Synthesis of 5-bromomethylisoxazoles and their reactions with secondary amines

Article abstract of DOI:10.1007/s11178-005-0314-8

Treating R-3-chloro-4-bromo-2-buten-1-ones with hydroxylamine hydrochloride afforded 3-alkyl(aryl, furyl)-5-bromomethylisoxazoles. By reaction of the latter with secondary amines new previously unknown aminoisoxazoles were synthesized. 2005 Pleiades Publi

Full text of DOI:10.1007/s11178-005-0314-8

Russian Journal of Organic Chemistry, Vol. 41, No. 8, 2005, pp. 1192−1195. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 8, 2005,
pp. 1215−1218.
Original Russian Text Copyright © 2005 by Aliev.
Synthesis of 5-Bromomethylisoxazoles and Their Reactions
with Secondary Amines
A.G.Aliev
Institute of Polymer Material, National Academy of Azerbaijan, Sumgait, AZ 5004Azerbaijan
Received July 8, 2004
Abstract—Treating R-3-chloro-4-bromo-2-buten-1-ones with hydroxylamine hydrochloride afforded 3-alkyl(aryl,
furyl)-5-bromomethylisoxazoles. By reaction of the latter with secondary amines new previously unknown
aminoisoxazoles were synthesized.
Among the numerous known methods of haloisoxazole
synthesis [1–4] the most common procedures are based
on reactions between β-chlorovinyl ketones and hydroxyl-
amine hydrochloride that as a rule afford a mixture of
two isomers [2, 3]. It is known however [3, 4] that
a reaction of chloromethyl β-chlorovinyl ketone gives rise
to a pure 5-chloromethylisoxazole.
Unlike alkyl-3-chloro-4-bromo-2-buten-1-ones Ia–Id
the reaction of aryl(furyl)-3-chloro-4-bromo-2-buten-1-
ones Ie–Ig with hydroxylamine hydrochloride is more
unambiguous and results in a single isomer, namely,
3-aryl-(furyl)-5-bromomethylisoxazole IIe–IIg. This
result is caused apparently by the electron-withdrawing
effect of aryl and furyl substituents enhancing the
electrophilicity of the carbonyl reaction site.
The target of theis study was investigation applying
the procedure described in [3, 4] of reaction between
analogs of chloromethyl β-chlorovinyl ketone, easily
available synthons widely used in organic synthesis,
R-3-chloro-4-bromo-2-buten-1-ones, and hydroxylamine
hydrochloride.
Taking into account the practical importance of
isoxazoles [6–8] with the goal to find an efficient
procedure for preparation of 5-bromo-methylisoxazoles
IIa–IIg we investigated in this study the reaction of
ketones Ia–Ig with hydroxylamine. The reaction of
ketones Ia–Ig with an equimolar amount of hydroxylamine
hydrochloride in a water solution in the presence of
potassium hydroxide readily afforded isoxazoles IIa–IIg
in 53–85% yields.
In reaction of R-3-chloro-4-bromo-2-buten-1-ones Ia–
Id (R =Alk) with hydroxylamine hydrochloride we failed
to obtain in a pure state 3-R-5-bromomethylisoxazoles
IIa–IId. Compounds obtained were a mixture of
substances IIa–IId and their isomers 5-R-3-bromo-
methylisoxazoles IIIa–IIId.
In weak alkaline or neutral media the hydroxylamine
apparently first reacts with the carbonyl group to furnish
an intermediate oxime. Thereafter occurs essentially
intramolecular cyclization resulting in a single product,
3-R-5-bromomethylisoxazole IIa–IIg.
The attempt to separate these isomers was
unsuccessful due to the similarity in the boiling points.
The formation of a mixture of compounds IIa and IIIa
was proved by the corresponding 1H NMR spectrum, δ,
ppm: 2.12 s and 2.26 s [6H, CH3 (IIa) and CH3 (IIIa)],
4.42 s and 5.59 s [4H, CH2 (IIa) and CH2 (IIIa)], 6.05 s
and 6.19 s [2H, CH (IIa) and CH (IIIa)]. The most
probable cause of isomeric mixture formation is the
reaction of the hydroxylamine hydrochloride with two
reaction sites: a carbonyl group and a chlorine atom in
the position 3 of the molecule of alkyl 3,4-dihaloketones
Ia–Id. We formerly observed that the greatest mobility
characterized the halogen atom located at the β-carbon
in ketones Ia–Ig [5].
We found that at treating isoxazoles IIa–IIg with
a double amount of a secondary amine in the presence
of triethylamine easily occurred a replacement of bromine
atom by amino group to give in a high yield the
corresponding aminoisoxazoles IVa–IVf, Va–Vg, and
VIa–VIf.
The structure of isoxasoles II–VI was confirmed by
1
IR, UV, and H NMR spectra, and also by elemental
analysis and independent synthesis by reaction of 3-R-5-
chloromethylisoxazoles with the mentioned secondary
1070-4280/05/4108-1192©2005 Pleiades Publishing, Inc.

SYNTHESIS OF 5-BROMOMETHYLISOXAZOLES
1193
R
H2NOH
_ H2O, _ HCl
R C CH
O
C(Cl)
CH2Br
CH2Br
N
O
_
_
Iа Ig
IIа IIg
HN
R
O
O
HN
R
R
CH2N(C2H5)2
CH
CH
N
2
N
2
O
N
N
N
O
O
_
_
_
IVа IVf
Vа Vg
VIа VIf
R = CH3 (a), C2H5 (b), C3H7 (c), iso-C3H7 (d), C6H5 (e), para-CH3C6H4 (f), furyl (g).
amines. The spectral characteristics of aminoisoxazoles
IV–VI obtained by both procedures were identical.
3-Methyl-5-bromomethylisoxazole (IIa). Yield
85%, bp 67–68°C (2 mm Hg), Rf 0.60, nD20 1.5090, d420
1.4838. IR spectrum, ν, cm–1: 3148 (CH), 1640 (C=C,
1
EXPERIMENTAL
C=N), 570 (C–Br). H NMR spectrum, δ, ppm: 2.24 s
(3H, CH3), 4.59 s (2H, CH2), 6.09 s (1H, CH). UV spec-
trum, λmax, nm (ε): 240 (7900). Found, %: C 34.69;
H 3.91; Br 46.45; N 7.38. C5H6BrNO. Calculated,
%: C 34.09; H 3.41; Br 45.45; N 7.95.
IR spectra of compounds were recorded from thin
films on spectrophotometers UR-20 and Specord M-80,
UV spectra were measured on a spectrophotometer
1
Specord UV-Vis from methanol solutions. H NMR
3-Ethyl-5-bromomethylisoxazole (IIb). Yield 84%,
bp 77–78°C (2 mm Hg), Rf 0.58, nD20 1.5070, d420 1.4346.
IR spectrum, ν, cm–1: 3140 (CH), 1660 (C=C, C=N),
spectra were registered from 5–10% solutions of
compounds in CCl4, CDCl3, or CD3OD on a spectrometer
Tesla BS-487B (operating frequency 80 MHz). The purity
of compounds obtained was checked by TLC on Silufol
UV-254 plates, eluent methanol–chloroform – 25%
aqueous ammonia, 3:2:1, development in the iodine vapor.
Initial R-3-chloro-4-bromo-2-buten-1-ones were prepared
as described in [9].
1
620 (C–Br). H NMR spectrum, δ, ppm: 1.15 t and
2.55 q (5H, CH3CH2), 4.39 C (2H, CH2), 6.15 C (1H,
CH). UV spectrum, λmax, nm (ε): 230 (9900). Found, %:
C 37.44; H 4.57; Br 42.28; N 7.11. C5H8BrNO.
Calculated, %: C 37.89; H 4.21; Br 42.10; N 7.37.
3-Propyl-5-bromomethylisoxazole (IIc). Yield
80%, bp 96–98°C (2 mm Hg), Rf 0.54, nD20 1.4950, d420
1.3548. IR spectrum, ν, cm–1: 3130 (CH), 1650 (C=C,
3-Alkyl(aryl,furyl)-5-bromomethylisoxazoles IIa–
IIg. To a solution of 14 g (0.2 mol) of hydroxylamine
hydrochloride in 80 ml of methanol or ethanol at 10–15°C
was added dropwise while stirring 12 g (0.2 mol) of
potassium hydroxide dissolved in 180 ml of water, and
then at the same temperature was added dropwise
a solution of 0.2 mol of ketone I in 40 ml of MeOH
(EtOH). Then the reaction mixture was heated at 65–
70°C for 6 h [in the absence of potassium hydroxide
formed two isomers: 3-alkyl-5-bromo-methyl- (IIa–IId)
and 5-alkyl-3-bromomethylisoxazoles (IIIa–IIId)].
Compounds IIe–IIg were prepared without potassium
hydroxide. On cooling the reaction products were
separated, washed several times with a saturated water
solution of potassium or sodium carbonate till neutral
washings, combined with ether or benzene extracts from
the water layer, dried over MgSO4, and on removing the
solvent they were distilled in a vacuum in a nitrogen flow.
1
C=N), 520 (C–Br). H NMR spectrum, δ, ppm: 0.92 t,
1.62 m and 2.48 t [7H, CH3(CH2)2], 4.74 s (2H, CH2),
6.60 s (1H, CH). UV spectrum, λmax, nm (ε): 229 (10800).
Found, %: C 41.37; H 4.59; Br 39.70; N 7.00.
C7H10BrNO. Calculated, %: C 41.17; H 4.90; Br 39.22;
N 6.86.
3-Isopropyl-5-bromomethylisoxazole (IId). Yield
76%, bp 92–93°C (2 mm Hg), Rf 0.55, nD20 1.4970, d420
1.3620. IR spectrum, ν, cm–1: 3140 (CH), 1660 (C=C,
1
C=N), 620 (C–Br). H NMR spectrum, δ, ppm: 1.08 d
and 2.67 m [7H, CH(CH3)2], 4.07 s (2H, CH2), 6.61 s
(1H, CH). UV spectrum, λmax, nm (ε): 235 (9500). Found,
%: C 41.48; H 4.63; Br 39.51; N 6.48. C7H10BrNO.
Calculated, %: C 41.17; H 4.9; Br 39.22; N 6.86.
3-Phenyl-5-bromomethylisoxazole (IIe). Yield
70%, bp 143–145°C (2 mm Hg), Rf 0.61, nD20 1.5890, d420
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

ALIEV
1194
1.4780. IR spectrum, ν, cm–1: 3144 (CH), 1670 (C=C,
C=N), 580 (C–Br). 1H NMR spectrum, δ, ppm: 7.30 m
and 8.00 m (5H, Harom), 4.20 s (2H, CH2), 6.40 s (1H,
CH). UV spectrum, λmax, nm (ε): 239 (7500). Found, %:
C 50.85; H 3.71; Br 33.84; N 5.28. C10H8BrNO.
Calculated, %: C 50.42; H 3.36; Br 33.61; N 5.88.
d240 0.9496. IR spectrum, ν, cm–1: 3130 (CH), 1600 (C=C,
C=N). UV spectrum, λmax, nm (ε): 218 (5800). Found,
%: C 67.74; H 10.73; N 14.77. C11H20N2O. Calculated,
%: C 67.35; H 10.20; N 14.29.
3-Isopropyl-5-diethylaminomethylisoxazole
(IVd). Yield 80%, bp 98–99°C (1 mm Hg), Rf 0.60, nD20
1.4610, d420 0.9480. IR spectrum, ν, cm–1: 3140 (CH),
3-Toluyl-5-bromoethylisoxazole (IIf). Yield 69%,
bp 140–141°C (2 mm Hg), Rf 0.65, nD20 1.5930, d420 1.4550.
IR spectrum, ν, cm–1: 3146 (CH), 1670 (C=C, C=N),
1
1608 (C=C, C=N). H NMR spectrum, δ, ppm: 1.03 t
and 2.45 d [10H, (CH2CH3)2], 1.25 quintet [7H,
CH(CH3)2], 3.62 s (2H, CH2), 5.95 s (1H, CH). UV
spectrum, λmax, nm (ε): 220 (7300). Found, %: C 67.24;
H 10.31; N14.98. C11H20N2O. Calculated, %: C 67.35;
H 10.20; N 14.29.
1
580 (C–Br). H NMR spectrum, δ, ppm: 2.50 s (3H,
CH3), 7.40 m and 7.88 m (4H, Harom), 3.8 s (2H, CH2),
6.57 s (1H, CH). UV spectrum, λmax, nm (ε): 239 (7500).
Found, %: C 52.75; H 3.48; Br 31.28; N 5.87.
C11H10BrNO. Calculated, %: C 52.38; H 3.97; Br 31.75;
N 5.55.
3-Phenyl-5-diethylaminomethylisoxazole (IVe).
Yield 75%, bp 132–133°C (2 mm Hg), Rf 0.54, nD20 1.5660,
d240 1.0970. IR spectrum, ν, cm–1: 3150 (=CH), 1630 (C=C,
C=N). UV spectrum, λmax, nm (ε): 210 (8300). Found,
%: C 73.41; H 7.51; N 12.67. C14H18N2O. Calculated,
%: C 73.04; H 7.83; N 12.17.
3-Furyl-5-bromomethylisoxazole (IIg). Yield 53%,
bp 138–139°C (3 mm Hg), nD20 1.5820, d420 1.4780. Found,
%: C 42.29; H 2.87; Br 35.17; N 6.29. C8H6BrNO2.
Calculated, %: C 42.10; H 2.63; Br 35.09; N 6.14.
3-Alkyl(aryl, furyl)-5-dialkylaminomethyl-
isoxazoles IVa–IVf, Va–Vg, and VIa–VIf. To a solution
of 0.2 mol of a secondary amine (diethylamine, piperidine,
morpholine) and 0.2 mol of triethylamine in 150 ml of
benzene was added dropwise at stirring 0.1 mol of
3-alkyl(aryl, furyl)-5-bromomethylisoxazole II dissolved
in 30 ml of benzene at 30–35°C. Then the mixture was
heated to 50–60°C and stirred at this temperature for
5 h. On cooling the reaction mixture was diluted with
100 ml of saturated water solution of potassium or sodium
carbonate, washed till neutral washings, combined with
ether or benzene extracts from the water layer, dried
over MgSO4, and on removing the solvent the products
were distilled in a vacuum in a nitrogen flow.
3-Toluyl-5-diethylaminomethylisoxazole (IVf).
Yield 70%, bp 129–131°C (2 mm Hg), nD20 1.5610, d420
1.0925. Found, %: C 73.20; H 8.91; N 11.05. C15H20N2O.
Calculated, %: C 73.77; H 8.20; N 11.74.
3-Methyl-5-piperidinomethylisoxazole (Va). Yield
84%, bp 120–121°C (3 mm Hg), Rf 0.57, nD20 1.4924, d420
1.0098. IR spectrum, ν, cm–1: 3150 (=CH), 1620 (C=C,
1
C=N). H NMR spectrum, δ, ppm: 2.21 s (3H, CH3),
1.84 m and 2.75 t [10H, (CH2)5], 4.08 s (2H, CH2),
5.35 s (1H, CH). UV spectrum, λmax, nm (ε): 210 (5700).
Found, %: C 66.24; H 9.00; N 15.79. C10H16N2O.
Calculated, %: C 66.67; H 8.89; N 15.56.
3-Ethyl-5-piperidinomethylisoxazole (Vb). Yield
80%, bp 130–132°C (3 mm Hg), nD20 1.4910, nD20 0.9928.
Found, %: C 68.34; H 9.70; N 14.78. C11H18N2O.
Calculated, %: C 68.04; H 9.28; N 14.43.
3-Methyl-5-diethylaminomethylisoxazole (IVa).
Yield 89%, bp 77–78°C (1 mm Hg), Rf 0.70, nD20 1.4666,
d240 0.9880. IR spectrum, ν, cm–1: 3150 (CH), 1630 (C=C,
1
C=N). H NMR spectrum, δ, ppm: 0.97 t and 2.45 q
3-Propyl-5-piperidinomethylisoxazole (Vc). Yield
81%, bp 135–136°C (2 mm Hg), Rf 0.57, nD20 1.4890, d420
1.9832. IR spectrum, ν, cm–1: 3140 (CH), 1620 (C=C,
C=N). UV spectrum, λmax, nm (ε): 218 (5800). Found,
%: C 69.54; H 9.04; N 13.85. C12H2N2O. Calculated, %:
C 69.23; H 9.28; N 13.46.
[10H, (CH2CH3)2], 2.13 s (3H, CH3), 6.60 s (1H, CH).
UV spectrum, λmax, nm (ε): 225 (8500). Found, %:
C 64.70; H 9.91; N 16.21. C9H16N2O. Calculated, %:
C 64.29; H 9.52; N 16.67.
3-Ethyl-5-diethylaminomethylisoxazole (IVb).
Yield 84%, bp 89–90°C (3 mm Hg), Rf 0.63, nD20 1.4650,
d240 0.9698. IR spectrum, ν, cm–1: 3138 (CH), 1603 (C=C,
C=N). UV spectrum, λmax, nm (ε): 220 (6700). Found,
%: C 65.40; H 9.21; N 15.70. C10H18N2O. Calculated,
%: C 65.93; H 9.89; N 15.38.
3-Isopropyl-5-piperidinomethylisoxazole (Vd).
Yield 78%, bp 130–131°C (2 mm Hg), Rf 0.67, nD20 1.4850,
d240 0.9832. IR spectrum, ν, cm–1: 3150 (CH), 1610 (C=C,
C=N). UV spectrum, λmax, nm (ε): 220 (7200). Found,
%: C 69.70; H 9.21; N 13.99. C12H20N2O. Calculated,
%: C 69.23; H 9.61; N 13.46.
3-Propyl-5-diethylaminomethylisoxazole (IVc).
Yield 82%, bp 100–102°C (1 mm Hg), Rf 0.57, nD201.463,
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

SYNTHESIS OF 5-BROMOMETHYLISOXAZOLES
1195
219 (7100). Found, %: C 62.48; H 8.21; N 13.97.
C11H18N2O2. Calculated, %: C 62.86; H 8.57; N 13.33.
3-Phenyl-5-piperidinomethylisoxazole (Ve). Yield
74%, bp 140–141°C (2 mm Hg), Rf 0.57, nD20 1.5740, d420
1.1030. IR spectrum, ν, cm–1: 3150 (CH), 1630 (C=C,
C=N). UV spectrum, λmax, nm (ε): 210 (8200). Found,
%: C 74.78; H 7.88; N 11.05. C15H18N2O. Calculated,
%: C 74.38; H 7.44; N 11.70.
3-Phenyl-5-morpholinomethylisoxazole (VIe).
Yield 75%, bp 145–146°C (2 mm Hg), nD20 1.5760, d420
1.237. Found, %: C 68.85; H 6.97; N 11.73. C14H16N2O.
Calculated, %: C 68.85; H 6.56; N 11.48.
3-Toluyl-5-piperidinomethylisoxazole (Vf). Yield
70%, bp 137–138°C (3 mm Hg), nD20 1.5790, d420 1.1071.
Found, %: C 75.21; H 7.40; N 10.21. C16H20N2O.
Calculated, %: C 75.00; H 7.81; N 10.94.
3-Toluyl-5-morpholinomethylisoxazole (VIf). Yield
76%, bp 138–139°C (2 mm Hg), Rf 0.64, nD20 1.582, d420
1.1093. IR spectrum, ν, cm–1: 3150 (CH), 1625 (C=C,
1
C=N). H NMR spectrum, δ, ppm: 2.37 s (3H, CH3),
3-Furyl-5-piperidinomethylisoxazole (Vg). Yield
68%, bp 168–169°C (2 mm Hg). Found, %: C 67.71;
H 6.12; N 12.18. C13H16N2O2. Calculated, %: C 67.24;
H 6.89; N 12.07.
2.47 t and 3.60 t [8H, (CH2)4], 3.57 s (2H, CH2), 6.32 s
(1H, CH), 7.19 m and 7.60 m (4H, Harom). UV spectrum,
λ
max, nm (ε): 217 (6100). Found, %: C 69.21; H 6.17;
N 10.20. C15H18N2O2. Calculated, %: C 69.77; H 6.97;
N 10.85.
3-Methyl-5-morpholinomethylisoxazole (VIa).
Yield 87%, bp 118–120°C (2 mm Hg), Rf 0.67, nD20 1.4990,
d420 1.1119. IR spectrum, ν, cm–1: 3140 (CH), 1608 (C=C,
REFERENCES
1
C=N). H NMR spectrum, δ, ppm: 2.11 s (3H, CH3),
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2.34 t and 3.50 t [8H, (CH2)4], 3.46 s (2H, CH2), 5.88 s
(1H, CH). UV spectrum, λmax, nm (ε): 225 (6800). Found,
%: C 59.48; H 7.97; N 15.01. C9H14N2O2. Calculated,
%: C 59.34; H 7.69; N 15.38.
3-Ethyl-5-morpholinomethylisoxazole (VIb).
Yield 85%, bp 129–131°C (2 mm Hg), nD20 1.4960, d420
1.0883. Found, %: C 61.78; H 8.51; N 14.99.
C10H16N2O2. Calculated, %: C 61.22; H 8,16; N 14.29.
3-Propyl-5-morpholinomethylisoxazole (VIIc).
Yield 84%, bp 136–137°C (2 mm Hg), nD20 1.4920, d420
1.0640. Found, %: C 62.07; H 8.12; N 13.78.
C11H18N2O2. Calculated, %: C 62.86; H 8.57; N 13.33.
3-Isopropyl-5-morpholinomethylisoxazole (VId).
Yield 80%, bp 134–135°C (2 mm Hg), Rf 0.70, nD20 1.4910,
d420 1.0498. IR spectrum, ν, cm–1: 3150 (CH), 1620 (C=C,
1
C=N). H NMR spectrum, δ, ppm: 1.23 d and 3.20 q
[7H, CH(CH3)2], 2.40 t and 3.58 t [8H, (CH2)4], 3.54 s
(2H, CH2), 5.97 s (1H, CH). UV spectrum, λmax, nm (ε):
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005