Solid-Phase Synthesis of 5-Isoxazol-4-yl-[1,2,4]oxadiazoles

Article abstract of DOI:10.1021/jo0352124

A library of isoxazole and 1,2,4-oxadiazole-containing diheterocyclic compounds has been prepared. Our strategy was explored in solution phase first as follows. PMB-protected 3-butyn-2-ol was deprotonated with nBuLi, acylated with methyl chloroformate, and then employed in a nitrile oxide 1,3-dipolar cycloaddition (benzaldehyde oxime in the presence of bleach) to afford the isoxazole-substituted carboxylic acid methyl ester. Ester saponification with aqueous NaOH followed by a two-step condensation with benzamidoxime gave the final isoxazole-oxadiazole diheterocyclic product in good yield. With some modifications, we next explored this chemistry on Wang resin, which led to 18 final products that were cleaved from polymer beads with 50% TFA in dichloromethane.

Full text of DOI:10.1021/jo0352124

Solid -P h a se Syn th esis of 5-Isoxa zol-4-yl-[1,2,4]oxa d ia zoles
Chao Quan and Mark Kurth*
Department of Chemistry, One Shields Avenue, University of California,
Davis, California 95616
mjkurth@ucdavis.edu
Received August 18, 2003
A library of isoxazole and 1,2,4-oxadiazole-containing diheterocyclic compounds has been prepared.
Our strategy was explored in solution phase first as follows. PMB-protected 3-butyn-2-ol was
deprotonated with nBuLi, acylated with methyl chloroformate, and then employed in a nitrile oxide
1,3-dipolar cycloaddition (benzaldehyde oxime in the presence of bleach) to afford the isoxazole-
substituted carboxylic acid methyl ester. Ester saponification with aqueous NaOH followed by a
two-step condensation with benzamidoxime gave the final isoxazole-oxadiazole diheterocyclic product
in good yield. With some modifications, we next explored this chemistry on Wang resin, which led
to 18 final products that were cleaved from polymer beads with 50% TFA in dichloromethane.
In tr od u ction
Resu lts a n d Discu ssion
The synthesis of highly functionalized libraries of
organic molecules using solid-phase organic synthesis
methodology is recognized as a valuable tool for drug
discovery. The isoxazole ring system, which is typically
prepared by the 1,3-dipolar cycloaddition of a nitrile oxide
to an alkyne, is particularly interesting since it is readily
transformed into various biodynamic agents, including
those with antithrombotic, PAF antagonist, and hypo-
lipidemic properties.1 Oxadiazoles are important bioisos-
ters for esters and amides in drug discovery with reported
muscarinic agonist, benzodiazepine receptor agonist,
5-HT agonist, and antirhinoviral activities.2 However, the
incorporation of isoxazole and oxadiazole heterocycles
into a two-ring 5-isoxazol-4-yl-[1,2,4]oxadiazole system,
which we believe could be a useful diheterocyclic agent
with potential biological activities, has only been inves-
tigated synthetically by Neidlein in 1996.3 We report here
a novel solution-phase synthesis of the 5-isoxazol-4-yl-
[1,2,4]oxadiazole diheterocycles (e.g., I) from nitrile oxide
and alkynoate ester precursors, as well as the prepara-
tion of a small library of these compounds on solid phase
(Scheme 1).
Develop m en t of a Solu tion -P h a se Rou te to I. The
key intermediate in our synthetic strategy is isoxazole-
substituted methyl ester 5, prepared as outlined in
Scheme 2. PMB-protection of 3-butyn-2-ol was prepared
by deprotonation with sodium hydride in anhydrous THF
at 0 °C followed by addition of p-methoxybenzyl chloride
and TBAI (cat.).4 A THF solution of the resulting
p-methoxybenzyl-protected alkyne (2) was C-lithiated
with nBuLi in hexane at -78 °C5 and subsequently
acylated with methyl chloroformate to give 3 (R1 ) CH3).
o-Chlorobenzaldehyde oxime 4a , prepared from o-chlo-
robenzaldehyde hydroxylamine hydrochloride and so-
dium acetate in a mixture of ethanol and water, was
comixed with alkynoate 3 in THF and treated with bleach
at 0 °C.6,7 This modified Huisgen method for in situ nitrile
oxide formation delivered 3,4,5-trisubstituted isoxazole
5 in 70% yield.7 Although strong steric (γ-branched
moiety providing greater steric encumbrance than the
carbomethoxy moiety) and weak electronic factors favor
the formation of 5, it is of interest that this is the only
regioisomer obtained. The high regioselectivity was con-
firmed by the appearance of only one product in addition
to unreacted starting material signals in the crude
1
1
(1) (a) Nantermet, P. G.; Barow, J . C.; Lundell, G. F.; Pellicore, J .
M.; Rittle, K. E.; Young, M. B.; Friedanger, R. M.; Connoly, T. M.;
Condra, C.; Karczewski, J .; Bednar, R. M.; Gaul, S. L.; Gould, R. J .;
Prendergast, K.; Selnick, H. G. Bioorg. Med. Chem. Lett. 2002, 12, 319.
(b) Pruitt, J . R.; Pinto, D. J .; Estrella, M. J .; Bostrom, L. L.; Knabb, R.
M.; Wong, P. C.; Wright M. R.; Wexler R. R. Bioorg. Med. Chem. Lett.
2000, 10, 685. (c) Xue, C. B.; Roderick, J .; Mousa, S. A.; Olson, R. E.;
Degrado, W. F. Bioorg. Med. Chem. Lett. 1998, 8, 3499.
(2) (a) Macor, J . E.; Ordway, T.; Smith, R. L.; Verhoest, P. R.; Mack,
R. A. J . Org. Chem. 1996, 61, 3228. (b) Street, L. J .; Baker, R.; Book,
T.; Kneen, C. O.; MacLeod, A. M.; Merchant, K. J .; Showell, G. A.;
Saunders: J .; Herbert, R. H.; Freedman, S. B.; Harley, E. A. J . Med.
Chem. 1990, 33, 2690. (c) Tully, W. R.; Gardner, C. R.; Gillespie, R. J .;
Westwood, R. J . Med. Chem. 1991, 34, 2060. (d) Chen, C.; Senanayake,
C. H.; Bill, T. J .; Larsen, R. D.; Verhoeven, T. R.; Reider. P. J . J . Org.
Chem. 1994, 59, 3738. (e) Diana, G. D.; Volkots, D. L.; Nitz, T. J .;
Bailey, T. R.; Long, M. A.; Niranjan, V.; Aldous, S.; Pevear, D. C.;
Dutko, F. J . J . Med. Chem. 1994, 37, 2421.
product H NMR. NOE difference H NMR experiments
were performed to confirm the regiochemistry. Thus,
irradiation of the methyl ester moiety in 5 produced NOE
enhancement of all aromatic protons. This regioselectivity
is also consistent with similar results reported by others.8
We next performed the 1,3-dipolar cycloaddition on the
methyl ester derivative from propargyl alcohol (see 3; R1
(4) Marshall, J . A.; Sehon, C. A. J . Org. Chem. 1997, 62, 4313.
(5) Lai, G.; Colon, C. Synth. Commun. 1999, 29, 3011.
(6) Hayakawa, K.; Yodo, M.; Ohsuki, S.; Kanematsu, K. J . Am.
Chem. Soc. 1984, 106, 6735.
(7) Sammelson, R. E.; Miller, R. B.; Kurth, M. J . J . Org. Chem. 2000,
65, 2225.
(8) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984; Vol. I, page 339.
(3) Neidlein, R.; Li, S. J . Heterocycl. Chem. 1996, 33, 1943.
10.1021/jo0352124 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/07/2004
1470
J . Org. Chem. 2004, 69, 1470-1474

Synthesis of 5-Isoxazol-4-yl-[1,2,4]oxadiazoles
SCHEME 1. 1,2,4-Oxa d ia zole Syn th esis
Develop m en t of a Solid -P h a se R ou t e t o I. With
this solution-phase route in hand, we set out to imple-
ment this strategy on solid phase. 3-Butyn-2-ol was
loaded onto the trichloroacetimide derivative of Wang
resin through the action of BF3‚OEt2 to give 11 (R1
CH3), which was confirmed by the disappearance of the
strong CdN stretching band at 1664 cm-1 11
To avoid
)
.
deprotonation of the resin backbone in the alkyne acy-
lation step, we used LDA instead of nBuLi to lithiate the
resin-bound alkyne. Subsequent C-acylation with methyl
chloroformate was accomplished overnight at room tem-
perature (single bead FTIR, 1716 cm-1 CdO). Nitrile
oxide 1,3-dipolar cycloaddition to this resin-bound alkyne
employed benzaldehyde oximes and proceeded smoothly
with the aid of excess bleach (single bead FTIR, 1728
cm-1 CdO). Lithium hydroxide in a mixture of water,
methanol, and THF saponified the resin-bound methyl
ester at room temperature to give the carboxylic acid sub-
stituted isoxazole (single bead FTIR, 1731 cm-1 CdO)
required for 1,2,4-oxadiazole formation. This chemistry
plus Wang resin loaded with propargyl alcohol (11; R1 )
H) delivered a library of 18 5-isoxazol-4-yl-[1,2,4]oxadia-
zole compounds, by the two-step condensation of car-
boxylic acids 14 with various benzamidoxime derivatives
(14 f 15) in the presence of excess EDC in DMF (see
Table). The final products were released from the resin
by treatment with 50% TFA in dichloromethane. Crude
1H NMR of the resulting mixture shows that 16, the
consequence of incomplete carbomethoxylation of 11, is
the only identifiable side product of this chemistry. An
NOE difference NMR experiment on compound 10a (R1
) CH3 irradiation) confirmed that the solid-phase regio-
selectivity matched that of the solution phase.
SCHEME 2. Syn th esis of Isoxa zole-Su bstitu ted
Meth yl Ester In ter m ed ia tea
a
Reagents and conditions: (a) NaH, THF, 5 h; PMBCl, TBAI,
3 d. (b) nBuLi, anhydrous THF, -78 °C, 2 h; ClCO2Me, -78 °C f
rt, 5 h. (c) NaOCl, THF, 0 °C f rt, 3 d.
SCHEME 3. Solu tion -P h a se Syn th esis of th e
5-Isoxa zol-4-yl-[1,2,4]oxa d ia zole System a
In summary, a seven-step solid-phase synthesis of
5-isoxazol-4-yl-[1,2,4]oxadiazole diheterocyclics, which
proceed through an alkynoate intermediate, has been
developed. This work also reports the first library syn-
thesis of this class of compounds on solid phase in good
overall yield.
a
Reagents and conditions: (a) NaOH, H2O, reflux, overnight;
Exp er im en ta l Section 15
(b) EDC, 50 °C, overnight; (c) EDC, 115 °C, 3 h; (d) DDQ, DCM/
H2O )18:1, rt, 5 h.
Solu tion -P h a se Stu d ies. 1-Meth oxy-4-(1-m eth ylp r op -
2-yn yl)oxym eth ylben zen e (2). Marshall’s method4 was em-
ployed for the preparation of 2 from 3-butyn-2-ol (84% yield):
1H NMR (CDCl3) δ 1.45(d, 3H), 2.46(d, 1H), 3.8(s, 3H), 4.18(q,
1H), 4.44(d, 1H), 4.72(d, 1H), 6.89(d, 2H), 7.29(d, 2H); 13C NMR
(CDCl3) δ 22.0, 55.3, 63.8, 70.1, 73.0, 83.8, 113.8, 129.7, 129.8,
159.3. This crude product was employed in the next step
without further purification.
Meth yl 4-(4-Meth oxyben zyloxy)p en t-2-yn oa te (3). Al-
kyne 2 (1.6 g, 8.4 mmol) and anhydrous THF (25 mL) were
placed in a 50-mL round flask under nitrogen at -78 °C and
treated with n-BuLi in hexane (5.75 mL, 9.2 mmol, 1.6 M).
The temperature was maintained at -78 °C for 2 h at which
time ClCO2Me (0.87 g, 9.2 mmol) was added to the mixture
slowly over 20 min. After stirring at room temperature for 5
h, the reaction was quenched by the addition of water, the
solvent was removed, and the residue was dissolved in ether.
After washing with water and brine, the ethereal layer was
dried over Na2SO4 and concentrated by rotovaporation. Flash
chromatography gave 3 (2 g, 8.1 mmol, 96%) as light yellow
oil: 1H NMR (CDCl3) δ 1.49(d, 2H), 3.81(d, 2H), 4.29(q, 1H),
4.44(d, 1H), 4.72(d, 1H), 6.89(d, 2H), 7.29(d, 2H); 13C NMR
) H) and were pleased to again observe complete regio-
selectivity.
Saponification of cycloadduct 5 with refluxing aqueous
sodium hydroxide (1.5 equiv) gave 4-carboxyisoxazole 6
(Scheme 3). Adapting Porco’s two-step, one-pot condensa-
tion method,9 benzamidoxime 7a , readily prepared from
the benzonitrile derivative and hydroxylamine hydro-
chloride in 95% ethanol, was O-acylated with 6. Further
dehydration of this O-acyl benzamidoxime (8) with ad-
ditional 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (EDC) in refluxing 1,4-dioxane delivered
the targeted [1,2,4]oxadiazole in 40% yield. Subsequent
deprotection of the p-methoxybenzyl ether with 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) in methylene
chloride/water (18:1) gave the 5-isoxazol-4-yl-[1,2,4]oxa-
diazole diheterocycle 10 in good yield (69%).10
(9) Deegan, T. L.; Nitz, T. J .; Cebzanov, D.; Pufko, D. E.; Porco, J .
A. Bioorg. Med. Chem. Lett. 1999, 9, 209.
(10) (a) Sharma, G. V. m.; Rakesh, Tetrahedron lett. 2001, 42, 5571.
(b) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(11) Hanessian, S.; Xie, F. Tetrahedron Lett. 1998, 39, 733.
J . Org. Chem, Vol. 69, No. 5, 2004 1471

Quan and Kurth
SCHEME 4. Solid -P h a se Syn th esis of 5-Isoxa zol-4-yl-[1,2,4]oxa d ia zole Dih eter ocyclics
TABLE 1. Oxa d ia zole-Su bstitu ted Isoxa zoles Gen er a ted
fr om Wa n g Resin
and THF (20 mL) were place in a round-bottom flask and
cooled to 0 °C. Bleach (35 mL, 25 mmol, 5%) was added slowly
through an addition funnel, and the mixture was stirred at
room temperature for 3 d at which time the organic phase was
separated from the reaction mixture and the aqueous phase
was extracted with EtOAc (2×). The combined organic phase
was dried over Na2SO4, and the solvent was removed to give
the crude product, which was purified by flash chromatography
to give 5 (1.39 g, 3.5 mmol, 70%) as a oil: 1H NMR (CDCl3) δ
1.65(d, 3H), 3.66(s, 3H), 3.78(s, 3H), 4.49(d, 2H), 5.32(q, 1H),
6.85(d, 2H), 7.25(d, 2H), 7.38-7.47(m, 4H); 13C NMR (CDCl3)
δ 19.8, 51.7, 55.1, 68.5, 71.6, 110.1, 113.7, 126.5, 128.0, 129.3,
129.5, 129.6, 130.9, 131.0, 133.8, 159.3, 160.3, 161.5, 176.9.
Anal. Calcd for C21H20ClNO5: C, 62.77; H, 5.02; N, 3.49.
Found: C, 62.71; H, 4.99; N, 3.50.
3-(2-Ch lor op h en yl)-5-[1-(4-m et h oxyben zyloxy)et h yl]-
isoxa zole-4-ca r boxylic Acid (6). Isoxazole-substituted car-
boxylic acid methyl ester 5 (1.4 g, 3.5 mmol) in aqueous sodium
hydroxide (0.21 g, 5.25 mmol) was refluxed at 105 °C over-
night. The mixture was washed with EtOAc and the aqueous
was then acidified with dilute aqueous HCl to pH 1. The
resulting cloudy mixture was extracted with EtOAc, and this
organic phase was dried over Na2SO4. Removal of the solvent
gave the pure isoxazole-substituted carboxylic acid compound
(0.98 g, 2.5 mmol, 72%) as a off-white solid without further
purification: 1H NMR (CDCl3) δ 1.65(d, 3H), 3.77(s, 3H), 4.52-
(s, 2H), 5.33(q, 1H), 6.84(d,2H), 7.26(d,2H), 7.36-7.46(m, 4H);
13C NMR (CDCl3) δ 20.0, 55.2, 69.0, 72.0, 109.4, 113.8, 126.6,
127.6, 129.1, 129.5, 129.7, 130.9, 131.1, 133.9, 159.5, 160.6,
165.8, 178.3. Anal. Calcd for C20H18ClNO5‚1/2H2O: C, 60.54;
H, 4.83; N, 3.53. Found: C, 61.10; H, 4.70; N, 3.64.
entry
product
R1
R2
R3
overall yield (%)
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
o-Cl
o-Cl
o-Cl
p-Cl
p-Cl
p-Cl
o-OMe
o-OMe
o-OMe
p-OMe
p-OMe
p-OMe
o-OMe
o-OMe
o-OMe
p-OMe
p-OMe
p-OMe
p-CH3
p-Cl
p-OMe
p-CH3
p-Cl
p-OMe
p-CH3
p-Cl
p-OMe
p-CH3
p-Cl
p-OMe
p-CH3
p-Cl
p-OMe
p-CH3
p-Cl
15
8
16
12
20
13
15
13
14
23
23
27
20
20
27
20
15
7
9
10
11
12
13
14
15
16
17
18
H
H
H
H
H
p-OMe
(CDCl3) δ 21.2, 52.7, 55.2, 63.6, 70.7, 76.6, 87.2, 113.8, 129.2,
129.7, 153.7, 159.4.
Gen er a l P r oced u r e for th e Syn th esis of Ben za ld eh yd e
Oxim es (4). Benzaldehyde (10 mmol) was added to hydroxy-
lamine hydrochloride (1.39 g, 20 mmol) in water and ethanol
(30 mL, 1:5) at 0 °C followed by the addition of sodium acetate
(2.46 g, 30 mmol). The mixture was stirred at room temper-
ature for 2 h at which time the ethanol was removed by
rotovaporation. Water was added and the aqueous phase was
extracted with DCM (2×). The combined organic layer was
dried over Na2SO4 and concentrated to give the oxime products
Gen er a l P r oced u r e for th e Syn th esis of Ben za m i-
d oxim es (7). Triethylamine (3.2 mL, 23 mmol) was added to
a mixture of benzyl nitrile (10 mmol) and hydroxylamine
hydrochloride (1.5 g, 22 mmol) in 15 mL of 95% ethanol in
water. The resulting solution was refluxed at 75 °C overnight.
After the mixture cooled to room temperature, 15 mL of water
was added and ethanol was removed by rotovap to precipitate
product 7a -c. N-Hydroxy-4-methyl-benzamidine (7a ):8 mp
136-137 °C; 1H NMR (CDCl3) δ 2.38(s, 3H), 4.87(s, 2H), 7.24-
(d, 2H), 7.52(d, 2H). N-Hydroxy-4-chloro-benzamidine (7b):14
1
4a -d . 2-Chlorobenzaldehyde oxime (4a ):12 mp 68-69 °C; H
NMR (CDCl3) δ 7.26-7.35(m, 2H), 7.4(q, 1H), 7.81(q, 1H).
4-Chlorobenzaldehyde oxime (4b):12 mp 96-97 °C; 1H NMR
(CDCl3) δ 7.38(d, 2H), 7.49(d, 2H), 8.11(s, 1H). 2-Methoxyben-
zaldehyde oxime (4c):13 mp 90-91 °C; 1H NMR (CDCl3) δ 3.87-
(s, 3H), 6.92(d, 1H), 6.97(t, 1H), 7.36(t, 1H), 7.66(d, 1H), 8.48(s,
1H), 8.67(s, 1H). 4-Methoxybenzaldehyde oxime (4d ):12 mp 48-
49 °C; 1H NMR (CDCl3) δ 3.83(s, 3H), 4.78(broad, 1H), 6.92(d,
2H), 7.54(d, 2H), 8.11(s, 1H).
1
mp 128-129 °C; H NMR (CDCl3) δ 4.88(broad, 2H), 7.38(d,
Meth yl 3-(2-Ch lor op h en yl)-5-[1-(4-m eth oxyben zyloxy)-
eth yl]isoxa zole-4-ca r boxyla te (5). Methyl ester 3 (1.24 g,
5 mmol), 2-chlorobenzaldehyde oxime (4a ; 0.86 g, 5.5 mmol),
(13) Coustard, J . M.; J acquesy, J . C.; Violeau, B. Tetrahedron Lett.
1992, 33, 8085.
(14) Renodon-Corniere, A.; Dijols, S.; Perollier, C.; Lefevre-Grobo-
illot, D.; Boucher, J .-L.; Attias, R.; Sari, M.-A.; Stuehr, D.; Mansuy, D.
J . Med. Chem. 2002, 45, 944.
(12) Giurg, M.; Mlochowski, J . Polish J . Chem. 1997, 71, 1093.
1472 J . Org. Chem., Vol. 69, No. 5, 2004

Synthesis of 5-Isoxazol-4-yl-[1,2,4]oxadiazoles
2H), 7.57(d, 2H). N-Hydroxy-4-methoxy-benzamidine (7c):14
mp 114-115 °C; H NMR (CDCl3) δ 3.83(s, 3H), 4.83(broad,
2H), 6.92(d, 2H), 7.57(d, 2H).
R esin -Bou n d Isoxa zole-Oxa d ia zole Dih et er ocyclic
Com p ou n d s (15). Resin-bound isoxazole-substituted carboxy-
lic acid 14 (0.5 g, 0.49 mmol) was treated with amidoximes
7a -c (1.5 mmol) and EDC (0.48 g, 2.5 mmol) in DMF, and
heated to 75 °C overnight. The mixture was then refluxed at
115 °C for another 5 h at which time the resin was washed
thoroughly with DCM, MeOH, and DCM and dried under high
vacuum pump.
Gen er a l P r oced u r e for Resin Clea va ge. Resin with the
desired 5-isoxazol-4-yl-[1,2,4]oxadiazole 15 was placed in a 10-
mL polyethylene fritted tube and treated with 50% TFA in
DCM for 2 h. The solution was drained from the tube, and
the solvent was removed by rotovap. Flash chromatography
with a mixture of hexane and ethyl acetate delivered the pure
final diheterocyclic products.
1
5-{3-(2-Ch lor o-ph en yl)-5-[1-(4-m eth oxy-ben zyloxy)-eth -
yl]-isoxa zol-4-yl}-3-p-tolyl-[1,2,4]oxa d ia zole (9). A mixture
of isoxazole carboxylic acid 6 (390 mg, 1 mmol), benzamidoxime
(180 mg, 1.2 mmol), and EDC (383 mg, 2 mmol) in 5 mL of
1,4-dioxane was stirred at 50 °C under nitrogen overnight. The
reaction mixture was then heated to 115 °C for another 3 h.
The crude product was purified by flash chromatography to
give the pure compound (200 mg, 0.4 mmol, 40%) as an oil:
1H NMR (CDCl3) δ 1.76(d, 3H), 2.40(s, 3H), 3.66(s, 3H), 4.56-
(q, 2H), 6.74(d,2H), 7.17(d,2H),7.26(d,2H),7.3-7.6(m, 4H), 7.87-
(d, 2H); 13C NMR (CDCl3) δ 19.6, 21.5, 54.9, 68.0, 71.8, 104.6,
113.6, 123.3, 126.8, 127.0, 127.2, 127.3, 129.2, 129.4, 129.7,
131.3, 131.5, 133.9, 141.7, 159.2, 159.4, 168.0, 168.2, 175.2.
Anal. Calcd for C28H24ClN3O4‚H2O: C, 64.68; H, 5.04; N, 8.08.
Found: C, 65.13; H, 4.75; N, 8.14.
1-{3-(2-Ch lor o-p h en yl)-4-[3-(4-ch lor o-p h en yl)-[1,2,4]-
oxa d ia zol-5-yl]-isoxa zol-5-yl}-eth a n ol (10b). Mp 110-111
1
°C; H NMR (CDCl3) δ 1.82(d, 3H), 5.40-5.49(m, 2H), 7.42-
7.57(m, 6H), 7.96(d, 2H); 13C NMR (CDCl3) δ 19.7, 63.4, 103.6,
124.0, 126.7, 127.0, 128.7, 129.4, 130.0, 131.3, 131.9, 134.0,
138.1, 160.0, 166.8, 169.3, 178.4.
P MB Dep r otection to 1-[3-(2-Ch lor o-p h en yl)-4-(3-p-
tolyl-[1,2,4]oxa d ia zol-5-yl)-isoxa zol-5-yl]-eth a n ol (10a ).
DDQ(136 mg, 0.6 mmol) was added to the solution of isoxazole-
oxadiazole 9 (200 mg, 0.4 mmol) in 4.75 mL of DCM and water
(18:1). After 5 h, the reaction mixture was filtered, and the
pure product (105 mg, 0.28 mmol, 70%) was obtained by flash
1-{3-(2-Ch lor o-p h en yl)-4-[3-(4-m eth oxy-p h en yl)-[1,2,4]-
oxa d ia zol-5-yl]-isoxa zol-5-yl}-eth a n ol (10c). Mp 113-114
1
°C; H NMR (CDCl3) δ 1.82(d, 3H), 3.87(s, 3H), 5.41(q, 1H),
1
6.99(d,2H), 7.41-7.45(sex, 1H), 7.50-7.56(m, 3H),7.96(d,2H);
13C NMR (CDCl3) δ 19.7, 55.4, 63.5, 103.9, 114.4, 117.8, 126.7,
127.0, 129.1, 130.0, 131.3, 131.8, 134.0, 160.0, 162.4, 167.2,
168.8, 178.2.
chromatography: mp 141-142 °C; H NMR (CDCl3) δ 1.79-
(d,3H), 2.40(s, 3H), 7.27(d, 2H), 7.35-7.51(m, 4H), 7.89(d, 2H);
13C NMR (CDCl3) δ 19.7, 12.6, 63.4, 103.8, 122.6, 126.7, 127.0,
127.3, 130.0, 131.3, 131.8, 134.0, 142.3, 159.9, 167.5, 168.9,-
178.3. Anal. Calcd for C20H16ClN3O3: C, 62.91; H, 4.22; N,
11.01. Found: C, 63.12; H, 4.20; N, 10.92.
1-[3-(4-Ch lor o-p h en yl)-4-(3-p -t olyl-[1,2,4]oxa d ia zol-5-
1
yl)-isoxa zol-5-yl]-eth a n ol (10d ). Mp 129-130 °C; H NMR
(CDCl3) δ 1.79(d,3H), 2.44(s, 3H), 5.372(q, 1H), 5.58(d, 1H),
7.31(d, 2H), 7.51(d, 2H), 7.64(d, 2H), 7.92(d, 2H); 13C NMR
(CDCl3) δ 19.5, 21.6, 63.3, 102.3, 122.5, 125.5, 127.4, 129.0,
129.8, 130.6, 137.0, 142.5, 160.9, 167.7, 169.1, 179.2. Anal.
Calcd for C20H16ClN3O3: C, 62.91; H, 4.22; N, 11.01. Found:
C, 62.72; H, 4.09; N, 10.67.
Solid -P h a se Stu d ies. Tr ich lor oa cetim id e Resin . Wang
resin (1.3 mmol/g, 1 g, 1.3 mmol) in dry dichloromethane was
treated with trichloroaceonitrile (3.75 g, 26 equiv). After the
mixture was cooled to 0 °C, DBU (158 mg, 1.04 mmol) was
added slowly, and the reaction was stirred for 1 h. Single bead
IR analysis showed complete disappearance of the hydroxy
stretching band at 3500 cm-1 of the Wang resin with appear-
1-{3-(4-Ch lor o-p h en yl)-4-[3-(4-ch lor o-p h en yl)-[1,2,4]-
oxa d ia zol-5-yl]-isoxa zol-5-yl}-eth a n ol (10e). Mp 159-160
ance of a strong CdN signal at 1664 cm-1
.
1
°C; H NMR (CDCl3) δ 1.80(d, 2H), 5.26(d, 1H), 5.40(q, 1H),
Resin -Bou n d Ben zyl Eth er (11). The trichloroacetimide
resin (1 g, 1.09 mmol) was treated with 3-butyn-2-ol (229 mg,
3.27 mmol) and a catalytic amount of BF3‚OEt2. Ether forma-
tion was confirmed by the disappearance of CdN stretching
band at 1664 cm-1. The similar procedure was performed to
obtain Wang resin bound propargyl alcohol.
7.49-7.52(m, 4H), 7.63(d, 2H), 7.98(d, 2H); 13C NMR (CDCl3)
δ 19.6, 63.3, 102.1, 123.9, 125.4, 128.7, 129.0, 129.5, 130.6,
137.0, 138.2, 160.9, 167.0, 169.4, 179.2. Anal. Calcd for C19H13
-
Cl2N3O3: C, 56.74; H, 3.26; N, 10.45. Found: C, 56.86; H, 3.24;
N, 10.24.
1-{3-(4-Ch lor o-p h en yl)-4-[3-(4-m eth oxy-p h en yl)-[1,2,4]-
oxa d ia zol-5-yl]-isoxa zol-5-yl}-eth a n ol (10f). Mp 153-154
°C; 1H NMR (CDCl3) δ1.79(d, 3H), 3.88(s, 3H), 5.37(q, 1H),
5.60(d, 1H), 7.01(d, 2H), 7.51(d, 2H), 7.64(d, 2H), 7.68(d, 2H);
13C NMR (CDCl3) δ 19.5, 55.4, 63.3, 102.4, 114.5, 117.7, 125.5,
129.0, 130.6, 136.9, 160.9, 162.4, 167.4, 168.9, 179.1. Anal.
Calcd for C20H16ClN3O4‚1/2H2O: C, 59.78; H, 4.21; N, 10.33.
Found: C, 59.48; H, 4.13; N, 10.23.
Resin -Bou n d 4-Hyd r oxy-2-p en tyn oic Acid Meth yl Es-
ter (12). Resin-bound benzyl ether 11 (0.5 g, 0.61 mmol) was
treated with LDA (0.9 mL, 1.8 mmol, 2.0 M in hexane) at -78
°C under nitrogen for 3 h. After slow addition of ClCO2Me (179
mg, 1.8 mmol), the reaction mixture was warmed to room
temperature and stirred overnight: IR (neat) 1716 cm-1
.
Resin -Bou n d Isoxa zole Ca r boxylic Acid Meth yl Ester
(13). Resin-bound 4-hydroxy-2-pentynoic acid methyl ester 12
(0.5 g, 0.57 mmol) was mixed with benzaldehyde oximes 4a -d
(1.71 mmol) in THF and then treated with excess bleach (8.6
1-[3-(2-Meth oxy-p h en yl)-4-(3-p-tolyl-[1,2,4]oxa d ia zol-5-
1
yl)-isoxa zol-5-yl]-eth a n ol (10g). Mp 184-185 °C; H NMR
(CDCl3) δ 1.69(d, 3H), 2.34(s, 3H), 3.55(s,3H), 5.27(q, 1H), 5.68-
(broad, 1H), 6.92(d, 1H), 7.00(t, 1H), 7.21(d, 2H), 7.42(d, 2H),
7.84(d,2H); 13C NMR (CDCl3) δ 19.6, 21.6, 55.2, 63.3, 103.9,
110.0, 114.2, 116.3, 120.7, 122.8, 127.3, 129.7, 130.6, 132.1,
142.1, 157.5, 159.5, 167.3, 169.8, 177.6. Anal. Calcd for
mL, 5.7 mmol) for 3 d: IR (neat) 1728 cm-1
.
Resin -Bou n d Isoxa zole-Su bstitu ted Ca r boxylic Acid
(14). Resin-bound isoxazole-substituted carboxylic acid methyl
ester 13 (0.5 g, 0.49 mmol) was treated with LiOH (58 mg, 2.4
mmol) in a mixture of water, methanol, and THF (1:1:3) at
room temperature for 3 d. The resin was washed with MeOH
and water, MeOH, DCM, MeOH, and DCM and then neutral-
ized with dilute HCl in MeOH and THF (1:3): IR (neat) 1720
C
21H19N3O4 : C, 66.83; H, 5.07; N, 11.13. Found: C, 66.84; H,
5.00; N, 10.98.
1-[4-[3-(4-Ch lor o-p h en yl)-[1,2,4]oxa d ia zol-5-yl]-3-(2-
m eth oxy-p h en yl)-isoxa zol-5-yl]-eth a n ol (10h ). 1H NMR
(CDCl3) δ 1.79(d, 3H), 3.65(s, 3H), 5.36(broad, 1H), 5.48(broad,
1H), 7.02(d, 1H), 7.10(t, 1H), 7.48-7.56(m, 4H), 7.98(d, 2H);
13C NMR (CDCl3) δ 19.6, 55.3, 63.4, 103.9, 111.1, 116.2, 120.8,
124.1, 128.7, 129.4, 130.7, 132.3, 138.0, 157.5, 159.6, 166.6,
170.2, 177.5.
1-{3-(2-Meth oxy-ph en yl)-4-[3-(4-m eth oxy-ph en yl)-[1,2,4]-
oxadiazol-5-yl]-isoxazol-5-yl}-eth an ol (10i). 1H NMR (CDCl3)
δ 1.80(d, 3H), 3.65(s, 3H), 3.88(s, 3H), 5.38(q, 1H), 5.79(d, 1H),
6.99-7.02(m, 3H), 7.09(sex, 1H), 7.50-7.55(m, 2H), 7.97(d,
cm-1
.
(15) While we attempted to obtain elemental analysis data for all
isolated compounds, the data for 3, 10b, 10c, 10h , 10i, 10m , 10p , 10q,
and 10r came back outside of the (0.4% acceptable window. Fortu-
nately, as evidenced by the corresponding 1H and 13C NMR data (see
Supporting Information), these compounds are pure. We conclude that
these compounds absorbed moisture during shipping and handling.
Compound 8 is an un-isolated intermediate; therefore, elemental
analyses are not reported.
J . Org. Chem, Vol. 69, No. 5, 2004 1473

Quan and Kurth
2H); 13C NMR (CDCl3) δ 19.6, 55.3, 55.4, 63.5, 104.1, 111.1,
114.5, 116.1, 117.8, 120.8, 129.1, 130.7, 132.2, 157.5, 159.6,
162.3, 167.0, 169.7, 177.6.
1-[3-(4-Meth oxy-p h en yl)-4-(3-p -tolyl-[1,2,4]oxa d ia zol-5-
yl)-isoxa zol-5-yl]-eth a n ol (10j). Mp 131-132 °C; 1H NMR
(CDCl3) δ 1.78(d,3H), 2.43(s, 3H), 3.88(s, 3H), 7.03(d, 2H), 7.31-
(d, 2H), 7.64(d, 2H), 7.93(d, 2H); 13C NMR (CDCl3) δ 19.9, 22.0,
31.3, 55.7, 63.6, 102.5, 114.3, 119.3, 122.9, 127.5, 130.0, 130.9,
142.5, 161.5, 161.6, 167.8, 169.6, 179.0. Anal. Calcd for
{3-(2-Meth oxy-p h en yl)-4-[3-(4-m eth oxy-p h en yl)-[1,2,4]-
oxa d ia zol-5-yl]-isoxa zol-5-yl}-m eth a n ol (10o). Mp 155-156
°C; 1H NMR (CDCl3) δ 3.66(s, 3H), 3.88(s, 3H), 5.08(d, 1H),
5.20(q, 1H), 7.00-7.03(m, 3H), 7.10(t, 1H), 7.51-7.55(m, 2H),
7.98(d, 2H); 13C NMR (CDCl3) δ 55.5, 55.7, 56.8, 105.7, 111.3,
114.7, 116.5, 118.3,121.0, 129.3, 130.9, 132.5, 157.8, 159.6,
162.6, 167.4, 169.8, 175.0. Anal. Calcd for C20H17N3O5‚1/
2H2O: C, 61.85; H, 4.67; N, 10.82. Found: C, 62.23; H, 4.67;
N, 10.60.
C
21H19N3O4: C, 66.83; H, 5.07; N, 11.13. Found: C, 67.19; H,
[3-(4-Met h oxy-p h en yl)-4-(3-p -t olyl-[1,2,4]oxa d ia zol-5-
yl)-isoxa zol-5-yl]-m eth a n ol (10p ). Mp 182-183 °C; 1H NMR
(CDCl3) δ 2.44(s, 3H), 3.89(s, 3H), 5.07(s, 2H), 7.04(d, 2H), 7.32-
(d, 2H), 7.68(d, 2H), 7.94(d, 2H); 13C NMR (CDCl3) δ 21.6, 55.4,
56.5, 103.7, 114.1, 119.0, 122.6, 127.4, 129.8, 130.7, 142.4,
161.3, 161.5, 167.8, 169.4, 176.2.
[4-[3-(4-Ch lor o-ph en yl)-[1,2,4]oxadiazol-5-yl]-3-(4-m eth -
oxy-p h en yl)-isoxa zol-5-yl]-m et h a n ol (10q ). Mp 176-177
°C; 1H NMR (CDCl3) δ 3.89(s,3H), 5.8(s, 2H), 7.05(d, 2H), 7.50-
(d, 2H), 7.67(d,2H), 7.99(d, 2H); 13C NMR (CDCl3) δ 55.4, 56.5,
114.2, 118.8, 124.0, 128.3, 128.7, 129.5, 130.7, 138.1, 161.3,
161.6, 167.1, 169.7, 176.2.
5.09; N, 11.10.
1-[4-[3-(4-Ch lor o-p h en yl)-[1,2,4]oxa d ia zol-5-yl]-3-(4-
m eth oxy-p h en yl)-isoxa zol-5-yl]-eth a n ol (10k ). Mp 121-
122 °C; 1H NMR (CDCl3) δ 1.79(d, 3H), 3.89(s, 3H), 5.38(q,
1H), 5.46(broad, 1H), 7.04(d, 2H), 7.49(d, 2H), 7.62(d, 2H), 7.99-
(d, 2H); 13C NMR (CDCl3) δ 19.5, 55.4, 63.4, 102.2, 114.1, 118.9,
123.9, 128.7, 129.5, 130.6, 138.1, 161.4, 161.5, 166.9, 169.8,
178.8. Anal. Calcd for C20H16ClN3O4: C, 60.39; H, 4.05; N,
10.56. Found: C, 60.01; H, 3.96; N, 10.29.
1-{3-(4-Meth oxy-ph en yl)-4-[3-(4-m eth oxy-ph en yl)-[1,2,4]-
oxa d ia zol-5-yl]-isoxa zol-5-yl}-eth a n ol (10l). Mp 112-113
°C; 1H NMR (CDCl3) δ 1.78(d, 3H), 3.87(s, 3H), 3.88(s, 3H),
6.99-7.04(m, 4H), 7.63(d, 2H), 7.98(d, 2H); 13C NMR (CDCl3)
δ 19.5, 55.4, 55.5, 63.3, 102.3, 114.1, 114.5, 117.8, 119.1, 129.1,
130.7, 161.4, 161.5, 162.4, 167.3, 169.4, 178.9. Anal. Calcd for
{3-(4-Meth oxy-p h en yl)-4-[3-(4-m eth oxy-p h en yl)-[1,2,4]-
oxa d ia zol-5-yl]-isoxa zol-5-yl}-m eth a n ol (10r ). Mp 173-174
1
°C; H NMR (CDCl3) δ 3.88(S, 3H), 3.89(s,3H), 5.06-5.15(m,
2H), 7.01-7.06(m, 4H), 7.68(d, 2H), 7.99(d, 2H); 13C NMR
(CDCl3) δ 55.3, 55.5, 56.5, 103.7, 114.1, 114.5, 117.8, 119.0,
129.1, 130.7, 161.3, 161.5, 162.4, 167.5, 169.3, 176.1.
C
21H19N3O5‚H2O: C, 62.68; H, 5.01; N, 10.44. Found: C, 62.56;
H, 4.68; N, 10.25.
[3-(2-Met h oxy-p h en yl)-4-(3-p -t olyl-[1,2,4]oxa d ia zol-5-
yl)-isoxa zol-5-yl]-m eth a n ol (10m ). Mp 118-119 °C; 1H NMR
(CDCl3) δ 2.43(s, 3H), 3.65(s, 3H), 5.09(d, 1H), 5.24(q, 1H),
7.02(d, 1H), 7.10(t, 1H), 7.31(d, 2H), 7.52(d, 2H), 7.93(d, 2H);
13C NMR (CDCl3) δ 21.6, 55.3, 56.5, 105.4, 111.1, 116.2, 120.7,
122.8, 127.3, 129.7, 130.7, 132.2, 142.2, 157.5, 159.3, 167.5,
169.7, 174.7.
Ack n ow led gm en t. We thank the National Science
Foundation and Cystic Fibrosis Foundation for financial
support of this research. The 400-MHz NMR spectrom-
eters used in this study were funded in part by a grant
from NSF (CHE-9808183).
[4-[3-(4-Ch lor o-ph en yl)-[1,2,4]oxadiazol-5-yl]-3-(2-m eth -
oxy-p h en yl)-isoxa zol-5-yl]-m eth a n ol (10n ). Mp 162-163
°C; 1H NMR (CDCl3) δ 3.65(s, 3H), 5.11(s, 2H), 5.18(broad, 1H),
7.02(d, 1H), 7.11(t, 1H), 7.48-7.54(m, 4H), 7.98(d, 2H); 13C
NMR (CDCl3) δ 55.3, 56.5, 105.2, 111.1, 116.1, 120.8, 124.2,
128.7, 129.4, 130.7, 132.3, 138.0, 157.5, 159.4, 166.8, 170.0,
174.7. Anal. Calcd for C19H14ClN3O4: C, 59.46; H, 3.68; N,
10.95. Found: C, 60.00; H, 3.72; N, 10.85.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR for compounds 3, 10b, 10c, 10h , 10i, 10m , 10p , 10q,
and 10r . This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0352124
1474 J . Org. Chem., Vol. 69, No. 5, 2004