pubs.acs.org/joc
TABLE 1. Initial Results
An Alkynyliodide Cycloaddition Strategy for the
Construction of Iodoisoxazoles
James A. Crossley and Duncan L. Browne*
Department of Chemistry, University of Sheffield,
Sheffield S3 7HF, U.K.
entry
solvent
1:2
1:2
1:1.1
1:2
1:1.1
time
temp (°C)a
yield (%)
Received June 9, 2010
1
2
3
4
THF
THF
DME
THF
20 min
20 min
20 min
18 h
100 (MW)
100 (MW)
120 (MW)
reflux (SHP)
78
65
83
51b
aMW = microwave, SHP = stirrer hot plate. bRecovered starting
material also observed.
cycloadditions,3 we opted to assess their potential to undergo
simple thermal cycloadditions with alkynyliodides toward the
synthesis of iodoisoxazoles; our results are reported herein.
Isoxazoles are important biologically active motifs featured in
a variety of pharmaceutical and agrochemical products.4 A
plethora of methods exist for their synthesis, including conden-
sation between hydroxylamine and 1,3-dicarbonyl compounds
or R,β-unsaturated carbonyls, and [3 þ 2] cycloadditions be-
tween nitrile oxides and alkynes.5 However, the latter approach is
often hampered with issues relating to poor cycloaddition regios-
electivity or nitrile oxide dimerization.6 With these issues in mind,
we commenced our studies by using mesityl N-oxide (a stable,
isolable nitrile oxide).7 During the course of our initial studies, we
sought a practical procedure for the synthesis of alkynyliodides.
While several methods for their synthesis are reported in the
literature, we found that those reported by Hein et al.2d were most
practical in terms of operational simplicity and applicability.
With mesityl N-oxide and a range of alkynyliodides in hand, we
commenced our analysis of the thermally induced cycloaddition.
Initially treating N-oxide 1 with 2 equiv of alkynyliodide 2 in a
solution of THF at 100 °C in the microwave for 20 min pleasingly
delivered the desired iodoisoxazole 3 in 78% yield (entry 1,
Table 1). Attempts to lower the ratio of N-oxide to alkynyliodide
to 1:1.1, respectively, resulted in a diminished yield (65%, entry 2,
Table 1). However, switching solvents to dimethoxyethane
(DME) and conducting the reaction with 2 equiv of alkyne at
The thermally promoted cycloaddition between alkynyl-
iodides and nitrile oxides is reported. The process offers
excellent regioselectivity and a broad scope with respect
to both the iodoalkynes and chloro-oximes. Further
functionalization of the highly decorated iodoisoxazole
motifs can be achieved via Suzuki cross-coupling.
Aromatic and heteroaromatic halides constitute an extremely
useful set of molecules in modern day organic synthesis. The
ability to transform a C-X bond into a C-C or C-Y bond
(where Y is a heteroatom) has been studied and described
extensively.1 Given the importance of such scaffolds, we were
intrigued by the prospect of an alternative route to their synth-
esis. Currently, most C-X bonds are installed once the aromatic
system is already in place via an electrophilic or nucleophilic
substitution reaction. Often such processes require the employ-
ment of strong reagents such as PCl5, ICl, or X2 in strong acid.
Our proposed route to circumvent this extra halogenation step
features the concomitant synthesis and iodination of the targeted
ring system through the cycloaddition of an alkynyliodide. We
were surprised to find that there are relatively few reports on the
cycloaddition of alkynyliodides, particularly toward functiona-
lized heterocycles.2 Indeed, perhaps the most notable example is
that reported by Hein et al. in 2009, where alkynyliodides were
found to react with azides under copper-catalyzed conditions to
furnish a broad range of iodotriazoles in good yields and as
single regioisomers.2d Given our recent interest in nitrile oxide
(4) Giomi, D.; Cordero, F. M.; Machetti, F. In Comprehensive Hetero-
cyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; Vol. 4, p 365.
(5) For a variety of recent methods for the preparation of isoxazoles, see:
(a) Sheng, S.-R.; Liu, X.-L.; Xu, Q.; Song, C.-U. Synthesis 2003, 2763. (b) Hansen,
T. V.; Wu, P.; Fokin, V. V. J. Org. Chem. 2005, 70, 7761. (c) Ahmed, M. S. M.;
Kobayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487. (d) Waldo, J. P.; Larock, R. C.
Org. Lett. 2005, 7, 5203. (e) Moore, J. E.; Davies, M. W.; Goodenough, K. M.;
Wybrow, R. A. J.; York, M.; Johnson, C. N.; Harrity, J. P. A. Tetrahedron 2005,
61, 6707. (f) Itoh, K.-I.; Sakamaki, H.; Nakazato, N.; Horiuchi, A.; Horn, E.;
Horiuchi, A. Synthesis 2005, 3541. (g) Denmark, S. E.; Kalleymeyn, J. M. J. Org.
(1) Metal-Catalyzed Cross-Coupling Reactions II; de Meijere, A., Dieder-
ich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
ꢀ
ꢁ
Chem. 2005, 70, 2839. (h) Beha, S.;Giguere, D.;Patnam, R.;Roy, R.Synlett 2006,
1739. (i) Cecchi, L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem. 2006, 4852.
( j) Bourbeau, M. P.; Rider, J. T. Org. Lett. 2006, 8, 3679. (k) Dadiboyena, S.; Xu,
J.; Hamme, A. T., II. Tetrahedron Lett. 2007, 48, 1295. (l) Waldo, J. P.; Larock,
(2) For examples of metal-mediated cycloadditions of alkynyliodides, see:
(a) Yoo, W.-J.; Allen, A.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 5853.
(b) Yamamoto, Y.; Hattori, K. Tetrahedron 2008, 64, 847. (c) Miura, T.; Murata,
H.;Kiyota, K.;Kusama, H.;Iwasawa, N.J. Mol. Catal. A 2004, 213, 59. (d)Hein,
J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V. Angew. Chem.,
Int. Ed. 2009, 48, 8018. For a thermally promoted cycloaddition, see:
(e) Iwasawa, T.; Kamei, T.; Hama, K.; Nishimoto, Y.; Nishiuchi, M.; Kawamura,
Y. Tetrahedron Lett. 2008, 49, 5244 (footnote 12).
€
R. C. J. Org. Chem. 2007, 72, 9643. (m) Willy, B.; Rominger, F.; Muller, T. J. J.
Synthesis 2008, 293. (n) Xu, J.; Hamme, A. T., II. Synlett 2008, 919. (o) Grecian,
S.; Fokin, V. V. Angew. Chem., Int. Ed. 2008, 47, 8285.
(6) Grundmann, C. Synthesis 1970, 344.
(7) Grundmann, C.; Frommeld, H.-D.; Flory, K.; Datta, S. K. J. Org.
Chem. 1968, 33, 1464.
(3) Crossley, J. A.; Browne, D. L. Tetrahedron Lett. 2010, 51, 2271.
5414 J. Org. Chem. 2010, 75, 5414–5416
Published on Web 07/07/2010
DOI: 10.1021/jo1011174
r
2010 American Chemical Society