Synthesis of isoxazoles via electrophilic cyclization

Article abstract of DOI:10.1021/ol052027z

(Chemical Equation Presented) A variety of 3,5-disubstituted 4-halo(seleno)isoxazoles are readily prepared in good to excellent yields under mild reaction conditions by the reaction of 2-alkyn-1-one O-methyl oximes with ICI, I₂, Br₂,

Full text of DOI:10.1021/ol052027z

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5203-5205
Synthesis of Isoxazoles via Electrophilic
Cyclization
Jesse P. Waldo and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received August 22, 2005
ABSTRACT
A variety of 3,5-disubstituted 4-halo(seleno)isoxazoles are readily prepared in good to excellent yields under mild reaction conditions by the
reaction of 2-alkyn-1-one O-methyl oximes with ICl, I2, Br2, or PhSeBr.
The biological activity of substituted isoxazoles1 has made
them a focus of medicinal chemistry over the years.
Isoxazoles are potent, selective agonists at human cloned
dopamine D4 receptors2 and exhibit GABAA antagonist,3
analgesic,4 antiinflammatory,4 ulcerogenic,4 antimicrobial,5
antifungal,5 COX-2 inhibitory,6 antinociceptive,7 and anti-
cancer8 activity.
carbonyl compounds,11 and R,â-unsaturated nitriles.12 The
reaction of an oxime-derived dianion and an ester13 or
amide14 also provides isoxazoles. [3 + 2] Cycloaddition
reactions between alkynes and nitrile oxides have also been
developed.15 However, these methods often require strong
bases, strong mineral acids, or high temperatures or provide
poor regioselectivity.
Many synthetic methods have been employed in the
synthesis of isoxazoles,9 including reactions of hydroxyl-
amine with 1,3-dicarbonyl compounds,10 R,â-unsaturated
It has been known for over a century that isoxazoles can
be halogenated to give 4-haloisoxazoles.16 However, even
the mildest conditions for the halogenation of isoxazoles
frequently require the use of harsh acids and high tempera-
tures.16c
(1) For a brief review see: Carlsen, L.; Do¨pp, D.; Do¨pp, H.; Duus, F.;
Hartmann, H.; Lang-Fugmann, S.; Schulze, B.; Smalley, R. K.; Wakefield,
B. J. In Houben-Weyl, Methods in Organic Chemistry; Schaumann, E., Ed.;
Georg Thieme Verlag: Stuttgart, Germany, 1992; Vol. E8a, pp 45-204.
(2) Rowley, M.; Broughton, H. B.; Collins, I.; Baker, R.; Emms, F.;
Marwood, R.; Patel, S.; Ragan, C. I. J. Med. Chem. 1996, 39, 1943.
(3) Frolund, B.; Jorgensen, A. T.; Tagmose, L.; Stensbol, T. B.;
Vestergaard, H. T.; Engblom, C.; Kristiansen, U.; Sanchez, C.; Krogsgaard-
Larsen, P.; Liljefors, T. J. Med. Chem. 2002, 45, 2454.
(9) For a recent review, see: Wakefield, B. J. In Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations; Shaumann, E., Ed.;
Georg Thieme Verlag: Stuttgart, 2001; Vol. 11, pp 229-288.
(10) Bandiera, T.; Gru¨nanger, P.; Albini, F. M. J. Heterocycl. Chem.
1992, 29, 1423.
(4) Daidone, G.; Raffa, D.; Maggio, B.; Plescia, F.; Cutuli, V. M. C.;
Mangano, N. G.; Caruso, A. Arch. Pharm. Pharm. Med. Chem. 1999, 332,
50.
(5) Tomita, K.; Takahi, Y.; Ishizuka, R.; Kamamura, S.; Nakagawa, M.;
Ando, M.; Nakanishi, T.; Nakamura, T.; Udaira, H. Ann. Sankyo Res. Lab.
1973, 1, 25; Chem. Abstr. 1974, 80, 120808.
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Wiley: Hoboken, 2002; Vol. 59, pp 361-472.
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10.1021/ol052027z CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/15/2005

Scheme 1
Recent work by our group and others has shown the
The O-methyl oximes are readily prepared by stirring the
ynone in the presence of methoxylamine hydrochloride,
pyridine, and Na2SO4 at room temperature using methanol
as the solvent.32 When R1 is a bulky group relative to the
alkyne moiety, the desired Z isomer is the predominant
product. However, if R1 is significantly less bulky, a mixture
of isomers often results and the desired isomer must be
separated by column chromatography. The yields of the
desired Z-O-methyl oximes from the ynones are generally
good, and these compounds are easily isolated by column
chromatography on silica gel.
electrophilic cyclization of functionally substituted acetylenes
to be an efficient way of generating benzo[b]thiophenes,17
isoquinolines and naphthyridines,18 isocoumarins and R-
pyrones,19 benzofurans,20 furans,21 indoles,22 furopyridines,23
cyclic carbonates,24 2,3-dihydropyrroles and pyrroles,25
pyrilium salts and isochromenes,26 and bicyclic â-lactams.27
This work prompted us to examine the possible synthesis of
isoxazoles by the electrophilic cyclization of 2-alkyn-1-one
O-methyl oximes. We now report our success.
A three-step approach to isoxazoles has been examined
involving (i) preparation of the ynone, (ii) formation of the
O-methyl oxime, and (iii) electrophilic cyclization (Scheme
1).
The ynones required for this methodology are readily
prepared by the palladium/copper-catalyzed Sonogashira
coupling of an acid chloride with a terminal acetylene28 or
by allowing the lithium acetylide to react with an aldehyde,
followed by oxidation of the secondary alcohol.29 The
requisite ynones can also be conveniently prepared by the
Pd-catalyzed carbonylative coupling of terminal acetylenes
with aryl iodides30 or treatment of a silyl acetylene with an
acid chloride in the presence of aluminum chloride.31
To study the scope of this electrophilic cyclization strategy,
the reactions of O-methyl oximes 1 and 2 with different
electrophiles (ICl, I2, Br2, and PhSeBr) at room temperature
have been studied (Table 1, entries 1-6). O-Methyl oxime
1 reacts at room temperature in CH2Cl2 with ICl (Table 1,
entry 1) to afford isoxazole 10 in a good yield. Treating
O-methyl oxime 1 with I2 in CH3CN (entry 2) also affords
the expected isoxazole 10 in good yield, although more of
the electrophile was required to generate a high yield. The
use of I2 in CH2Cl2 resulted in lowered yields. Br2 and
PhSeBr can also be utilized in the cyclization process (entries
3-5). However, the reactions require more electrophile and
longer reaction times.
(17) (a) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011. (b)
Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (c) Flynn, B. L.;
Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651.
Since ICl provided a higher yield and a shorter reaction
time for the parent system, compared with I2 (compare entries
1 and 2), this procedure was chosen to test the scope of the
cyclization process. Alkynes bearing vinylic and alkyl groups
provide good yields of the desired 4-iodoisoxazoles (entries
6 and 7). The reaction is not inhibited by the presence of
bulky tert-butyl or TIPS groups (entries 8 and 9). However,
2.0 equiv of ICl is required in the latter reaction. When 1.2
equiv of ICl is used for the alkyne bearing a TIPS group, a
comparable yield is achieved, but the reaction takes longer.
(18) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3, 2973.
(b) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437.
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Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (c) Oliver, M. A.;
Gandour, R. D. J. Org. Chem. 1984, 49, 558. (d) Biagetti, M.; Bellina, F.;
Carpita, A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 58, 5023. (e) Rossi,
R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron 2003, 59,
2067.
(20) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
1999, 1432.
(21) (a) Bew, S. P.; Knight, D. W. J. Chem. Soc., Chem. Commun. 1996,
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Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769.
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Chem., Int. Ed. 2003, 42, 2406. (b) Muhammad, A.; Knight, D. W.
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We have also examined the effect on the yield of varying
the nature of the group R1, while retaining R2 as a phenyl
group. The reaction works well when R1 is a hydrogen, an
alkyl chain, or a bulky alkyl group (entries 10-12). The
N-methyl-3-indolyl heterocycle also gave a respectable yield
of 55% (entry 13). The use of more ICl in the latter example
did not provide a higher yield. In all cases, the desired
isoxazoles have been obtained in good yields with no
evidence of any products arising from simple addition of
the electrophile to the alkyne.
(28) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977, 1977.
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Org. Lett., Vol. 7, No. 23, 2005

Table 1. Synthesis of Substituted Isoxazolesa
a All reactions were carried out in CH2Cl2 (10 mL/mmol) at room temperature using 0.25 mmol of starting material unless otherwise specified. b Isolated
yields after column chromatography. c The reaction was carried out in CH3CN.
Our investigation has shown that highly substituted isox-
azoles can be formed in good to excellent yields using mild
reaction conditions. The preparation of starting materials is
very general and can be applied to a wide variety of
substrates. We believe that this approach to substituted
isoxazoles should be quite useful in synthesis considering
the many ways one can transform the resulting halogen and
selenium functional groups. For example, the 3-haloisox-
azoles should be useful in many palladium-catalyzed pro-
cesses, such as Sonogashira,33 Suzuki,34 and Heck35 reactions.
Chemical Methodologies and Library Development Center
of Excellence (P50 GM069663) for support of this research
and Johnson Matthey, Inc., and Kawaken Fine Chemicals
Co., Ltd., for donations of palladium catalysts.
Supporting Information Available: Experimental pro-
cedures and characterization data for all starting materials
and products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL052027Z
(34) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Lloyd-
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Wiley-VCH: Weinheim, 1998; pp 49-97. (d) Miyaura, N. Chem. ReV.
1995, 95, 2457.
Acknowledgment. We gratefully acknowledge the Na-
tional Institute of General Medical Sciences (GM070620)
and the National Institutes of Health Kansas University
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