Synthesis of (isoxazol-4-ylmethyl)triphenylphosphonium salts derived from 5-alkyiand 5-aryl-3-methylisoxazoles

Article abstract of DOI:10.1055/s-1998-2126

The synthesis of (isoxazol-4-ylmethyl)triphenylphosphonium salts derived from 5-alkyl- and 5-aryl-3-methylisoxazoles has been carried out. This method involves the preparation of several 4-(chloromethyl)isoxazoles which are suitable precusors for these phosphonium salts. The phosphonium salts were completely characterized by spectroscopic methods and were obtained in very good to quantitative yields.

Full text of DOI:10.1055/s-1998-2126

SYNTHESIS
Short Papers
1104
Synthesis of (Isoxazol-4-ylmethyl)triphenylphosphonium Salts Derived from 5-Alkyl-
and 5-Aryl-3-methylisoxazoles
Alicia Maestro, Jose M. Báñez,* Juan A. López, María Cristina Romero-Ávila
Departamento de Química Orgánica, E.T.S. Ingenieros Industriales, Universidad de Valladolid, ES-47071 Valladolid, Spain
Fax +34(983)423310; E-mail: JMBSanz@dali.eis.uva.es
Received 29 October 1997; revised 5 January 1998
epoxidation.5, 6 On the other hand, the presence of an isox-
azole ring that can act as a masked aldolic moiety, such as
Abstract: The synthesis of (isoxazol-4-ylmethyl)triphenylphos-
phonium salts derived from 5-alkyl- and 5-aryl-3-methylisox-
azoles has been carried out. This method involves the preparation
β-enamino ketone, β-diketone, etc. These groups are also
of several 4-(chloromethyl)isoxazoles which are suitable precu-
sors for these phosphonium salts. The phosphonium salts were
of interest because they allow the synthesis of new hetero-
cycles, for example, pyrazoles7 that currently have great
completely characterized by spectroscopic methods and were
obtained in very good to quantitative yields.
importance in pharmaceutical chemistry.
Key words: 4-(chloromethyl)isoxazoles, (isoxazol-4-ylmethyl)-
triphenylphosphonium salts, polyhydroxylated chain sugar
homologs
The synthesis of (isoxazol-4-ylmethyl)triphenylphospho-
nium salts derived from 5-alkyl- and 5-aryl-3-methylisox-
azoles is shown in Scheme 1.
The preparation of the compounds 1–6 is carried out by
two different methods. The compounds 3,5-dimethylisox-
azole (1) and 3-methyl-5-phenylisoxazole (2) are ob-
tained from the appropiate diketones by direct
cyclization8, 9 in 99% and 81% yield, respectively. Isox-
azoles 3–6 are obtained from unsaturated α,β-oxo oximes
according to the Alberola procedure.10 It should be point-
ed out that compound 6 is obtained in low yield11 and with
trace amounts of 4-(p-dimethylaminophenyl)-4,5-dihy-
droisoxazole. This was not discussed in the reported pro-
cedure.10
Chain extension in the carbohydrate series is of great in-
terest for organic chemists. For this purpose, over the last
few years several synthetic strategies have been devel-
oped.1 Of special interest is the method employed by
Dondoni2 where D-tetrose and D-pentose derivatives were
synthesized via alkenylthiazoles using 2,3-O-isoprop-
ylidene-D-glyceraldehyde as the initial substrate.
With this idea in mind, our group has developed a synthet-
ic method to 4-alkenylisoxazoles I. These compounds will
be employed as key intermediates for the extension of the
polyhydroxylated chain of sugars.3
The formation of 4-(chloromethyl) derivatives of 5-alkyl-
and 5-aryl-3-methylisoxazoles has also been carried out
by two different methods. The compound 7, 4-(chloro-
methyl)-3,5-dimethylisoxazole, is obtained by the general
procedure of Kochetkov.12 However, this method does
not give the desired compounds 8–11. In these cases un-
transformed starting materials are recovered. The em-
ployed procedure for the preparation of compounds 8–11
is described in the experimental part (glacial acetic acid
In order to obtain these compounds, the synthesis of ap- and high temperature, 100–110 °C). The results are sum-
propiate precusors such as 4-alkyltriphenylphosphonium marized in Table1.
salts II has been carried out. Their preparation is de-
Although the achieved yields are moderate, this procedure
scribed in the present work.
has the advantage of affording the suitable C4-functional-
The use of 4-alkenylisoxazoles offers many advantages. ization of the isoxazole ring in a single step. No influence
On one hand, the easy stereocontrolled functionalization of the presence of methyl or phenyl groups in the C5 po-
of the double bond by cis-dihydroxylation4 or asymmetric sition of the isoxazole ring was observed. In contrast, an
Scheme 1

SYNTHESIS
August 1998
1105
Table 1. Chloromethylation of 3,5-Disubstituted Isoxazoles
ing a Bruker AC-300 spectrometer. Chemical-shift values are ex-
pressed in ppm (δ), relative to TMS as internal reference. The 13C
NMR spectra were recorded with a Bruker AC-300 spectrometer. MS
were recorded by direct introduction of the sample into a Hewlett–
Packard 5988 A (70 eV) spectrometer. Elemental analyses were de-
termined with a Perkin–Elmer elemental analyzer 2400 CHN. Mps
were determined with a Gallenkamp MFB-595 device. Solvents and
reagents were purified by conventional methods. TLC was performed
on glass plates coated with silica gel G (Merck), spots being detected
with iodine vapors or by charring with 10% H2SO4 in EtOH.
Entry
R
Compound Time
(h)
Temp
(°C)
Yield
(%)
1
2
3
4
5
CH3
C6H5
p-CH3C6H4
p-CH3OC6H4 10
p-O2NC6H4 11
7
8
9
3
3
2
2
2
35–40
40
37
60
50
32a
Synthesis of starting materials – all employed isoxazoles were pre-
pared following methods described in literature8–10 except 5-(p-di-
methylaminophenyl)-3-methylisoxazole (6) which had not been pre-
viously synthesized. For this compound, the starting oxime was pre-
pared from 4-(p-dimethylaminophenyl)but-3-en-2-one according to
the Alberola procedure.10 The reaction crude was chromatographed
giving the isoxazole 6 which was purified by recrystallization. A
white solid was obtained; yield: 4.20%; mp 142–143°C (EtOH).
100–110
100–110
100–110
110–110
a See experimental part for compound 11.
increase of the chloromethylated product is noticed when
a donor group is present in the para position of the ben-
zene ring (entries 3 and 4). Another consequence of the
activation of the benzene ring is that 4-(chloromethyl)-5-
(3-chloromethyl-4-methoxyphenyl)-3-methylisoxazole is
isolated together with compound 10. As a secondary prod-
uct, 4-(acetoxymethyl)-3-methyl-5-phenylisoxazole is
obtained, resulting in the synthesis of compound 8; to im-
prove its yield, the acetoxy derivative is hydrolyzed and
chlorinated giving rise to the desired compound.13
Chloromethylation of 3,5-Disubstituted Isoxazoles; General Pro-
cedure:14
HCl gas was bubbled through a stirred solution of 5-aryl-3-methyl-
isoxazole 2–5 (30 mmol), paraformaldehyde (1.80 g, 60 mmol) and
anhyd ZnCl2 (5.65 g, 56 mmol) in glacial HOAc (34 mL). The mix-
ture was heated to 100–110°C and monitored by TLC (Et2O/hexane
1:4). After 2 h, the mixture was hydrolyzed with cracked ice and sub-
sequently neutralized with solid Na2CO3, and extracted several times
with CHCl3. The organic extract was dried (anhyd Na2SO4) and then
concentrated in vacuo. The obtained residue was chromatographed
(Et2O/hexane 1:7).
Finally, the (isoxazol-4-ylmethyl)triphenylphosphonium
salts are prepared from the previously described chloro-
methyl derivatives and triphenylphosphine. The reaction
is carried out using both reagents in a molar ratio 1:1 with
anhydrous xylene as solvent. The results are shown in Ta-
ble 2. In all cases the yields are excellent.
4-(Chloromethyl)-3-methyl-5-phenylisoxazole (8): white solid; yield
37%; mp 55–56°C (hexane).
1H NMR: δ = 2.40 (s, 3H), 4.57 (s, 2H), 7.4–7.8 (m, 5H).
13C NMR: δ = 9.9, 35.4, 111.1, 127.3, 129.2, 130.5, 160.3, 167.2.
IR (KBr): ν = 3016, 2978, 1616, 1574, 1450, 1172, 734, 690 cm–1.
MS: m/z (%) = 207 (22.78, M+), 209 (7.58, M+ + 2).
Anal. (C11H10ClNO): Calcd for C, 63.75; H, 4.87; N, 6.76. Found: C,
63.67; H, 4.87; N, 6.72.
Table 2. Synthesis of the Phosphonium Salts
4-(Chloromethyl)-3-methyl-5-(p-tolyl)isoxazole (9): white solid;
yield: 60%; mp 90–91°C (hexane).
1H NMR: δ = 2.39 (s, 3H), 2.43 (s, 3H), 4.56 (s, 2H), 7.34 and 7.65
(dd, 4H).
13C NMR: δ = 9.9, 21.5, 35.5, 110.5, 124.3, 127.1, 129.8, 140.9,
160.2, 167.4.
IR (KBr): ν =3022, 2955, 1618, 1518, 1465, 819 cm–1.
MS: m/z (%) = 221 (26.61, M+), 223 (8.46, M+ + 2).
Anal. (C12H12ClNO): Calcd for C, 65.14; H, 5.47; N, 6.33. Found: C,
65.25; H, 5.33; N, 6.52.
R
Sub- Com-
strate pound
Time
Yield (%)
CH3
C6H5
p-CH3C6H4
p-CH3OC6H4 10
p-O2NC6H4 11
7
8
9
12
13
14
15
16
6 h + 16 h 30 min
6 h + 14 h 30 min
6 h + 9 h 15 min
6 h + 12 h 45 min
7 h + 12 h
76
91
4-(Chloromethyl)-5-(p-methoxyphenyl)-3-methylisoxazole (10):
white solid; yield:50%; mp 105–107°C (hexane).
1H NMR: δ = 2.39 (s, 3H), 3.88 (s, 3H), 4.56 (s, 2H), 7.01–7.74 (m, 4H).
13C NMR: δ = 9.9, 35.7, 55.4, 109.9, 114.4, 128.8, 119.8, 161.3,
160.2, 167.3.
quantitative
quantitative
85
IR (KBr): ν =3016, 2937, 1616, 1516, 1440, 1253, 1172, 835 cm–1.
MS: m/z (%) = 237 (34.69, M+), 239 (11.35, M+ + 2).
Anal. (C12H12NO2): Calcd for C, 60.64; H, 5.09; N, 5.89. Found: C,
60.66; H, 5.11; N, 6.52.
In summary, it has been demonstrated that the proposed
synthetic strategy is an efficient and short route to (isox-
azol-4-ylmethyl)phosphonium salts. These compounds,
as previously mentioned, are adequate precursors for 4-
alkenylisoxazoles which can be used for the extension of
the polyhydroxylated chain of carbohydrates.
4-(Chloromethyl)-3-methyl-5-(p-nitrophenyl)isoxazole (11): the sep-
aration of the chloromethylated product and starting isoxazole was
not possible. The compound 11 was identified by NMR but not iso-
lated. The yield was measured from the 1H NMR spectrum of the mix-
ture of unreacted isoxazole and choromethylated product.
IR spectra were measured using a Nicolet FT-IR-20-SX spectropho-
tometer. 1H NMR spectra for solutions in CDCl3 were measured us-
1H NMR: δ = 2.44 (s, 3H), 4.57 (s, 2H), 7.90–8.44 (m, 4H).

SYNTHESIS
Short Papers
1106
13C NMR: δ = 9.8, 34.4, 113.4, 124.4, 128.1, 132.9, 148.3, 160.6,
164.5.
Anal. (C30H27ClNO2P) Calcd for C, 72.07; H, 5.44; N, 2.80. Found:
C, 71.78; H, 5.50; N, 2.61.
MS: m/z (%) = 252 (24.06, M+), 254 (7.92, M+ + 2).
[3-Methyl-5-(p-nitrophenyl)isoxazol-4-ylmethyl]triphenylphospho-
nium Chloride (16): white solid; yield: 84%; mp 272–273°C (EtOH).
1H NMR: δ = 1.70 (s, 3H), 5.80 (d, J = 13.9 Hz, 2H), 7.47–7.76 (m,
15H), 8.03 and 8.19 (dd, 4H).
Synthesis of Alkyltriphenylphosphonium salts 12–16; General
Procedure:
A solution of 3,5-dialkyl-4-(chloromethyl)isoxazole 7–11 (17 mmol)
and Ph3P (17 mmol) in anhyd xylene (31 mL) was heated at reflux for
ca. 6 h. The suspension was cooled and filtered off. The filtering was
heated up to reflux for an additional time of 9 to 17 h according to the
particular cases. The solid was again removed by filtration and
washed with Et2O and benzene.
13C NMR: δ = 9.2, 17.9, 104.1, 116.5, 123.9, 129.2, 130.0, 132.5,
134.2, 135.3, 148.2, 161.4, 165.8.
IR (KBr): ν = 3007, 2976, 1601, 1565, 1520, 1437, 1346, 1111, 852
cm–1.
Anal. (C29H24ClN2O3P) Calcd for C, 67.64; H, 4.70; N, 5.44. Found:
C, 66.50; H, 4.68; N, 5.75.
(3,5-Dimethylisoxazol-4-ylmethyl)triphenylphosphonium Chloride
(12): cream-coloured solid; yield: 76%; mp 296–297°C (EtOH/H2O)
(lit.15 305–308°C16).
We are grateful to M. L. Rodríguez for her assistance with the
English translation.
1H NMR: δ = 1.43 (s, 3H), 1.67 (d, J = 28 Hz, 3H), 4.43 (d, J =
12.8 Hz, 2H), 7.55–7.58 (m, 15H).
13C NMR: δ = 10.2, 11.8, 20.3, 101.9, 117.6, 130.2, 134.6, 135.2,
160.3, 169.9.
(1) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F.; Tetrahe-
dron 1990, 46, 265.
MS: m/z = 372 (M+ – Cl).
Lee, A. W. M.; Masamune, S.; Martin, V. S.; Sharpless, K. B.;
Walker, F. J. J. Am. Chem. Soc. 1982, 104, 3515.
Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed-III, L. A.;
Sharpless, K. B.; Walker, F. J. Tetrahedron 1990, 46, 245.
(2) Dondoni, A.; Merino, P. Synthesis 1992, 196.
(3) Maestro, A.; Báñez, J. M.; López, J. A.; Romero-Avila, M. C.
in press.
(4) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24,
3943.
(5) Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune,
S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J. J. Org.
Chem. 1982, 47, 1373.
Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(6) Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
1109.
(3-Methyl-5-phenylisoxazol-4-ylmethyl)triphenylphosphonium Chlo-
ride (13): white solid; yield: 91%; mp 275–277°C (EtOH).
1H NMR: δ = 1.74 (s, 3H), 5.66 (d, J = 13.2 Hz, 2H), 7.29–7.71 (m,
20H).
13C NMR: δ = 10.4, 20.2, 102.0, 117.0, 127.3, 127.7, 129.1, 130.1,
130.3, 134.2, 135.1, 161.5, 168.8.
IR (KBr): ν = 3009, 2922, 1610, 1438, 1111, 742, 692 cm–1.
MS: m/z = 262 (Ph3P+).
Anal. (C29H25ClNOP): Calcd for C, 74.12; H, 5.36; N, 2.98. Found:
C, 74.13; H, 5.37; N, 2.93.
[3-Methyl-5-(p-tolyl)isoxazol-4-ylmethyl]triphenylphosphonium
Chloride (14): white solid; quantitative yield; mp 278–279°C
(EtOH).
1H NMR: δ = 1.73 (s, 3H), 2.36 (s, 3H), 5.66 (d, J = 13.1 Hz, 2H),
7.13 and 7.33 (dd, 4H), 7.48–7.72 (m, 15H).
13C NMR: δ =10.4, 20.2, 21.4, 101.6, 117.0, 124.4, 127.5, 129.7,
130.1, 134.2, 135.1, 140.6, 161.4, 169.1.
(7) Kozikowsky, A. P.; Goldstein, S. J. Org. Chem. 1983, 48, 1139.
(8) Morgan, G. T.; Burgess, H. J. Chem. Soc. 1921, 697.
(9) Lampe, W.; Smolinska, J. Rocz. Chem. 1954, 28, 163. Chem.
Abstr. 1955, 49, 10, 8922.
IR (KBr): ν =3009, 2976, 1614, 1438, 1111, 825 cm–1.
MS: m/z = 262 (Ph3P+).
Anal. (C30H27ClNOP) Calcd for C, 74.45; H, 5.62; N, 2.89. Found: C,
74.03; H, 5.71; N, 2.19.
(10) Alberola, A.; Báñez, J. M.; Calvo, L.; Rodríguez, M. T.; Sañu-
do, M. C. J. Heterocycl. Chem. 1993, 30, 467.
(11) See experimental part.
[5-(p-Methoxyphenyl)-3-methylisoxazol-4-ylmethyl]triphenylphos-
phonium Chloride (15): white solid; quantitative yield; mp 265–
266°C (EtOH).
(12) Kochetkov, N. K.; Khomutova, E. D.; Bazilevskii, M. V.
Zh. Obshch. Khim. 1958, 28, 2736. Chem. Abstr. 1959, 53, 10G,
9187.
1H NMR: δ = 1.67 (s, 3H), 3.83 (s, 3H), 5.50 (d, J = 12.5 Hz, 2H),
6.84 and 7.36 (dd, 4H), 7.50–7.78 (m, 15 H).
(13) i. NaOH, H2O, ii. SOCl2, pyridine.
(14) Saucy, G.; Scott, J. W. J. Org. Chem. 1972, 37, 1652.
(15) Alberola, A.; Pérez Serrano, A.; Rodriguez, M. T.; Orozco, C.
Ann. Chim. 1989, 85, C, 13. Chem. Abstr. 1990, 113, 28, 40522.
(16) The melting point of these compounds depends upon the rate of
heating.
13C NMR: δ = 10.2, 20.2, 55.5, 100.9, 114.5, 117.2, 119.6, 129.3,
130.1, 134.2, 135.1, 161.1, 161.3, 169.0.
IR (KBr): ν = 3009, 2837, 1608, 1514, 1438, 1249, 1111, 841 cm–1.
MS: m/z = 463 (M+ – Cl).