Reaction of β-dimethylaminovinyl ketones with hydroxylamine: A simple and useful method for synthesis of 3- and 5-substituted isoxazoles

Article abstract of DOI:10.1002/jhet.5570450337

(Chemical Equation Presented) The regioselective synthesis of 3- and 5-substituted-isoxazoles from the reaction of β-dimethylaminovinyl ketones [R-C(O)CH=CH-NMe₂, where R = Ph, MeO-4-C₆H₄, F-4-C₆H₄, C

Full text of DOI:10.1002/jhet.5570450337

May-Jun 2008
879
Reaction of β-Dimethylaminovinyl Ketones with Hydroxylamine:
a Simple and Useful Method for Synthesis of 3- and 5-Substituted
Isoxazoles
Fernanda A. Rosa, Pablo Machado, Helio G. Bonacorso, Nilo Zanatta and
Marcos A. P. Martins*
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Quimica, Universidade Federal de Santa
Maria, 97105-900 Santa Maria, RS, Brazil
mmartins@base.ufsm.br
Received December 11, 2007
R
R
O
HO
NH2OH
NH2OH
+
N
N
+
R
O
N
N
O
R
NMe2
R
HO
O
O
1,5-Isomer
1,3-Isomer
R = Ph, MeO-4-C6H4, F-4-C6H4, Cl-4-C6H4, Br-4-C6H4, O2N-4-C6H4, fur-2-yl, thien-2-yl, pyrrol-2-yl,
Et,!CCl3
The regioselective synthesis of 3- and 5-substituted-isoxazoles from the reaction of β-dimethyl-
aminovinyl ketones [R-C(O)CH=CH-NMe2, where R = Ph, MeO-4-C6H4, F-4-C6H4, Cl-4-C6H4, Br-4-C6H4,
O2N-4-C6H4, fur-2-yl, thien-2-yl, pyrrol-2-yl, Et and CCl3] and hydroxylamine hydrochloride varying only
the reaction conditions (with and without the addition of pyridine) is reported.
J. Heterocyclic Chem., 45, 879 (2008).
INTRODUCTION
these compounds possibly not acting at a common
receptor site [8].
The synthesis of isoxazole and its derivatives has been
a subject of continuous interest because of the numerous
applications for such heterocycles in the pharmaceutical
and agrochemical industry [1]. Recently, these
compounds have been found to be an integral part of the
selective inhibitors of the transglutaminase human 2 being
thus important prototypes for treatment of Huntington’s,
Alzheimer’s, and Parkinson’s diseases [2]. Other
pharmacological activities of this core involve the potent
and selective antagonism of NMDA receptor [3],
antagonism of the GABAA receptor, in the low nanomolar
range, [4] and in vitro antiprotozoal activities [5].
Therefore, continuous efforts have been devoted to the
development of more general, efficient, and regioselective
methods for the synthesis of this class of compounds. The
synthesis of isoxazoles is relatively well explored using
the so-called [3+2] atom fragments, where β−diketones or
α,β−unsaturated ketones are used as 3-atom building
blocks, and hydroxylamine is the 2-atom fragment.
However, the main limitation with these cycloconden-
sation reactions is the lack of regioselectivity of the
obtained products [6-7]. The use of the unsymmetrical β-
dicarbonyl compounds in the cyclocondensation reaction
can lead to two possible isomers, and thus, the
development of regioselective methods for the synthesis
of heterocycle compounds became an important research
area. In addition, the regioisomers 3- and 5-substituted-
isoxazoles have shown different pharmacological
activities in rodent parasite screen demonstrating still that
As part of our research program, we have reported the
general synthesis of 1,1,1-trihalo-4-alkoxy-3-alken-2-ones,
a β-diketone derivative, and demonstrated their usefulness
in the preparation of heterocycles by studying the
regiochemistry of the ring closure [9]. These studies have
shown that a determining factor in establishing the
regiochemistry of the heterocyclic ring is the presence of
the haloalkyl group (R) in the precursors, because of its
great electronic effects, which change the electron-density
distribution in the β-diketone derivatives, and consequently,
the relative reactivity of the carbonyl group. However, data
from the literature have shown that when the R moiety is
not of haloalkyl group, the cyclocondensation reaction with
hydroxylamine hydrochloride leads to a mixture of
5-substituted-isoxazoles (1,5-isomer) and 3-substituted-
isoxazoles (1,3-isomer) (figure 1) [10-14]. In continuation
of our work, we report here a practical and systematic
methodology for preparation of
a series of aryl-,
heteroaryl-, -ethyl and trichloromethyl-3-substituted-
isoxazoles and/or 5-substituted-isoxazoles from the reaction
of β-dimethylaminovinyl ketones and hydroxylamine
varying only the reaction conditions (with and without the
addition of pyridine).
R
N
N
R
O
O
1,5-isomer
1,3-isomer
Figure 1

880
F. A. Rosa, P. Machado, H. G. Bonacorso, N. Zanatta and M. A. P. Martins
Vol 45
RESULTS AND DISCUSSION
precursors with R = Ph, Cl-4-C6H4, thien-2-yl was a
mixture of the 3-substituted-4,5-dihydroisoxazoles 5 and
5-substituted-isoxazoles 4. For precursors with R = MeO-
4-C6H4, F-4-C6H4, Br-4-C6H4, Et a mixture of 3-
substituted-isoxazoles 6 and 5-substituted-isoxazoles 4
was obtained. These isomeric mixture were easily
separate by difference of solubility, the 1,5-isomer had
good solubility in CHCl3 while the 1,3-isomer, in
agreement with the literature [8], did not show solubility
in several organic solvents and thus could be easily
isolated by filtration. The regioselectivity of the ring
closure reaction was observed as follows: for R = O2N-4-
C6H4, fur-2-yl, 3-substituted-4,5-dihydro isoxazoles 5
Enaminones are versatile synthons for the synthesis of a
variety of heterocycles, and their preparation has been
recognized for some time. The convenient synthesis of β-
dimethylaminovinyl ketones from the reaction of aryl
ketones and formamide acetal has already been described
[14-17]. Thus, the β-dimethylaminovinyl ketones 2 were
prepared in good yields by the one-step reaction of
substituted ketones, N,N-dimethylformamide dimethyl
acetal and BF3•OEt2 in toluene under reflux for 24 hours
(Scheme 1). The structures of 2a-j were confirmed by
NMR spectroscopy (1H and 13C) and MS spectra.
were obtained; for
R = pyrrol-2-yl, 5-substituted-
Scheme 1
isoxazole 4 was obtained, and for R = CCl3, 5-substituted-
4,5-dihydroisoxazoles 3 were obtained. From GC/MS
data, the presence of compounds 6a (R = Ph), 6b (R =
MeO-4-C6H4), 6c (R = F-4-C6H4), 6d (R = Cl-4-C6H4), 6e
(R = Br-4-C6H4), 6f (R = O2N-4-C6H4), 6g (R = fur-2-yl),
6h (R = thien-2-yl), 6j (R = Et) in less than 8% yields,
was also identified (Scheme 1). From these results, one
can observe that the ring closure reaction is regioselective
for some precursors (2f, 2g, 2i, 2k). Thus, it was not
possible to affirm that the regioselectivity depended on
the structure of the R moiety in the cases studied.
O
C
OMe
NMe2
MeO
C
+
R
Me
H
1a-j
i
68-98%
O
R
NMe2
2a-j
In a second stage the reaction was carried out using the
same reaction conditions, however, without the use of
pyridine. Under this condition, a high regioselectivity of
the ring closure reaction was observed. Regardless of the
structure of the R moiety of the precursors, the
cyclocondensation reaction was highly regioselective,
furnishing preferentially 5-substituted-isoxazole 4, in
good yields (Scheme 1, Table 1). The structure of 4 was
confirmed by X-ray diffraction (Figure 2) [20]. In both
methodologies, the product obtained when R = CCl3 was
the 5-trichloromethyl-4,5-dihydroisoxazole, which is in
full agreement with the literature [9]. This fact have been
attributed to strong electron-withdrawing of the
trichloromethyl group which stabilizes the hemi-acetal
portion leading to formation of 5-trichloromethyl-4,5-
dihydroisoxazole ring exclusively [9].
ii or iii
R
R
HO
HO
N
N
N
N
R
O
O
O
H
O
R
6
3
5
4
i = BF3
!
OEt2, toluene, reflux, 24 hours
HCl, pyridine, ethanol, reflux, 16 hours
HCl, ethanol, reflux, 16 hours
ii = NH2OH
iii = NH2OH
!
!
1,2
a
b
c
d
e
f
R
Ph MeO-4-C6H4 F-4-C6H4 Cl-4-C6H4 Br-4-C6H4 O2N-4-C6H4
1,2
g
h
i
j
k
R
fur-2-yl thien-2-yl pyrrol-2-yl Et CCl3
Considering that the reaction of 1,1,1-trihalo-4-alkoxy-
3-alken-2-ones with hydroxylamine hydrochloride is
usually carried out in the presence of pyridine [18,19], we
used pyridine in ethanol under reflux for 16 hours in the
preliminary investigation. The result obtained for
Figure 2. ORTEP of 5-(4-chlorophenyl)-isoxazole 4d; reaction carried
without the use of pyridine.

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Reaction of β-Dimethylaminovinyl Ketones with Hydroxylamine:
881
Table 1
Substituted-isoxazoles obtained from the reaction of β-dimethylaminovinyl ketones with hydroxylamine hydrochloride.
With pyridine
Compound
4a + 5a
4b + 6b
4c + 6c
4d + 5d
4e + 6e
5f
Without pyridine
R
Ph
Yield (%)[a]
29 : 37
57 : 11
54 : 9
17 : 44
77 : 4
79
R
Ph
Compound
Yield (%)[a]
4a
4b
4c
4d
4e
4f
76
76
70
81
77
67
53
65
74
52
81
MeO-4-C6H4
F-4-C6H4
Cl-4-C6H4
Br-4-C6H4
O2N-4-C6H4
Fur-2-yl
Thien-2-yl
Pyrrol-2-yl
Et
MeO-4-C6H4
F-4-C6H4
Cl-4-C6H4
Br-4-C6H4
O2N-4-C6H4
Fur-2-yl
Thien-2-yl
Pyrrol-2-yl
Et
5g
4h + 5h
4i
82
30 : 35
72
4g
4h
4i
4j + 6j
3k
49 : 8
76
4j
3k
CCl3
CCl3
[a] Yield of isolated product or mixture of products.
The regioselectivity observed when the reaction was
carried out without pyridine could be explained by the
stronger reactivity of the C-β, which was increased as the
concentration of HCl, coming from the hydroxylamine
hydrochloride, increased.
synthesis of 5-substituted-isoxazole derivatives from
enaminones, e.g. Molina’s [21] and Lin’s [22] methods,
they have reported disadvantages, mainly due to their
limited scope and the use of more reaction steps than the
procedure here showed.
The presence of HCl in the reaction protonated the
carbonyl oxygen, which increased the reactivity of the C-
β. As the attack was favored in the C-β, the addition of
the NH2 group on this carbon occurred first, followed by
the addition of the OH group to the carbonyl carbon to
give the 5-substituted-isoxazole 4 (Scheme 2). Although
other methods have been reported for the regioselective
On the other hand, the use of the pyridine conduced to
loss of regioselectivity in the reactions as a mixture of
isoxazole derivatives were obtained, however, in some
cases, this method showed high regioselectivity in the ring
closure with the formation of the 3-substituted-isoxazole
derivatives as majority product. This finding was obtained
when the R = Ph, Cl-4-C6H4, O2N-4-C6H4, fur-2-yl, thien-
Scheme 2
H
HO
NH
H
NHOH
O
O
O
NMe2
NHOH
HO
HO
-HNMe2
N
NH
O
O
R
R
NMe2
R
R
R
3
-H2O
N
R
O
4
H
H
NHOH
H
NMe2
NMe2
OH
O
O
N
N
HO
R
-H2O
O
O
R
R
R
R
NMe2
NMe2
R
NMe2
N
N
H
-HNMe2
O
R
O
N
N
H
H2O
-H
OH
O
O
R
R
N
N
5
6

882
F. A. Rosa, P. Machado, H. G. Bonacorso, N. Zanatta and M. A. P. Martins
Vol 45
Thermovar apparatus and are uncorrected. IR spectra were
obtained with a Bruker Tensor 27 spectrometer using films or
KBr pellets of the compounds. The CHN elemental analyses
were performed on a Perkin-Elmer 2400 CHN elemental
analyzer (Federal University of Rio Grande do Sul, UFRGS/
Brazil).
General Synthesis of β-dimethylaminovinyl ketones. A
mixture of compound (1) (20 mmol), dimethylformamide
dimethyl acetal (2.38 g, 24 mmol) and BF3•OEt2 (3 drops) in
toluene (10 mL) was heated at 110°C for 24 hours. The mixture
was then evaporated under reduced pressure to give a solid. The
solid was washed with hexane and collected by filtration, and
finally dried. The final products are solids.
2-yl. Noteworthily, when the R = O2N-4-C6H4 and fur-2-yl
the products exhibited opposite regioselectivity conducing
to formation of compounds 5f and 5g exclusively.
This control of the regiochemistry in the closure of
isoxazole rings by varying the reaction conditions on the
same precursors was later reported by Umada et al. [23]
however, this report did not use an enaminone but a
trifluoracetyl-β-diketone derivative of the 4-homo-
adamantone as substrate. The synthesis of the 3-
substituted-isoxazole derivatives have been scarcely
literature reported, the few methods involve 1,3-dipolar
cycloadditions [8,24], use of strong bases as BuLi [25], or
the use of the reagents not readily available [26]. These
few reports concerned with the synthesis of 3-substituted-
isoxazoles do, to the best of our knowledge, of the great
part of the 3-substituted-isoxazoles 5 and 6 compounds
reported here at first time. The loss of regioselectivity in
the reactions with pyridine could be due the C-β was not
activated as the pyridine used in stoichiometric amount
with the hydroxylamine hydrochloride trapped the
hydrochloric acid forming the pyridine hydrochloride and
free hydroxylamine which could then allow a nucleophilic
attack on both electrophilic centers of the enaminone
(carbonyl-carbon and C-β) (Scheme 2). Further
investigations are necessary to clarify the effect of
pyridine on these cyclocondensation reactions specially
with regards to their capacity to control the
regiochemistry of ring closure.
In summary, a concise and useful method for the
regioselective synthesis of 5-substituted-isoxazoles and,
for some substituents, 3-substituted-isoxazoles is
described. The method is performed under mild
conditions and without the use of expensive reagents or
methods of separation. The regioisomers were easily
separated by difference in their solubility in organic
solvents. Our findings suggests that the increase of the
acid medium seemed to play an important role in the
regioisomeric formation of the isoxazoles from β-
dimethylaminovinyl ketones and that the use of pyridine
conduces an interesting result as in some case switching
the regiochemistry of ring closure in the isoxazole
derivatives.
(E)-3-Dimethylamino-1-phenyl-2-propen-1-one (2a). Yield
13.60 mmol (68%); mp 89-90 °C (from hexane); IR (KBr) 3454,
1
3010, 2807, 1639, 1584 cm-1; H NMR (DMSO-d6) δ 2.90 (s,
3H, N-Me), 3.12 (s, 3H, N-Me), 5.71 (d, 1H, J = 12 Hz, H-2),
7.41-7.89 (m, 5H, Ph) 7.79 (d, 1H, J = 12 Hz, H-3); 13C NMR
(DMSO-d6) δ 36.9 (N-Me), 44.3 (N-Me), 92.0 (C-2), 127.2,
127.9, 130.6, 140.3 (Ph), 154.0 (C-3), 188.3 (C-1); MS m/z (%)
175 (M+, 43), 158 (100), 143 (5), 131 (10), 98 (90). Anal. Calcd
for C11H13NO: C 75.40; H, 7.48; N, 7.99. Found: C 75.22; H
7.19; N 7.70.
(E)-3-Dimethylamino-1-(4-methoxyphenyl)-2-propen-1-
one (2b). Yield 16.20 mmol (81%); mp 85-87 °C (from hexane);
IR (KBr) 3430, 3060, 2980, 1674, 1600 cm-1; 1H NMR (DMSO-
d6) δ 3.85 (s, 3H, O-Me), 2.89 (s, 3H, N-Me), 3.11 (s, 3H, N-
Me), 5.71 (d, 1H, J = 12 Hz, H-2), 6.91 (d, 2H, Ph), 7.79 (d, 1H,
J = 12 Hz, H-3), 7.90 (d, 2H, Ph); 13C NMR (DMSO-d6) δ 36.4
(N-Me), 44.0 (N-Me), 55.9 (O-Me), 91.3 (C-2), 114.2, 130.0,
133.1, 162.3 (Ph), 155.3 (C-3) 186.8 (C-1); MS m/z (%) 205
(M+, 38), 188 (100), 162 (10), 135 (38), 98 (48). Anal. Calcd for
C12H15NO2: C 70.22; H 7.37; N 6.82. Found: C 70.09; H 7.11; N
6.71.
(E)-3-Dimethylamino-1-(4-fluorophenyl)-2-propen-1-one
(2c). Yield 14.00 mmol (70%); mp 94-96 °C (from hexane); IR
1
(KBr) 3418, 3070, 2926, 1644, 1598 cm-1; H NMR (CDCl3) δ
2.90 (s, 3H, N-Me), 3.12 (s, 3H, N-Me), 5.66 (d, 1H, J = 12 Hz,
H-2), 7.07-7.91 (m, 4H, Ph), 7.79 (d, 1H, J = 12 Hz, H-3); 13C
NMR (CDCl3) δ 37.0, (N-Me), 44.8 (N-Me), 91.3 (C-2), 114.7,
129.5, 136.5, 164.2 (Ph), 154.1 (C-3), 186.9 (C-1); MS m/z (%)
193 (M+, 38), 176 (100), 161 (5), 149 (7), 123 (30), 109 (16), 98
(52). Anal. Calcd for C11H12FNO: C 68.38; H 6.26; N 7.25.
Found: C 68.30; H 6.12; N 6.97.
(E)-3-Dimethylamino-1-(4-chlorophenyl)-2-propen-1-one
(2d). Yield 16.00 mmol (80%); mp 85-87 °C (from hexane); IR
1
(KBr) 3340, 3070, 2970, 1646, 1580 cm-1; H NMR (CDCl3) δ
2.94 (s, 3H, N-Me), 3.14 (s, 3H, N-Me), 5.66 (d, 1H, J = 12 Hz,
H-2), 7.37 (d, 2H, Ph), 7.79 (d, 1H, J = 12 Hz, H-3), 7.84 (d, 2H,
Ph); 13C NMR (CDCl3) δ 36.5 (N-Me), 44.3 (N-Me), 90.8 (C-2),
127.5, 128.2, 136.0, 138.2 (Ph), 153.8 (C-3), 185.8 (C-1); MS
m/z (%) 209 (M+, 30), 192 (90), 174 (5), 157 (10), 139 (30), 98
(100). Anal. Calcd for C11H12ClNO: C 63.01; H 5.77; N 6.68.
Found: C 62.68; H 5.61; N 6.28.
EXPERIMENTAL
Unless otherwise indicated, all common reagents and solvents
were used as obtained from commercial suppliers without
further purification. Yields listed are of isolated compounds. 1H,
and 13C NMR spectra were recorded on a Bruker DPX 400
spectrometer (1H at 400.13 MHz and 13C at 100.63 MHz) 298
K, digital resolution of ±0.01ppm, 0.5 M in CDCl3 or DMSO-d6,
using TMS as an internal standard. Mass spectra were registered
in a HP 5973 MSD connected to a HP 6890 GC and interfaced
by a Pentium PC. Crystallographic data was obtained on a
Bruker Kappa APEX-II CCD 3 kW Sealed Tube System
diffractometer. Melting points were determined with a Reichert
(E)-3-Dimethylamino-1-(4-bromophenyl)-2-propen-1-one
(2e). Yield 14.40 mmol (72%); mp 70-72 °C (from hexane); IR
1
(KBr) 3416, 2908, 2808, 1640, 1575; H NMR (CDCl3) δ 2.93
(s, 3H, N-Me), 3.15 (s, 3H, N-Me), 5.65 (d, 1H, J = 12 Hz, H-2),
7.81 (d, 1H, J = 12 Hz, H-3), 7.53 (d, 2H, Ph), 7.76 (d, 2H, Ph);
13C NMR (CDCl3) δ 37.2 (N-Me), 44.9 (N-Me), 91.5 (C-2),
125.3, 129.0, 131.1, 139.1 (Ph) 154.4 (C-3), 187.0 (C-1); MS
m/z (%) 253 (M+, 37), 238 (100), 183 (19), 169 (9), 157 (34),

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Reaction of β-Dimethylaminovinyl Ketones with Hydroxylamine:
883
131 (11), 98 (97). Anal. Calcd for C11H12BrNO: C 51.99; H 4.76;
N 5.51. Found: C 51.88; H 4.63; N 5.79.
General synthesis of isoxazoles using pyridine. A mixture
of compound 2 (1 mmol), hydroxylamine hydrochloride (0.139
g, 2 mmol) and pyridine (0.158 g, 2 mmol) in ethanol (15 mL)
was stirred for 16 hours at 78°C. After completion of the
reaction, the ethanol was evaporated on a rotary evaporator and
the residue was diluted with CHCl3 (15 mL). Because of the
poor solubility in CHCl3 of the compounds assigned as 1,3-
isomers, these were collected by filtration. The organic layer
was them washed with water (3×30 mL), dried over magnesium
sulfate and the solvent evaporated on a rotary evaporator to
afforded the compounds assignment as 1,5-isomers. When
necessary, both 1,3- and 1,5-isomers were purified by
recrystallization from hot hexane.
(E)-3-Dimethylamino-1-(4-nitrophenyl)-2-propen-1-one (2f).
Yield 19.60 mmol (98%); mp 139-141 °C (from hexane); IR
1
(KBr) 3458, 2947, 2862, 1642, 1605 cm-1; H NMR (CDCl3) δ
2.97 (s, 3H, N-Me), 3.20 (s, 3H, N-Me), 5.68 (d, 1H, J = 12 Hz,
H-2), 7.86 (d, 1H, J = 12 Hz, H-3), 8.01 (d, 2H, Ph), 8.25 (d, 2H,
Ph); 13C NMR (CDCl3) δ 37.3 (N-Me), 45.1 (N-Me), 91.8 (C-2),
123.2, 128.2, 145.9, 148.8 (Ph), 155.1 (C-3), 185.8 (C-1); MS
m/z (%) 220 (M+, 30), 203 (92), 157 (15), 130 (6), 98 (100).
Anal. Calcd for C11H12N2O3: C 60.00; H 5.49; N 12.72. Found: C
60.06; H 5.30; N 12.90.
(E)-3-Dimethylamino-1-(fur-2-yl)-2-propen-1-one
Yield 14.80 mmol (74%); mp 84-86 °C (from hexane); IR (KBr)
(2g).
General synthesis of isoxazoles without use of pyridine. A
mixture of compound
1
3417, 2921, 2807, 1639, 1577 cm-1; H NMR (CDCl3) δ 2.95 (s,
2 (1 mmol) and hydroxylamine
hydrochloride (0.139 g, 2 mmol) in ethanol (15 mL) was stirred
for 16 hours at 78°C. After completion of the reaction, the
ethanol was evaporated on a rotary evaporator and the residue
was extracted with CHCl3, washed with water (3×30 mL), dried
over magnesium sulfate and again the solvent evaporated on a
rotatory evaporator. The residue was then purified by
recrystallization from hot hexane, affording the pure 5-
substituted-isoxazoles.
3H, N-Me), 3.14 (s, 3H, N-Me), 5.68 (d, 1H, J = 12 Hz, H-2),
6.48 (dd, 1H, Furyl), 7.06 (d, 1H, Furyl), 7.49 (d, 1H, Furyl),
7.80 (d, 1H, J = 12 Hz, H-3); 13C NMR (CDCl3) δ 37.2 (N-Me),
44.9 (N-Me), 91.3 (C-2), 111.7, 113.2, 144.0, 154.6 (Furyl),
153.4 (C-3) 177.3 (C-1); MS m/z (%) 165 (M+, 64), 150 (10),
136 (100), 120 (11), 98 (59). Anal. Calcd for C9H11NO2: C
65.44; H 6.71; N 8.48. Found: C 65.15; H 6.38; N 8.10.
(E)-3-Dimethylamino-1-(thien-2-yl)-2-propen-1-one (2h).
Yield 15.60 mmol (78%); mp 113-115 °C (from hexane); IR
(KBr) 3453, 2998, 2804, 1636, 1546 cm-1; 1H NMR (CDCl3) δ
2.83 (s, 3H, N-Me), 3.01 (s, 3H, N-Me), 5.60 (d, 1H, J = 12
Hz, H-2), 7.04 (dd, 1H, Thienyl), 7.44 (d, 1H, Thienyl), 7.60
(d, 1H, Thienyl), 7.71 (d, 1H, J = 12 Hz, H-3); 13C NMR
(CDCl3) δ 36.5 (N-Me), 44.3 (N-Me), 90.9 (C-2), 127.1,
127.7, 129.6, 147.0 (Thienyl), 152.9 (C-3), 179.9 (C-1); MS
m/z (%) 181 (M+, 71), 164 (95), 148 (100), 131 (33), 111 (91),
98 (83). Anal. Calcd for C9H11NOS: C 59.64; H 6.12; N 7.73.
Found: C 59.44; H 5.88; N 7.92.
5-Phenylisoxazole (4a). Oil; IR (film) 3063, 1615, 1590,
1
1459, 764, 690 cm-1; H NMR (CDCl3) δ 6.48 (d, 1H, J = 1.7
Hz, H-4), 7.41-7.76 (m, 5H, Ph), 8.25 (d, 1H, J = 1.7 Hz, H-3);
13C NMR (CDCl3) δ 98.5 (C-4), 125.6, 127.1, 128.8, 130.0 (Ph),
150.6 (C-3), 169.1 (C-5); MS m/z (%) 145 (M+, 100), 105 (75),
90 (15), 77 (61). Anal. Calcd for C9H7NO: C 74.47; H 4.86; N
9.65. Found: C 74.08; H 4.84; N 9.60.
3-Phenyl-5-hydroxy-4,5-dihydroisoxazole (5a). mp 120-
121 °C (from hexane); IR (KBr) 3413, 3046, 1446, 1364, 766,
1
692 cm-1; H NMR (DMSO-d6) δ 3.48 (dd, 1H, JHa-Hb = 17 Hz,
JHa-H5 = 5 Hz, Ha-4), 3.50 (dd, 1H, JHb-Ha = 17 Hz, JHb-H5 = 9
(E)-3-Dimethylamino-1-(pyrrol-2-yl)-2-propen-1-one (2i).
Yield 16.40 mmol (82%); mp 191-193 °C (from hexane); IR
Hz, Hb-4), 5.81 (dd, 1H, JH5-Ha = 5 Hz, JH5-Hb
= 9 Hz, H-5),
7.53-7.66 (m, 5H, Ph); 13C NMR (DMSO-d6) δ 35.9 (C-4), 93.1
(C-5), 129.3, 129.8, 130.0, 130.2 (Ph), 156.2 (C-3); MS m/z (%)
145 (M+, -H2O, 76), 119 (10), 105 (58), 77 (100). Anal. Calcd
for C9H9NO2: C 66.25; H 5.56; N 8.58. Found: C 65.88; H 5.52;
N 8.57.
1
(KBr) 3391, 2931, 2802, 1627, 1524 cm-1; H NMR (DMSO-d6)
δ 2.94 (s, 6H, N-(Me)2), 5.63 (d, 1H, J = 12 Hz, H-2), 6.10 (dd,
1H, Pyrrolyl), 6.78 (d, 1H, Pyrrolyl), 6.88 (d, 1H, Pyrrolyl), 7.58
(d, 1H, J = 12 Hz, H-3); 13C NMR (DMSO-d6) δ 37.0 (N-Me),
44.0 (N-Me), 91.3 (C-2), 108.8, 111.7, 122.0, 133.6 (Pyrrolyl),
151.7 (C-3), 177.7 (C-1); MS m/z (%) 164 (M+, 100), 147 (43),
136 (4), 120 (10), 98 (30). Anal. Calcd for C9H12N2O: C 65.83;
H 7.37; N 17.06. Found: C 65.78; H 6.91; N 16.69.
3-Phenylisoxazole (6a). (compound not isolated) MS m/z
(%) 145 (M+, 96), 144 (100), 116 (24), 103 (8), 89 (27), 77 (84).
5-(4-Methoxyphenyl)isoxazole (4b). mp 61-63 °C (from
hexane); IR (KBr) 3007, 2938, 2840, 1615, 1595, 1463, 832,
1
731, 679 cm-1; H NMR (CDCl3) δ 3.80 (s, 3H, O-Me), 6.36 (d,
(E)-5-Dimethylamino-4-peten-3-one (2j). Yield 16.40 mmol
1
(82%); oil ; IR (KBr) 3422, 2,972, 1665, 1620, 1580 cm-1; H
1H, J = 1.7 Hz, H-4), 6.93 (d, 2H, Ph), 7.68 (d, 2H, Ph), 8.22 (d,
1H, J = 1.7 Hz, H-3); 13C NMR (CDCl3) δ 55.1 (O-Me), 97.1
(C-4), 114.2, 119.9, 127.2, 160.9 (Ph), 150.6 (C-3), 169.1 (C-5);
MS m/z (%) 175 (M+, 100), 160 (12), 135 (61), 92 (52), 77 (66).
Anal. Calcd for C10H9NO2: C 68.56; H 5.18; N 8.00. Found: C
68.19; H 5.15; N 7.93.
3-(4-Methoxy phenyl)isoxazole (6b). (compound not
isolated) MS m/z (%) 175 (M+, 100), 160 (22), 146 (49), 132
(86), 77 (61), 63 (77).
5-(4-Fluorophenyl)isoxazole (4c). mp 51-53 °C (from
hexane); IR (KBr) 3120, 3091, 1614, 1598, 1462, 915, 804 cm-1;
1H NMR (CDCl3) 6.45 (d, 1H, J = 1.7 Hz, H-4), 7.12-7.74 (m,
4H, Ph), 8.26 (d, 1H, J = 1.7 Hz, H-3); 13C NMR (CDCl3) δ 98.3
(C-4), 115.9, 123.5, 127.7, 163.5 (Ph), 150.7 (C-3), 168.1 (C-5);
MS m/z (%) 163 (M+, 100), 123 (86), 95 (65), 75 (38). Anal.
Calcd for C9H6FNO: C 66.26; H 3.71; N 8.59. Found: C 65.91;
H 3.69; N 8.52.
NMR (CDCl3) δ 1.00 (t, 3H, Me), 2.88 (s, 3H, N-Me), 2.27 (q,
2H, CH2), 2.96 (s, 3H, N-Me), 5.00 (d, 1H, J = 12 Hz, H-2), 7.44
(d, 1H, J = 12 Hz, H-3); 13C NMR (CDCl3) δ 12.0 (Me), 28.5
(CH2), 35.9 (N-Me), 42.1 (N-Me), 95.9 (C-4), 154.8 (C-5),
190.5 (C-3); MS m/z (%) 127 (M+, 13), 98 (100), 70 (8), 55 (44).
Anal. Calcd for C7H13NO: C 66.11; H 10.30; N 11.01. Found: C
66.04; H 10.35; N 11.22.
(E)-4-Dimethylamino-1,1,1-trichloro-3-buten-2-one (2k).
Yield 13.60 mmol (68%); mp 47-49 °C (from hexane); IR (KBr)
1
3452, 2812, 1660, 1587 cm-1; H NMR (CDCl3) δ 2.97 (s, 3H,
N-Me), 3.21 (s, 3H, N-Me), 5.59 (d, 1H, J = 12 Hz, H-2), 7.80
(d, 1H, J = 12 Hz, H-3); 13C NMR (CDCl3) δ 37.4 (N-Me), 45.4
(N-Me), 84.9 (C-2), 98.0 (CCl3), 157.2 (C-3), 180.4 (C-1); MS
m/z (%) 215 (M+, 5), 152 (10), 98 (100). Anal. Calcd for
C6H8Cl3NO: C 33.29; H 3.72; N 6.47. Found: C 33.01; H 4.18;
N 6.85.

884
F. A. Rosa, P. Machado, H. G. Bonacorso, N. Zanatta and M. A. P. Martins
Vol 45
3-(4-Fluorophenyl) isoxazole (6c). (compound not
C7H5NO2: C 62.23; H 3.73; N 10.37. Found: C 61.90; H 3.69; N
10.28.
isolated) MS m/z (%) 163 (M+, 8), 162 (7), 153 (82), 136 (23),
121 (36), 107 (7), 95 (100), 75 (38), 68 (9).
5-(4-Chlorophenyl)isoxazole (4d). mp 82-84 °C (from
3-(Fur-2-yl)-5-hydroxy-4,5-dihydroisoxazole (5g). mp
157-159 °C (from hexane); IR (KBr) 3286, 2916, 1598, 1493,
893 cm-1; 1H NMR (DMSO-d6) δ 3.38 (dd, 1H, JHa-Hb = 17 Hz,
JHa-H5 = 5 Hz, Ha-4), 3.40 (dd, 1H, JHb-Ha = 17 Hz, JHb-H5 = 9 Hz,
Hb-4), 5.68 (dd, 1H, JH5-Ha = 5 Hz, JH5-Hb = 9 Hz, H-5), 6.47 (dd,
1H, Furyl), 6.73 (d, 1H, Furyl), 7.49 (d, 1H, Furyl); 13C NMR
(DMSO-d6) δ 35.8 (C-4), 92.7 (C-5), 111.8, 112.4, 144.2, 144.9
(Ph), 148.3 (C-3); MS m/z (%) 135 (M+, -H2O, 100), 95 (55), 68
(21), 52 (77). Anal. Calcd for C7H7NO3: C 54.91; H 4.61; N
9.15. Found: C 54.66; H 4.59; N 9.09.
1
hexane); IR (KBr) 3128, 1609, 1491, 1458, 833, 803 cm-1; H
NMR (CDCl3) δ 6.50 (d, 1H, J = 1.7 Hz, H-4), 7.41 (d, 2H, Ph),
7.70 (d, 2H, Ph), 8.28 (d, 1H, J = 1.7 Hz, H-3); 13C NMR
(CDCl3) δ 98.9 (C-4), 125.6, 127.0, 129.1, 136,1 (Ph), 150.7 (C-
3), 168.1 (C-5); MS m/z (%) 179 (M+, 100), 139 (94), 111 (57),
89 (28), 75 (38). Anal. Calcd for C9H6ClNO: C 60.19; H 3.37; N
7.80. Found: C 59.86; H 3.35; N 7.76.
3-(4-Chlorophenyl)-5-hydroxy-4,5-dihydroisoxazole (5d).
mp 76-48 °C (from hexane); IR (KBr) 3395, 2924, 1598, 1497,
3-(Fur-2-yl)isoxazole (6g). (compound not isolated) MS m/z
(%) 135 (M+, 100), 107 (46), 93 (5), 78 (23), 68 (4).
5-(Thien-2-yl)isoxazole (4h). oil; IR (film) 3109, 1611,
1
826 cm-1; H NMR (DMSO-d6) δ 3.42 (dd, 1H, JHa-Hb = 17 Hz,
JHa-H5 = 5 Hz, Ha-4), 3.50 (dd, 1H, JHb-Ha = 17 Hz, JHb-H5 = 9
Hz, Hb-4), 5.83 (dd, 1H, JH5-Ha = 5 Hz, JH5-Hb = 9 Hz, H-5), 7.51
(d, 2H, Ph), 7.67 (d, 2H, Ph); 13C NMR (DMSO-d6) δ 35.7 (C-
4), 93.4 (C-5), 128.0, 128.8, 129.2, 134.4 (Ph), 155.4 (C-3); MS
m/z (%) 179 (M+, -H2O, 98), 139 (77), 111 (81), 75 (100). Anal.
Calcd for C9H8ClNO2: C 54.70; H 4.08; N 7.09. Found: C 54.31;
H 4.05; N 7.02.
3-(4-Chlorophenyl) isoxazole (6d). (compound not isolated)
MS m/z (%) 179 (M+, 100), 178 (99), 150 (32), 137 (10), 123
(17), 111 (47), 89 (30), 75 (59).
1
1592, 1467, 708 cm-1; H NMR (CDCl3) δ 6.37 (d, 1H, , J = 1.7
Hz, H-4), 7.09 (dd, 1H, Thienyl), 7.42 (d, 1H, Thienyl), 7.49 (d,
1H, Thienyl), 8.23 (d, 1H, J = 1.7 Hz, H-3); 13C NMR (CDCl3) δ
98.2 (C-4), 126.8, 127.8, 127.9, 140.3 (Ph), 150.5 (C-3), 164.1
(C-5); MS m/z (%) 151 (M+, 100), 111 (98), 96 (34), 69 (12).
Anal. Calcd for C7H5NOS: C 55.61, H 3.33; N 9.26. Found: C
55.37; H 3.30; N 9.21.
3-(Thien-2-yl)-5-hydroxy-4,5-dihydroisoxazole (5h). mp
133-135 °C (from hexane); IR (KBr) 3261, 3099, 1612, 1467,
1352, 713 cm-1; 1H NMR (DMSO-d6) δ 3.46 (dd, 1H, JHa-Hb = 17
Hz, JHa-H5 = 5 Hz, Ha-4), 3.49 (dd, 1H, JHb-Ha = 17 Hz, JHb-H5 = 9
Hz, Hb-4), 5.80 (dd, 1H, JH5-Ha = 5 Hz, JH5-Hb = 9 Hz, H-5), 7.13
(dd, 1H, Thienyl), 7.38 (d, 1H, Thienyl), 7.65 (d, 1H, Thienyl);
13C NMR (DMSO-d6) δ 36.5 (C-4), 93.3 (C-5), 127.6, 128.5,
129.3, 131.3 (Thienyl), 152.2 (C-3); MS m/z (%) 151 (M+, -H2O,
100), 131 (14), 111 (53), 96 (48), 69 (43). Anal. Calcd for
C7H7NO2S: C 49.69; H 4.17; N 8.28. Found: C 49.33; H 4.14; N
8.22.
5-(4-Bromophenyl)isoxazole (4e). mp 114-115 °C (from
1
hexane); IR (KBr) 3127, 1606, 1489, 1402, 803, 494 cm-1; H
NMR (CDCl3) δ 6.52 (d, 1H, J = 1.7 Hz, H-4), 7.63 (m, 4H, Ph),
8.29 (d, 1H, J = 1.7 Hz, H-3); 13C NMR (CDCl3) δ 99.0 (C-4),
124.4, 126.0, 127.1, 132.1 (Ph), 150.7 (C-3), 168.1 (C-5); MS
m/z (%) 223 (M+, 100), 183 (77), 155 (41), 89 (43), 75 (36).
Anal. Calcd for C9H6BrNO: C 48.25; H 2.70; N 6.25. Found: C
47.90; H 2.65; N 6.19.
3-(4-Bromo phenyl)isoxazole (6e). (compound not isolated)
MS m/z (%) 223 (M+, 100), 213 (39), 196 (34), 184 (33), 155
(70), 116 (42), 102 (50), 89 (57), 75 (98).
5-(4-Nitrophenyl)isoxazole (4f). mp 163-165 °C (from
hexane); IR (KBr) 3105, 1605, 1577, 1517, 1334, 852, 695 cm-1;
1H NMR (CDCl3) δ 6.74 (d, 1H, J = 1.7 Hz, H-4), 7.98 (d, 2H,
Ph), 8.35 (d, 2H, Ph), 8.38 (d, 1H, J = 1.7 Hz, H-3); 13C NMR
(CDCl3) δ 101.3 (C-4), 124.4, 126.6, 132.6, 148.5 (Ph), 151.0
(C-3), 168.8 (C-5); MS m/z (%) 190 (M+, 100), 160 (25), 150
(30), 104 (29), 89 (76). Anal. Calcd for C9H6N2O3: C 56.85; H
3.18; N 14.73. Found: C 56.46; H 3.17; N 14.63.
3-(Thien-2-yl)isoxazole (6h). (compound not isolated) MS
m/z (%) 151 (M+, 100), 122 (42), 109 (4), 96 (4), 69 (22).
5-(Pyrrol-2-yl)isoxazole (4i). mp 88-90 °C (from hexane);
1
IR (KBr) 2936, 1623, 1535, 1474, 865, 732 cm -1; H NMR
(CDCl3) δ 6.23 (d, 1H, J = 1.7 Hz, H-4), 6.30 (dd, 1H, Pyrrolyl),
6.67 (d, 1H, Pyrrolyl), 6.92 (d, 1H, Pyrrolyl), 8.20 (d, 1H, J =
1.7 Hz, H-3); 13C NMR (CDCl3) δ 95.7 (C-4), 109.9, 110.3,
120.0, 121.1 (Pyrrolyl), 150.6 (C-3), 163.1 (C-5); MS m/z (%)
134 (M+, 100), 94 (67), 79 (38), 66 (36). Anal. Calcd for
C7H6N2O: C 62.68; H 4.51; N 20.88. Found: C 62.32; H 4.47; N
20.77.
3-(4-Nitrophenyl)-5-hydroxy-4,5-dihydroisoxazole (5f).
mp 136-137 °C (from hexane); IR (KBr) 3522, 3089, 1598,
5-Ethylisoxazole (4j). oil; IR (film) 2960, 1684, 1595,
1
1
1582, 1516, 1343, 854, 690 cm-1; H NMR (DMSO-d6) δ 3.50
1469, 820 cm -1; H NMR (CDCl3) δ 1.20 (t, 3H, Me), 2.73 (q,
(dd, 1H, JHa-Hb = 17 Hz, JHa-H5 = 5 Hz, Ha-4), 3.56 (dd, 1H, JHb-
Ha = 17 Hz, JHb-H5 = 9 Hz, Hb-4), 5.96 (dd, 1H, JH5-Ha = 5 Hz, JH5-
2H, CH2), 5.97 (d, 1H, J = 1.7 Hz, H-4), 8.04 (d, 1H, J = 1.7 Hz,
H-3); 13C NMR (CDCl3) δ 12.7 (Me), 27.4 (CH2), 93.2 (C-4),
148.9 (C-3), 184.5 (C-5); MS m/z (%) 97 (M+, 76), 68 (100), 55
(27); Anal. Calcd for C5H7NO: C 61.84, H 7.27, N 14.42. Found:
C 61.62; H 7.24; N 14.37.
= 9 Hz, H-5), 7.92 (d, 2H, Ph), 8.28 (d, 2H, Ph); 13C NMR
Hb
(DMSO-d6) δ 35.2 (C-4), 94.3 (C-5), 123.9, 127.4, 135.3, 147.8
(Ph), 155.4 (C-3); MS m/z (%) 190 (M+, -H2O, 82), 160 (8), 143
(27), 116 (16), 89 (100). Anal. Calcd for C9H8N2O4: C 51.93; H
3.87; N 13.46. Found: C 51.63; H 3.84; N 13.37.
3-Ethylisoxazole (6j). (compound not isolated) MS m/z (%)
97 (M+, 72), 82 (18), 54 (100).
3-(4-Nitrophenyl) isoxazole (6f). (compound not isolated)
MS m/z (%) 190 (M+, 100), 189 (86), 174 (8), 160 (9), 143(21),
132 (7), 116 (12), 89 (67), 76 (26).
5-Trichloromethyl-5-hydroxy-4,5-dihydroisoxazole (3k).
mp 100-102 °C (from hexane); IR (KBr) 3326, 2846, 1623,
1296, 1081, 845, 797 cm-1; 1H NMR (CDCl3) δ 3.29 (dd, 1H, JHa-
Hb = 17 Hz, JHa-H3 = 1.7 Hz, Ha-4), 3.68 (dd, 1H, JHb-Ha = 17 Hz,
JHb-H3 = 1.7 Hz, Hb-4), 7.32 (d, 1H, J = 1.7 Hz, H-3); 13C NMR
(CDCl3) δ 44.8 (C-4), 100.8 (CCl3), 109.6 (C-5), 147.2 (C-3);
MS m/z (%) 186 (MH+, - H2O, 1), 86 (100), 68 (34). Anal. Calcd
for C4H4Cl3NO2: C 23.50; H 1.97; N 6.85. Found: C 23.23; H
1.93; N 6.77.
5-(Fur-2-yl)isoxazole (4g). oil; IR (film) 3133, 1670, 1641,
1
1195, 1012, 789 cm-1; H NMR (CDCl3) δ 6.44 (d, 1H, J = 1.7
Hz, H-4), 6.52 (dd, 1H, Furyl), 6.90 (d, 1H, Furyl), 7.53 (d, 1H,
Furyl), 8.26 (d, 1H, J = 1.7 Hz, H-3); 13C NMR (CDCl3) δ 98.1
(C-4), 110.3, 111.7, 143.0, 143.9 (Furyl), 150.2 (C-3), 160,9 (C-
5); MS m/z (%) 135 (M+, 100), 95 (81), 68 (9,7). Anal. Calcd for

May-Jun 2008
Reaction of β-Dimethylaminovinyl Ketones with Hydroxylamine:
885
[9] Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.;
Sinhorin, A. P.; Flores, A. F. C.; Bonacorso, H. G.; Zanatta, N.
Curr. Org. Synth. 2004, 1, 391; and references therein.
[10] Wilson, R. D.; Burness, D. M. J. Org. Chem. 1966, 31,
1565.
[11] Brederek, H.; Herlinger, H.; Schweizer, E. H. Chem. Ber.
1960, 93, 1208-1211.
[12] Munno, A. De.; Bertini, V.; Lucchesini, F. J. Chem. Soc.,
Perkin Trans. 2 1977, 1121.
[13] Lin, Y.-I.; Lang, S. A. J. Heterocycl.Chem. 1977, 14, 345.
[14] Tseng, S-S.; Epstein, J. W.; Brabander, H. J.; Francisco,
G. J. Heterocycl. Chem. 1987, 24, 837.
[15] Chimichi, S.; Boccalini, M.; Hassan, M. M. M.; Viola,
G.; Dall’Acqua, F.; Curini, M. Tetrahedron 2006, 62, 90.
[16] Reidlinger, C.; Dworczak, R.; Junek, H. Monatsh. Chem.
1998, 129, 1207.
The presence of compounds 6a-h,j was detected only by mass
spectrometry. Because their low yields, these compounds were
not isolated and characterized by others analyses methods.
Acknowledgement.
Nacional de Desenvolvimento Científico
The authors thank the Conselho
Tecnológico
e
(CNPq/PADCT) and Fundação de Amparo à Pesquisa do Estado
do Rio Grande do Sul (FAPERGS) for financial support. The
fellowships from CNPq, CAPES and FAPERGS are also
acknowledged.
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