of
20% TFA in dichloromethane to obtain the (E)-acid deriv-
atives 12a-d. These acids underwent facile cyclization8
in the presence of hydroxy tosyloxy iodoso benzene
(HTIB) to yield the (E)-g-butyrolactone derivatives (13a-
d). As evident from Table 1, since only compound (Z)-11c
was obtained in satisfactory yield, as a model, adopting
the similar synthetic protocol, it was converted to the cor-
responding (Z)-g-butyrolactone derivative.
The Baylis-Hillman reaction on 3-aryl-5-isoxazolecar-
boxaldehyde was realized by adding the aldehydes (1a-e)
to a pre-stirred (15-20 minutes) mixture of DABCO and
activated alkenes (Scheme). Within 10-15 minutes the re-
action went to completion as evidenced by TLC (chloro-
form: ethyl acetate, 8: 2 v/v). The products were isolated
in good yields by usual work up procedures and purified
by column chromatography (Table 1). In no case was for-
mation of dimerized product observed. Titration studies
with respect to the amount of base required for the reac-
tion led to the conclusion that even 1 mol% of base is suf-
ficient to drive the reaction to completion. The change of
base from DABCO to DBU yielded similar results.2h
Since 5-isoxazolecarboxaldehyde is an activated alde- In conclusion, our study describes 3-aryl-5-isoxazolecar-
hyde, it was considered appropriate to compare the rate of boxaldehyde as fast reacting substrates for the Baylis-
Baylis-Hillman reaction with some other activated alde- Hillman reaction leading to useful synthetic molecules.
hyde, such as furfuraldehyde that has been reported4e to
undergo fast Baylis-Hillman reaction under identical
Mps were determined in capillary tubes on a hot stage apparatus
conditions. Indeed it was observed that in comparison to
containing silicon oil and are uncorrected. IR spectra were recorded
furfuraldehyde, 5-isoxazolecarboxaldehyde shows more
than five folds better reactivity under similar reaction con-
ditions. During the studies it was also observed that addi-
tion of various solvents influenced the rate of reaction.
The best results were obtained when reaction was attempt-
ed without solvent followed by DMSO as well as DMF. In
a model experiment, the time taken for the quantitative
conversion of compound 1b to product 3b in the presence
of various solvents was determined (Table 2).
on a Perkin-Elmer FTIR spectrophotometer as KBr disc or neat. 1H
NMR spectra were recorded on a Bruker Avance DRX-300 or
Bruker DPX-200 FT spectrometers, using TMS as an internal refer-
ence; chemical shifts (d) are in ppm and J values are in Hz. Mass
spectra were recorded on a JEOL JMS-D-300 at 70 eV and the
FABMS was recorded on JEOL/ SX-102 spectrometers. Elemental
analyses were performed using a Carlo Erba 1108 microanalyzer.
R.t. is the temperature range between 20 °C and 35 °C.
Baylis-Hillman Reaction; General Procedure
To a mixture of DABCO (0.056 g, 0.5 mmol) and appropriate alk-
ene (10 mmol) that has been stirred at r.t. for 20 min was added the
appropriate aldehyde (1a-e) (10 mmol) under stirring and the reac-
tion was allowed to proceed for a period as indicated in Table 1.
(Even when all the reactants including aldehyde were mixed simul-
taneously, the reaction was complete in less than 1 h). Thereafter,
10% HCl (50 mL) was added to neutralize the base, and the reaction
mixture was extracted with EtOAc (2 ¥ 100 mL).The organic layers
were combined, washed with brine (100 mL), dried (Na2SO4), and
evaporated under vacuum to yield an oily residue. The residue was
purified by column chromatography over silica gel (230-400 mesh)
(hexane/EtOAc, 70:30) to yield the adducts as white solids or pale
yellow oils.
In order to study the synthetic utility of these Baylis-Hill-
man adducts, acetylations of compound 3a-d and 5a-d
were carried out to obtain the corresponding acetylated
derivatives 8a-d and 9a-d, respectively. The acetylated
products 8a-d upon reaction with hydrazine hydrate in
methanol furnished 1, 2-pyrazolin-3-ones (10a-d) within
10 minutes. These compounds were obtained as a mixture
of E- and Z- isomers, which were not separated.
Table 2 Influencea of Solvents on the Reaction Time (1b to 3b).
Entry
Solvent
Time
15 min
45 min
45 min
3 h
Acetylation; General Procedure
1
2
3
4
5
6
Neat
To a solution of the appropriate compound from 3a-d or 5a-d
(4 mmol) in dry CH2Cl2 (5 mL) was added pyridine (0.38 mL,
4mmol) followed by catalytic amount of 4-(N,N-dimethylami-
no)pyridine. To this was added dropwise a solution of acetyl chlo-
ride (0.67 mL, 9 mmol) in dry CH2Cl2 (3 mL) with stirring at 0 °C.
After the addition was complete, the reaction was continued at r.t.
for 5-7 h. The excess solvent and pyridine were removed under re-
duced pressure to afford a residue, which was taken up in EtOAc
(100 mL) and H2O (100 mL). The organic phase was separated,
washed with brine (80 mL), dried (Na2SO4), and concentrated in
vacuo. Purification of the residue by column chromatography over
silica gel (230-400 mesh) (hexane/EtOAc, 80:20) furnished the
acetyl derivatives (8a-d, 9a-d)
DMSO (2 mL)
DMF (2 mL)
CH2Cl2 (2 mL)
MeOH (2 mL)
THF (2 mL)
6 h
6.5 h
a The comparison was carried out by reacting 1b (1 mmol) with ethyl-
acrylate (1 equiv) in the presence of DABCO (5 mol %).
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5-Isoxazolecarboxaldehyde
279
Table 3 Spectroscopic Data of Representative Compounds
Product
MS (EI)
m/z (%)
1H NMR (CDCl3, 200 MHz/ 300 MHz) d, J (Hz)
IR (KBr/Neat)
n (cm−1)
2ba,c
273 (M+, 65.3), 212
(30.5), 158 (96.0)
2.39 (s, 3 H), 3.70 (d, 1 H, J = 8.0), 3.79 (s, 3H) 5.67 (d, 1 H, J =
8.0), 6.02 (s, 1 H), 6.36 (s, 1 H), 7.25 (d, 2 H, J = 8.0), 7.58 (d, 2 H,
J = 8.0)
3369, 1718
3485, 1708
3489, 1706
3ba,c
4ba,c
287 (M+,14.7), 241
(22.5), 186 (28.6), 160
(40.3), 158 (100)
1.29 (t, 3 H, J = 7.0), 2.39 (s, 3 H), 3.73 (d, 1 H, J = 8.0), 4.20 (q,
2 H, J = 7), 5.67 (d, 1 H, J = 8.0), 5.99 (s, 1 H), 6.45 (s, 1 H), 6.56
(s, 1 H), 7.22 (d, 2 H, J = 8.0), 7.59 (d, 2 H, J = 8.0)
315 (M+, 13.1), 228
(13.2), 186 (11.0), 167
(72.7), 158 (46.0)
0.89 (t, 3 H, J = 7.0), 1.22-138 (m, 2 H), 1.60-1.68 (m, 2 H), 2.39
(s, 3 H), 3.79 (d, 1 H, J = 8.0), 4.15 (t, 2 H, J = 7.0), 5.73 (d, 1 H,
J = 7.0), 6.12 (s, 1 H), 6.47 (s, 1 H), 6.50 (s, 1 H), 7.24 (d, 2 H, J =
8.0), 7.67 (d, 2 H, J = 8.0)
5ba,c
315 (M+, 11.1), 144 (98)
1.47 (s, 9 H), 2.39 (s, 3 H), 3.71 (d, 1 H, J = 8.0), 5.61 (d, 1 H, J =
8.0), 5.90 (s, 1 H), 6.38 (s, 1 H), 6.54 (s, 1 H), 7.25 (d, 2 H, J = 8.0),
7.60 (d, 2 H, J = 8.0)
3305, 1720
6ba,c
7ba,d
240 (M+, 28.6), 189
(14.3), 158 (81.5)
2.40 (s, 3 H), 3.05 (br s, 1 H), 5.53 (s, 1 H), 6.22 (s, 1 H), 6.68 (s,
1 H), 7.27 (d, 2 H, J = 8.0), 7.69 (d, 2 H, J = 8.0)
3398, 2225
3370, 1669
257 (M+, 18.8), 215
(31.8), 186 (42.1), 158
(100)
2.33 (s, 3 H), 2.40 (s, 3 H), 3.78 (d, 1 H, J = 8.0), 5.67 (d, 1 H, J =
7.0), 6.17, (s, 1 H), 6.56 (s, 1 H), 7.29 (d, 2 H, J = 8.0), 7.67 (d,
2 H, J = 8.0)
8ba,d
9ca,c
329 (M+, 15.4), 186
(47.6), 158 (100)
1.27 (t, 3 H, J = 7.0), 2.17 (s, 3 H), 2.39 (s, 3 H), 4.22 (q, 2 H, J =
7.0), 6.07 (s, 1 H), 6.55 (s, 1 H), 6.56 (s, 1 H), 7.24 (d, 2 H, J = 8.0),
7.77 (d, 2 H, J = 8.0)
1755, 1722
1751, 1718
1686
377 (M+, 2.4), 354 (4.2),
322 (11.0), 216 (23.5),
196 (32.1)
1.45 (s, 9 H), 2.18 (s, 3 H), 5.97 (s, 1 H), 6.48 (s, 1 H), 6.71 (s, 1H),
6.86 (s, 1H), 7.33-7.49 (m, 3 H), 7.70-7.76 (m, 1 H)
10ba,c
255 (M+, 59.2),
196 (16.1), 158 (100)
(DMSO-d6) (mixture of E- and Z-isomers): 2.38 (s, 3 H), 2.40 (s,
3 H), 2.57 (m, 4 H), 6.58 (m, 2 H), 7.28-7.34 (m, 4 H, Ar-H), 7.71-
7.76 (m, 6 H)
(E)-11cb,d
375 (M+, 19.6), 321
(14.7), 278 (29.3), 276
(70.6), 232 (16.3)
1.55 (s, 9 H), 2.19 (s, 3 H), 2.71 (t, 2 H, J = 7.0), 2.99 (t, 2 H, J =
7.0), 6.92 (s, 1 H), 7.36-7.53 (m, 4 H), 7.73-7.73 (m, 1 H)
1710, 1643
(Z)-11cb,d
(E)-12ca,c
FABMS 375
1.56 (s, 9 H), 2.19 (s, 3 H), 2.71 (s, 4 H), 6.45 (s, 1 H), 6.91 (s, 1 H),
7.33-7.49 (m, 3 H), 7.69-7.74 (m, 1 H)
1716, 1654
1695, 1639
319 (M+, 56.7), 278
(37.1), 275 (100)
(CDCl3+DMSO-d6): 2.23 (s, 3 H), 2.81 (t, 2 H, J = 7.0), 3.08 (t,
2 H, J = 7.0), 7.01 (s, 1 H), 7.37-7.47 (m, 3 H), 7.62 (s, 1 H), 7.72-
7.77 (m, 1 H)
(Z)-12ca,d
(E)-13cb,c
319 (M+, 53.6), 278
(39.7), 276 (100)
2.20 (s, 3 H), 2.79 (s, 4 H), 6.72 (s, 1 H), 7.12 (s, 1 H), 7.33-7.48
(m, 3 H), 7.69-7.73 (m, 1 H)
1699, 1649
1755, 1660
317 (M+, 34.4), 276
(68.2), 274 (100)
2.35 (s, 3 H), 3.50 (ddd, 1 H, J = 3.0, 9.0, 20.0), 3.66 (2dd, 1H,
J = 3.0, 9.0, 20.0) 4.99 (dd, 1 H, J = 5.0, 9.0), 6.99 (s, 1 H), 7.36-
7.50 (m, 4 H), 7.72-7.77 (m, 1 H)
(Z)-13cb,d
317 (M+, 9.0), 179 (11.8),
178 (100)
2.35 (s, 3 H), 3.25 (ddd, 1 H, J = 2.0, 6.0, 16.0), 3.43 (ddd, 1 H, J =
2.0, 9.0, 20.0), 4.91 (dd, 1 H, J = 6.0, 8.0), 7.05-7.07 (m, 1 H),
7.35-7.52 (m, 3 H), 7.70-7.74 (m, 1 H), 8.02 (s, 1 H)
1766, 1728
a 200 MHz
b 300 MHz.
c KBr.
d Neat.
under stirring. As soon as addition was complete, the reaction mix-
ture turned yellow and solid separated out. The product was filtered,
washed with H2O repeatedly and dried. The products were recrys-
tallized from EtOH.
Pyrazolin-3-ones; General Procedure
To the solution of the appropriate compound (8a-d) (0.6 mmol) in
MeOH (2 mL) was added hydrazine hydrate (0.12 mL, 2.4 mmol)
Synthesis 2001, No. 2, 276–280 ISSN 0039-7881 © Thieme Stuttgart · New York

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A. Patra et al.
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Michael Addition; General Procedure
J.; Kim, J. N. Tetrahedron Lett. 2000, 41, 2613.
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G. Tetrahedron 2000, 56, 2397.
A mixture of the appropriate compound (9a-d) (2.6 mmol), acetyl-
acetone (0.54 mL, 5.2 mmol), K2CO3 (0.54 g, 3.8 mmol) in 95%
EtOH (20 mL) was refluxed over a water bath for 2 h. The excess
of EtOH was removed under reduced pressure and the residue was
extracted with EtOAc (2 ¥ 100 mL). The EtOAc layers were com-
bined, dried (Na2SO4), and the organic solvent was removed in vac-
uo. The crude products were purified by column chromatography
over silica gel (230-400 mesh) (hexane/EtOAc, 90:10) to yield first
the E-isomer (major) followed by the elution of Z-isomer (minor).
g) Chamakh, A; M’hirsi, M.; Villieras, J.; Lebreton, J.; Amri,
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Hydrolysis; General Procedure
To an appropriate compound from (E)-11a-d, (Z)-11c (3.3 mmol)
was added 20% trifluoroacetic acid (10 mL) in CH2Cl2 and the re-
action mixture was stirred at r.t. for 6 h. Thereafter, the excess sol-
vent was evaporated and the residue was triturated with hexane to
furnish pure acids. These acids were recrystallized from MeOH.
g-Butyrolactones; General Procedure
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To the solution of the appropriate compound from (E)-12a-d or
(Z)-12c (2.4 mmol) in dry CH2Cl2 (15 mL) was added HTIB (0.940
g, 2.4 mmol) and the reaction was stirred at r.t. for 16 h. The reac-
tion mixture was then quenched with H2O (50 mL) and extracted
with CH2Cl2 (2 ¥ 50 mL). The organic layers were pooled, dried
(Na2SO4), and evaporated to obtain a residue. This residue, on fil-
tration through a small band of silica gel, furnished pure g-butyro-
lactone derivatives.
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Acknowledgement
The authors A. P. and B. S. J. gratefully acknowledge the financial
support from Volkswagen, Germany and CSIR, India, respectively,
in the form of fellowship. Authors also acknowledge the technical
assistance provided by Mr. Raju Arora.
(7) The E and Z stereochemistry was assigned on the basis of
NOE studies and the protons were assigned on the basis of
Hetero Multiple Quantum COSY (HMQC) experiments.
(8) Moriarty, R. M.; Vaid, R. K.; Hopkins, T. E.; Vaid, B. K.;
Prakash, O. Tetrahedron Lett. 1990, 31, 201.
References
(1) CDRI Communication No. 6031, Indian Patent applied vide
application no. NF 399/99 & 400/99.
(2) a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996,
52, 8001; and references cited therein.
b) Basavaiah, D.; Muthukumaran, K.; Sreenivasulu, B.
Synthesis 2000, 545.
c) Kim, H. S.; Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee, H.
Article Identifier:
1437-210X,E;2001,0,02,0276,0280,ftx,en;P06000SS.pdf
Synthesis 2001, No. 2, 276–280 ISSN 0039-7881 © Thieme Stuttgart · New York