The reaction of hydroxylamine with aryl trifluoromethyl-β-diketones: Synthesis of 5-hydroxy-5-trifluoromethyl-Δ2-isoxazolines and their dehydration to 5-trifluoromethylisoxazoles

Article abstract of DOI:10.1016/j.jfluchem.2006.03.009

Reaction of hydroxylamine hydrochloride with aryl trifluoromethyl-β-diketones affords 5-hydroxy-5-trifluoromethyl-Δ²-isoxazolines rather than the reported 3-trifluoromethylisoxazoles. The structural assignment is based on the analysis of their

Full text of DOI:10.1016/j.jfluchem.2006.03.009

Journal of Fluorine Chemistry 127 (2006) 880–888
www.elsevier.com/locate/fluor
The reaction of hydroxylamine with aryl trifluoromethyl-b-diketones:
2
Synthesis of 5-hydroxy-5-trifluoromethyl-D -isoxazolines and their
dehydration to 5-trifluoromethylisoxazoles
*
Vinod Kumar, Ranjana Aggarwal, Shiv P. Singh
Department of Chemistry, Kurukshetra University, Kurukshetra 136 119, India
Received 1 February 2006; received in revised form 13 March 2006; accepted 20 March 2006
Available online 29 March 2006
Abstract
Reaction of hydroxylamine hydrochloride with aryl trifluoromethyl-b-diketones affords 5-hydroxy-5-trifluoromethyl-D -isoxazolines rather
2
1
13
19
than the reported 3-trifluoromethylisoxazoles. The structural assignment is based on the analysis of their NMR ( H, C and F) spectral data and
of their dehydration products, 5-trifluoromethylisoxazoles.
#
2006 Elsevier B.V. All rights reserved.
Keywords: Trifluoromethylisoxazolines; Trifluoromethylisoxazoles; NMR spectroscopy; Fluorinated-b-diketones; Fluorinated diazodiketones
1
. Introduction
NH or NH at the carbonyl carbon attached to the aryl group
2
(COAr) instead of COCF [9].
3
The reaction of trifluoromethyl-b-diketones 2 with bifunc-
In continuation of this study, we thought it worthwhile to
tional nucleophiles 1 such as hydrazines and hydroxylamine
leads to the formation of fluorinated pyrazoles and isoxazoles,
respectively. This reaction in principle, may lead to the
formation of three compounds: the 3-trifluoromethyl aromatic
derivatives 3, 5-trifluoromethyl aromatic derivatives 5 and the
investigate the reaction of a variety of aryl trifluoromethyl-b-
diketones 2a–f and 6a–f with a related bifunctional nucleo-
phile, hydroxylamine at variable pH values. This study assumes
added significance in view of the report of the formation of
3-trifluoromethylisoxazoles which necessarily requires nucleo-
2
hydrated 5-hydroxy-5-trifluoromethyl-D -pyrazolines or iso-
xazolines 4 (Scheme 1).
philic attack of NH of hydroxylamine on the carbonyl of the
2
COCF moiety.
3
Numerous synthetic routes to these heterocycles particu-
larly, pyrazoles and trifluoromethylisoxazoles have been
described in the literature [1–4]. We have also reported the
synthetic and mechanistic aspects of the reaction of several
trifluoromethyl-b-diketones with hydrazines and have estab-
lished structure of the products through a rigorous analysis of
2. Results and discussion
It is interesting that Sloop et al. recently reported the
formation of 3-trifluoromethylisoxazole by the reaction of
hydroxylamine 1 with 1-phenyl-4,4,4-trifluorobutane-1,3-
dione and 1,1,1-trifluoropentane-2,4-dione. Due to some
mixup, the product has been described as 5-trifluoromethyli-
1
13
19
their ( H, C and F) NMR spectral characteristics [5–8] and
it has been observed by us that the ratio of the three products
depends on the reaction conditions as well as on the substitution
pattern of the hydrazines and b-diketones. The substituents on
hydrazines influence the nucleophilicity of both the nitrogens
and the initial nucleophilic attack may take place either by the
1
soxazole at other place in the same paper. In the H NMR
spectra of isomeric 3(5)-trifluoromethylisoxazoles reported by
authors [11] bearing methyl group at position-3(5), the 4-H
proton has been reported to appear at the same d value, i.e.
6.4 ppm in both the isomers. Also, in H NMR spectra of 5-
trifluoromethyl-3-phenylisoxazole or 3-trifluoromethyl-5-phe-
nylisoxazole the 4-H proton appeared at the same d value, i.e.
1
*
Corresponding author. Tel.: +91 1744 238523;
6.4 ppm. However, with our experience and from the literature
reports, the characteristic signal due to 4-H proton in H NMR
fax: +91 1744 238277/238628.
1
E-mail address: shivpsingh@rediffmail.com (S.P. Singh).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.03.009

V. Kumar et al. / Journal of Fluorine Chemistry 127 (2006) 880–888
881
Scheme 1.
2
spectra of such compounds is expected to appear upfield (i.e. d
ꢀ
D -isoxazolines 4, which are precursors of 5-trifluoromethy-
lisoxazoles 5. The structure of the products 4 was assigned on
6.7 ppm) for 3-trifluoromethylisoxazoles and downfield (i.e. d
7.00 ppm) for 5-trifluoromethylisoxazoles [10,13]. Such a
1
13
19
ꢀ
the basis of a combined use of H, C and F NMR
spectroscopy.
structural assignment made by Sloop et al. appears to be
inconsistent as to much confusion in mind that how for both the
isomers, 3(5)-methyl and phenyl substituted isoxazoles 4-H
proton resonates at the same d value.
The chemical shifts and coupling constants of diastereotopic
protons (C –H H ) of 4 had recently been established by us on
4
A B
1
the basis of theoretical calculations and H NMR spectroscopy
We had repeated the work under similar reaction conditions
by treating the hydroxylamine with fluorinated-b-diketone 2a
in the presence of conc. sulphuric acid (pH 0.30) and had
obtained a single product mp 138–139 8C displaying signals in
[10]. The H proton which is cis to CF resonates downfield (d
A
3
3.70) as doublet (JHAHB = ꢀ18 Hz) while H , the other proton
B
which is cis to OH, resonates upfield (d 3.49) as quartet due to
the coupling of HB with C –CF as well (JH H = ꢀ18 Hz,
5
3
A
B
1
4J
the H NMR spectrum, a doublet at d 3.70 ppm (J = ꢀ18 Hz)
= ꢀ1.3 Hz) Theoretical calculations (GIAO) and
H ꢁCF
B
.
3
and a quartet at d 3.49 ppm (J = ꢀ18 Hz, J = ꢀ1.3 Hz) due to
molecular modelling have shown that there are two energy
minima depending on the conformation of the OH group. The
most stable conformation has OH group pointing towards
oxygen atom of isoxazole ring and the less stable one has the
two methylene protons suggesting the formation of 5-hydroxy-
5
2
-trifluoromethyl-D -isoxazoline 4a. Also, the reaction of
hydroxylamine hydrochloride 1 (X = O) with fluorinated-b-
diketones 2a–f bearing differently substituted phenyl ring gives
OH pointing towards methylene carbon. The energy difference
ꢁ1
1
exclusively a single product ( H NMR of crude reaction
between two conformations is in the order of 19.2 kJ mol
1
.
3
mixture) when it was carried out in presence of sodium acetate
in almost neutral medium (pH 6.7). Similar results were
obtained on performing the reaction at different pH (Scheme 2).
The products were identified as 5-hydroxy-5-trifluoromethyl-
Thestructureof4wasfurthersupportedby CNMRinwhich
2
carbon-5 resonated as a quartet at d 103 ppm ( J
while C-4 and C-3 resonated as singlets at d 42 and 156 ppm,
= 34.5 Hz)
CF
3
1
respectively [13]. A sharp signal in F NMR spectrum at d
9
Scheme 2.

882
V. Kumar et al. / Journal of Fluorine Chemistry 127 (2006) 880–888
Scheme 3.
Scheme 4.
ꢁ
83 ppm also makes the firm evidence in support of the structure
of isoxazoline [10,14]. The IR spectra of compounds 4a–f
It was thus decided to re-investigate this reaction. Such a
study also appeared promising, as many such compounds have
shown diverse biological properties.
ꢁ
1
showed a broad band at 3200 cm due to OH stretch. These
results are in close agreement with our earlier report [10].
The reaction between 1 and 6a–f were performed under the
conditions described earlier and it was observed that there was
2
exclusive formation of 5-hydroxy-5-trifluoromethyl-D -isoxa-
zolines 7 in these reactions as well (Scheme 3). The products
were characterized by a rigorous analysis of their IR and NMR
spectra. In IR spectra, two absorption bands are due to NH and
ꢁ
1
0
OH str. at ꢀ3317 and ꢀ3219 cm which indicate that 7 a–f
exist in their tautomeric form 7a–f (Scheme 4).
1
The H NMR spectroscopy is not much helpful to in
While this work was in progress, we came across with a
literature report describing the reaction between 1 and 1-aryl-2-
1
distinguishing the structure of the isomers. In C NMR spectra
3
(
p-fluorophenyldiazo)-4,4,4-trifluorobutane-1,3-diones 6. The
authors have reported the formation of 3-trifluoromethylisox-
of compounds 7a–f carbon-5 resonated as a quartet at d
2
ꢀ99 ppm ( J
= 38.25 Hz) while C-4 and C-3 resonated as
CF
3
1
azoles on the basis of IR and H NMR spectroscopy. In IR
singlets at d ꢀ132 and ꢀ155 ppm, respectively. A sharp signal
1
9
spectra the reported compounds showed N N str. in range
(
in F NMR spectrum at d ꢁ80 ppm also provides a firm
evidence in support of the structure of isoxazoline. These
results are in close agreement with our results (Scheme 3) and
also with our earlier work [10].
ꢁ
1
1510–1560 cm ), C C (C N) str. in range 1600–1620 cm )
ꢁ1
1
and in H NMR spectra a complex multiplet appears at d 7.00–
.8 ppm. Such a structure assigned to the products appeared to
7
be untenable on the basis of the present work and also with our
experience of analogous study of the reaction of hydrazines and
aryl trifluoromethyl-b-diketones [9]. The structure, 3-trifluor-
omethylisoxazoles, as reported by the authors [12] could not be
These observations suggest that the nucleophilic attack of
NH2 of hydroxylamine takes place on the more reactive
carbonyl carbon attached to the aryl group (i.e. COAr) of the
diketones (Scheme 5), which is in conformity with our earlier
report [9].
1
established on the basis of H NMR spectroscopy alone. The
position of the carbons of isoxazole ring needs to be assigned
Acid-catalyzed dehydration of 4 and 7 generated corre-
sponding 5-trifluoromethylisoxazoles 5 and 8, which were
1
3
using C NMR spectroscopy as well.

V. Kumar et al. / Journal of Fluorine Chemistry 127 (2006) 880–888
883
Scheme 5.
unambiguously characterized by a careful analysis of their
1
respectively [13b]. Had there been formation of the other
isomer, i.e. 3-trifluoromethyl-5-phenylisoxazole, the signal for
C-3, C-4 and C-5 would have appeared at d 152 (q), 104 (s) and
at d 162 (s) ppm, respectively [13]. In the C NMR spectra of
the compounds 8a, carbons-3 and 5 resonated at about the same
value as shown in compounds 5a–f, which supported the
13
19
1
NMR ( H, C and F) spectra. In the H NMR spectra of 5a–f,
a signal appeared as a doublet at d ꢀ7.00 ppm due to the
1
3
coupling between 4-H of isoxazole and 5-CF which is in close
3
agreement with the value reported earlier by us [10] and the
other workers [15,13b]. Had the CF group in isoxazole been
3
present at position-3, the signal as a singlet would have
appeared as an upfield signal at d ꢀ6.6–6.7 ppm [13]. As
location of CF group at postion-5 of isoxazole ring. These
3
values are in close agreement with our earlier observations [10].
19
1
expected, in the H NMR spectra of compounds 8a the
The F NMR spectra of compounds 5 and 8 exhibited a sharp
1
9
characteristic signal for 4-H were found to be absent.
Furthermore, the signals for isoxazole carbons 3, 4 and 5 in
compounds 5 appeared at d 162 (s), 103 (s) and at 159 (q) ppm,
signal as a singlet at d ꢀ ꢁ65 ppm. F NMR is not of much help
for distinguishing a pair of isomeric 3(5)-trifluoromethylisox-
azolesasthevaluesareveryclose[15]. Incontrast, the positionof
Table 1
13
C NMR data of compounds 6a–f
0
0
0
0
0
0
00
00
00
00
00
00
C-4
Compounds C-1
C-2
C-3
C-4
C-1
C-2 , 6
C-3 , 5
C-4
C-1
C-2 , 6
C-3 , 5
CH
3
6a
6b
6c
6d
6e
6f
192.29 133.14 176.75
117.31
1
130.46
133.10
128.28
137.61
137.00
4
118.56
116.91
2
161.39
1
–
2
3
(
q, JCF
33)
190.57 132.46 176.75
(q, JCF
(q, JCF
(q, JCF
= 8.25)
118.62
(q, JCF
(q, JCF
=
= 290.25)
117.19
= 2.25)
136.89
= 23.25) = 246.75)
133.75
4
(d, JCF
131.16
3
(d, JCF
= 9)
115.46
3
(d, JCF
165.80
1
(d, JCF
116.94
2
(q, JCF
161.39
1
(q, JCF
–
–
–
2
1
4
3
(
q, JCF
33)
191.04 131.81 176.74
(q, JCF
(d, JCF
(q, JCF
=
= 290.25) = 3.75)
= 21.75) = 253.5) = 2.25)
= 8.25
118.76
= 23.25) = 246.75)
117.25
1
(q, JCF
131.81
135.75
128.80
143.19
129.78
128.65
129.16
113.61
123.56
139.64
127.25
163.98
149.68
136.82
4
(q, JCF
117.01
2
(q, JCF
161.54
1
(q, JCF
2
3
(
q, JCF
33)
190.59 131.25 176.08
(q, JCF
=
= 290.25)
116.61
= 3)
= 8.25)
118.08
= 23.25) = 247.5)
130.95
131.21
128.82
136.18
4
(q, JCF
116.40
2
(q, JCF
160.91
1
(q, JCF
2
1
3
(
q, JCF
33)
189.92 131.32 176.35
(q, JCF
(q, JCF
=
= 290.25)
117.27
= 3)
= 8.25)
118.26
= 23.25) = 247.5)
137.11
4
(q, JCF
116.45
2
(q, JCF
161.11
1
(q, JCF
55.51
–
2
1
3
(
q, JCF
(q, JCF
(q, JCF
=
32.25) = 290.25)
= 3)
= 8.25)
119.18
= 23.25) = 246.75)
191.09 131.14 176.71
2
117.21
1
(q, JCF
136.60
4
(q, JCF
117.25
2
(q, JCF
161.52
1
(q, JCF
3
(
q, JCF
33)
(q, JCF
=
= 290.25)
= 3)
= 8.25)
= 23.25) = 247.5)

884
V. Kumar et al. / Journal of Fluorine Chemistry 127 (2006) 880–888
Table 2
13
C NMR data for compounds 4a–f and 5a–f
0
0
0
0
0
0
C-4
Compounds
C-3
C-4
41.97
C-5
C-1
C-2 , 6
C-3 , 5
CF
3
CH
3
4
4
4
4
4
4
5
5
5
5
5
5
a
b
c
d
e
f
155.99
102.33
2
126.75
127.97
125.95
130.18
120.95
1
(q, JC–F
–
(
q, JC–F
=
34.5 Hz)
= 282 Hz)
121.92
156.15
155.07
155.08
155.57
155.13
162.59
161.71
161.81
161.75
161.17
160.89
43.05
41.80
103.55
123.99
4
(q, JCF
129.09
3
(q, JC–F
116.28
164.42
1
(q, JC–F
–
–
–
2
2
1
(
q, JC–F
34.5 Hz)
102.55
(q, JC–F
= 21.75 Hz)
127.18
(q, JC–F
=
= 3.75 Hz)
125.22
= 9 Hz)
128.97
= 250.5 Hz)
136.34
= 282 Hz)
120.86
2
1
(
q, JC–F
34.5 Hz)
102.54
(q, JC–F
=
= 282 Hz)
120.86
41.72
125.71
120.19
133.54
127.36
123.65
127.34
128.64
1276.63
129.22
129.05
131.26
120.19
123.11
126.96
116.20
124.66
161.86
147.86
130.94
164.37
2
1
(
q, JC–F
33.75 Hz)
103.20
(q, JC–F
=
= 282 Hz)
122.04
43.25
55.44
2
1
(
q, JC–F
33.75 Hz)
103.50
(q, JC–F
=
= 282 Hz)
121.14
41.27
–
2
1
(
q, JC–F
34.5 Hz)
159.24
(q, JC–F
=
= 282 Hz)
117.90
a
b
c
d
e
f
103.46
103.37
103.35
103.32
103.24
103.62
–
2
1
(
q, JC–F
42 Hz)
159.44
(q, JC–F
=
= 268.5 Hz)
117.90
–
2
4
3
2
1
1
(
q, JC–F
42 Hz)
159.42
(q, JC–F
(q, JC–F
(q, JC–F
(q, JC–F
(q, JC–F
=
= 3.75 Hz)
126.32
= 8.25 Hz)
129.24
= 21.75 Hz)
128.10
= 250.5 Hz)
136.32
= 268.5 Hz)
117.85
–
2
1
(
q, JC–F
42 Hz)
159.55
(q, JC–F
=
= 268.5 Hz)
117.81
126.29
119.77
133.28
128.42
128.43
127.99
132.53
114.61
124.50
125.53
162.17
149.30
–
2
1
(
q, JC–F
42 Hz)
159.46
(q, JC–F
=
= 268.5 Hz)
117.91
55.43
–
2
1
(
q, J
42 Hz)
160.23
(q, JC–F
=
= 268.5 Hz)
117.65
2
1
(
q, J
(q, JCF
=
42.75 Hz)
= 268.5 Hz)
Table 3
13
C NMR data of compounds 7a–f and 8a
0
0
0
0
0
0
00
00
00
00
00
00
C-4
Compounds C-3 C-4 C-5
C-1
C-2 , 6
C-3 , 5
C-4
C-1
C-2 , 6
C-3 , 5
CF
3
CH
3
7
7
7
7
7
7
8
a
b
c
d
e
f
156.02 132.11
154.52 133.27
155.05 131.28
155.13 131.32
155.15 132.44
153.32 132.78
98.40
2
126.36
4
128.58
128.16
2
130.98
1
138.45
4
115.16
3
116.20
2
158.96
1
121.70
1
–
3
(
q, JCF
(d, JCF
(d, JCF
= 8.25)
129.91
(d, JCF
(d, JCF
(d, JCF
(d, JCF
= 7.5)
(d, JCF
(d, JCF
(q, JCF
=
38.25) = 3)
= 21.75) = 249.75) = 3)
= 23.25) = 240.75) = 285.75)
98.97
2
q, JCF
123.23
124.59
125.77
118.71
131.56
126.93
115.65
128.94
131.93
113.99
123.01
128.70
164.02
137.35
125.12
161.61
148.14
130.75
138.79
4
(d, JCF
114.93
3
(d, JCF
116.06
2
(d, JCF
158.59
1
(d, JCF
122.13
1
(q, JCF
–
–
–
(
=
36)
= 3)
= 7.5)
= 23.25) = 240.75) = 287.25)
98.53
2
q, JCF
129.34
129.54
129.60
128.16
129.23
138.18
4
(d, JCF
115.26
3
(d, JCF
116.38
2
(d, JCF
159.17
1
(d, JCF
121.73
1
(q, JCF
(
=
38.25)
= 3)
= 8.25)
115.27
= 23.25) = 241.5)
= 285.75)
121.75
98.75
2
q, JCF
138.18
4
(d, JCF
116.43
2
(d, JCF
159.18
1
(d, JCF
3
1
(
(d, JCF
(q, JCF
=
38.25)
= 3)
= 8.25)
115.11
= 23.25) = 240.75) = 285.75)
98.86
2
q, JCF
138.53
4
(d, JCF
116.20
2
(d, JCF
158.77
1
(d, JCF
122.08
1
(q, JCF
55.32
3
(
(d, JCF
=
36)
= 3)
= 7.5)
= 22.25) = 240.75) = 287.25)
98.99
2
q, JCF
138.10
4
(d, JCF
114.58
3
(d, JCF
115.57
2
(d, JCF
158.16
1
(d, JCF
121.42
1
(q, JCF
–
–
(
=
36)
= 3)
= 8.25)
125.47
= 23.25) = 240.75) = 287.25)
a
159.31 119.94 149.0
2
149.05
4
(d, JCF
116.45
2
(d, JCF
165.51
1
(d, JCF
117.30
1
(q, JCF
3
(
q, JCF
(d, JCF
=
43.25)
= 3)
= 9)
= 23.25) = 253.5)
= 268.50)

V. Kumar et al. / Journal of Fluorine Chemistry 127 (2006) 880–888
885
ꢁ ꢁ1
1
ꢁ1
their signals is a very significant tool for distinction between
isomeric 3(5)-trifluoromethylpyrazoles [2].
(KBr): 1690 cm (CO), 3214 cm (OH str.) and 3319 cm
1
00
00
(NH str.); H NMR (CDCl ) d: 7.13–7.23 (m, 2H, 3 , 5 -H),
3
0 0 00 00
7.44 (d, 2H, 3 , 5 -H, J = 8.4 Hz), 7.48–7.52 (m, 2H, 2 , 6 -H),
0
The spectral data of these compounds are consistent with the
results observed earlier [10]. It is obvious that the structure of
the products 4, 7 and 5, 8 reported by earlier workers need to be
corrected.
0
0
7.55 (d, 2H, 2 , 6 -H, J = 8.4 Hz), 14.17 (bs, 1H, NH or OH,
0
1
9
D O exchangeable); F NMR (CDCl ) d: ꢁ71.4 (s, 3F, CF ),
2
3
3
0
0
+
+
ꢁ114.5 (s, 1F, 4 -F). MS (m/z): 372 (M ) and 374 (M + 2) in
the ratio showing typical chlorine isotope profile (3:1),
C H ClF N O requires 372. Anal. calc.: N, 7.53% (found:
3
. Experimental
1
6
9
4 2 2
7.38).
Melting points were determined in open capillaries in
electrical apparatus and are uncorrected. IR spectra were
3.1.1.4. 1-( p-Bromophenyl)-2-( p-fluorophenyldiazo)-4,4,4-
1
recorded on a Buck Scientific IR M500 instrument and H
trifluorobutane-1,3-dione (6d). mp 101–102 8C, yield 84%.
IR (KBr): 1690 cm
1
NMR and C NMR spectra were run on a Brucker instrument
3
ꢁ1
ꢁ1
(CO), 3214 cm (OH str.) and
3319 cm (NH str.); H NMR (CDCl ) d: 7.16–7.68 (m,
1
9
ꢁ1
1
at 300 and 75 MHz, respectively. F NMR spectra were run on
DRX 300 and DPX 400 at 282 and 376 MHz, respectively,
3
0
00
8H, p-FPh -H, p-BrPh -H), 14.19 (bs, 1H, NH or OH, D O
2
1
using CDCl as solvent. The internal standard for F spectra
9
19
exchangeable); F NMR (CDCl ) d: ꢁ71.2 (s, 3F, CF ),
3
3
3
1
3
00
+
+
was CFCl , setting the CFCl signal at d 0.00 ppm. C NMR
3
ꢁ114.1 (s, 1F, 4 -F). MS (m/z): 416 (M ) and 418 (M + 2) in
the ratio showing typical bromine isotope profile (1:1);
C H BrF N O requires 416. Anal. calc.: N, 6.73% (found:
3
data for the compounds are presented in Tables 1–3.
Fluorinated b-diketones 2a–f and 6a–f were synthesized
according to the literature procedures [16,12].
1
6
9
4 2 2
6.54).
3
.1. General procedure
3.1.1.5. 1-( p-Methoxyphenyl)-2-( p-fluorophenyldiazo)-4,4,4-
trifluorobutane-1,3-dione (6e). mp 120–121 8C, yield 79%. IR
(KBr): 1690 cm (CO), 3214 cm (OH str.) and 3319 cm
ꢁ1
ꢁ1
ꢁ1
3.1.1. Synthesis of 1-aryl-2-( p-fluorophenyldiazo)-4,4,4-
trifluorobutane-1,3-diones (6a–f)
1
(NH str.); H NMR (CDCl ) d: 3.88 (s, 3H, OCH ), 6.93 (d, 2H,
3 3
0
0 00 00
, 5 -H, J = 8.7 Hz), 7.13–7.19 (m, 2H, 3 , 5 -H), 7.43–7.48
0
3
00 00 0 0
(m, 2H, 2 , 6 -H), 7.65 (d, 2H, 2 , 6 -H, J = 8.7 Hz), 13.62 (bs,
0
3
.1.1.1. 1-Phenyl-2-( p-fluorophenyldiazo)-4,4,4-trifluorobu-
tane-1,3-dione (6a). Procedure: 4-fluoroaniline (2.22 g,
.02 mol) was dissolved in a mixture of conc. HCl and water
20 ml, 1:1). It was cooled to 0 8C and a cold aq. solution of
1
9
1H, NH or OH, D O exchangeable); F NMR (CDCl ) d:
3
2
0
0
+
0
ꢁ71.2 (s, 3F, CF ), ꢁ114.4 (s, 1F, 4 -F). MS (m/z): 368 (M );
3
(
C H F N O requires 368. Anal. calc.: N, 7.61% (found:
1
7 12 4 2 3
sodium nitrite (1.38 g, 0.02 mol in 10 ml water) was added to it
slowly maintaining the temperature upto 5 8C. The cold
diazotized solution was added dropwise to a cooled mixture of
7.49).
3.1.1.6. 1-( p-Nitrophenyl)-2-( p-fluorophenyldiazo)-4,4,4-tri-
fluorobutane-1,3-dione (6f). mp 110 8C, yield 83%. IR (KBr):
1690 cm (CO), 3214 cm (OH str.) and 3319 cm (NH
1
str.); H NMR (CDCl ) d: 7.14–7.28 (m, 2H, 3 , 5 -H), 7.54–
1
-phenyl-4,4,4,-trifluorobutane-1,3 dione (4.32 g, 0.02 mol)
ꢁ ꢁ1 ꢁ1
1
and sodium acetate (10 g) in 20 ml of 50% ethanol. The stirring
was continued for 1 h and the crystals separated were filtered,
washed with water, dried and recrystallized from ethanol to
yield 6a, mp 110 8C [12] (104 8C), yield 87%. IR (KBr):
00
00
3
0
0
00
0
0
7.59 (m, 2H, 2 , 6 -H), 7.70 (d, 2H, 2 , 6 -H, J = 8.7 Hz), 8.31
0
0
0
(d, 2H, 3 , 5 -H, J = 8.7 Hz), 13.62 (bs, 1H, NH or OH, D O
0
2
ꢁ
1
ꢁ1
19
exchangeable); F NMR (CDCl ) d: ꢁ71 (s, 3F, CF ), ꢁ114.1
1
690 cm (CO), 3214 cm (OH str. due to enolic form) and
3
3
ꢁ
1
319 cm (NH str.); H NMR (CDCl ) d: 7.15–7.28 (m, 9H,
1
00
+
(s, 1F, 4 -F). MS (m/z): 383 (M ), C H F N O requires 383.
3
Ph -H, p-FPh -H), 14.07 (bs, 1H, NH or OH, D O exchange-
3
16 9 4 3 4
0
00
Anal. calc.: N, 10.96% (found: 10.72).
2
1
9
00
able); F NMR (CDCl ) d: ꢁ71 (s, 3F, CF ), ꢁ114 (s, 1F, 4 -
3
3
+
F). MS (m/z): 338 (M ); C H F N O requires 338. Anal.
2
3.1.2. Synthesis of 3-aryl-5-hydroxy-5-trifluoromethyl-D -
isoxazolines (4a–f and 7a–f)
1
6 10 4 2 2
calc.: N, 8.28% (found: 8.02).
The compounds 6b–f were prepared similarly.
2
3.1.2.1. 3-( p-Bromophenyl)-5-hydroxy-5-trifluoromethyl-D -
isoxazoline (4d). Procedure: an ethanolic solution (25 ml) of
hydroxylamine hydrochloride salt (0.35 g, 5 mmol) and sodium
acetate (0.41 g, 5 mmol) was refluxed on water bath for 15
minutes (pH 6.7). 4-( p-Bromophenyl)-1,1,1-trifluorobutane-
2,4-dione 2d (1.47 g, 5 mmol) was subsequently added and
solution was refluxed further for 4 h. The reaction was
monitored by TLC. The solvent was evaporated and residue
obtained was extracted with chloroform. The organic phase was
dried over anhydrous sodium sulphate and chloroform was
3
.1.1.2. 1-( p-Fluorophenyl)-2-( p-fluorophenyldiazo)-4,4,4-
trifluorobutane-1,3-dione (6b). mp 98–99 8C, yield 85%. IR
ꢁ
1
KBr): 1690 cm (CO), 3214 cm (OH str.) and 3319 cm
ꢁ1
ꢁ1
(
1
NH str.); H NMR (CDCl ) d: 6.97–7.56 (m, 8H, p-FPh -H, p-
0
(
FPh -H), 14.02 (bs, 1H, NH or OH, D O exchangeable);
3
0
0
19
F
2
0
NMR (CDCl ) d: ꢁ71 (s, 3F, CF ), ꢁ106 (s, 1F, 4 -F), ꢁ115 (s,
3
3
00
F, 4 -F). MS (m/z): 356 (M ); C H F N O requires 356.
16 9 5 2 2
+
1
Anal. calc.: N, 7.86% (found: 7.76).
1
distilled off. The TLC and H NMR of the crude solid obtained
showed the formation of single product. The compound
3
.1.1.3. 1-( p-Chlorophenyl)-2-( p-fluorophenyldiazo)-4,4,4-
trifluorobutane-1,3-dione (6c). mp 104 8C, yield 89%. IR
was recrystallized from ethanol to give pure solid 3d, mp

886
V. Kumar et al. / Journal of Fluorine Chemistry 127 (2006) 880–888
ꢁ
1
+
1
str.); H NMR (CDCl ) d: 3.42 (qd, 1H, 4-H, J
09–110 8C [13] (60 8C), yield 86%. IR (KBr): 3255 cm (OH
HRMS (m/z): 276.0353 (M ), C H F N O requires 276.0357.
10 7 3 2 4
1
= 17.7 Hz,
JH–F = 1.2 Hz), 3.58 (bs, 1H, OH), 3.62 (d, 1H, 4-H,
Anal. calc.: N, 10.14% (found: 9.85).
3
gem
4
0
0
Jgem = 18 Hz), 7.45 (d, 2H, 3 , 5 -H, J = 8.7 Hz), 7.51 (d,
0
3.1.2.7. 3-Phenyl-4-( p-fluorophenyldiazo)-5-hydroxy-5-tri-
fluoromethylisoxazoline (7a). mp 160 8C, yield 82%. IR
(KBr): 3219 cm (OH str.) and 3317 cm (NH str.); H
0
0
19
H, 2 , 6 -H, J = 8.4 Hz); F NMR (CDCl ) d: ꢁ83.4.
2
0
3
+
+
ꢁ1
ꢁ1
1
HRMS (m/z): 308.9599 (M ), 310.9576 (M + 2) in the ratio
showing typical bromine isotope profile (1:1); C H BrF NO
requires: 308.9612.
1
NMR (CDCl ) d: 3.80 (bs, 1H, OH, D O exchangeable), 6.97–
1
0
7
3
2
3
2
00 00 00 00 0 0 0
6.99 (m, 4H, 2 , 6 , 3 , 5 -H), 7.41–7.44 (m, 3H, 3 , 4 , 5 -H),
0 0
7.91 (d, 2H, 2 , 6 -H, J = 7.6 Hz), 9.27 (bs, 1H, NH, D O
0 2
Anal. calc.: N, 4.54% (found: 4.27).
Compounds 4a, 4b, 4c, 4e, 4f and 7a–f were prepared by
employing similar procedure.
1
9
exchangeable) (see Footnote 1); F NMR (CDCl ) d: ꢁ80 (s,
3
0
0
+
3F, CF ), ꢁ122 (s, 1F, 4 -F). HRMS (m/z): 353.0790 (M ),
3
C H F N O requires 353.0787. Anal. calc.: N, 11.89%
1
6 11 4 3 2
3
.1.2.2. 3-Phenyl-5-hydroxy-5-trifluoromethylisoxazoline
(found: 11.74).
(
IR (KBr): 3195 cm (OH str.); H NMR (CDCl ) d: 3.44 (qd,
4a). mp 140–41 8C [13,14] (147 8C, 144–145 8C), yield 90%.
ꢁ
1
1
3
3.1.2.8. 3-( p-Fluorophenyl)-4-( p-fluorophenyldiazo)-5-hy-
4
H, 4-H, Jgem = 17.7 Hz, J
1
3
7
= 1.2 Hz), 3.50 (bs, 1H, OH),
0
H–F
droxy-5-trifluoromethylisoxazoline (7b). mp 170–172 8C, yield
0
0
ꢁ1
ꢁ1
.65 (d, 1H, 4-H, Jgem = 18 Hz), 7.33–7.44 (m, 3H, 3 , 4 5 -H),
19
85%. IR (KBr): 3210 cm
1
(OH str.) and 3315 cm (NH str.);
H NMR (CDCl ) d: 3.82 (bs, 1H, OH, D O exchangeable) (see
0
0
.58–7.60 (m, 2H, 2 , 6 -H); F NMR (CDCl ) d: ꢁ83.4 (s, 3F,
3
3
2
+
0 0 00 00 00 00
CF ). HRMS (m/z): 231.0507 (M ); C H F NO requires
3
Footnote 1), 7.06–7.18 (m, 6H, 3 , 5 , 2 , 3 , 5 and 6 -H), 7.97
= 3.3 Hz), 9.23 (bs, 1H, NH,
10
8
3
2
0
0
4
(dd, 2H, 2 , 6 -H, J = 7.6 Hz, J
2
31.0505. Anal. calc.: N, 6.06% (found: 5.98).
0
H–F
1
9
D O exchangeable) (see Footnote 1); F NMR (CDCl ) d: ꢁ80
2
3
0
00
3
.1.2.3. 3-( p-Fluorophenyl)-5-hydroxy-5-trifluoromethylisox-
(
s, 3F, CF ), ꢁ110 (s, 1F, 4 -F), ꢁ122 (s, 1F, 4 -F). MS (m/z):
3
+
71 (M ), C H F N O requires 371. Anal. calc.: N, 11.32%
azoline (4b). mp 116–117 8C [13] (118 8C), yield 88%. IR
3
(found: 11.23).
1
6 10 5 3 2
ꢁ
KBr): 3203 cm (OH str.); H NMR (CDCl ) d: 3.50 (qd, 1H,
3
1
1
(
4
4
-H, Jgem = 17.7 Hz, J
8 Hz), 3.69 (bs, 1H, OH), 7.08-7.15 (m, 2H, 3 , 5 -H), 7.61–
= 1.2 Hz), 3.70 (d, 1H, 4-H, Jgem =
H–F
0 0
1
3
.1.2.9. 3-( p-Chlorophenyl)-4-( p-fluorophenyldiazo)-5-hy-
0
0
19
7
.65 (m, 2H, 2 , 6 -H); F NMR (CDCl ) d: ꢁ83 (s, 3F, CF ),
3
3
droxy-5-trifluoromethylisoxazoline (7c). mp 140 8C, yield
88%. IR (KBr): 3219 cm (OH str.) and 3315 cm (NH
00
109 (s, 1F, 4 -F). HRMS (m/z): 249.0412 (M ); C H F NO
10 7 4 2
+
ꢁ1
ꢁ1
ꢁ
1
str.); H NMR (CDCl ) d: 3.78 (bs, 1H, OH, D O exchangeable)
requires 249.0414. Anal. calc.: N, 5.62% (found: 5.58).
3
2
0
0
00
00
00
(
see Footnote 1), 6.95–6.97 (m, 4H, 2 , 3 , 5 and 6 -H), 7.30
3
.1.2.4. 3-( p-Chlorophenyl)-5-hydroxy-5-trifluoromethylisox-
0 0 0 0
d, 2H, 3 , 5 -H, J = 7.8 Hz), 7.77 (d, 2H, 2 , 6 -H, J = 7.5 Hz),
0 0
(
1
9
azoline (4c). mp 120 8C [13] (65–66 8C), yield 87%. IR
9
.15 (bs, 1H, NH, D O exchangeable) (see Footnote 1);
2
F
ꢁ
1
1
KBr): 3204 cm (OH str.); H NMR (CDCl ) d: 3.42 (qd, 1H,
(
00
3
NMR (CDCl ) d: ꢁ80 (s, 3F, CF ), ꢁ120 (s, 1F, 4 -F). HRMS
3
3
4
-H, Jgem = 18 Hz, JH–F = 1.2 Hz), 3.62 (d, 1H, 4-H,
+
(m/z): 387.0391 (M ) and 389.0364 (M + 2) in the ratio
+
4
Jgem = 18 Hz), 4.05 (bs, 1H, OH, D O exchangeable), 7.39
2
showing typical chlorine isotope profile (3:1), C H ClF N O
4 3 2
1
6
10
0
0
0
0
(
d, 2H, 3 , 5 -H, J = 8.7 Hz), 7.52 (d, 2H, 2 , 6 -H, J = 8.7 Hz);
9
requires 387.0397. Anal. calc.: N, 10.85% (found: 10.72).
1
F NMR (CDCl ) d: ꢁ83.3 (s, 3F, CF ). HRMS (m/z):
3
3
+
+
2
65.0110 (M ) and 267.0066 (M + 2) in the ratio showing
typical chlorine isotope profile (3:1), C H ClF NO requires
3
.1.2.10. 3-( p-Bromophenyl)-4-( p-fluorophenyldiazo)-5-hy-
1
0
7
3
2
droxy-5-trifluoromethylisoxazoline (7d). mp 165 8C, yield
2
65.0117. Anal. calc.: N, 5.27% (found: 5.19).
ꢁ1 ꢁ1
4%. IR (KBr): 3214 cm (OH str.) and 3319 cm (NH
8
str.); H NMR (CDCl ) d: 3.78 (bs, 1H, OH, D O exchangeable)
1
3
2
3
.1.2.5. 3-( p-Methoxyphenyl)-5-hydroxy-5-trifluoromethyli-
00 00 00 00
(
see Footnote 1), 7.03–7.10 (m, 4H, 2 , 3 , 5 and 6 -H), 7.56 (d,
soxazoline (4e). mp 118 8C [13] (54–55 8C), yield 84%. IR
0 0 0 0
H, 3 , 5 -H, J = 8.1 Hz), 7.80 (d, 2H, 2 , 6 -H, J = 8.4 Hz),
0 0
2
ꢁ
1
1
KBr): 3198 cm (OH str.); H NMR (CDCl ) d: 3.49 (qd, 1H,
(
19
F
3
9.21 (bs, 1H, NH, D O exchangeable) (see Footnote 1);
2
4
-H, Jgem = 17.7 Hz, JH–F = 1.2 Hz), 3.69 (d, 1H, 4-H,
4
Jgem = 17.8 Hz), 3.85 (s, 3H, OCH ) 4.15 (bs, 1H, OH, D O
00
NMR (CDCl ) d: ꢁ80 (s, 3F, CF ), ꢁ120 (s, 1F, 4 -F). HRMS
3
3
+
+
(m/z): 430.9862 (M ) and 432.9852 (M + 2) in the ratio
3
2
0
0
exchangeable), 6.93 (d, 2H, 3 , 5 -H, J = 8.7 Hz), 7.58 (d, 2H,
19
showing typical bromine isotope profile (1:1), C H BrF N O
4 3 2
1
6
10
0
0
2
MS (m/z): 261.0616 (M ), C H F NO requires 261.0612.
, 6 -H, J = 8.7 Hz); F NMR (CDCl ) d: ꢁ83.4 (s, 3F, CF ).
3
3
requires 430.9872. Anal. calc.: N, 9.74% (found: 9.65).
+
11 10 3 3
Anal. calc.: N, 5.36% (found: 5.23).
3.1.2.11. 3-( p-Methoxyphenyl)-4-( p-fluorophenyldiazo)-5-hy-
droxy-5-trifluoromethylisoxazoline (7e). mp 145–146 8C,
yield 78%. IR (KBr): 3211 cm (OH str.) and 3315 cm
3
.1.2.6. 3-( p-Nitrophenyl)-5-hydroxy-5-trifluoromethylisoxa-
ꢁ
ꢁ1
ꢁ1
1
zoline (4f). mp 152–53 8C, yield 76%. IR (KBr): 3186 cm
1
NH str.); H NMR (CDCl ) d: 3.81 (bs, 1H, OH, D O
(
exchangeable) (see Footnote 1), 3.83 (s, 3H, OCH ), 6.92 (d,
3
2
1
OH str.); H NMR (CDCl ) d: 3.43 (qd, 1H, 4-H,
(
Jgem = 17.7 Hz,
3
3
4
JH–F = 1.2 Hz), 3.61 (d, 1H, 4-H,
0
0
Jgem = 18 Hz), 7.78 (d, 2H, 2 , 6 -H, J = 9 Hz), 8.04 (d, 2H,
19
3
0
0
1
, 5 -H, J = 8.7 Hz); F NMR (CDCl ) d: ꢁ83.5 (s, 3F, CF ).
These values may be interchangeable.
3
3

V. Kumar et al. / Journal of Fluorine Chemistry 127 (2006) 880–888
887
0
0
00
00
00
00
2
H), 7.90 (d, 2H, 2 , 6 -H, J = 8.4 Hz), 9.22 (bs, 1H, NH, D O
H, 3 , 5 -H, J = 8.4 Hz), 7.02–7.05 (m, 4H, 2 , 3 , 5 and 6 -
0
(3:1); C H ClF NO requires 247. Anal. calc.: N, 5.67%
5
0
10
3
0
(found: 5.51).
0
2
1
9
exchangeable) (see Footnote 1); F NMR (CDCl ) d: ꢁ80 (s,
3
00
+
3
C H F N O requires 383.0893. Anal. calc.: N, 10.96%
F, CF ), ꢁ121 (s, 1F, 4 -F). HRMS (m/z): 383.0875 (M ),
3.1.3.4. 3-( p-Methoxyphenyl)-5-trifluoromethylisoxazole
1
3
1
7 13 4 3 3
(5e). mp 72–73 8C [13] (74–75 8C), and yield 84%. H NMR
4
d: 3.87 (s, 3H, OCH ), 6.95 (d, 1H, 4-H, J
(
found: 10.82).
= 0.9 Hz), 7.00
d, 2H, 3 , 5 -H, J = 8.7 Hz), 7.75 (d, 2H, 2 , 6 -H, J = 8.7 Hz);
3
H–F
0
0
0
0
(
1
0
0
9
+
3
.1.2.12. 3-( p-Nitrophenyl)-4-( p-fluorophenyldiazo)-5-hydro-
F NMR (CDCl ) d: ꢁ65 (s, 3F, CF ). MS (m/z): 243 (M ),
3
3
xy-5-trifluoromethylisoxazoline (7f). mp 152–153 8C, yield
C H F NO requires 243. Anal. calc.: N, 5.76% (found: 5.67).
11 8 3 2
ꢁ ꢁ1
1
7
1
9%. IR (KBr): 3214 cm (OH str.) and 3319 cm (NH str.);
00
00
00
00
H NMR (CDCl ) d: 7.05–7.08 (m, 4H, 2 , 3 , 5 and 6 -H),
3
3.1.3.5. 3-( p-Nitrophenyl)-5-trifluoromethylisoxazole
1
0
0
0
0
8.22 (d, 2H, 2 , 6 -H, J = 8.7 Hz), 8.33 (d, 2H, 3 , 5 -H,
J = 8.7 Hz), 8.46 (bs, 1H, OH, D O exchangeable) (see
(5f). mp 110 8C, and yield 77%. H NMR d: 7.12 (s, 1H, 4-H),
0
0 0 0 0
8.04 (d, 2H, 2 , 6 -H, J = 9 Hz), 8.38 (d, 2H, 3 , 5 -H,
0
0
2
1
9
Footnote 1), 9.29 (bs, 1H, NH, D O exchangeable) (see
2
J = 8.7 Hz); F NMR (CDCl ) d: ꢁ65 (s, 3F, CF ). MS (m/z):
0
3
3
1
9
+
258 (M ), C H F N O requires 258. Anal. calc.: N, 10.85%
(found: 10.61).
Footnote 1); F NMR (CDCl ) d: ꢁ81 (s, 3F, CF ), ꢁ122 (s, 1F,
3
3
10 5 3 2 3
0
0
+
-F). HRMS (m/z): 398.0643 (M ), C H F N O requires
98.0638. Anal. calc.: N, 14.07% (found: 13.89).
4
3
1
6 10 4 4 4
3
.1.3.6. 3-Phenyl-4-( p-fluorophenyldiazo)-5-trifluoromethyli-
1
3
.1.3. Dehydration of 5-hydroxy-5-
soxazole (8a). mp 60–61 8C, yield 82%. H NMR (CDCl ) d:
7
3
0 00
.21–7.93 (m, 9H, Ph -H and p-FPh -H); F NMR (CDCl ) d:
3
19
trifluoromethylisoxazolines (4a–f and 7a) into 5-
trifluoromethylisoxazoles (5a–f and 8a)
0
0
+
ꢁ
63.9 (s, 3F, CF ), ꢁ116 (s, 1F, 4 -F). MS (m/z): 335 (M ),
3
Procedure: an ethanolic solution (15ml) of 5-hydroxy-5-
trifluoromethylisoxazoline 4d (0.5 g, 1.6 mmol) and 0.2 ml
conc. sulphuric acid was refluxed for 48 h or a glacial acetic
acid solution (25 ml) of 4d (0.5 g, 1.6 mmol) and 0.2 ml conc.
sulphuric acid was refluxed for 16 h. The excess of solvent was
evaporated and poured the reaction mixture into water. Solid so
C H F N O requires 335. Anal. calc.: N, 12.54% (found:
1
6 9 4 3
1
2.52).
Acknowledgements
We are grateful to the UGC, New Delhi, India for financial
assistance. We also thank the UCSF (USA) Mass spectrometry
Facility (A.L. Burlingame, Director) supported by the NIH
NCRR BRTP RR01614 for running the high-resolution mass
spectra. Thanks are also due to RSIC, Lucknow, India for
providing elemental analysis, low-resolution mass spectra and
obtained was filtered, dried and recrystallized from ethanol
1
(
5d), mp 63 8C [13] (63–64 8C), and yield 84%. H NMR d:
4
.99 (d, 1H, 4-H, J
0
= 0.9 Hz), 7.61–7.69 (m, 4H, p-BrPh -
H–F
6
1
9
H); F NMR (CDCl ) d: ꢁ64.8 (s, 3F, CF ). HRMS (m/z):
3
3
+
+
290.9497 (M ) and 292.9496 (M + 2) in the ratio showing
typical bromine isotope profile (1:1), C H BrF NO requires
1
9
1
0
5
3
F NMR spectra.
2
90.9507. Anal. calc.: N, 4.81% (found: 4.70).
Compounds 5a, 5b, 5c, 5e, 5f and 8a were prepared by
similar procedure.
References
[
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9
3
8
1
6
.1.3.1. 3-Phenyl-5-trifluoromethylisoxazole (5a). mp 80–
1
1 8C [13,14] (80 8C), and yield 89%. H NMR d: 7.00 (s,
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3
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(
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.1.3.2. 3-( p-Fluorophenyl)-5-trifluoromethylisoxazole
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(
0 0
6
2
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19
0
0
(
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3
3
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31 (M ), C H F NO requires 231. Anal. calc.: N, 6.06%
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1
0 5 4
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(
(
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.1.3.3. 3-( p-Chlorophenyl)-5-trifluoromethylisoxazole
1
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6
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0
0
19
0
0
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3
3
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1