K. H. Kang et al. / Tetrahedron Letters 42 (2001) 1057–1060
1059
O
H
O
CH=N-OH
F
O
H
N
4% NaOCl
N
N
N
N
+
+
N
O
N
CH2Cl2, r.t. , 2h
N
F
O
F
A
B
4
Scheme 3.
References
ranging from 70% to 100%. The result was quite
compatible with general solid-phase synthesis as excess
amount of nitrile oxides ensured complete conversion
of 1 to 3 and did not pose severe contamination of the
products. The purity and the identity of the products
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1
were confirmed by H NMR and GC–MS or HPLC.
All compounds were obtained as single isomeric prod-
ucts, though cycloaddition reaction could produce two
regioisomeric products. Thus, a library of 20 isoxazoles
and 20 isoxazolines was constructed (Table 1).
5. Poerter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper,
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Studer, A.; Curran, D. P. Tetrahedron 1997, 53, 6681–
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tor; Academic Press: San Diego, 1994.
11. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John
Wiley & Sons: New York, 1984; Vol. 1, p. 2.
12. Propargylic amines and allylic amines were prepared as
follows. Propargyl (allyl) bromide (0.50 mol) was added
over 20 min to a mixture of an amine (1.10 mol) in
diethyl ether (500 ml). The reaction was stirred at room
temperature for 18 hours. The resulting suspension was
cooled to 0°C. The product was filtered and washed well
with dry Et2O and dried in vacuo.
13. 1-Phenylpiperazine (1 equiv.) and Et3N (2 equiv.) was
added to a stirred solution of propiolic acid (1.2 equiv.)
and PCl5 (1.2 equiv.) in CH2Cl2 at 40°C. After an hour of
stirring, reaction mixture was washed with brine and
water. Concentration followed by flash chromatography
produced 4 in 67% yield.
The main impurities were unreacted oxime derivatives
and the impurities could be eliminated from the prod-
ucts by additional liquid–liquid extraction before the
salt formation, though current protocol gave a satisfac-
tory result.
An interesting result was observed when a conjugated
alkyne, 413 was subjected to the reaction with oxime a
(Scheme 3). Though we expected a single isomeric
product formation based on the literature example,14
a
mixture of regioisomeric products (A, B with 1.57:1
ratio)15,16 was obtained in 64.9% yield. This unexpected
result is quite noteworthy since this reaction could
easily double the size of a library of isoxazol(in)es with
an advantage of producing spatially well differentiated
regioisomeric products that could show distinctive bio-
logical activities.
In summary, 1,3-dipolar cycloaddition reaction of
nitrile oxides to alkenes or alkynes was developed into
a solution-phase combinatorial chemistry for the con-
struction of a library of 20 isoxazoles and 20 isoxazoli-
nes with good yield and purity. This methodology can
readily be expanded to a bigger library construction
and will serve a complimentary method to the solid-
phase combinatorial synthesis. The isoxazol(in)es with
biogenic amines could serve as a part of ‘privileged
structures’17 for various receptors. Currently we are
exploring to construct the mixture library of isomeric
cycloaddition products and the application to lead a
new search for GPCRs.
14. Meyer, A. G.; Easton, C. J.; Lincoln, S. F.; Simpson, G.
W. J. Org. Chem. 1998, 63, 9069–9075.
15. Compound A: H NMR (300 MHz, CDCl3): l 7.82 (2H,
1
Acknowledgements
dd, J=7 Hz, J=12 Hz), 7.33 (2H, t, J=9 Hz), 7.19
(2H, t, J=12 Hz), 7.12 (1H, s), 7.00 (3H, m), 3.99 (4H,
1
This work was supported by The Korea Ministry of
Science and Technology.
br s), 3.32 (4H, br s). Compound B: H NMR (300 MHz,
CDCl3): l 8.65 (1H, s), 7.77 (2H, dd, J=6 Hz, J=12