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Development of methodologies for the
regioselective synthesis of four series of
Cite this: RSC Adv., 2018, 8, 4773
regioisomer isoxazoles from b-enamino diketones†
Raı G. M. Silva,a Michael J. V. da Silva,a Andrey P. Jacomini,a Sidnei Moura,b
´
a
Davi F. Back,c Ernani A. Bassoa and Fernanda A. Rosa
*
Four methodologies are reported for the regioselective synthesis of four series of regioisomer isoxazoles
from cyclocondensation of b-enamino diketones and hydroxylamine hydrochloride. Regiochemical
control was achieved by varying reaction conditions and substrate structure. The mild reaction
conditions used to access 4,5-disubstituted, 3,4-disubtituted, and 3,4,5-trisubstituted regioisomer
isoxazoles, as well as the pharmacological and synthetic potential of the products, make these novel
methodologies very powerful.
Received 14th December 2017
Accepted 20th January 2018
DOI: 10.1039/c7ra13343j
rsc.li/rsc-advances
functionalized isoxazoles from b-enamino diketone and hydrox-
ylamine. The b-enamino diketones have been employed as
Introduction
precursors in functionalized heterocycles synthesis due to their
excellent 1,3-dielectrophilic system, and in general they allow
better control of regioselectivity.6
The isoxazole is an important framework because it is the core
structure of remarkable medicinal products.1 For example,
parecoxib (anti-inammatory); sulfamethoxazole (antibiotic);
leunomide (antirheumatic); isocarboxazid (antidepressant);
and risperidone (antipsychotic) (Fig. 1). Moreover, isoxazoles are
masked 1,3-dicarbonyl equivalents,2 which serve as precursors
for natural product synthesis, as for example tetracycline anti-
biotics.2c–h For this reason, many synthetic methods have been
reported for the synthesis of functionalized isoxazoles,3 including
ring construction with functionalized precursors by 1,3-dipolar
cycloadditions4 or cyclocondensation5 reactions. One of the most
popular, oldest, and most important methods for the synthesis of
isoxazoles is cyclocondensation of 1,3-dicarbonyl with hydroxyl-
amine (Claisen isoxazole synthesis).5a–i However, this approach
suffers from frequent formation of a regioisomeric mixture of
isoxazoles with poor selectivity, harsh reaction conditions, and
a limited reaction scope. Furthermore, obtaining 4-substituted
isoxazoles using this approach has been challenging. However,
development of new cyclocondensation reactions has received
little attention. Despite these challenges, our research group was
motivated to develop a new methodology for synthesis of
Over time, we have developed regioselective synthetic meth-
odologies for the synthesis of multifunctionalized heterocycles
from b-enamino diketones and different dinucleophiles.6 Varia-
tions in reaction conditions,6e Lewis acid,6f and b-enamino dike-
tone structure6e,f have resulted in regiochemical control of
pyrazoles,6a–c,e,f pyrazolo-pyridazinones,6b,c pyrimidines,6d and their
derivatives. Thus, we believe that the enamino diketones are
potential precursors for the regioselective synthesis of functional-
ized isoxazoles by cyclocondensation with hydroxylamine. To our
knowledge, there is only a single report in the literature regarding
isoxazole synthesis from enamino diketone and hydroxylamine,
where the authors have used a symmetrical b-enamino diketone.7
a
´
´
Departamento de Quımica, Universidade Estadual de Maringa (UEM), 87030-900,
´
Maringa, PR, Brazil. E-mail: farosa@uem.br
b
´
´
e Sinteticos, Instituto de Biotecnologia,
Laboratorio de Produtos Naturais
Universidade de Caxias do Sul (UCS), 95070-560, Caxias do Sul, RS, Brazil
c
´
Departamento de Quımica, Universidade Federal de Santa Maria (UFSM), 97110-970,
Santa Maria, RS, Brazil
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for all compounds, copies of NMR spectra, and
crystallographic data. CCDC [CCDC-1589617 (2a), CCDC-1589618 (3a),
CCDC-1589619 (4a), CCDC-1589620 (5a)]. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c7ra13343j
Fig. 1 Examples of medicinal products with the isoxazole moiety.
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Table 1 Optimization of reaction conditions of 1a with NH2OH$HCl to
access 4,5-disubstituted isoxazoles regioisomers 2a and 3a
regioselectivelya
Ratiob
i
(%)
Scheme
1 Possible regioisomer isoxazoles obtained by cyclo-
condensation of b-enamino diketone with hydroxylamine.
Entry Solvent
Base
Time (h)/Temp. (ꢀC) 2a 3a Yieldc (%)
Furthermore, a study of reactivity of the b-enamino diketone
system with hydroxylamine has not yet been reported.
1
2
3
4
5
6
7
8
EtOH
—
—
—
Py
10/25
16/25
10/25
2/25
2/25
2/25
35 65 73
65 35 81
40 60 68
64 36 71
MeCN
EtOH/H2O
EtOH
MeCN
MeCN
MeCN
EtOH
MeCN
MeCN
EtOH
Analysing the reactive potential of the b-enamino diketone
precursor in the cyclocondensation reaction with hydroxyl-
amine, we observed that it would lead to formation of six
regioisomer isoxazoles (Scheme 1). Thus, continuing our
interest in this area, we report herein four methodologies to
obtain functionalized 4,5-disubstituted isoxazoles, 3,4-
disubstituted isoxazoles, and 3,4,5-trisubstituted isoxazoles
by regiochemical control of the cyclocondensation reaction of
b-enamino diketones with hydroxylamine.
Py
DBU
K2CO3 2/25
—
—
Py
Py
76 24 87
d
—
—
—
—
d
1/reux
23 77 76
54 46 78
45 55 80
62 38 74
9
10
11
3/reux
1/reux
1/reux
a
Reaction conditions: 1a (0.5 mmol), NH2OH$HCl (0.6 mmol, 1.2
b
equiv.), base (0.6 mmol, 1.2 equiv.), solvent (4 mL). Calculated from
the 1H-NMR spectrum of crude product. c Isolated yield (regioisomeric
mixture). d 2a and 3a as intractable mixtures of several products.
Results and discussion
We began this study using the b-enamino diketone 1a8 and
hydroxylamine hydrochloride (NH2OH$HCl) as model
substrates (Table 1). Gratifyingly, in EtOH at room temperature,
these substrates performed well, leading to a regioisomeric
mixture of the 4,5-disubstituted isoxazoles 2a and 3a with
selectivity favouring 3a in good yield (Table 1, entry 1). The
structure of 2a and 3a were established by NMR spectral data
and unambiguously conrmed by X-ray crystallography9a,b (see
Fig. SI 1 and 2 for full details, ESI†). Encouraged by these
results, other reaction conditions were investigated (Table 1).
First, based on data recently reported by Souza et al.,6e we
examined MeCN and the mixture H2O/EtOH (1 : 1) as solvents
in the reaction of 1a with NH2OH$HCl (Table 1, entries 2 and 3).
The use of the aprotic polar solvent MeCN resulted in 2a as the
main product in good yield (Table 1, entry 2).
On the other hand, the protic polar solvents mixture H2O/EtOH
yielded 3a as the main product (Table 1, entry 3), but this solvent
was found to be less regioselective than EtOH (Table 1, entry 1).
Next, we examined the reaction mediated by bases at room
temperature (Table 1, entries 4–7, 10 and 11). Interestingly, only
pyridine was compatible with the reaction, favouring the regio-
selective formation of 2a in EtOH and mainly in MeCN (Table 1,
entries 4 and 5). The reactions of other bases led to the formation
of 2a and 3a as intractable mixtures of several products (Table 1,
entries 6 and 7). Finally, by reacting 1a with NH2OH$HCl in EtOH
at reux, 3a was formed with higher regioselectivity (Table 1, entry
8) than at room temperature (Table 1, entry 1). In contrast, varying
the reaction temperature in MeCN we discovered that increasing
the temperature can jeopardize the regioselectivity of the reaction
(Table 1, entry 9). In general, regioisomer 2a was favoured in
MeCN with pyridine at room temperature (Table 1, entry 5),
whereas 3a was preferentially formed in EtOH at reux (Table 1,
entry 8).
Having established the reaction conditions for synthesis of
both regioisomeric 4,5-disubstituted isoxazoles 2a and 3a with
moderate regioselectivity, we became interested in reversing the
reactivity of the b-enamino diketone 1a toward hydroxylamine
hydrochloride by varying the reaction conditions, so as to access
3,4-disubstituted isoxazoles regioselectively. To our surprise,
when 1a was reacted with NH2OH$HCl in the presence of the
Lewis acid carbonyl activator BF3 (BF3$OEt2) (0.5 equiv.) in
MeCN at room temperature, the desired 3,4-disubstituted iso-
xazole 4a was formed as the main product (Table 2, entry 1). The
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structure of 4a was unambiguously established from its spectral
and X-ray crystallographic data9c (see Fig. SI 3 for full
details, ESI†).
By optimization of reaction conditions using this protocol,
we observed that regioselectivity for the formation of isoxazole
4a was dependent on the amount of BF3 (Table 2, entries 1–4)
and the solvent used (Table 2, entries 5 and 6). We obtained 4a
with high regioselectivity (90%) in good yield (79%) employing 2
equivalents of BF3 in MeCN with pyridine at room temperature
(Table 2, entry 5). The by-product mixed with 4a under these
conditions (Table 2, entry 5) was isolated and characterized as
3,5-disubstituted 4-formyl-isoxazole 5a based on NMR spectral
analysis and single crystal X-ray analysis9d (see Fig. SI 4 for full
details, ESI†).
On the basis of these observations, we have devoted our efforts
to developing a methodology which allows to access 5a regiose-
lectively. According to the data recently reported by da Silva
et al.,6f the presence of an aminoalkyl secondary group with high
steric demand (i-PrNH– or t-BuNH–) bound to the b-carbon of the
b-enamino diketone system in combination with the Lewis acid
carbonyl activator BF3 provides conditions for the regiocontrolled
reaction of b-enamino diketones with aryl hydrazines to give 3,5-
disubstituted 4-formyl-N-arylpyrazoles with high regioselectivity.
Thus, we tested the viability of this approach for the regiose-
lective preparation of 3,5-disubstituted 4-formyl-isoxazole 5a.
When we tested the reaction of b-enamino diketone 6a (ref. 6f)
(1.0 equiv.), prepared from 1a (ref. 8) (Scheme 2), with NH2-
OH$HCl (1.2 equiv.) in MeCN and BF3$OEt2 (2.0 equiv.) at reux
for 1 h, the desired isoxazole 5a was obtained with 100% regio-
selectivity and in good yield (80%) (Scheme 2, ROUTE I).
Subsequently, the efficiency of this protocol was further
improved by developing a sequential one-pot procedure to
Scheme 2 ROUTE I – Synthesis of 3,5-disubstituted 4-formyl-iso-
xazol 5a from b-enamino diketone 6a; ROUTE II – sequential one-pot
procedure to obtain 5a from b-enamino diketone 1a.
obtain isoxazole 5a directly from the b-enamino diketone 1a
(Scheme 2, ROUTE II). The best results for this procedure were
obtained by in situ generation of the b-enamino diketone
precursor 6a from treatment of 1a with tert-butylamine (1.05
equiv.) in MeCN at room temperature for 2 h, followed by the
addition of NH2OH$HCl (1.2 equiv.) and BF3$OEt2 (2.0 equiv.)
under reux of MeCN for 3 h (Scheme 2, ROUTE II). Through
this procedure 5a was also obtained with 100% regioselectivity
and a similar yield when prepared directly from the b-enamino
diketone precursor 6a (Scheme 2, ROUTE I).
Having in hand the optimal reaction conditions to access
4,5-disubstituted (regioisomers 2a and 3a, Table 1, entries 5 and
Table 2 Optimization of reaction conditions of 1a with NH2OH$HCl mediated by BF3$OEt2 to access 3,4-disubstituted isoxazole 4a
regioselectivelya
i
Ratiob (%)
Entry
Solvent
BF3$OEt2 (equiv.)
Time (h)
2a
3a
4a
5a
Yieldc (%)
1
2
3
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
0.5
1.0
1.5
2.0
2.0
2.0
18
20
24
24
5
37
22
9
—
—
64
13
8
—
—
—
36
50
70
81
90
90
—
—
—
10
10
10
—
—
—
—
79
79
—
4
5d
6d
2
a
b
Reaction conditions: 1a (0.5 mmol), NH2OH$HCl (0.6 mmol, 1.2 equiv.), room temperature, solvent (4 mL). Calculated from the 1H-NMR
spectrum of crude product. c Isolated yield (regioisomeric mixture). d Pyridine (1.4 equiv.).
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8, respectively), 3,4-disubstituted (regioisomer 4a, Table 2, entry corresponding products in good to excellent yields (62–90%)
5), and 3,5-disubstituted 4-formyl (regioisomer 5a, Scheme 2, (Table 3, entries 2–5, 7–10, 12–15, and 17–20). In general, the
ROUTE II) isoxazoles regioselectively from b-enamino diketone electronic nature of the Ar substituent on the b-enamino diketone
1a and NH2OH$HCl, we examined the scope of this reaction 1a–e imposed a small effect on the regioselectivity of the reaction
under the conditions reported above, varying the electronic for methods A and B. For method A, the substrate bearing the
properties of the b-enamino diketone substrate 1. The results stronger p-OMe (1e) electron-donating substituent provided low
are summarized in Table 3.
regioselectivity for the formation of the isoxazole regioisomer 2
Similar to the b-enamino diketone substrate 1a (Table 3, (Table 3, entry 5), while the p-NO2 electron-withdrawing
entries 1, 6, 11 and 16), all substrates examined (1b–e) were substituent provided high regioselectivity (Table 3, entry 1).
found to undergo the desired transformation to give the For the other substituents (Table 3, entries 2–4), regioisomer 2
was obtained with moderate regioselectivity. On the other hand,
for method B we did not see a clear correlation of the electronic
nature of the substituents (Ar) with the regioselectivity of the
Table 3 Substrate scopea
formation of isoxazole 3 (Table 3, entries 6–10). In contrast,
regardless of the different electronic properties of the Ar
substituent on b-enamino diketone 1a–e, isoxazoles
regioisomer 4 and 5 were always obtained with high regiose-
lectivity (Table 3, entries 11–20).
Finally, through detailed analysis of the NMR spectral data of
the new isoxazoles reported here, we observed that difference in
the chemical shis of 1H and 13C allow a simple assignment of
the different regioisomeric forms obtained. For example, we use
isoxazoles 2a, 3a, 4a, and 5a as a model to show these differ-
ences (Fig. 2).
For the disubstituted isoxazoles 2a, 3a, and 4a, the hydrogen
atom attached to the isoxazole nucleus (H3 for 2a and 3a, H5 for
4a – Fig. 2) have notable differences in the chemical shis of 1H
NMR spectrum. The H3 atom in 3a (8.59 ppm) is more shielded
than the H5 atom in 4a (8.89 ppm) by a difference of approxi-
mately 0.30 ppm, whereas H5 (4a) is more shielded than the H3
atom in 2a (9.12 ppm) by about 0.23 ppm (Fig. 2). With regard to
13C NMR spectra of disubstituted isoxazoles, the major differ-
ences between the chemical shis of the 4,5 (2a and 3a) and the
3,4 (4a)-disubstituted regioisomers are related to the carbon
atoms C3 in 2a and 3a, and C5 in 4a (Fig. 2). This is because the
C5 atom signal (compound 4a) is approximately 10 ppm more
deshielded than the corresponding atom (C3) in 2a and 3a
(Fig. 2). For the 4,5-disubstituted regioisomers 2a and 3a, the
signal of the ketone carbonyl attached at the 4-position of the
isoxazole ring shows considerable differences in the chemical
shis of the 13C NMR spectrum, because the ketone carbonyl
signal in 2a is more shielded than the ketone carbonyl in 3a by
Entry
Substrate (Ar)
Method
Ratiob (%)
Yieldc (%)
1
2
3
4
5
6
7
8
1a (4-NO2C6H4)
1b (4-FC6H4)
1c (Ph)
1d (4-MeC6H4)
1e (4-OMeC6H4)
1a (4-NO2C6H4)
1b (4-FC6H4)
1c (Ph)
1d (4-MeC6H4)
1e (4-OMeC6H4)
1a (4-NO2C6H4)
1b (4-FC6H4)
1c (Ph)
1d (4-MeC6H4)
1e (4-OMeC6H4)
1a (4-NO2C6H4)
1b (4-FC6H4)
1c (Ph)
A
A
A
A
A
B
B
B
B
B
C
C
C
C
C
D
D
D
D
D
2a(76), 3a(24)
2b(62), 3b(38)
2c(65), 3c(35)
2d(60), 3d(40)
2e(58), 3e(42)
2a(23), 3a(77)
2b(20), 3b(80)
2c(20), 3c(80)
2d(20), 3d(80)
2e(35), 3e(65)
4a(90), 5a(10)
4b(90), 5b(10)
4c(90), 5c(10)
4d(90), 5d(10)
4e(90), 5e(10)
5a(100)
87 (65)
88 (53)
89 (57)
90 (52)
90 (50)
76 (58)
82 (65)
81 (64)
81 (63)
83 (52)
79 (70)
81 (71)
72 (64)
73 (65)
83 (74)
(75)
9
10
11
12
13
14
15
16
17
18
19
20
5b(100)
(65)
5c(100)
(62)
1d (4-MeC6H4)
1e (4-OMeC6H4)
5d(100)
(70)
5e(100)
(68)
a
Reaction conditions: 1b–e (0.5 mmol), NH2OH$HCl (0.6 mmol, 1.2
equiv.), solvent (4 mL). Calculated from the 1H-NMR spectrum of
crude product. Isolated yields (regioisomeric mixture); yields in
b
c
Fig. 2 1H and 13C NMR chemical shifts of the regioisomers 2a, 3a, 4a,
and 5a.
parentheses are yields of the main regioisomer isolation by column
chromatography.
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about 8.3 ppm (Fig. 2). Unambiguously, 3,5-disubstituted 4- 2 (a) D. P. Curran, J. Am. Chem. Soc., 1983, 105, 5826; (b)
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chemical shis of aldehyde hydrogen and carbon of the 1H and
13C NMR spectra (Fig. 2).
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Conclusions
In summary, we have developed four methodologies for the
regioselective synthesis of polyfunctionalized isoxazoles by
cyclocondensation of b-enamino diketones with hydroxyl-
amine. The regiochemistry of the reaction has been controlled
by: the solvent; use of pyridine; the Lewis acid carbonyl acti-
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
The authors are grateful for the nancial support from CNPq/
Brazil (CNPq/Universal Process No. 45920/2014-8) and
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4778 | RSC Adv., 2018, 8, 4773–4778
This journal is © The Royal Society of Chemistry 2018