A new and efficient approach to isoxazolines. First synthesis of 3-aryl-5-dichloromethyl-2-isoxazolines

Article abstract of DOI:10.1016/j.tet.2011.05.110

An efficient synthetic method for 3-aryl-5-dichloromethyl-2-isoxazolines has been established. Reactions between anhydrous chloral and acetophenones in hot acetic acid lead to 1-aryl-4,4,4-trichloro-3-hydroxybutan-1-ones (chloralacetophenones), which prov

Full text of DOI:10.1016/j.tet.2011.05.110

Tetrahedron 67 (2011) 5811e5815
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new and efficient approach to isoxazolines. First synthesis
of 3-aryl-5-dichloromethyl-2-isoxazolines
*
Antonio Guirado , Bruno Martiz, Raquel Andreu, Delia Bautista
ꢀ
Departamento de Química Organica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30071 Murcia, Apartado 4021, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2011
Received in revised form 26 May 2011
Accepted 27 May 2011
Available online 2 June 2011
An efficient synthetic method for 3-aryl-5-dichloromethyl-2-isoxazolines has been established.
Reactions between anhydrous chloral and acetophenones in hot acetic acid lead to 1-aryl-4,4,4-trichloro-
3-hydroxybutan-1-ones (chloralacetophenones), which provided 1-aryl-4,4-dichlorobut-3-en-1-ones
(2,2-dichlorovinylacetophenones) by dehydration and subsequent electrochemical reduction. These
b
,g
-unsaturated enones reacted with hydroxylamine yielding oxime intermediates whose treatment
with aqueous sodium hydroxide gave novel 3-aryl-5-dichloromethyl-2-isoxazolines in fair to high yields.
The molecular structure of member of this family of compounds, 5-dichoromethy1-3-(4-
methoxyphenyl)-2-isoxazoline, was determined by X-ray crystallography.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isoxazolines
Chloral
Acetophenones
Enones
a
Oximes
1. Introduction
oxides and ethylenic double bonds was discovered to be a better
preparative procedure.28e31 However, sometimes the formation of
two regioisomers is an unavoidable problem of this alternative
methodology.31
The chemistry of 2-isoxazolines has been excellently
reviewed,1e5 showing that these compounds are of great interest. 2-
Isoxazolines have been reported as biologically active compounds
with antifungal,6 antibacterial7,8 and antidiabetic9,10 properties.
Certain drugs useful against cardiovascular11 diseases and as anti-
coagulants12,13 contain a 2-isoxazoline moiety. A wide range of ef-
ficient reactions involving either ring cleavage or ring retention can
be selectively promoted from chiral and achiral 2-isoxazolines,
evidencing a high value as synthetic intermediates.1e4,14e26 There-
fore, the research on the synthesis of this class of compounds de-
serves much attention.
In an effort to improve the earlier oximation route, the use of
nonconjugated
b,g-unsaturated ketones as a substitute of conju-
gated -unsaturated enones is a highly valuable option since
a,b
disturbing Michael reactions can be avoided. Nevertheless, un-
conjugated enones are more difficultly available than conjugated
isomers. Besides, they must be prepared with a special care due to
its proclivity to isomerise, giving the most stable conjugated
compounds. The main synthetic methods for b,g-unsaturated ke-
tones involve either acylations of allylic organometallics32e35 or
additions of organometallic compounds to aldehydes followed by
oxidation of the generated allyl alcohols.36e39
The first isolated 2-isoxazoline was obtained in 1895 by the a,b-
unsaturated ketone/hydroxylamine reaction3 that, in general, gives
deficient results, mainly due to participation of Michael addition
processes. The oximation reaction of conjugated enones is far more
In recent years we have worked on developing new approaches
to heterocyclic compounds starting from chloral. Chloral is an in-
expensive, multipurpose starting material for organic synthesis.40 It
is able to react with amides and acetophenones to yield primary
derivatives from which we developed a number of significant syn-
thetic processes on the basis of a conjunction of chemical and
electrochemical reactions.41e49 One of the most advantageous fea-
tures of this synthetic approach lies in the access to specifically
chlorinated compounds. Severe preparative problems of chemical
incompatibility with the usual chlorinating reagents can be avoided
by using suitable prechlorinated intermediates derived fromchloral.
A recent report about this purpose was the direct highly efficient
complex than one might expect, yielding isoxazolines along with b-
hydroxylamino oximes and further products. Serious limitations in
purification and yield are usual disadvantages of this procedure
since its final result is not easily controllable given that it depends
sensitively on several experimental variables, such as pH, nature of
solvent and reagent ratio.27 Nevertheless, it was the most practiced
synthetic method until 1,3-dipolar cycloaddition between nitrile
* Corresponding author. Tel.: þ34 868 887 490; fax: þ34 868 884 148; e-mail
electrogeneration of a previously unknown class of b,g-unsaturated
address: anguir@um.es (A. Guirado).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.110

5812
A. Guirado et al. / Tetrahedron 67 (2011) 5811e5815
enones: 1-aryl-4,4-dichlorobut-3-en-1-ones 4 (2,2-dichlorovinyl
acetophenones) by cathodic reduction of 1-aryl-4,4,4-trichlorobut-
2-en-1-ones 3 (2,2,2-trichloroethylideneacetophenones) in a protic
medium.47 These unconjugated enones were found to be key in-
termediates to achieve the first synthesis of 3-aryl-5-
dichloromethyl-2-pyrazolines.49 Given this previous success and
the propitious structure of compounds 4 in order to avoid compet-
glacial acetic acid. In this case clean reactions occurred, providing the
expected products in high yields. Given the non-spontaneous cycli-
zation of derivatives 5 into the corresponding isoxazolines 6, we
successfully attempted to promote a closing to the heterocyclic ring
by adding a base, since under basic catalysis
b
,
g
-unsaturated oximes
5 are able to isomerise9 to the corresponding
a,b-unsaturated oximes
50 with a high electrophilic activity so that an intramolecular Michael
addition process can occur. Thus, compounds 5 in ethanol solution
were treated with aqueous sodium hydroxide (ratio 1:1) for a few
minutes. Complete transformations into single products were ob-
served. These were isolated and identified by usual techniques as the
corresponding 3-aryl-5-dichloromethyl-2-isoxazolines 6, a new
class of isoxazoline derivatives. Yields were high in all cases. Geo-
metrical characteristics of this class of compounds were determined
by single crystal X-ray crystallography of 5-dichloromethyl-3-(4-
methoxyphenyl)-2-isoxazoline 6f (Fig. 1). Selected bond lengths
and bond angles for this crystal structure are given in Table 1. The
packing shows parallel chains to the b axis formed by molecules
associated by hydrogen bonds (Fig. 2).
itive formation of b-hydroxylamino oximes in reactions with hy-
droxylamine, we recognised the opportunity to attempt an
approach to 5-dichloromethyl-2-isoxazolines, which are hitherto
unknown compounds of interest in themselves, but as well as being
attractive intermediates to investigate the synthesis of a variety of
isoxazoline derivatives, including compounds pertinent to fine
chemical and pharmaceutical industries.
2. Results and discussion
In an effort to obtain a good approach for still unavailable iso-
xazolines 6 we decided to explore a plausible synthetic route based
on our previously developed electrochemical method for the syn-
thesis of dichlorinated b,g
-unsaturated enones,47 since these com-
pounds could undergo effective oximation reactions followed by
internal nucleophilic additions directly yielding the targeted iso-
xazolinecompounds (Scheme 1). Trichloroethylideneacetophenones
3 were efficiently prepared by reaction of acetophenones 1 with
anhydrous chloral, leading to chloralacetophenones 2 that were
subsequently dehydrated. Intermediates 3 were subjected to elec-
trochemical reduction in a protic medium accordingly to our pre-
viously described protocol.47 Owing to the peculiar mechanism of
this reaction48 the respective 2,2-dichlorovinylacetophenones 4
were selectively generated in high to quantitative yields. The con-
version of these compounds into previously undescribed oximes 5
was tested by treatment with hydroxylamine hydrochloride as well
as using free hydroxylamine under different experimental condi-
tions. The best results were obtained by carrying out reactions with
free hydroxylamine in the presence of equimolecular amounts of
Fig. 1. Thermal ellipsoid plot (50% level) of compound 6f in the crystal.
In conclusion, a proficient and general new method for the syn-
thesis of dichloromethyl-2-isoxazolines involving chloral de-
rivatives is reported. Good yields and easy availability of starting
materials are valuable, noteworthyadvantages of the method, which
allows a privileged access to previously unattainable products. Not
O
O
O
OH
Cl3CCHO
- H2O
Ar
Ar
CCl3
Cl
Ar
CCl3
1
3 (75-95%)
2
(70-89%)
2e,
H
-
N-OH
O
N-OH
OH
H2NOH
Ar
Ar
CCl2
CCl2
Ar
CHCl2
4 (75-95%)
5 (70-88%)
5'
entry
Ar
a
b
c
d
e
f
C6H5
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
N
O
4-CH3-C6H4
4-CH3O-C6H4
4-NO2-C6H4
4-Ph-C6H4
Ar
CHCl2
6 (70-92%)
g
h
Scheme 1.

A. Guirado et al. / Tetrahedron 67 (2011) 5811e5815
5813
Table 1
corresponding enone 4 (3 mmol) dissolved in ethanol (20 mL). The
mixture was stirred at room temperature for 9 h. The solvent was
removed under reduced pressure. Then, cool water (40 mL) was
added and the insoluble solid was collected by filtration and
washed with cool chloroform, leaving a small amount of insoluble
material that was eliminated by filtration. The chloroform solution
was dried over anhydrous magnesium sulfate. After evaporation of
solvent the solid residue was crystallised from petroleum ether
(60e80 ꢀC). Compound 5g was previously purified by column
chromatography (silica gel/hexaneeethyl ether, ratio 3:1).
Selected bond lengths and bond angles in crystal structure of 6f
ꢁ
Bond lengths (A)
Cl(1)eC(11)
Cl(2)eC(11)
N(1)eC(8)
N(1)eO(2)
1.7777(18)
1.7862(18)
1.280(2)
O(2)eC(10)
C(8)eC(9)
C(9)eC(10)
C(10)eC(11)
1.451(2)
1.503(2)
1.524(3)
1.523(3)
1.431(2)
Bond angles (ꢀ)
C(8)eN(1)eO(2)
N(1)eO(2)eC(10)
N(1)eC(8)eC(4)
N(1)eC(8)eC(9))
C(4)eC(8)eC(9)
C(8)eC(9)eC(10)
108.86(15)
108.87(13)
121.86(17)
114.12(16)
124.00(16)
100.71(15)
O(2)eC(10)eC(11)
O(2)eC(10)eC(9)
C(11)eC(10)eC(9)
C(10)eC(11)eCl(1)
C(10)eC(11)eCl(2)
Cl(1)eC(11)eCl(2)
107.28(15)
104.74(14)
111.55(15)
110.55(13)
108.90(13)
109.30(10)
3.2.1. 2,2-Dichlorovinylacetophenone oxime (5a). Yield 80%; crys-
tallisation from petroleum ether gave white prisms; mp 60e62 ꢀC.
Found C 52.11; H 3.91; N 6.13. C10H9Cl2NO requires: C 52.20; H 3.94;
N 6.09; 1H NMR
d
(CDCl3, 300 MHz) 3.70 (d, 2H, J¼7.2 Hz), 5.99 (t,
1H, J¼7.2 Hz), 7.38e7.44 (m, 3H), 7.57e7.62 (m, 2H); 13C NMR
d
(CDCl3, 75.4 MHz) 27.66 (CH2), 122.26 (CCl2), 124.16 (CH), 126.43
(CH), 128.85 (CH), 129.85 (CH), 134.80 (C), 155.60 (C]N); MS, m/z
(%) 231 (Mþþ2, 5), 229 (Mþ, 3), 212 (6), 194 (19), 145 (24), 117 (52),
105 (100), 76 (90); IR (Nujol) 3229, 1619, 1338, 1292, 1083, 943, 867,
757, 689, 647 cmꢁ1
.
3.2.2. 2,2-Dichlorovinyl-40-fluoroacetophenone oxime (5b). Yield
70%; crystallisation from petroleum ether gave yellow plates;
mp 80e82 ꢀC. Found C 48.39; H 3.44; N 5.62. C10H8Cl2FNO
requires: C 48.41; H 3.25; N 5.65; 1H NMR
d
(CDCl3, 400 MHz)
3.69 (d, 2H, J¼7.2 Hz), 5.98 (t, 1H, J¼7.2 Hz), 7.11 (m, 2H), 7.60
(m, 2H); 13C NMR
(CDCl3, 100.8 MHz) 27.63 (CH2), 115.91 (d,
d
J¼21.8 Hz) (CH), 122.45 (CCl2), 123.91 (CH), 128.34 (d, J¼8.3 Hz)
(CH), 130.90 (d, J¼3.1 Hz) (C), 154.72 (C]N), 163.75 (d,
J¼255.7 Hz) (C); MS, m/z (%) 249 (Mþþ2, 4), 247 (Mþ, 7), 230
(3), 212 (80), 214 (28), 195 (13), 135 (100), 121 (67), 109 (24),
95 (61), 75 (25); IR (Nujol) 3214, 1599, 1511, 1333, 1158, 1078,
1045, 964, 942, 877, 839, 770, 670 cmꢁ1
.
3.2.3. 2,2-Dichlorovinyl-40-chloroacetophenone oxime (5c). Yield
85%; crystallisation from petroleum ether gave yellow prisms; mp
86e88 ꢀC (dec). Found C 45.33; H 3.05; N 5.28. C10H8Cl3NO re-
quires: C 45.40; H 3.05; N 5.29; 1H NMR
d (CDCl3, 400 MHz) 3.67 (d,
2H, J¼7.2 Hz), 5.96 (t, 1H, J¼7.2 Hz), 7.38 (d, 2H, J¼8.7 Hz), 7.54 (d,
2H, J¼8.7 Hz), 8.45 (br s, 1H); 13C NMR
d (CDCl3, 100.8 MHz) 27.42
Fig. 2. View of (C11eH11/O2) and (C11eC2/H2) interactions in crystal structure of 6f.
(CH2), 122.59 (CCl2), 123.75 (CH), 127.72 (CH), 129.08 (CH), 133.15
(C), 135.98 (C), 154.76 (C]N); MS, m/z (%) 265 (Mþþ2, 2), 263 (Mþ,
3), 228 (4), 247 (3), 180 (22), 151 (100), 139 (49), 137 (83), 111 (95),
113 (31), 102 (42), 75 (69); IR (Nujol) 3229, 1619, 1592, 1493, 1331,
only are the prepared compounds of interest in themselves, the
presence of a dichloromethyl substituent also suggests an attractive
synthetic potential through hydrolysis, substitution and elimination
reactions, which merits further exploration.
1290, 1097, 1054, 1039, 945, 866, 827 cmꢁ1
.
3.2.4. 2,2-Dichlorovinyl-40-bromoacetophenone oxime (5d). Yield
88%; crystallisation from petroleum ether gave yellow prisms; mp
100e103 ꢀC. Found C 38.58; H 2.56; N 4.50. C10H8BrCl2NO requires:
3. Experimental
3.1. General
C 38.87; H 2.61; N 4.53; 1H NMR
d (CDCl3, 400 MHz) 3.65 (d, 2H,
J¼7.2 Hz), 5.94 (t, 1H, J¼7.2 Hz), 7.46 (d, 2H, J¼8.6 Hz), 7.54 (d, 2H,
J¼8.6 Hz), 8.95 (br s, 1H); 13C NMR
d (CDCl3, 100.8 MHz) 27.38 (CH2),
NMR spectra were determined on Bruker AV-300 or Bruker AV-
400 with tetramethylsilane as internal reference. Electron-impact
mass spectra were obtained on a Thermoquest trace MS spec-
trometer under an ionizing voltage of 70 eV. IR spectra (Nujol
emulsions) were recorded on a Nicolet Impact 400 Spectrometer.
Microanalyses were performed on a Carlo Erba EA-1108 analyzer.
122.58 (CCl2), 123.74 (CH), 124.26 (C), 127.93 (CH), 132.04 (CH),
133.64 (C), 154.80 (C]N); MS, m/z (%) 309 (Mþþ2, 7), 307 (Mþ, 6),
291 (9), 272 (17), 274 (21), 257 (19), 223 (26), 195 (45), 197 (45), 181
(66), 183 (99), 154 (42), 156 (42), 102 (100), 75 (73); IR (Nujol) 3226,
1629, 1587, 1328, 1186, 1072, 1007, 942, 869, 824 cmꢁ1
.
€
Melting points were determined on a Buchi Melting point B-540,
and are uncorrected. Compounds 2e4 were prepared as previously
3.2.5. 2,2-Dichlorovinyl-40-methylacetophenone oxime (5e). Yield
75%; crystallisation from petroleum ether gave yellow prisms; mp
86e88 ꢀC. Found C 54.47; H 4.64; N 5.76. C11H11Cl2NO requires: C
described.49
3.2. Preparation of 2,2-dichlorovinylacetophenone oximes 5
54.12; H 4.54; N 5.74; 1H NMR
d (CDCl3, 400 MHz) 2.38 (s, 3H), 3.68
(d, 2H, J¼7.2 Hz), 5.98 (t, 1H, J¼7.2 Hz), 7.21 (d, 2H, J¼8.0 Hz), 7.49
A 50% aqueous solution of hydroxylamine (0.2 mL; 3.6 mmol),
water (1 mL) and acetic acid (3.6 mmol) was added to the
(d, 2H, J¼8.0 Hz), 8.90 (br s, 1H); 13C NMR
d (CDCl3, 100.8 MHz)
21.39 (CH3), 27.56 (CH2), 122.08 (CCl2), 124.31 (CH), 126.30 (CH),

5814
A. Guirado et al. / Tetrahedron 67 (2011) 5811e5815
129.55 (CH), 131.89 (C), 140.01 (C), 155.44 (C]N); MS, m/z (%) 245
(Mþþ2, 64), 243 (Mþ, 81), 226 (8), 208 (98), 210 (64), 191 (31), 157
(19), 132 (71), 134 (100), 116 (84), 117 (52), 118 (63), 109 (69), 89
(55), 91 (50), 73 (30), 65 (73); IR (Nujol) 3222, 1619, 1238, 1293,
(ddd, 1H, J¼9.9, 7.2, 4.1 Hz), 5.87 (d, 1H, J¼4.1 Hz), 7.39e7.46
(m, 3H), 7.67e7.72 (m, 2H); 13C NMR
(CDCl3, 75.4 MHz) 37.10
d
(CH2), 71.93 (CH), 83.75 (CH), 126.95 (CH), 128.50 (C), 128.90
(CH), 130.68 (CH), 156.29 (C]N); MS, m/z (%) 231 (Mþþ2, 28),
229 (Mþ, 45), 194 (5), 146 (74), 127 (24), 118 (100), 91 (47), 77
(83), 51 (37); IR (Nujol) 1602, 1569, 1357, 1253, 1226, 1169,
1189, 1080, 1040, 966, 938, 867, 818 cmꢁ1
.
3.2.6. 2,2-Dichlorovinyl-40-methoxyacetophenone oxime (5f). Yield
81%; crystallisation from petroleum ether gave yellow prisms; mp
87e89 ꢀC. Found C 50.80; H 4.23; N 5.29. C11H11Cl2NO2 requires: C
1076, 951, 894, 862, 763, 694 cmꢁ1
.
3.3.2. 5-Dichloromethyl-3-(40-fluorophenyl)-2-isoxazoline (6b). Yield
87%; crystallisation from petroleum ether gave yellow plates; mp
100e101 ꢀC. Found C 48.26; H 3.20; N 5.70. C10H8Cl2FNO requires: C
50.79; H 4.26; N 5.38; 1H NMR
d (CDCl3, 400 MHz) 3.67 (d, 2H,
J¼7.2 Hz), 3.84 (s, 3H), 5.98 (t, 1H, J¼7.2 Hz), 6.93 (d, 2H, J¼8.9 Hz),
7.56 (d, 2H, J¼8.9 Hz); 13C NMR
d
(CDCl3, 100.8 MHz): 27.55 (CH2),
48.41; H 3.25; N 5.65; 1H NMR
d (CDCl3, 400 MHz) 3.54 (dd, 1H,
55.50 (CH3), 114.28 (CH), 122.12 (CCl2), 124.30 (CH), 126.92 (C),
127.90 (CH), 155.25 (C]N), 161.01 (C); MS, m/z (%) 261 (Mþþ2, 16),
259 (Mþ, 26), 242 (6), 224 (22), 226 (7), 207 (13), 192 (7), 147 (69),
133 (100), 109 (18), 90 (21), 77 (15), 63 (15); IR (Nujol) 3243, 1602,
J¼17.5, 9.7 Hz), 3.60 (dd, 1H, J¼17.5, 7.3 Hz), 5.12 (ddd, 1H, J¼9.7, 7.3,
4.1 Hz), 5.87 (d, 1H, J¼4.1 Hz), 7.12 (m, 2H), 7.69 (m, 2H); 13C NMR
d
(CDCl3, 100.8 MHz) 37.13 (CH2), 71.86 (CH), 83.83 (CH), 116.10 (d,
J¼22.0 Hz) (CH), 124.77 (d, J¼3.3 Hz) (C), 128.96 (d, J¼8.6 Hz) (CH),
155.33 (C]N), 164.12 (d, J¼251.4 Hz) (C); MS, m/z (%) 249 (Mþþ2,
12), 247 (Mþ, 18), 212 (1), 164 (60), 136 (100), 121 (15), 109 (39), 95
(65), 75 (43); IR (Nujol) 1654, 1600, 1514, 1351, 1239, 1221, 1163, 943,
1514, 1338, 1302, 1258, 1179, 1029, 939, 879, 833 cmꢁ1
.
3.2.7. 2,2-Dichlorovinyl-40-nitroacetophenone oxime (5g). Yield
72%; crystallisation from petroleum ether gave yellow plates; mp
104e106 ꢀC. Found C 43.75; H 2.88; N 10.17. C10H8Cl2N2O3 requires:
886, 869, 841, 771 cmꢁ1
.
C 43.66; H 2.93; N 10.18; 1H NMR
d
(CDCl3, 400 MHz) 3.72 (d, 2H,
3.3.3. 5-Dichloromethyl-3-(40-chlorophenyl)-2-isoxazoline (6c). Yield
72%; crystallisation from petroleum ether gave white needles; mp
97e98 ꢀC. Found C 45.48; H 2.89; N 5.33. C10H8Cl3NO requires: C
J¼7.3 Hz), 5.96 (t, 1H, J¼7.3 Hz), 7.80 (d, 2H, J¼9.0 Hz), 8.26 (d, 2H,
J¼9.0 Hz); 13C NMR
d (CDCl3, 100.8 MHz) 27.14 (CH2), 123.11 (CCl2),
123.22 (CH), 124.01 (CH), 127.25 (CH), 140.87 (C), 148.45 (C), 153.99
(C]N); MS, m/z (%) 276 (Mþþ2,1), 274 (Mþ, 2); 256 (8), 239 (8), 241
(27), 210 (10), 162 (100), 148 (14), 119 (68), 102 (42), 76 (47), 75 (47),
63 (15), 50 (23); IR (Nujol) 3200, 1623, 1595, 1517, 1338, 1189, 1108,
45.40; H 3.05; N 5.29; 1H NMR
d (CDCl3, 300 MHz) 3.53 (dd, 1H,
J¼17.4, 9.7 Hz), 3.59 (dd, 1H, J¼17.4, 7.2 Hz), 5.13 (ddd, 1H, J¼9.7, 7.2,
4.2 Hz), 5.87 (d, 1H, J¼4.2 Hz), 7.40 (d, 2H, J¼8.7 Hz), 7.62 (d, 2H,
J¼8.7 Hz); 13C NMR
d (CDCl3, 75.4 MHz) 36.91 (CH2), 71.80 (CH),
1083, 1041, 941, 856, 846, 693, 655 cmꢁ1
.
83.93 (CH), 126.99 (C), 128.17 (CH), 129.20 (CH), 136.73 (C), 155.40
(C]N); MS, m/z (%) 265 (Mþþ2, 9), 263 (Mþ, 10), 228 (1), 180 (41),
182 (13), 152 (100), 125 (32), 111 (58), 75 (63); IR (Nujol) 1598, 1493,
1406, 1363, 1252, 1212, 1091, 1010, 971, 896, 865, 842, 824, 754,
3.2.8. 2,2-Dichlorovinyl-40-phenylacetophenone oxime (5h). Yield
84%; crystallisation from petroleum ether gave pale yellow powder;
mp 109e112 ꢀC. Found C 62.80; H 4.25; N 4.62. C16H13Cl2NO re-
689 cmꢁ1
.
quires: C 62.76; H 4.28; N 4.57; 1H NMR
d (CDCl3, 400 MHz) 3.73 (d,
2H, J¼7.2 Hz), 6.02 (t, 1H, J¼7.2 Hz), 7.37 (tt, 1H, J¼7.3, 1.2 Hz), 7.46
3.3.4. 3-(40-Bromophenyl)-5-dichloromethyl-2-isoxazoline (6d). Yield
74%; crystallisation from petroleum ether gave yellow prisms; mp
100e101 ꢀC. Found C 38.88; H 2.57; N 4.50. C10H8BrCl2NO requires: C
(t, 2H, J¼7.7 Hz), 7.61e7.65 (m, 4H), 7.70 (d, 2H, J¼8.5 Hz), 8.30 (br s,
1H); 13C NMR
d (CDCl3, 100.8 MHz) 27.55 (CH2),122.27 (CCl2),124.19
(CH), 126.81 (CH), 127.13 (CH), 127.49 (CH), 127.84 (CH), 128.97 (CH),
133.57 (C), 140.21 (C), 142.57 (C), 155.23 (C]N); MS, m/z (%) 307
(Mþþ2, 11), 305 (Mþ, 16), 289 (2), 270 (20), 272 (6), 252 (12), 192
(51), 193 (44), 178 (100), 179 (57), 150 (30), 152 (31), 108 (6), 76 (7);
IR (Nujol) 3246, 1613, 1329, 1256, 1081, 959, 935, 869, 836, 764, 735,
38.87; H 2.61; N 4.53; 1H NMR
d (CDCl3, 400 MHz) 3.55 (dd, 1H,
J¼17.4, 9.9 Hz), 3.59 (dd, 1H, J¼17.4, 7.1 Hz), 5.13 (ddd, 1H, J¼9.9, 7.1,
4.1 Hz), 5.87 (d, 1H, J¼4.1 Hz), 7.55 (s, 4H); 13C NMR
d (CDCl3,
100.8 MHz) 36.82 (CH2), 71.78 (CH), 83.90 (CH), 125.05 (C), 127.37
(C), 128.36 (CH), 132.14 (CH), 155.51 (C]N); MS, m/z (%) 309 (Mþþ2,
54), 307 (Mþ, 32), 311 (20), 272 (1), 224 (81), 226 (78), 196 (100), 198
(98), 154 (32), 127 (12), 117 (62), 102 (58), 90 (24), 75 (90); IR (Nujol)
1599, 1568, 1362, 1308, 1252, 1226, 1168, 1076, 950, 894, 862, 763,
696, 674 cmꢁ1
.
3.3. Preparation of 3-aryl-5-dichloromethyl-2-isoxazolines 6
734, 693 cmꢁ1
.
A sodium hydroxide solution (1.5 mmol) in water (1.5 mL) was
added to
a
solution of the corresponding 2,2-dichlorovinyl-
3.3.5. 5-Dichloromethyl-3-(40-methylphenyl)-2-isoxazoline
(6e). Yield 85%; crystallisation from petroleum ether gave yellow
prisms; mp 99e100 ꢀC. Found C 54.15; H 5.43; N 5.70. C11H11Cl2NO
acetophenone oxime 5 (1.5 mmol) in ethanol (10 mL). The mixture
was stirred at room temperature for 10e30 min (the course of re-
actions can be checked by TLC; silica gel/dichloromethaneehexane,
ratio 4:1). After elimination of solvent under reduced pressure,
water (40 mL) was added. The residue was collected by filtration and
crystallised from petroleum ether (60e80 ꢀC) or extracted with
dichloromethane (2ꢂ25 mL), which was dried over anhydrous
magnesium sulfate and evaporated to dryness. The crude com-
pounds obtained were purified by column chromatography (silica
gel/dichloromethaneehexane, ratio 4:1) and crystallised from pe-
troleum ether. Chromatography of product 6a was performed with
ethyl acetateehexane, ratio 1:3.
requires: C 54.12; H 4.54; N 5.74; 1H NMR
d (CDCl3, 300 MHz) 2.39
(s, 3H), 3.53 (d, 1H, J¼14.7, 9.7 Hz), 3.60 (d, 1H, J¼17.4, 7.2 Hz), 5.09
(ddd, 1H, J¼9.7, 7.2, 4.2 Hz), 5.85 (d, 1H, J¼4.2 Hz), 7.23 (d, 2H,
J¼8.4 Hz), 7.58 (d, 2H, J¼8.4 Hz); 13C NMR
d (CDCl3, 75.4 MHz)
21.54 (CH3), 37.24 (CH2), 72.00 (CH), 83.62 (CH), 125.67 (C), 126.90
(CH), 129.59 (CH), 141.03 (C), 156.22 (C]N); MS, m/z (%) 245
(Mþþ2, 13), 243 (Mþ, 19), 208 (2), 160 (54), 132 (100), 117 (17), 105
(36), 91 (79), 77 (11), 65 (27), 51 (8); IR (Nujol) 1610, 1354, 1222,
1112, 900, 824, 772 cmꢁ1
.
3.3.6. 5-Dichloromethyl-3-(4-methoxyphenyl)-2-isoxazoline
(6f). Yield 90%; crystallisation from petroleum ether gave yellow
plates; mp 98e99 ꢀC. Found C 51.87; H 4.40; N 5.43. C11H11Cl2NO2
3.3.1. 5-Dichloromethyl-3-phenyl-2-isoxazoline (6a). Yield 73%;
crystallisation from petroleum ether gave yellow plates; mp
120e121 ꢀC. Found C 52.17; H 3.90; N 6.08. C10H9Cl2NO re-
requires: C 50.79; H 4.26; N 5.38; 1H NMR
d (CDCl3, 400 MHz) 3.53 (d,
quires: C 52.20; H 3.94; N 6.09; 1H NMR
d
(CDCl3, 300 MHz)
1H, J¼17.3, 9.9 Hz), 3.58 (d, 1H, J¼17.3, 7.0 Hz), 3.84 (s, 3H), 5.07 (ddd,
3.56 (dd, 1H, J¼17.4, 9.9 Hz), 3.62 (dd, 1H, J¼17.4, 7.2 Hz), 5.11
1H, J¼9.9, 7.0, 4.3 Hz), 5.85 (d, 1H, J¼4.25 Hz), 6.93 (d, 2H, J¼8.8 Hz),

A. Guirado et al. / Tetrahedron 67 (2011) 5811e5815
5815
7.63 (d, 2H, J¼8.8 Hz); 13C NMR
d
(CDCl3, 100.8 MHz) 37.36 (CH2),
Supplementary data
55.47 (CH3), 72.04 (CH), 83.55 (CH), 114.32 (CH), 121.00 (C), 128.53
(CH), 155.82 (C]N), 161.53 (C); MS, m/z (%) 261 (Mþþ2, 53), 259 (Mþ,
72), 224 (3), 176 (100), 148 (74), 133 (41), 121 (94), 115 (21), 91 (11), 77
(70), 63 (30); IR (Nujol) 1607, 1516, 1421, 1310, 1252, 1179, 1040, 1020,
X-ray structural data of compound 6f; NMR spectra of com-
pounds 5 and 6. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2011.05.110.
893, 863, 833, 772 cmꢁ1
.
References and notes
3.3.7. 5-Dichloromethyl-3-(40-nitrophenyl)-2-isoxazoline (6g). Yield
86%; crystallisation from petroleum ether gave yellow plates; mp
141e142 ꢀC. Found C 43.73; H 2.98; N 10.15. C10H8Cl2N2O3 requires
€
1. Grunanger, P.; Vita-Finzi, P. InThe Chemistryof Heterocyclic Compounds. Isoxazoles;
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2. Sutharchanadevi, M.; Murugan, R. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A., Rees, C., Scriven, E., Eds.; Pergamon: Oxford, 1996; Vol. 3, Chapter
3.03.
3. Lang, S. A. J.; Lin, Y.-i In Comprehensive Heterocyclic Chemistry; Katritzky, A.,
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4. Koroleva, E. V.; Lakhvich, F. A. Russ. Chem. Rev. 1997, 66, 27.
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II; Gupta, R. R., Hassner, A., Eds.; Springer: Berlin, 2008; Vol. 13, Chapter 1.
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C 43.66; H 2.93; N 10.18; 1H NMR
d (CDCl3, 400 MHz) 3.59 (dd, 1H,
J¼17.4, 10.5 Hz), 3.66 (dd, 1H, J¼17.4, 6.9 Hz), 5.22 (ddd, 1H, J¼10.5,
6.9, 3.9 Hz), 5.92 (d, 1H, J¼3.9 Hz), 7.87 (d, 2H, 9.0 Hz), 8.29 (d, 2H,
J¼9.0 Hz); 13C NMR
d (CDCl3, 100.8 MHz) 36.45 (CH2), 71.53 (CH),
84.53 (CH), 124.20 (CH), 127.75 (CH), 134.51 (C), 148.91 (C), 154.87
(C]N); MS, m/z (%) 276 (Mþþ2, 5), 274 (Mþ, 8); 191 (74), 163 (100),
117 (68), 89 (14), 76 (31); IR (Nujol) 1583, 1518, 1346, 1319, 1251,
1153, 1107, 899, 848, 752 cmꢁ1
.
3.3.8. 3-(40-Biphenylil)-5-dichloromethyl-2-isoxazoline (6h). Yield
72%; crystallisation from petroleum ether gave white prisms;
mp 188e190 ꢀC. Found C 62.87; H 4.35; N 4.55. C16H13Cl2NO
10. Mosher, M. D.; Emmerich, L. G.; Frost, K. S.; Anderson, B. J. Heterocycl. Chem.
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requires C 62.76; H 4.28; N 4.57; 1H NMR
d (CDCl3, 300 MHz)
3.59 (dd, 1H, J¼17.5, 9.9 Hz), 3.66 (dd, 1H, J¼17.5, 7.1 Hz), 5.14
(ddd, 1H, J¼9.9, 7.1, 4.2 Hz), 5.89 (d, 1H, J¼4.2 Hz), 7.35e7.41 (m
1H), 7.47 (tt, 2H, J¼8.7, 1.3 Hz), 7.59e7.68 (m, 4H), 7.77 (d, 2H,
11. Jiang, R.; Marquart, T.; Zablocki, J.; Elzein, E.; Palle, V.; Ibrahim, P. WO
2004069818, 2004; CA 141, 190805.
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J¼8.7 Hz); 13C NMR
d (CDCl3, 100.8 MHz) 37.12 (CH2), 71.95
(CH), 83.78 (CH), 126.16 (CH), 127.30 (C), 127.43 (CH), 127.56
(CH), 128.04 (CH), 129.02 (CH), 140.09 (C), 143.47 (C), 156.07
(C]N); MS, m/z (%) 307 (Mþþ2, 37), 305 (Mþ, 57), 270 (1), 222
(93), 194 (66), 179 (23), 167 (75), 152 (100), 139 (9), 127 (14), 97
(10), 83 (10), 75 (21), 51 (11); IR (Nujol) 1601, 1487, 1409, 1254,
15. Hansen, J. F.; Kim, Y. I.; McCrotty, S. E.; Strong, S. A.; Zimmer, D. E. J. Heterocycl.
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€
€
20. Muller, I.; Jager, V. Tetrahedron Lett. 1982, 23, 4777.
3.4. X-ray structure determination of compound 6f
€
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Crystaldata:C11H11Cl2NO2, Mr¼260.11, orthorhombic,spacegroup
€
3
ꢁ
ꢁ
bca, a¼7.9158(4), b¼19.9817(9), c¼30.1266(14) A, U¼4526.7(14) A
at ꢁ173 ꢀC; Z¼16, Dx¼1.527 g cmꢁ3, F (000)¼2144,
m
¼0.56 mmꢁ1
.
Data collection: A colourless block 0.34ꢂ0.21ꢂ0.14 mm3 was moun-
ted in inertoilon a glass fibre and transferred tothe cold gas stream of
the diffractometer (Bruker SMART APEX CCD). Data were collected
27. See Ref. 1, p 462.
28. Quilico, A.; D’Alcontres, G. S.; Grunanger, P. Nature 1950, 166, 226.
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using monochromated Mo Ka radiation in w-scan. Absorption cor-
rectionwas applied on the basis of multi-scans (Program SADABS). Of
46,949 measured reflections, 4622 were unique (Rint¼0.026) and
were used for all calculations. Structure refinement: The structures
were refined anisotropically against F2 (program SHELXL-97).50 The
hydrogen atoms were refined using rigid methyl groups or a riding
model. The final wR2 value was 0.092 for all reflections and 291 pa-
36. Hathaway, S. J.; Paquette, L. A. J. Org. Chem. 1983, 48, 3351.
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40. Luknitskii, F. I. Chem. Rev. 1975, 75, 259.
rameters, with R10.0358 for reflections with I>2s(I); max. Dr 0.72 e/
A , S 1.140.
3
ꢁ
Complete crystallographic data (excluding structure factors)
have been deposited at the Cambridge Crystallographic Data Centre
under the number CCDC 815039. Copies may be requested free of
charge from The Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, England (e-mail: deposit@ccdc.cam.ac.uk).
ꢀ
41. Guirado, A.; Andreu, R.; Cerezo, A.; Galvez, J. Tetrahedron 2001, 57, 4925.
42. Guirado, A.; Andreu, R.; Zapata, A.; Cerezo, A.; Bautista, D. Tetrahedron 2002, 58,
5087.
ꢀ
43. Guirado, A.; Andreu, R.; Galvez, J.; Jones, P. G. Tetrahedron 2002, 58, 9853.
44. Guirado, A.; Andreu, R.; Martiz, B.; Galvez, J. Tetrahedron 2004, 60, 987.
ꢀ
45. Guirado, A.; Andreu, R.; Martiz, B.; Bautista, D.; Ramírez de Arellano, C.; Jones,
P. G. Tetrahedron 2006, 62, 6172.
46. Guirado, A.; Andreu, R.; Martiz, B.; Perez-Ballester, S. Tetrahedron 2006, 62, 9688.
47. Guirado, A.; Martiz, B.; Andreu, R.; Bautista, D.; Galvez, J. Tetrahedron 2007, 63,
Acknowledgements
ꢀ
ꢀ
1175.
We gratefully acknowledge the financial support of the
48. Guirado, A.; Martiz, B.; Andreu, R.; Galvez, J. Electrochim. Acta 2008, 53, 7138.
49. Guirado, A.; Martiz, B.; Andreu, R.; Bautista, D. Tetrahedron 2009, 65, 5958.
50. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.
ꢀ
ꢀ
ꢀ
ꢀ
Fundacion Seneca of the Comunidad Autonoma de la Region de
Murcia (project 08755/PI/08).