Efficient regioselective synthesis of 4- and 5-substituted isoxazoles under thermal and microwave conditions

Article abstract of DOI:10.1002/jhet.5570450521

(Chemical Equation Presented) The [2+3] cycloaddition reaction between nitrile oxides 2 and the captodative olefins 1 or the methyl crotonate derivatives 4 is regioselective and leads to the formation of the 5-substituted amino-isoxazole 3 or the 4-substi

Full text of DOI:10.1002/jhet.5570450521

Sep-Oct 2008
1385
Efficient Regioselective Synthesis of 4- and 5-Substituted
Isoxazoles under Thermal and Microwave Conditions
Jamal Lasri* [a], Suman Mukhopadhyay [a] and M. Adília Januário Charmier*[a,b]
[a] Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, TU Lisbon, Av. Rovisco Pais,
1049-001, Lisbon, Portugal.
[b] Universidade Lusófona de Humanidades e Tecnologias, Av. Campo Grande nº 376,
1749-024, Lisbon, Portugal.
e-mail: jamal.lasri@ist.utl.pt; adilia.charmier@ist.utl.pt
Received February 18, 2008
R1
NR2
CN
R1CH
C
NR2
O
R
N
+
-
O
RC
N
MeO2C
R
Me
O
CO2Me
Cl
N
MeCH
C
The [2+3] cycloaddition reaction between nitrile oxides 2 and the captodative olefins 1 or the methyl
crotonate derivatives 4 is regioselective and leads to the formation of the 5-substituted amino-isoxazole 3
or the 4-substituted methoxycarbonyl-isoxazole 5 derivatives, respectively. All these reactions are greatly
accelerated by microwave irradiation without changing their regioselectivity with respect to the thermal
conditions.
J. Heterocyclic Chem., 45, 1385 (2008).
INTRODUCTION
RESULTS AND DISCUSSION
Heterocyclic compounds are of considerable interest
because of their extensive use in the design of biologically
active molecules and advance organic materials [1].
Isoxazoles are very important class of compounds among
them because of their presence in many biologically
active systems [2]. Moreover it can be used as a potential
synthetic reagent as masked 1,3-dicarbonyl systems due
to their ring-opening reactions [3]. Among the several
synthetic strategies to isolate isoxazole compounds most
of them are based on the high reactivity of the CꢀN+-O-
group, which reacts with the aliphatic triple bond and
double bond to afford the isoxazole and isoxazoline,
respectively [4]. Regioselectivity is one of the most
interesting features of this type of cycloaddition reactions
where the nature of the substituent play an important role
in the formation of the final products [5]. Recently, we
have reported [6] that microwave irradiation can
accelerate the 1,3-dipolar cycloaddition reactions
remarkably. Herein we describe one convenient
regioselective methodology to obtain 4- or 5-substituted
isoxazole derivatives by the action of the nitrile oxides on
methyl crotonate derivatives or captodative olefins,
respectively, under thermal as well as microwave
conditions.
We have studied the reactions of the captodative
alkenes (R1)C(H)=C(R2)(CN) 1 with various alkyl/aryl
nitrile oxides RCꢀN+O- 2. To prevent the dimerization
of nitrile oxides they were prepared in situ in the
presence of dipolarophiles. Generally, the [2+3]
cycloaddition reactions between olefins 1 and nitrile
oxides 2 are not very fast and it takes 1-3 days
depending on the nature of the olefin used under
stirring at room temperature or refluxing conditions.
The solvent was removed under reduced pressure and
the residue was purified by column chromatography on
silica gel by elution with hexane/ethyl acetate
producing isoxazoles 3 as exclusive products, in
moderate to very good yields (98-41%) (Scheme 1).
The expected isoxazolines could not be detected most
likely due to the evolution of HCN gas, which helps in
driving the reaction to give isoxazoles.
These reactions are greatly accelerated by focused
microwave irradiation (70 ºC, 300 Watt), taking 1-3 h,
whereas conventional heating methods require much
longer times. The yields of the isoxazoles 3 synthesized
by this way are comparable with the thermal method (see
Experimental Section).

1386
J. Lasri, S. Mukhopadhyay and M. A. Januário Charmier
Vol 45
Scheme 1
Scheme 2
R2
O
R1
O
H
R
CN
CN
R2
+
N
-
O
+
RC
R1CH
C
H
N
H
O
H+, H2O
N
O
O
1a: R1 = H, R2 = Morph
1b: R1 = H, R2 = NMePh
1c: R1 = Ph, R2 = NH2
2a: R = Me
2b: R = Et
2c: R = Ph
Ph
Ph
N
N
- HCN
R2
3c´
3c
2d: R = 2-OH-3-Cl-C6H3
1d: R1 = Ph, R2 = NHCO2Et
Morph =
N
O
R1
4
5
3
O
R
N
confirm that the isoxazoles are substituted at 5-position by
the amino moiety [11].
3a: R = Me, R1 = H, R2 = Morph
3b: R = Et, R1 = H, R2 = Morph
3c: R = Ph, R1 = H, R2 = Morph
3d: R = 2-OH-3-Cl-C6H3, R1 = H, R2 = Morph
3e: R = Me, R1 = H, R2 = NMePh
3f: R = Ph, R1 = H, R2 = NMePh
3g: R = Me, R1 = Ph, R2 = NH2
3h: R = Ph, R1 = Ph, R2 = NH2
The [2+3] cycloaddition reaction between nitrile oxides
2 and the captodative olefins 1 is regioselective and leads
to the formation of the isoxazoles 3 as unique products
substituted in position 5 by the amino moiety instead of
the expected isoxazolines, by eliminating HCN gas. The
transient existence of the isoxazolines may be explained
due to the presence of two groups (cyano and amino)
geminal to the ꢁ oxygen atom.
3i: R = Me, R1 = Ph, R2 = NHCO2Et
3j: R = Ph, R1 = Ph, R2 = NHCO2Et
The obtained isoxazoles 3a-j were characterized by
elemental analyses, IR and 1H and 13C{1H} spectro-
scopies, and FAB-MS. Their IR spectra do not show the
typical NꢀC band at ca. 2240 cm-1 and display two strong
bands ca. 1570 cm-1 and ca. 1600 cm-1 corresponding to
N=C and C=C, respectively, due to the isoxazole ring, in
agreement with the literature [7]. In the 1H NMR
spectrum of the compounds 3a-3f the ethylenic proton
was detected in the range 4.95-5.90 ppm. To ascertain the
position of the amino moiety for the di-substituted
isoxazoles 3a-3f, we compare these results with similar
compound synthesized earlier. Döpp et al [8] reported the
synthesis of the 4-(3-phenylisoxazol-5-yl)morpholine 3c
by reacting benzonitrile oxide with 4-ethynylmorpholine.
The authors found the signal for the ethylenic proton at
5.30 ppm whereas in our case we observed it at 5.35 ppm
confirming that the amino moiety is in position 5. In the
13C{1H} NMR of 3a-3f the corresponding signals of C-3,
C-4 and C-5 are detected in the range of 161.3-169.4,
74.1-81.3 and 169.1-179.2 ppm, respectively and these
results are in agreement with those reported in the
literature [9].
To orient the regioselectivity of the cycloaddition
reaction towards the 4-substituted cycloadducts, we have
purposefully taken two geminal groups (CO2Me, Cl) in
the same ethylenic carbon atom. The reaction between ꢁ-
chloro methyl crotonate 4a and nitrile oxides 2 furnished
the isoxazoles 5 as the exclusive products, in moderate to
good yields (63-39%) (Scheme 3). The expected
isoxazolines could not be detected also in this case
because of the evolution of HCl gas, which helps in
driving the reaction to give the final compounds. The
presence of chloro substituent geminal to the ester
functional group in 4a reinforces the electron-
withdrawing effect of methoxycarbonyl group and helps
the nucleophilic attack to occur at ꢂ carbon atom. Similar
reactions without the chloro substituent furnished
mixtures of isoxazolines where the major product is the
result of nucleophilic attack at ꢁ position [5e].
Scheme 3
Me
O
MeO2C
Cl
H
CO2Me
Cl
+
-
O
+
Moreover, the acid hydrolysis of the isoxazole 3c
gives the lactone 3c´ as exclusive product which has
been confirmed by the characteristic IR band of the
carboxylic group of lactone at 1805 cm-1 [4c,10]. This
result also strongly suggests that the initial isoxazole 3c
was substituted by the morpholine in the position 5
(Scheme 2).
RC
N
MeCH
C
R
N
2a: R = Me
2c: R = Ph
2e: R = Br
4a
- HCl
Me
MeO2C
4
5
3
O
R
N
1
Comparison of H and 13C{1H} NMR spectroscopic
5a: R = Me
5c: R = Ph
5e: R = Br
data between the tri-substituted isoxazoles 3g-3j with the
similar compounds reported previously by other groups

Sep-Oct 2008
Efficient Regioselective Synthesis of 4- and 5-Substituted Isoxazoles
1387
EXPERIMENTAL
The obtained isoxazoles 5 were characterized by
elemental analyses, IR and 1H and 13C{1H}
spectroscopies, and FAB-MS. Their IR show the typical
bands of isoxazole ring along with a strong band at ca.
Material and instrumentation. Solvents and reagents were
purchased from Aldrich and dried by usual procedures. The
captodative olefins 1 [13], the methyl crotonate derivatives 4
[14], the olefins 6 [15] and the nitrile oxides 2a-2b [16], 2c-2d
[5e] and 2e [17] were prepared according to published methods.
C, H and N elemental analyses were carried out by the
1
1730 cm-1 due to the carbonyl of ester. All the H and
13C{1H} NMR are in agreement with the literature [12].
In another alternative route strategic introduction of
electron-donating group containing amino moiety like
morpholine at ꢀ with respect to the ester makes it possible
to synthesize the same isoxazoles 5 starting from methyl
3-morpholinobut-2-enoate 4b and nitrile oxides 2. In this
case the morpholine could be isolated at the end and no
traces of isoxazolines have been observed (Scheme 4).
Similar results were reported earlier when pyrrolidine
enamine of ethyl acetoacetate reacts with nitroethane to
give ethyl 3,5-dimethyl-4-isoxazolecarboxylate in good
yields [12a].
1
Microanalytical Service of the Instituto Superior Técnico. H
and 13C NMR spectra (in CDCl3) were measured on a Varian
Unity 300 spectrometer at ambient temperature. Positive-ion
FAB mass spectra were obtained on a Trio 2000 instrument by
bombarding 3-nitrobenzyl alcohol (NBA) matrixes of samples
with 8 keV (ca 1.28 x 1015 J) Xe atoms. H and 13C chemical
1
shifts (ꢂ) were expressed in ppm relative to Si(Me)4. Infrared
spectra (4000-400 cm-1) were recorded on a Bio-Rad FTS
3000MX and a Jasco FT/IR-430 instruments in KBr pellets and
the wavenunbers are in cm-1. The microwave irradiation
experiments were undertaken in a focused microwave CEM
Discover reactor (10 mL, 13 mm diameter, 300 W) which is
fitted with a rotational system and an IR detector of temperature.
Scheme 4
Synthesis of isoxazoles 3 and 5.
Me
Morph
MeO2C
H
(i) Conventional method. In a typical experiment, 0.02 mol of
nitroethane, 0.04 mol of phenyl isocyanate and 0.02 mol of olefin
were dissolved in 30 mL of dry benzene. A solution of 0.02 mol of
triethylamine dissolved in 10 mL of benzene was added drop wise
with constant stirring. The reaction was carried out for 20 min at
room temperature upon which a precipitation of diphenyl urea was
observed along with the evolution of carbon dioxide. Then the
mixture was refluxed for 2 days. After cooling it was diluted with
10 mL of benzene and the diphenyl urea was filtered off. The
solvent of resulting mixture was removed in vacuo. The crude
residue was purified by column chromatography on silica
(Hexane/Ethyl acetate 4:1) followed by evaporation of the solvent
in vacuo to give the final isoxazole.
(ii) By focused microwave irradiation in solution. The
reagents and solvent were added to a cylindrical Pyrex tube
which was then placed in a focused microwave CEM Discover
reactor (10 mL, 13 mm diameter, 300 W) which is fitted with a
rotational system and an IR detector of temperature. After two
hours of reaction at 70 ºC, the mixture was allowed to cool
down, the solvent was removed in vacuo and the crude residue
was purified as indicated in (i).
Compound 3a: Method (i) (78% yield), method (ii) (80%
yield). Oil. IR (cm-1): 1600 (C=N) and (C=C). 1H NMR (CDCl3),
ꢂ: 2.20 (s, 3H, CH3), 3.10-3.45 (m, 4H, CH2), 3.50-3.95 (m, 4H,
CH2), 4.95 (s, 1H, CH). 13C{1H} NMR (CDCl3), ꢂ: 11.7 (CH3),
46.6 (CH2), 65.9 (CH2), 79.5 (CH), 161.3 (C=N), 170.9 (NCO).
FAB+-MS, m/z: 168 [M]+. Anal. Calcd for C8H12N2O2: C, 57.13;
H, 7.19; N, 16.65. Found: C, 57.23; H, 7.06; N, 16.57.
Compound 3b: Method (i) (75% yield), method (ii) (77%
yield). Oil. IR (cm-1): 1600 (C=N) and (C=C). 1H NMR (CDCl3),
ꢂ: 1.10 (t, JHH 6 Hz, 3H, CH3), 2.65 (q, JHH 6 Hz, 2H, CH2), 3.10-
3.45 (m, 4H, CH2), 3.50-3.95 (m, 4H, CH2), 4.95 (s, 1H, CH).
13C{1H} NMR (CDCl3), ꢂ: 12.7 (CH3), 20.0 (CH2CH3), 46.8
(CH2), 65.2 (CH2), 78.1 (CH), 166.9 (C=N), 170.9 (NCO).
FAB+-MS, m/z: 182 [M]+. Anal. Calcd for C9H14N2O2: C, 59.32;
H, 7.75; N, 15.37. Found: C, 59.34; H, 7.76; N, 15.35.
Me
+
-
+
RC N O
C
CHCO2Me
O
Morph
R
N
2a: R = Me
2c: R = Ph
2e: R = Br
4b
- MorphH
Morph =
N
O
5a, 5c, 5e
The [2+3] cycloaddition reaction between nitrile oxides
2 and methyl crotonate derivatives 4 is regioselective and
leads to the formation of the isoxazoles 5 as exclusive
product substituted in position 4 by the methoxycarbonyl
group.
Interestingly, sometimes the presence of halo or
methylthio atoms in position ꢁ or ꢀ with respect to the
ester of the type (X)(Y)C=C(Z)(CO2Me) (6a X = Me, Y =
Cl, Z = H; 6b X = Me, Y = SMe, Z = H; 6c X =
CH(OMe)2, Y = Br, Z = H; 6d X = CH(OMe)2, Y = H, Z
= Br) inhibits the [2+3] cycloaddition reaction completely
and only the starting material was recovered
quantitatively. Similar observations were also reported
[12a] in the case of ꢀ-alkoxyacrylic esters.
CONCLUSIONS
The results of this work show that the [2+3]
cycloaddition reaction between nitrile oxides 2 and the
captodative olefins 1 or the methyl crotonate derivatives 4
is regioselective and leads to the formation of the 5-
substituted amino-isoxazole
3 or the 4-substituted
methoxycarbonyl-isoxazole 5 derivatives, respectively, as
exclusive products. Microwave irradiation promotes the
[2+3] cycloaddition reaction by shortening the reaction
time without changing the regioselectivity relatively to
conventional heating method.
Compound 3c: Method (i) (98% yield), method (ii) (97%
yield). Mp: 89 °C. IR (cm-1): 1600 (C=N) and (C=C). 1H NMR
(CDCl3), ꢂ: 3.20-3.50 (m, 4H, CH2), 3.65-3.95 (m, 4H, CH2),

1388
J. Lasri, S. Mukhopadhyay and M. A. Januário Charmier
Vol 45
5.35 (s, 1H, CH), 7.20-7.80 (m, 5H, aromatic). 13C{1H} NMR
(CDCl3), ꢀ: 46.8 (CH2), 65.9 (CH2), 76.9 (CH), 126.6-129.8
(Caromatic), 169.4 (C=N), 171.4 (NCO). FAB+-MS, m/z: 230 [M]+.
Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.14; N, 12.17. Found:
C, 68.10; H, 6.17; N, 12.34.
Compound 3d: Method (i) (51% yield), method (ii) (56%
yield). Mp: 92 °C. IR (cm-1): 1600 (C=N) and (C=C). 1H NMR
(CDCl3), ꢀ: 3.20-3.50 (m, 4H, CH2), 3.65-3.95 (m, 4H, CH2),
5.90 (s, 1H, CH), 7.00-7.70 (m, 3H, aromatic). 13C{1H} NMR
(CDCl3), ꢀ: 49.4 (CH2), 64.0 (CH2), 74.1 (CH), 125.8-163.3
(Caromatic), 163.4 (C=N), 179.2 (NCO). FAB+-MS, m/z: 280 [M]+.
Anal. Calcd for C13H13N2ClO3: C, 55.62; H, 4.66; N, 9.98.
Found: C, 55.62; H, 4.65; N, 9.96.
Compound 3e: Method (i) (58% yield), method (ii) (60%
yield). Oil. IR (cm-1): 1610 (C=N) and (C=C). 1H NMR (CDCl3),
ꢀ: 2.18 (s, 3H, CH3), 3.30 (s, 3H, CH3N), 5.00 (s, 1H, CH), 7.00-
8.00 (m, 5H, aromatic). 13C{1H} NMR (CDCl3), ꢀ: 11.7 (CH3),
38.2 (CH3N), 81.3 (CH), 122.6-144.9 (Caromatic), 161.4 (C=N),
169.1 (NCO). FAB+-MS, m/z: 188 [M]+. Anal. Calcd for
C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.26; H,
6.62; N, 15.01.
NMR (CDCl3), ꢀ: 2.50 (s, 3H, CH3CN), 2.75 (s, 3H, CH3), 3.95
(s, 3H, CH3O). 13C{1H} NMR (CDCl3), ꢀ: 8.2 (CH3CO), 10.5
(CH3), 53.9 (CH3O), 124.3 (CCO2), 158.8 (C=N), 162.5
(CH3CO), 165.5 (CO2CH3). FAB+-MS, m/z: 155 [M]+. Anal.
Calcd for C7H9NO3: C, 54.18; H, 5.85; N, 9.03. Found: C, 54.05;
H, 5.85; N, 9.01.
Compound 5c: Method (i) (63% yield), method (ii) (65%
yield). Oil. IR (cm-1): 1725 (CO2Me), 1600 (C=C) and (C=N).1H
NMR (CDCl3), ꢀ: 2.75 (s, 3H, CH3), 3.95 (s, 3H, CH3O), 7.25-
7.95 (m, 5H, aromatic). 13C{1H} NMR (CDCl3), ꢀ: 8.9 (CH3),
52.6 (CH3O), 120.4 (CCO2), 128.1-131.0 (Caromatic), 155.7 (C=N),
158.3 (CH3CO), 168.9 (CO2CH3). FAB+-MS, m/z: 217 [M]+.
Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found:
C, 66.42; H, 5.10; N, 6.34.
Compound 5e: Method (i) (39% yield), method (ii) (40%
yield). Oil. IR (cm-1): 1750 (CO2Me), 1598 (C=C) and (C=N).1H
NMR (CDCl3), ꢀ: 2.70 (s, 3H, CH3), 3.95 (s, 3H, CH3O).
13C{1H} NMR (CDCl3), ꢀ: 8.8 (CH3), 52.9 (CH3O), 122.3
(CCO2), 144.3 (CH3CO), 155.7 (C=N), 156.9 (CO2CH3). FAB+-
MS, m/z: 219 [M]+. Anal. Calcd for C6H6BrNO3: C, 32.75; H,
2.75; N, 6.37. Found: C, 32.79; H, 2.73; N, 6.42.
Compound 3f: Method (i) (74% yield), method (ii) (76%
yield). Mp: 81 °C. IR (cm-1): 1610 (C=N) and (C=C). 1H NMR
(CDCl3), ꢀ: 3.30 (s, 3H, CH3N), 5.50 (s, 1H, CH), 7.00-8.00 (m,
10H, aromatic). 13C{1H} NMR (CDCl3), ꢀ: 38.3 (CH3N), 78.7
(CH), 122.9-144.8 (Caromatic), 163.7 (C=N), 169.7 (NCO). FAB+-
MS, m/z: 250 [M]+. Anal. Calcd for C16H14N2O: C, 76.77; H,
5.64; N, 11.20. Found: C, 76.79; H, 5.59; N, 11.48.
Acknowledgement. This work has been partially supported
by the Fundação para a Ciência e a Tecnologia (FCT) and its
POCI 2010 program (FEDER funded) (Portugal). S. M.
expresses gratitude to FCT for his post-doc fellowship (grant
SFRH/BPD/14690/2003) and J. L. to the FCT and the Instituto
Superior Técnico (IST) for a research contract (Ciência 2007
program).
Compound 3g: Method (i) (55% yield), method (ii) (59%
yield). Mp: 158 °C. IR (cm-1): 1600 (C=N) and (C=C). 1H NMR
(CDCl3), ꢀ: 2.50 (s, 3H, CH3), 4.50 (s, br, 2H, NH), 7.20-7.60
(m, 5H, aromatic). 13C{1H} NMR (CDCl3), ꢀ: 11.6 (CH3), 109.1
(CPh), 127.1-128.9 (Caromatic), 167.4 (C=N), 174.2 (NCO). FAB+-
MS, m/z: 175 [M+1]+. Anal. Calcd for C10H10N2O: C, 68.95; H,
5.78; N, 16.08. Found: C, 68.76; H, 5.78; N, 16.25.
Compound 3h: Method (i) (72% yield), method (ii) (70%
yield). Mp: 160 °C. IR (cm-1): 1600 (C=N) and (C=C). 1H NMR
(CDCl3), ꢀ: 4.60 (s, br, 2H, NH), 7.20-7.80 (m, 10H, aromatic).
13C{1H} NMR (CDCl3), ꢀ: 95.3 (CPh), 127.4-136.7 (Caromatic),
162.1 (NCO), 167.6 (C=N). FAB+-MS, m/z: 236 [M]+. Anal.
Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.85. Found: C,
76.75; H, 5.26; N, 11.70.
Compound 3i: Method (i) (41% yield), method (ii) (44%
yield). Mp: 150 °C. IR (cm-1): 1730 (CO2Et), 1600 (C=C), 1570
(C=N). 1H NMR (CDCl3), ꢀ: 1.20 (t, JHH 7.1 Hz, 3H, CH3), 2.20
(s, 3H, CH3), 3.50 (q, JHH 7.1 Hz, 2H, CH2), 6.50 (s, br, 1H,
NH), 7.00-7.60 (m, 5H, aromatic). 13C{1H} NMR (CDCl3), ꢀ:
11.5 (CH3), 14.5 (CH3CH2), 61.3 (CH2), 108.3 (CPh), 128.1-
129.6 (Caromatic), 153.1 (NHCO), 156.4 (C=N), 161.3 (NCO).
FAB+-MS, m/z: 246 [M]+. Anal. Calcd for C13H14N2O3: C, 63.40;
H, 5.73; N, 11.37. Found: C, 63.46; H, 5.75; N, 11.34.
Compound 3j: Method (i) (47% yield), method (ii) (50%
yield). Mp: 155 °C. IR (cm-1): 1733 (CO2Et), 1590 (C=C), 1570
(C=N). 1H NMR (CDCl3), ꢀ: 1.18 (t, JHH 7.0 Hz, 3H, CH3), 4.18
(q, JHH 7.0 Hz, 2H, CH2), 7.00-7.60 (m, 10H, aromatic), 9.20 (s,
br, 1H, NH). 13C{1H} NMR (CDCl3), ꢀ: 14.2 (CH3), 62.7 (CH2),
107.5 (CPh), 128.1-129.6 (Caromatic), 152.5 (NHCO), 157.3
(C=N), 162.2 (NCO). FAB+-MS, m/z: 308 [M]+. Anal. Calcd for
C18H16N2O3: C, 70.10; H, 5.23; N, 9.08. Found: C, 69.94; H,
5.14; N, 9.23.
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Compound 5a: Method (i) (39% yield), method (ii) (40%
yield). Oil. IR (cm-1): 1730 (CO2Me), 1610 (C=C) and (C=N).1H

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