ORGANIC
LETTERS
2007
Vol. 9, No. 20
4009-4012
Direct
r-Oxytosylation of Carbonyl
Compounds: One-Pot Synthesis of
Heterocycles
Oliver R. S. John, Niall M. Killeen, Deborah A. Knowles, Sze Chak Yau,
Mark C. Bagley, and Nicholas C. O. Tomkinson*
School of Chemistry, Main Building, Cardiff UniVersity, Park Place,
Cardiff, CF10 3AT, United Kingdom
Received July 25, 2007
ABSTRACT
N-Methyl-O-tosylhydroxylamine is an effective reagent for the direct
r-oxytosylation of carbonyl compounds. The reactions proceed smoothly
at room temperature in the presence of both moisture and air and functional group tolerance in the substrate is good. With nonsymmetrical
substrates regioselectivity for primary over secondary centers is observed and complete regiospecificity for primary over tertiary centers is
obtained. Addition of a bis-heteronucleophile directly to the crude reaction mixture in a one-pot process leads to the corresponding heterocyclic
product.
Hydroxylamines have a rich and distinguished chemistry,1
the inherent weakness of the N-O bond frequently being
used to provide a thermodynamic driving force for their
associated transformations.2 This has allowed for established
transformations such as the Lossen3 and Beckmann4 re-
arrangements, as well as the development of effective
electrophilic aminating5 and oxygenating6 agents revealing
their synthetic versatility. It has also been effectively
exploited in a variety of [3,3]-sigmatropic rearrangement
processes providing access to a broad range of densely
functionalized materials.7
We have recently reported the N-alkyl-O-acyl reagents 1
to be effective for the one-pot R-oxyacylation of carbonyl
compounds,8 the key bond-forming process involving [3,3]-
sigmatropic rearrangement of the enamine intermediate 4,
driven by cleavage of the weak N-O bond and formation
of a stronger C-O bond (Figure 1). We were intrigued to
discover if an analogous reagent could be developed for the
transfer of an oxysulfonyl group, providing synthetically
(7) For some typical examples see: (a) Reis, L. V.; Lobo, A. M.;
Prabhakar, S.; Duarte, M. P. Eur. J. Org. Chem. 2003, 1, 190-208. (b)
Clark, A. J.; Al-Faiyz, Y. S. S.; Patel, D.; Broadhurst, M. J. Tetrahedron
Lett. 2001, 42, 2007-2009. (c) Clark, A. J.; Al-Faiyz, Y. S. S.; Broadhurst,
M. J.; Patel, D.; Peacock, J. L. J. Chem. Soc., Perkin Trans. 1 2000, 1117-
1127. (d) Lantos, I.; Zhang, W.-Y. Tetrahedron Lett. 1994, 35, 5977-5980.
(e) Reis, L. V.; Lobo, A. M.; Prabhakar, S. Tetrahedron Lett. 1994, 35,
2747-2750. (f) Cummins, C. H.; Coates, R. M. J. Org. Chem. 1983, 48,
2070-2076. (g) House, H. O.; Richey, F. A. J. Org. Chem. 1969, 34, 1430-
1439.
(8) (a) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, K. L.; Jones, T.
C.; Killeen, N. M.; Taylor, P. H.; Thomas, S. P.; Tomkinson, N. C. O.
Org. Lett. 2005, 7, 5729-5732. (b) Beshara, C. S.; Hall, A.; Jenkins, R.
L.; Jones, T. C.; Parry, R. T.; Thomas, S. P.; Tomkinson, N. C. O. Chem.
Commun. 2005, 1478-1479. (c) Hall, A.; Jones, K. L.; Jones, T. C.; Killeen,
N. M.; Porzig, R.; Taylor, P. H.; Yau, S. C.; Tomkinson, N. C. O. Synlett
2006, 3435-3438. (d) Hall, A.; Huguet, E. P.; Jones, K. L.; Jones, T. C.;
Killeen, N. M.; Yau, S. C.; Tomkinson, N. C. O. Synlett 2007, 293-297.
(1) For recent advances in hydroxylamine chemistry see: Khlestkin, V.
K.; Mazhukin, D. G. Curr. Org. Chem. 2003, 7, 967-993.
(2) The N-O bond strength in hydroxylamine has been calculated to be
63 kcal mol-1: Wiberg, K. B. J. Phys. Chem. 1992, 96, 5800-5803.
(3) Bauer, L.; Exner, O. Angew. Chem., Int. Ed. 1974, 13, 376-385.
(4) Gawley, R. E. Org. React. 1988, 35, 1-420.
(5) For recent progress in the area see: (a) Berman, A. M.; Johnson, J.
S. J. Org. Chem. 2006, 71, 219-224. (b) Berman, A. M.; Johnson, J. S. J.
Org. Chem. 2005, 70, 364-366. (c) Berman, A. M.; Johnson, J. S. Synlett
2005, 1799-1801. (d) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc.
2004, 126, 5680-5681.
(6) For examples see: Davis, F. A.; Chen, B. C. Chem. ReV. 1992, 92,
919-934.
10.1021/ol701774y CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/08/2007