One-pot copper(I)-catalyzed synthesis of 3,5-disubstituted isoxazoles

Article abstract of DOI:10.1021/jo050163b

3,5-Disubstituted isoxazoles are obtained in good yields by a convenient one-pot, three-step procedure utilizing a regioselective copper(I)-catalyzed cycloaddition reaction between in situ generated nitrile oxides and terminal acetylenes. Most functional

Full text of DOI:10.1021/jo050163b

SCHEME 1. One-Pot Synthesis of
3,5-Disubstituted Isoxazoles
One-Pot Copper(I)-Catalyzed Synthesis of
3,5-Disubstituted Isoxazoles
Trond V. Hansen,† Peng Wu, and Valery V. Fokin*
Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
fokin@scripps.edu
Received January 26, 2005
time,5 its applications to the synthesis of isoxazoles are
scarce. In the reported procedures, the yields of isoxazole
products are often quite low, side reactions result in
impurities, and both regioisomers are often obtained.6
Furthermore, nitrile oxides are not very stable them-
selves and dimerize readily, especially when electron-rich
substituents are present.7c Since isoxazoles are often
encountered in molecules of medicinal interest,7 a simple
and efficient procedure for their synthesis would be a
welcome advance. Herein, we report an experimentally
convenient, one-pot three-step process for the regioselec-
tive synthesis of 3,5-disubstituted isoxazoles from alde-
hydes and alkynes, whereupon nitrile oxide intermedi-
ates are generated in situ and further reacted without
isolation.
An aldehyde is first converted to the corresponding
aldoxime via reaction with hydroxylamine. Without
isolation, the aldoxime is transformed to the correspond-
ing nitrile oxide using 1.05 equiv of chloramine-T trihy-
drate, which acts as both a halogenating agent and a
base.8 In the presence of a catalytic amount of copper(I),
obtained from comproportionation of Cu metal and cop-
per(II) sulfate, the in situ generated nitrile oxide under-
goes a stepwise addition to a copper(I) acetylide4b at
ambient temperature, furnishing the 3,5-disubstituted
isoxazole (Scheme 1).
3,5-Disubstituted isoxazoles are obtained in good yields by
a convenient one-pot, three-step procedure utilizing a regi-
oselective copper(I)-catalyzed cycloaddition reaction between
in situ generated nitrile oxides and terminal acetylenes.
Most functional groups do not interfere with the reaction,
which can be performed in aqueous solvents without protec-
tion from oxygen. Since all reagents are used in stoichio-
metric amounts, formation of byproducts is minimized.
Introduction
The copper(I)-catalyzed “fusion” of terminal acetylenes
and organic azides to give exclusively 1,4-disubstituted
1,2,3-triazoles1 is a quintessential example of a click
reaction.2 Owing to its efficiency and reliability, it has
quickly found many applications in chemistry, biology,
and materials science.3 In addition, this mode of reactiv-
ity of the in situ generated copper(I) acetylides is not
limited to azides as dipoles, and nitrones, nitrile oxides,
and azomethine imines have been shown to participate
in similar catalytic transformations.4
Although the uncatalyzed 1,3-dipolar cycloaddition of
nitrile oxides to acetylenes has been known for a long
Nitrile oxides generated from a range of aliphatic
aldehydes readily participate in this transformation. The
† On leave from The School of Pharmacy, University of Oslo, PO
BOX 1155, N-0316 Blindern, Oslo, Norway.
(1) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057. (b) Rostovsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
(5) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 1, pp 1-176.
(2) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004.
(6) Lang, S. A.; Lin, Y.-I. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol VI/
4B, pp 1-130.
(3) For recent examples, see: (a) Wu, P.; Feldman, A. K.; Nugent,
A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun, L.; Fre´chet, J. M. J.;
Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2004, 43, 3863.
(b) Collman, J. P.; Deveraj, N. K.; Chidsey, C. E. D. Langmuir 2004,
20, 1051. (c) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless,
K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192. (d) Anderson, J.
C.; Schultz, P. G. J. Am. Chem. Soc. 2003, 125, 11782. (e) Link, A. J.;
Tirell, D. A. J. Am. Chem. Soc. 2003, 125, 11164. (f) Speers, A. E.;
Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc. 2003, 125, 4686.
(4) (a) Lo, M. M.-C.; Fu, G. C. J. Am Chem. Soc. 2002, 124, 4572.
(b) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovsev, V. V.; Fokin, V. V.;
Noodleman, L.; Sharpless, K. B. J. Am. Chem. Soc. 2005, 127, 210. (c)
Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 10778.
(7) (a) Ja¨ger, V.; Colinas, P. A. In The Chemistry of Heterocyclic
Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, W. H., Eds.; Wiley: New York, 2003; Vol 59, pp 361-472. (b)
Cicchi, S.; Cordero, F. M.; Giomi, D. Prog. Heterocycl. Chem. 2003, 15,
261. (c) Gru¨nanger, P.; Vita-Finzi, P. In The Chemistry of Heterocyclic
Compounds: Isoxazoles; Taylor, E. C., Weissberger, A. Eds.; Wiley-
Interscience: New York, 1991; Part I, Vol. 49, pp 1-416.
(8) (a) Hassner, A.; Lokanatha Rai, K. M. Synthesis 1989, 57. (b)
Other halogenation agents such as sodium hypochlorite or tert-butyl
hypochlorite were also tried, but superior yields were obtained with
chloramine-T.
10.1021/jo050163b CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/13/2005
J. Org. Chem. 2005, 70, 7761-7764
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TABLE 1. Isoxazoles Prepared from Aliphatic Aldehydes and Terminal Alkynes
a At 80 °C without copper catalyst, a mixture of 3,5- and 3,4-disubstituted isoxazoles (5:1) was isolated in 55% combined yield. b At 80
°C without copper catalyst, a mixture of 3,5- and 3,4-disubstituted isoxazoles (10:1) was isolated in 50% combined yield.
3,5-disubstituted isoxazole products are obtained in
moderate to good yields after a simple filtration or
aqueous workup. Trace amounts of toluenesulfonamide
and unreacted acetylene are easily removed by recrys-
tallization or by passing the product through a short plug
of silica.
The same sequence can be applied to aromatic alde-
hydes, affording the products in 60-76% yields. The
yields obtained in this one-pot procedure compare favor-
ably to other reported syntheses of isoxazoles, especially
in cases with alkenyl or activated aryl or heteroaryl
group, such as p-anisyl or R-furyl, respectively.7a
The scope of this transformation is demonstrated by
the wide range of substituents tolerated in both the
aldehyde/nitrile oxide and acetylene components. For
example, propyolic acid, after neutralization with sodium
bicarbonate, undergoes cycloaddition reaction with nitrile
oxide derived from p-anisaldehyde to afford the isoxazole
16 in 61% yield (Table 2, entry 9). Likewise, ketone
functionality is not affected under the conditions of the
reaction (Table 1, entry 7; Table 2, entries 3 and 12).
Cycloaddition of nitrile oxides to olefins resulting in
isoxazolines is well precedented.7a Nevertheless, in the
presence of a copper(I) catalyst, this side reaction was
not observed. Thus, nitrile oxide obtained from trans-
cinnamaldehyde reacted only with the terminal acetylene
of 1-ethynylcyclohexene (Table 1, entry 1).
The reaction exhibits excellent regioselectivity. By
comparison with previously reported data and by NMR
studies, the products were determined to be 3,5-disub-
stituted regioisomers.9 Furthermore, LC-MS and 1H
NMR analyses of the crude reaction mixtures confirmed
that in all cases no 3,4-regioisomers were formed, even
though the uncatalyzed reactions may proceed with
(9) Caramella, P.; Gru¨nanger, P. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley-Interscience: New York, 1984; Vol.
1, p 337 and references therein.
7762 J. Org. Chem., Vol. 70, No. 19, 2005

TABLE 2. Isoxazoles Prepared from Aromatic Aldehydes and Terminal Acetylenes
a At 80 °C without copper(I), 3,5- and 3,4-disubstituted isoxazoles (3:1) were isolated in 51% combined yield.
J. Org. Chem, Vol. 70, No. 19, 2005 7763

complete. Chloramine-T trihydrate (5.9 g, 21 mmol) was added
in small portions over 5 min, followed by CuSO4‚5H2O (0.15 g,
0.6 mmol) and copper turnings (ca. 50 mg). 1-Ethynylcyclohexene
(2.23 g, 21 mmol) was added, pH was adjusted to ca. 6 by
addition of a few drops of 1 M NaOH, and stirring was continued
for another 6 h. The reaction mixture was poured into ice/water
(150 mL), and 10 mL of dilute NH4OH was added to remove all
copper salts. The product was collected by filtration, redissolved,
and passed through a short plug of silica gel (ethyl acetate/
hexanes 1:6, Rf ) 0.6) affording 3.4 g (68%) of 5-cyclohex-1-enyl-
3-styrylisoxazole as an off-white solid, mp 138-139 °C. 1H NMR
(CDCl3, 600 MHz): δ ) 7.52 (d, J ) 7.4 Hz, 2H), 7.38 (m, 2H),
7.32 (m, 1H), 7.14 (d, J ) 6.2 Hz, 2H), 6.64 (m, 1H), 6.31 (s,
appreciable rate. This is also in agreement with the
proposed mechanism of the catalytic cycloaddition re-
ported in a recent article.4b
In conclusion, a regioselective, experimentally conve-
nient one-pot copper(I)-catalyzed procedure for rapid
preparation of isoxazoles has been developed. The isola-
tion and handling of potentially harmful and unstable10
hydroximoyl chlorides is avoided, as nitrile oxides are
obtained directly from oximes. All reagents are used in
stoichiometric quantities, thus further simplifying puri-
fication of products. The sequence exhibits wide scope,
is tolerant of most functional groups, and performs well
in aqueous solvents without the need for protection from
oxygen. It is equally reliable for both small-scale discov-
ery and preparative scale synthetic applications (cf.
Experimental Section).
1H), 2.36 (m, 2H), 2.25 (m, 2H), 1.78 (m, 2H), 1.69 (m, 2H). 13
C
NMR (CDCl3, 150 MHz): δ ) 170.9, 161.7, 135.9, 135.4, 130.2,
128.8, 128.76, 126.9, 125.2, 116.5, 95.1, 25.4, 25.2, 22.1, 21.7.
HRMS calcd. for (MH+): 252.1383, found: 252.1381.
Acknowledgment. We thank Prof. K. Barry Sharp-
less for helpful discussions, the National Institute of
General Medical Sciences, National Institutes of Health
(GM-28384), and Pfizer, Inc. for financial support.
T.V.H. thanks the U.S.-Norway Fulbright Foundation
for a Fulbright fellowship. P.W. thanks the Skaggs
Foundation for a predoctoral fellowship.
Experimental Section
General Procedure for Preparation of 3,5-Disubstituted
Isoxazoles. Typical experimental procedure for synthesis of 3,5-
disubstituted isoxazoles, as exemplified for 5-cyclohex-1-enyl-
3-styrylisoxazole (1). trans-Cinnamaldehyde (2.6 g, 20 mmol) was
added to the solution of hydroxylamine hydrochloride (1.46 g,
21 mmol) in 80 mL of 1:1 t-BuOH:H2O. To this was added NaOH
(0.84 g, 21 mmol), and after being stirred for 30 min at ambient
temperature, TLC analysis indicated that oxime formation was
Supporting Information Available: Spectral character-
ization of all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) It has been reported that some hydroximoyl chlorides are strong
skin irritants and may cause allergic reactions; see ref 5a, p 365.
JO050163B
7764 J. Org. Chem., Vol. 70, No. 19, 2005