1831

Agric. Biol Chem., 50 (7), 1831-1837, 1986

Synthesis of 3-Hydroxyisoxazoles from jS-Ketoesters

and Hydroxylamine
Kazuo Sato,* Soji Sugai and Kazuo Tomita
Agricultural Chemicals Research Laboratories, Sankyo Co., Ltd.,
1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140, Japan
Received January 14, 1986

An efficient synthesis of 3-hydroxyisoxazoles from jS-ketoesters and hydroxylamine was

investigated. The reaction of the sodium salts of /?-ketoesters and hydroxylamine at a low
temperature, followed by quenching with an excess of cone. HC1under heating gave predominantly
3-hydroxyisoxazoles involving 4-sulfenylated 3-hydroxyisoxazoles. Starting from the prepared 4-
(2,4-dichlorobenzyl)-3-hydroxy-5-methylisoxazole, a potential herbicidal compound, 4-(2,4-
dichlorobenzoyl)-3-hydroxy-5-methylisoxazole, was also synthesized in five steps.

Since Claisen reported that the reaction of our

(3a)5)
laboratories,
and the
3-hydroxy-5-methylisoxazole
phosphorothioate (4)6) of 3-
1,3-diketones and hydroxylamine resulted in
the first formation of isoxazoles,1} mucheffort hydroxy-5-phenylisoxazole (3b) have been
commercialized under the name Tachigaren
has been focused on isoxazole chemistry.2) The
isolation of ibotenic acid (1), the insecticidal and Karphos, respectively. The former is a soil
constitution of Amanita strobiliformis by fungicide that exhibits a plant growth promot-
Takemoto et al.,3*\ and mucimol (2), an in- be used on rice, and the latter ing activity as well, which can predominantly
is a broad-
secticidal substance of A. pantherina, by Onda
et a/.,3b) which was a potent agonist of the spectrum systemic insecticide.
neurotransmitter y- aminobutyric acid A number of synthetic routes to 3-hydroxy-
(GABA),4) promoted new syntheses of various isoxazoles have been reported.2) Amongthem,
3-hydroxyisoxazoles and their derivatives. In the reaction of /?-ketoesters (diketene) and
NH2
1

0 0
CH3
C6H5
A?
3a
0 0
/ R1xS^NHOH x

, ^-V^OR3 ,
OH

r\, O NHjOH
R2
9.
0^0
R1" To "NHOH
Rz
10
R2
R1^
*
2 1
0J^Ih

H+
1^/0H
3& rfsCHa.f^sH
3b R1=C6H5.R2=H

Fig. 1.
1832 K. Sato, S. Sugai and K. Tomita

0 0 NaOH
hydroxylamine, which seemed to be the most C H 3A^SOC2H5
plausible and practical one, generally gave 3- 5aC
MeOH- H2O
isoxazolin-5-one (8), accompanied with 3-hy- H3>^NX2H5
lla
NH2OH
-30°C

droxyisoxazoles (3) as ettheal.7)minor(Fig.product,

reported by Jacquier 1). One
as
solution for preparing 3-hydroxyisoxazoles CH
12a 3a^ 8a
regioselectively was achieved by the ketaliza-
tion of /?-ketoesters, followed by the reaction Fig. 2.
of hydroxylamine and subsequent acid-hydrol-
ysis.^ According to this procedure, the com-
mercialized compound 3a and the intermediate quickly heating at 80°C for an hour to give 3a
3b were practically synthesized. In the applica- in 72.2% yield, no quantity of the regioisomer
tion of this method to synthesize 4-substituted 8a being detected (Fig. 2). Identification of the
3-hydroxyisoxazoles, however, the initial step assumed reaction intermediate 12a has not yet
to ketalize the 2-substituted jS-ketoesters gen- been completed for reasons of its instability. In
erally didn't proceed smoothly. a similar fashion, sixteen kinds of jS-ketoesters
Recently, another excellent solution was re- were allowed to react with hydroxylamine to
ported by Jacobsen et al.,9) whereby /?-keto- give the corresponding 3-hydroxyisoxazoles
esters or diketene reacted with hydroxylamine 3b~3q in good yields, as shown in Table I.
under the condition that pH was kept at about Among them, 3d, 3f~3k and the correspond-
10 throughout the reaction, followed by ing 8d and 8f~8k were newly synthesized
quenching with an excess of strong mineral compounds. From the analysis of IR and *H
acid to afford 3-hydroxyisoxazoles in good NMRspectra, compounds 8 existed as a mix-
yields. In this paper, we describe our inde- ture of 8 and 8A.10)
pendent synthesis of 3-hydroxyisoxazoles and Weextended this work to the synthesis of
related compounds. 4-sulfenylated 3-hydroxyisoxazoles. 4-Phenyl-
In the beginning of this work, we presumed thio and some 4-alkylthio-3-isoxazolin-5-ones
that the alkaline salt of /?-ketoesters would were reported by Sasaki et al.,n) but none
react with hydroxylamine to give 3-hydroxy- of the 4-sulfenylated 3-hydroxyisoxazoles has
isoxazoles after passing through the corre- been reported. By using the slightly modified
sponding hydroxamic acid. At the first at- reaction conditions already mentioned, nine
tempt, the initially formed sodium salt lla of kinds of 4-sulfenylated 3-hydroxyisoxazoles
ethyl acetoacetate was treated with hydroxyl- (14a ~ 14h) were newly synthesized from ethyl
amine at 0°C in a mixture of methanol and 2-sulfenylated acetoacetates (13a ~ 13h)12) and
water, followed by quenching with cone. HC1 hydroxylamine in moderate to low yields as
at 80°C to give, against our assumption, 3- shown in Table II. Because of the low solu-
methyl-3-isoxazolin-5-one (8a) as the major bility of sodium salts of the ethyl 2-sulfenyl-
product, together with a trace of 3-hy- ated acetoacetates 13a~13h in a mixture of
droxy-5-methylisoxazoles (3a). An exami- methanol and water at -30°C, the reaction
nation of the reaction conditions revealed was carried out at a higher temperature
that both temperatures in the formation (- 10°C) to result in the undesirable formation
of hydroxamic acid (12a) and in quenching of unstable 4-sulfenylated 3-methyl-3-isoxazo-
12a with cone. HC1 were crucial (Fig. 2). lin-5-ones except for 3-methyl-4-phenyl-3-iso-
At -30°C, hydroxylamine was added to a xazolin-5-one (15h), and in consequence the
solution of the sodium salt lla of ethyl aceto- yields of the objective 3-hydroxyisoxazoles
acetate. After stirring at.-30°C for 2hr, the 14a~14h in Table II were reduced.
reaction mixture was quenched by adding an In our laboratories, Pyrazolate, 4-(2,4-di-
excess of cone. HC1 at once at -20°C, and chlorobenzoyl)- 1 ,3-dimethyl-5-pyrazolyl p-
 Synthesis of 3-Hydroxyisoxazoles 1833

Table I. Synthesis of 3-Hydroxyisoxazoles (3) and 3-Isoxazolin-5-ones (8)

R2W* R^R1
< r2 ^b rf^O^ (A)'NH O^C/4
5 3 8 8A

R un* R l R 2 3 Y ie ld ( % ) m p (-C ) Y i e ld ( % ) m p (-C )

1) C HU H ab 7 2 .2 8 5 -8 7
蝣 [70 8 5 .5 - 8 6 - ]c
2) C H , C H , bb 7 3. 5 12 7
蝣 [ 80 12 2- 1 24 - ]
3) C H a C 2H , cb 6 9 .3 4 7 (5 0 )b 12 .2 n2j : 1.4 72 6
蝣 [32 56 ]
4) C H , ｫ ｰC 3H 7 d 7 5. 9 n 2D 4 : 1 .4 6 5 6 18. 1 n ｣ : 1 .4 8 2 5
5) C H , is o - C 3 H 7 e ft 5 6.6 93 8.0 oi l (de c.)
6) C H , n -C A iq f 70 .0 n｣: 1.462 0 2 3 .2 n % ¥ 1 .4 8 3 5
7) C H , is o -C 4 H 9 g 7 6 .1 n D2 4 l l. 0 n l 4 : 1 .4 9 4 0
8) C H 3 ｻ ｰC 5H ,. h 6 5 .7 ｫ 2o 4 26. 6 n 2D4: 1.485 4
9) C H , ｫ ｰC 6 H 13 74.9 nl4: 1.4642 2 5. 1 n ｣ ¥ 1 .4 8 3 7
10 ) C H , C 6H 5C H , 1. 5 9.0 120 8. 5 1 00 - 10 4
l l) C H , 2,4-Cl2 C6H3CH2 k 47 .4 174- 177 16 . 7 1 1 2- 1 14
12 ) ｫ ｰC 3H 7 H 1 8 9 .3 4 1 - 4 1. 5
蝣 [59 43 -44 - ]
13 ) iso -C 3 H 7 H m b 8 2.2 41 -42
[67 4 5 -4 6 1 6 oi l]
14 ) C y c lo p r o p y l H nb 84.0 1 0 6 - 10 7 ( 1 07 /
15 ) t- C A H q H o 8 5. 5 10 1 - 10 2
蝣 [73 99- 101 - ]
16 ) Q H , H pb 8 0. 0 1 65 (1 67 )"
蝣 [4 9 40
17 ) Q H s C H , <¥ b 8 8 .2 18 5- 1 87 (1 8 6- 18 7 )6

a /MCetoesters were commercially available except for 5k, 5mand 5n; 5k: see experimental part; 5m: see ref. 15a;
5n: see ref. 15b.
h Seeref.7.
c Brackets show Jacobson's results; see ref. 9.

toluenesulfonate (16b), was recently developed of Et3N yielded the desired 3-<9-sulfonate 18
as a paddy field herbicide and commercialized (74.1%), along with the 2-sulfonylated com-
under the name Sanbird.13) A real active com- pound 19 (10.9%). Bromination (NBS) and
pound of Pyrazolate is 4-(2,4-dichlorobenzo- subsequent hydrolysis (AgNO3-H2O) of com-
yl)-l,3-dimethyl-5-hydroxypyrazole (DTP, pound 18 afforded the 2,4-dichloro-a-hydroxy-
16a).13b) From the viewpoint of molecular benzyl derivative 21 in 55.3% yield. Jones'
modification based on the concept of bioiso- oxidation converted 21 into the corresponding
sterism,14) we were interested in the synthesis ketone 22 quantitatively, which was deprotect-
of 4-(2,4-dichlorobenzoyl)-3-hydroxy-5-meth-
ed with sodium methoxide to give the final
ylisoxazole (17), which had been regarded as a product 17 in 80.1% yield. Compound 17 was
bioisostere of DTP(16a). To synthesize the evaluated to have much less herbicidal activity
attractive compound 17, 4-(2,4-dichlorobenz- under paddy field conditions in comparison
yl)-3-hydroxy-5-methylisoxazole (3k) was re- with the herbicidal compound 16a.
quired as the starting material, which was In conclusion, the new reaction described
prepared by the reaction shown in Table I. enables us to synthesize various 3-hydroxy-
As illustrated in Fig. 3, the treatment of 3k isoxazoles.
with benzene sulfonyl chloride in the presence
 1834 K. Sato, S. Sugai and K. Tomita

Table II. Synthesis of 4-Sulphenylated 3-Hydroxyisoxazoles (14)

0 0

SR
**>
CeHsSxp^CHa
14

15h
13

A n a ly sis (% )
Y ie ld m p C al c d. ( Fo u nd )
14 R F o rm u la
(% ) (-C )
c H N s

a C H , 44. 3 97 10 0 C 5H 7N O 2S 4 1. 37 4 .86 9. 65 22 .0 9
(4 1 .1 0 4 .91 9.4 5 2 1.9 0 )
b C 2H 5 40. 0 42 - 44 C 6 H 9N O 2S 4 5. 2 7 5 .70 8.8 0
(4 4 .9 9 5 .9 0 8 .6 7)
c ｫ ｰC 3H 7 5 3.5 39 - 41 C 7 H n N O 2S 4 8.5 3 6. 40 8.0 9 18. 5 1
(4 8 .3 3 6. 49 8.2 3 18.5 0 )
d iso -C 3H 7 45. 9 54 57 C 7 H n N O 2S 4 8. 5 3 6. 40 8 .09 18.5 1
(4 8 .4 5 6. 53 7.8 8 18.3 7 )
e tl -CJla 68. 0 1. 5 0 9 0 C 8H 13N O 2S 5 1. 3 1 7.0 0 7. 48 17. 12
(5 1 .1 7 7. l l 7.3 2 1 7. 18 )
f ｫ ｰC sH t 4 9 .1 n % ¥ 1.5 1 10 C 9H 15N O 2S 5 3. 70 7. 51 6.9 6 15.9 3
(5 3 .9 2 7. 71 6 .86 16 .08)
g ｫ ｰQ H 13 38. 5 ｫ ?>2 : 1 .4 9 9 0 C lOH 17N O 2 S 5 5.7 8 7 .96 6. 51 1 4.8 9
(5 5 .9 9 8.0 8 6.6 4 15 .03)
ha Q H , 16.5 1 13 - 1 14 C lOH 9 N O 2 S 57 .9 5 4.3 8 6. 76
(5 7 .8 7 4. 56 6 . 78 )

3-Methyl-4-phenylthio-3-isoxazolin-5-one (15h) was obtained in 70% yield as the major product.

CH3 jg
16a R=H ' 12
16b R=SO2H^CH3

3k ll 20

ll ll
Fig. 3.

EXPERIMENTAL of ethyl acetoacetate (26.0g, 0.20mol) in dry THF (40ml)

was added dropwise to a stirred suspension of NaH(55%
All melting points (mp) were uncorrected. IR spectra dispersion, 9.2g, 0.21 mol, the mineral oil being removed
were measured as films for oils or as nujol mulls for solids by washing with dry THF several times) in dry THF
on a JASCO IRA-102 spectrometer. ^-NMR spectra (150ml) at 0°C under a nitrogen atmosphere for 70min,
were recorded at 60MHzwith TMSas an internal stan- and the mixture was further stirred for 1hr. To this
dard on a Varian EM-360Aspectrometer. solution was slowly added 2,4-dichlorobenzylchloride
(46.9g, 0.24mol) and the mixture was stirred at room
Ethyl 2-{2,4-dichlorobenzyt)acetoacetate (5k). A solution temperature for 18 hr before being refluxed for 3 hr. After
 Synthesis of 3-Hydroxyisoxazoles 1835

about half the solvent had been removed under reduced prepared. 13c ~ 13g were prepared in a similar manner12a)
pressure, the residue was poured into ice-cooled water by using alkylsulfenyl chlorides, which were obtained from
(300ml) and neutralized with cone. HC1. The resulting the corresponding alkyl mercaptanes and TV-chlorosuccin-
solution was extracted with ether, and the extract was imide.
washed with water and brine, dried over MgSO4 and
evaporated in vacuo. The residue was chromatographed on 4-n-Butylthio-3-hydroxy-5-methylisoxazole (14e). Ethyl
SiO2 to give 38.8g (67.2%) of5k. IR v^cm"1: 3050 (br. 2-rc-butylthioacetoacetate 13e (2.06g, 9.44mmol) was
w, OH), 1735 (s), 1710 (s, C-O). NMR (CDC13) (Sppm: added dropwise to a solution of NaOH (0.38g, 9.5mmol)
1.18 (1H, t, /=7Hz), 1.22(2H, t, /=7Hz), 1.96 (1H, s),
2.18 (2H, s), 3.1-4.0 (3.3H, m), 4.1 (1.4H, q, /=7Hz),
in MeOH(15ml) and water (5ml) at - 10°C. After stirring
for lOmin, to this solution was added a solution of
7.0-7.3 (3H, m), 12.81 (0.3H, br. s). Anal. Found: C, NH2OH (prepared from NH2OH à" HC1 (2.63 g, 37.8 mmol)
54.07; H, 4.80; Cl, 24.83. Calcd. for C13H14C12O3: C, and NaOH (1.5g, 37.8mmol)) in water (10ml), and the
53.98; H, 4.84; Cl, 24.57%. reaction mixture was further stirred for 2hr at - 10°C.
Acetone (2ml) was added at - 10°C to quench the excess
4-(2,4-Dichlorobenzyt)-3-hydroxy-5-methylisoxazole (3k) of NH2OH,subsequently followed by the addition of
and 4-(2,4-dichlorobenzy[)-3-methyl-3-isoxazolin-5-one
cone. HC1(8ml) at once, arid the reaction mixture was
(8k). 5k (10.0g, 34.6mmol) was added dropwise to a
quickly heated for 1 hr at 80°C. After cooling, the solution
solution of NaOH (1.43g, 35.8mmol) in MeOH (30ml) was poured into water (80ml), washed with rc-hexane and
and water (15ml) at -20°C. After stirring for lOmin, to extracted with ether. The extract was washed with brine,
this solution was added a solution of NH2OH(prepared dried over MgSO4and concentrated in vacuo. The residue
from NH2OHà"HC1 (4.81 g, 69.2mmol) and NaOH (2.90g, was chromatographed on SiO2 («-hexane-EtOAc= 10 :
72.7mmol)) in water (5ml) at -30°C, and the reaction 1-4:1) to give 1.0g (68.0%) of14e IR v^cm"1: 2800
mixture was further stirred for 2hr at -30°C. Acetone (br), 2650 (br), 2580 (br, OH), 1615 (C=N). NMR
(2ml) was added at -20°C to quench the excess of (CDC13) <5ppm: 0.9 (3H, t, /=6Hz), 1.2-1.7 (4H, m),
NH2OH,subsequently followed by the addition of cone. 2.38 (3H, s), 2.67 (2H, t, /=6.5Hz), ll.4 (1H, s). Anal.
HC1 (8ml) at once, and the reaction mixture was quickly Found: C, 51.17; H, 7.ll; N, 7.12; S, 17.18. Calcd. for
heated for 1 hr at 80°C. After cooling, the solution was C8H13NO2S: C, 51.31; H, 7.00; N, 7.48; S, 17.12%.
poured into water (100ml), washed with «-hexane and Compounds 14a~ 14d and 14f~14h were prepared in a
extracted with ether. The extract was washed with brine, similar manner. In the case of 14h, compound15h was also
dried over MgSO4and concentrated in vacuo. The residue obtained. 14a: IR v^f'em"1: 2650 (br), 2550 (br, OH),
was chromatographed on SiO2. Elution with «-hexane- 1605 (C=N). NMR (CDC13) <5ppm: 2.32 (3H, s), 2.42
isopropyl ether (2: 1 -1 :2) yielded 4.20g (47.4%) of 3k. (3H, s), ll.03 (1H, s). 14b: IR v^cm"1: 2880 (br), 2650
Further elution with acetone yielded 1.48g (16.7%) of 8k. (br), 2550 (br, OH). NMR (CDC13) <5ppm: 1.22 (3H, t,
Compounds 3a -3j, 31 -3q and 8c -8j were prepared in /=7Hz), 2.41 (3H, s), 2.70 (2H, q, 7=7Hz), 9.80(1H, s).
a similar manner. The analytical, IR and XHNMRdata 14c: IR v^cmT1: 2750 (br), 2650 (br), 2600 (br, OH),
are presented in Tables III and IV. 1615 (C=N). NMR (GDCI3) (5ppm: 1.00 (3H, t, /=7Hz),
1.57(2H, t, q,/=7Hz), 2.40(3H, s), 2.68 (2H, t, /=7Hz),

Ethyl 2-sulfenylated acetoacetate (13a - 13h). Following ll.0(1H, s). 14d: IR vUfcm"1: 2750 (br), 2650(br), 2600
the literature methods, 13a,12a) 13b12a) and 13h12b) were (br, OH). NMR (CDCI3) <Sppm: 1.20 (6H, t, /=7Hz),

Table III. Analytical Data of Newly Synthesized 3 and 8fl

Ca lc d . (% ) F o u n d (% )
C om pou nd F o rm u la
c H N C l c H N c¥

3d C 7H n N O 2 5 9.5 6 8.85 9.92 59 .6 4 8.01 9 .65

3f C 8H 13N O 2 6 1.9 1 8.44 9.03 6 2. 18 8.58 9 .65
3g C 8H 13N O , 6 1.9 1 8.44 9.03 6 1. 7 0 8.3 5 8.9 5
3h C 9H 15N O 2 6 3.8 8 8.9 3 8.2 8 6 4. 13 9.08 8.08
3i C lOH 1 7N O 2 6 5.5 4 9.35 7.64 6 5.7 8 9.51 7.44
3 j Cn H .N O, 69 .83 5.86 7.40 69 .4 9 5.7 5 7 .34
3k Cn H 9 N O 2 Cl 2 5 1. 19 3.52 5.42 27 .4 7 5 1. 4 7 3.65 5.29 2 7 .1 8
8j C , ,H n N O 2 69 .83 5.86 7 .40 70. 03 5.8 9 7 .3 7
8k Cn H9NO2Cl 5 1. 19 3.52 5 .42 27. 47 5 1.4 8 3. 5 6 5. 3 7 2 7. 59

8d ~8i didn't give satisfactory analytical data because of their instability.

1836 K. Sato, S. Sugai and K. Tomita

Table IV. IR and xH NMRData of Newly Synthesized 3 and 8

C om pou nd I R v m q Y cm *H NM R ( C DC U S p pr n O

(O H a n d C= N )
3d 2 7 0 0 (b r), 2 60 0 (b r), 1 6 6 0 . 0.9 1 ( 3H , t , 7 =7) , 1 .58 ( 2H, q, t, J= l, 7) , 2 .26 (3 H, s) ,
2.2 8 (2H , t , J =l) , l l.0 ( 1H, s) .
3f 2700 (b r), 2 60 0 (b r), 1 6 6 0 . 0. 79- 2. 35 ( 9H , m ), 2 .22 ( 3H , s), 1 0. 63 ( 1H, s ).
3g 2700 (b r), 2 6 50 (b r), 0. 9 2 (6 H, d , / =6 .5 ), 1. 7- 2. 1 ( 1H , m) , 2 .1 6 (2 H , d, / = 6. 5) ,
2600 (b r), 1 6 60 . 2.24 (3H , s) , 9.7 5 (1H , s) .
3h 2 70 0 (b r), 2 60 0 (b r), 16 6 0 . 0. 89 (3 H, t ,. 7 =5 .5 ), 1. 1- 1. 9 ( 6H , br . m ), 2 .0 - 2. 3
(2 H , b r . m ), 2 .2 5 (3 H , s), 1 0 .9 0 ( 1H , s).
3i 2 70 0 (b r), 2 60 0 (b r), 16 6 0 . 0. 88 ( 3H , t, / =4 .5 ), 1 .1 -1 .9 ( 8H, b r. s ), 2 .0 -2 .3
(2 H , b r . s), 2 .2 6 (3 H , s) , 10 .6 (1H , s).
3j 2 6 0 0 (b r), 1 6 60 . 2.20 (3H , s) , 3.6 5 (2 H, s ), 7. 33 ( 5H, s), l l.8 (1H, s).
3k 2 70 0 (b r), 2 60 0 (b r), 16 6 0 . 2. 27 (3 H, s), 3 .27 (2 H, s) , 7 .1 -7. 45 (3 H, m), 8 .17 (1 H, s) .
( NH an d C =O )
8d 3 10 0 (b r), 1 7 90 (w ), 16 9 0 . 0. 7-2 .2 (6. 6H , m ), 2. 10 (1. 2H , s ), 2. 19 (1. 8H , s ), 3.3 2
(0 .8 H , t, / = 6 ), 6 .5 (0 .6 H , b r . s).
8f 30 70 (b r), 1 7 9 0 (w ), 16 9 0 . 0. 7 - 1. 0 5 ( 3H , m ) , 1 . 05 - 1. 7 (4 H , m ), 1. 7 - 2. 2 5 ( 1. 8 H , m ),
2. 10 a nd 2.1 6 (3 H, s), 3.3 2 ( 0.4 H, t, / =5. 5), 6.7 (0 .8H , br , s ).
8g 30 50 (b r), 1 7 90 (w ), 16 9 0 . 0. 88 ( 6H , d, J =6 ), 1 .6 -2 .0 ( 1H , m) , 2. 15 ( 3H , s) , 7. 95
(1 H , b r .s).
8h 30 50 (b r), 1 7 9 0 (w ), 16 9 0 . 0. 90 ( 3H , t, / =5 ), 1 .1 -1 .7 ( 6H , br . s) , 1. 7- 2. 2 (1 .6 H, m ),
2. 12 a nd 2.1 9 ( 3H, s), 3. 35 (0.8 H, t, J=5 ), 7 .7 (0. 6H, br . s) .
8i 30 50 (b r), 1 7 9 0 (w ), 16 9 0 . 0. 89 ( 3H , t, / =5 ), 1 .1 -1 .7 ( 6H , br . s) , 1. 7- 2. 2 (1 .6 H, m ),
2. 09 and 2. 16 (3H , s) , 3 .32 (0 .8H , t , 7 =5) , 8 .3 (0. 6H, br. s).
8j 2 70 0 (b r), 1 6 7 0 . 2.0 0 (3H , s) , 3.47 (2H , s), 7.15 (5H , s), 9.5 (1H, s).
8k 2 6 50 (b r), 16 6 0 . 2. 08 (3 H, s) , 3.5 3 ( 2H , s ), 7. 0-7 .3 5 ( 3H, m ), 10 .47 ( 1H, s) .

/ is the coupling constant in Hz.

2.30(3H, s), 3.02(1H, q, q,J=l, 7Hz), ll.60(1H, s). 14f: fraction. 18: n2D4: 1.5750. IR vScm"1: 1440, 1380, 1190
IR v^cm"1: 2810 (br), 2670 (br), 2600 (br, OH), 1615 (SO2). NMR (CDC13) Sppm: 2.23 (3H, s), 3.68 (2H, s),
(C=N). NMR (CDC13) (5ppm: 0.89 (3H, t, /=7Hz), 7.07-7.93 (8H, m). Anal. Found: C, 51,04; H, 3.34;
1.1~1.7 (6H, m), 2.38 (3H, s), 2.66(2H, t, /=7Hz), ll.5 Cl, 17.58; N,.3.38; S, 8.13. Calcd. for C17H13C12NO4S:
(1H, s). 14g: IR v^cm"1: 2800 (br), 2650 (br), 2590 (br, C, 51.27; H, 3.29; Cl, 17.80; N, 3.52; S, 8.05%. 19: IR
OH), 1615 (C=N). NMR (CDC13) <Sppm: 0.88 (3H, t, v^cm"1: 1720, 1660 (C=O). NMR (CDC13) (5ppm:
J=5Hz), 1.1-1.7 (8H, m), 2.39 (3H, s), 2.67 (2H, t, 2.08 (3H, s), 3.33 (2H, s), 6.68-7.85 (8H, m). Anal.
/=7Hz), ll.0 (1H, s). 14h: IR v^cm"1: 3300-2200 Found: C, 50.99; H, 3.36; Cl, 17.60; N, 3.52; S, 8.26.
(br, OH), 1610 (C=N). NMR (CDC13) Sppm: 2.40 (3H, Calcd. for C17H13C12NO4S: C, 51.27; H, 3.29; Cl,
s), 7.32(5H, s), 9.80(1H, s). 15h: IR v^an"1: 2680(br, 17.80; N, 3.52; S, 8.05%.
NH), 1670 (C-O). NMR (DMSO-d6) 5ppm: 2.17 (3H, s),
6.8-7.47 (5H, m), 8.77 (1H, s). 3-Benzenesulfonyloxy-4-(2,4-dichloro-(x-hydroxybenzyl)-
5-methylisoxazole (21). A mixture of 18 (1.02g), NBS
3-Benzenesulfonyloxy-4-{2,4-dichlorobenzyl)-5-methyl- (0.48 g) and benzoyl peroxide (0.03 g) was refluxed for 1 hr.
isoxazole (18) and 2-benzenesulfonyl-4-(2,4-dichlorobenzyl)-
5-methyl-4-isoxazolin-3-one (19). Benzenesulfonyl chloride
After cooling, the reaction suspension was filtered, and the
filtrate was washed with water and brine, dried over
(0.376g) was added to a stirred solution of 3k (0.50g)
MgSO4and concentrated in- vacuo to give about 0.8 g of a
and Et3N (0.215g) in dry THF (30ml) at 0°C, and the crude 20. Without further purification, 20 was converted
mixture was stirred at room temperature for 3.5hr. into 21 as subsequently shown. 20: NMR(CDC13) Sppm:
About half, the solvent was removed in vacuo, and the 2.37 (3H, s), 6.15 (1H, s), 7.12-7.92 (8H, m).
residue was then poured into water and extracted with A solution of crude 20 (about 0.8g) in acetone (10ml)
ether. The extract was washed successively with water, was added to a mixture ofAgNO3 (1.1 g) and water (3ml).
HC1 aq., water, NaHCO3 aq. and brine, dried over After stirring for 4 days, about half the solvent was
MgSO4 and concentrated in vacuo. The residue was removed in vacuo, before the residue was diluted with
purified by chromatography on SiO2 to give 0.572g
water and extracted with ether. The extract was washed
(74.1%) of 18 and 0.084g (10.9%) of 19 as a less polar with brine, dried over MgSO4and concentrated in vacuo.
 1837
Synthesis of 3-Hydroxyisoxazoles

a) T. Takemoto, T. Nakajima and T. Yokobe, /.

The residue was purified by chromatography on SiO2 to
give 0.584g (55.3%) of 21 as crystals, mp: 98~103°C. Pharm. Bull, 84, 1232 (1964); b) M. Onda, M.
IR v^'cm"1; 3400 (OH), 1440, 1380, 1190 (SO2). NMR Fukumoto and M. Akagawa, Chem. Pharm. Bull.,
(CDC13) (5ppm: 2.25 (3H, s), 3.42 (1H, s), 5.87 (1H, s),.
12, 751 (1964); c) Eugster et al also reported the
7.17-7.93 (8H, m). Anal. Found: C, 49.17; H, 3.15; Cl, isolation of mucimol and ibotenic acid, see C. H.
17.29; N, 3.40; S, 7.84. Calcd. for C17H13C12NO5S: C, Eugster, G. F. R. Muller and R. Good, Tetrahedron
49.29; H, 3.16; Cl, 17.12; N, 3.38; S, 7.74%. Lett., 1965, 1813.
a) P. Krogsgaard-Larsen and G. A. R. Johnston, /.
Benzenesulfonyloxy-4-(2,4-dichlorobenzoyl)-5-rnethyl- Neurochem., 30, 1377 (1978); b) S. R. Snodgrass,
isoxazole (22). Jones' reagent (4.8ml) was added to a Nature, 273, 392 (1978); c) P. Worms, H. Depoorte
solution of 21 (1.24g) in acetone (20ml) with ice-cooling. and K. G. Lloyd, Life Sci., 25, 607 (1979); d) P.
After stirring for lOmin, the excess reagent was decom- Krogsgaard-Larsen and T. Roldskov-Christiasen,
posed with MeOH (5ml). The reaction mixture was Eur. J. Med. Chem., 14, 157 (1979); e) T. Honore, J.
diluted with ice-cooled water (120 ml) and extracted with Lauridsen and P. Krogsgaard-Larsen, J. Neuro-
CH2C12.The extract was washed with water and brine, chem., 38, 173 (1982).
dried over MgSO4and concentrated in vacuo. The residue K. Tomita, Y. Takahi, R. Ishizuka, S. Kamimura,
was chromatographed on SiO2 to give 1.23g of 22 quan- M. Nakagawa, M. Ando, T. Nakanishi, T.
titatively, mp: 90~91°C. IR v^cm"1: 1660 (C=O),
Nakamura and H. Okudaira, Ann. Rep. Sankyo Res.
1590 (C=N), 1440, 1380, 1190 (SO2). NMR (CDC13) Lab., 25, 1 (1973).
(Sppm: 2.65 (3H, s), 7.30-7.83 (8H, m). Anal, Found: C, K. Ando, K. Tomita, H. Tsuji, T. Asami, M.
49.23; H, 2.77; Cl, 17.14; N, 3.49; S, 7.79. Calcd. for Nakagawa, T. Nakamura, H. Okudaira and M.
C17HnCl2NO5S: C, 49.53; H, 2.69; Cl, 17.20; N, 3.40; S, Ishida, Ann. Rep. Sankyo Res. Lab., 29, 1 (1977).
7.78%. R. Jacquier, C. Petrus, F. Petrus and J. Verducci,
Bull. Soc. Chim. Fr., 1970, 2685.
4-(2,4-Dichlorobenzoyl)-3-hydroxy-5-methylisoxazole a) H. Goth, A. R. Gagneux, C. H. Eugster and H.
Schmid, Helv. Chim. Acta, 50, 137 (1967); b) R.
(17). A mixture of 22 (0.507g) and sodium methoxide
(0.204g) in MeOH(16ml) was stirred at room tempera- Jacquier, C. Petrus, F. Petrus and J. Verducci, Bull.
ture for 18hr. The reaction mixture was diluted with Soc. Chim. Fr., 1970, 1978.
N. Jacobsen, H. Kolind-Andersen and J.
water, acidified with cone. HC1and extracted with ether.
The extract was washed with brine, dried over MgSO4and Christensen, Can. J. Chem., 62, 1940 (1984).
concentrated in vacuo. The residue was purified by chro- R. Jacquier, C. Petrus, F. Petrus and J. Verducci,
matography on SiO2 to give 0.35g of a crude product. Bull. Soc. Chim. Fr., 1967, 3003.
This was recrystallized with CH2C12 to give 0.267g T. Sasaki, K. Hayakawa and S. Nishida, /. Chem.
(80.1%) of 17. mp: 160~161°C. IR v^'em"1: 2600 Soc, Chem. Commun., 1980, 1054.
(OH), 1660 (C=O), 1610 (C=N). NMR (CDC13) (5ppm: a) I. T. Kay, D. J. Lovejoy and S. Glue, J. Chem.
2.30 (3H, s), 6.57 (1H, s), 7.27-7.42 (3H, m). Anal. Soc, Chem. Commun., 1970, 445; b) L. Heinisch, Z.
Found: C, 48.86; H, 2.77; Cl, 28.89; N, 5.01. Calcd. for Chem., 10, 187 (1970).
CnH7Cl2NO3: C, 48.56; H, 2.59; Cl, 26.06; N, 5.15%.
a) M. Ishida, T. Matsui, T. Yanai, K. Kawakubo, T.
Honma, K. Tanizawa, M. Nakagawa and H.
Acknowledgments. Our thanks are due to Dr. M. Okudaira, Ann. Sankyo Res. Lab., 36, 44 (1984) (in
Ishida, the director of our laboratories, for his encourage- Japanese); b) T. Konotsune, K. Kawakubo and T.
ment throughout this work, and to Mr. T. Murakami and Yanai: "Advances in Pesticide Science," Part 2,
Dr. K. Tanaka in our laboratories for their helpful Zurich, 1978, ed. by Geissbuler, Pergamon Press,
discussion. Oxford, 1979, p. 94.
a) A. Burger: "Medicinal Chemistry," 3rd Ed., Wiley-
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