Direct α-oxytosylation of carbonyl compounds: One-pot synthesis of heterocycles

Article abstract of DOI:10.1021/ol701774y

N-Methyl-O-tosylhydroxylamine is an effective reagent for the direct α-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.

Full text of DOI:10.1021/ol701774y

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
tomkinsonnc@cardiff.ac.uk
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

Table 1. Reaction of 5 with Cyclohexanonea
% yield
entry
acid
solvent
of 11b
1
2
none
HCl
THF
THF
12
0
3
4
5
6
7
8
9
10
TFA
THF
THF
THF
DMSO
H2O
CH2Cl2
EtOAc
PhMe
43
72
17
0
MsOH
BzOH
MsOH
MsOH
MsOH
MsOH
MsOH
Figure 1. R-Functionalization of carbonyl compounds.
0
65
63
57
important R-oxytosyl carbonyl compounds (such as 11).9
Herein, we report on an effective method for the direct
R-oxytosylation of a wide variety of carbonyl compounds
using N-methyl-O-tosylhydroxylamine 5, which complements
and augments the Koser reagent,10,11 and demonstrate its
versatility in the one-pot preparation of a series of hetero-
cycles.
a All reactions were performed at room temperature at 0.5 M concentra-
tion for 24 h. b Isolated yield.
alternative reaction pathway was adopted, which gave the
desired product 11 (Table 1).
In the absence of acid the reaction was sluggish proceeding
in just 12% yield after 24 h (entry 1). Addition of a co-acid
to the reaction medium greatly accelerated the process
(entries 3-5) with methanesulfonic acid (entry 4) emerging
as the most efficient candidate. Examination of a variety of
solvents (entries 6-10) showed that apart from highly polar
reaction media the transformation worked well in a broad
spectrum of solvents any of which we found could be
adopted.
The target oxysulfonylation reagent 5 has been prepared
previously as a crystalline solid in three steps from N-
methylhydroxylamine hydrochloride in 72% overall yield.12
In our hands the reaction sequence worked well (66%) and
could be performed without the need for chromatography
on a large scale (see the Supporting Information for full
details).
In contrast to our proposed transformation the related
N-methyl-O-(4-nitrobenzene)sulfonylhydroxylamine 7 has
been shown to have a different reactivity profile by Hoffman
and co-workers.13 Addition of 7 to cyclohexanone 6 gave
the corresponding lactam 9 (73%) via the aminol intermediate
Having established effective reaction conditions for the
transformation we went on to examine the scope and
limitations of the protocol (Table 2). Under the aqueous
acidic reaction conditions hydrolytically unstable function-
alities remain in tact (entries 1-3). Additionally, substrates
that have been reported to be unreactive to Koser’s reagent
(cycloheptanone)10 also give the R-oxytosylated product upon
reaction with 5 in the presence of methanesulfonic acid (entry
5). In contrast to our observations with the R-oxybenzoylation
reagents 1,8 the oxytosylation reagent 5 was also effective
for the R-functionalization of primary centers which greatly
adds to the general applicability of the reagent (entry 6).
Examination of a series of nonsymmetrical substrates also
revealed an important trend in reactivity (entries 9-12).
Functionalization takes place exclusively at the primary
position when distinguishing primary and tertiary centers
(entry 9). Primary center functionalization is also favored
when discriminating primary and secondary centers, where
sterics appear to play an important role (entries 10-12). With
the more hindered 4-methylpentan-2-one a 4.2:1 selectivity
for the primary center was obtained (entry 10), for un-
branched linear ketones this selectivity droped to 2.6:1 in
favor of primary functionalization (entries 11 and 12).
Comparison of these results to those observed with the Koser
Figure 2. Reaction of cyclohexanone with 5 and 7.
8 (Figure 2).14 However, we were delighted to discover that
reaction between 5 and cyclohexanone 6 revealed that an
(9) For examples of the synthetic versatility of this functionality see:
(a) Nicolaou, K. C.; Montagnon, T.; Ulven, T.; Baran, P. S.; Zhong, Y.-L.;
Sarabia, F. J. Am. Chem. Soc. 2002, 124, 5718-5728. (b) Nicolaou, K. C.;
Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2000, 122, 10246-10248.
(10) Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.; Wettach,
R. H. J. Org. Chem. 1982, 47, 2487-2489.
(11) For alternative preparations and reaction conditions involving this
reagent see: (a) Yusubov, M. S.; Wirth, T. Org. Lett. 2005, 7, 519-521.
(b) Nabana, T.; Togo, H. J. Org. Chem. 2002, 67, 4362-4365. (c) Abe, S.;
Sakuratani, K.; Togo, H. J. Org. Chem. 2001, 66, 6174-6177. (d) Tuncay,
A.; Dustman, J. A.; Fisher, G.; Tuncay, C. I. Tetrahedron Lett. 1992, 33,
7647-7650.
(12) Tamura, Y.; Ikeda, H.; Morita, I.; Tsubouchi, H.; Ikeda, M. Chem.
Pharm. Bull. 1982, 30, 1221-1224.
(13) For an excellent review on this work see: Hoffman, R. V.
Tetrahedron 1991, 47, 1109-1135.
(14) Hoffman, R. V.; Salvador, J. M. Tetrahedron Lett. 1989, 30, 4207-
4210.
4010
Org. Lett., Vol. 9, No. 20, 2007

Table 2. Scope of Transformation
a Reaction performed at room temperature in THF. b Reaction performed at 40 °C in a 1:1 mixture of THF/PhMe. c Reaction performed in THF at 40 °C.
reagent shows a distinct advantage where selectivities of
1:1.57 have been reported for the reaction of butanone.10
Acetophenone, propiophenone, and â-ketoesters were also
effective substrates for the transformation (entries 13-16).
Mechanistically we believe that these reactions are pro-
ceeding in a similar fashion to that described previously.8
Condensation of the reagents provides the iminium ion 12,
which converts to the enamine 10. Subsequent [1,3]-shift of
the oxytosyl group15 followed by hydrolysis of the resulting
imine 13 leads to the observed reaction product 11. Interest-
ingly, a similar intermediate iminium ion has been invoked
previously by Barton16 and utilized by Jeffs17 in a Beckmann-
type rearrangement of nitrones. Thus, treatment of the nitrone
14 with tosylchloride in pyridine gave the O-sulfonylated
intermediate 15, which then underwent rearrangement, under
the basic reaction conditions, to give the corresponding amide
16 (Scheme 1). This Beckmann-type rearrangement has also
been reported in the preparation of â-lactams via stabilized
carbinolamine intermediates.18 Therefore, under acidic condi-
Scheme 1
(15) This type of group transfer has been proposed by Hoffman, in the
reaction of sulfonyl peroxides with enamines: Hoffman, R. V.; Jankowski,
B. C.; Carr, C. S.; Duesler, E. N. J. Org. Chem. 1986, 51, 130-135.
(16) (a) Barton, D. H. R.; Day, M. J.; Hesse, R. H.; Pechet, M. M. J.
Chem. Soc., Perkin Trans. 1 1975, 1764-1767. (b) Barton, D. H. R.; Day,
M. J.; Hesse, R. H.; Pechet, M. M. Chem. Commun. 1971, 945-946.
(17) Jeffs, P. W.; Molina, G. Chem. Commun. 1973, 3-4.
Org. Lett., Vol. 9, No. 20, 2007
4011

tions an alternative mechanistic pathway is available for
iminium ion intermediates of the type 12.
Scheme 2
Finally, we went on to investigate whether the R-oxytosyl
carbonyl compounds could be used directly in a one-pot
synthesis of heterocycles. The importance of the R-oxytosyl
functional group in synthesis was recently demonstrated by
Nicolaou and co-workers, who showed the reaction of
R-oxysulfonylketones (derived from the addition of sulfonic
acids to alkenes) with a series of nitrogen-, sulfur-, oxygen-,
and carbon-based nucleophiles allowed for the introduction
of an array of functionality including a wide variety of
biologically significant heterocycles.9
The byproducts from the reaction of 5 with a carbonyl
compound are methylamine and methanesulfonic acid, which
we did not consider would hinder the formation of hetero-
cycles from the R-oxytosyl precursors. Therefore, we added
benzothioamide 17 directly to the crude mixture from the
reaction between acetone and 5 and heated the resulting
solution at reflux for 18 h. Pleasingly, this led to the desired
thiazole 20 in an excellent 69% overall yield (Scheme 2).
In a similar manner, the reaction of acetone with 5 followed
by benzamidine hydrochloride 18 gave the imidazole 22
(63%) and reaction of cyclohexanone with 5 followed by
the addition of benzene-1,2-diamine 19 gave 23 (55%),
suggesting the overall transformation should be of broad
utility in the one-pot preparation of heterocyclic compounds
from ketones.
In summary, we have described the reactivity of N-methyl-
O-tosylhydroxylamine 5, which provides a new platform for
the direct R-oxytosylation of carbonyl compounds. The
reaction is tolerant of a range of functional groups and is
effective for a broad scope of substrate. The transformation
is particularly easy to perform and is tolerant of the presence
of both moisture and air, greatly adding to the practical utility
of the work. The reagent complements the reactivity of
Koser’s reagent and is effective for the reaction of less-
enolizable substrates such as cycloheptanone broadening the
scope of substrates for this class of transformation. It can
also be used in a one-pot method for the direct formation of
heterocyclic products from carbonyl compounds by the
addition of a bis-nucleophile to the reaction mixture and
heating to promote a cyclo-condensation process. The reagent
adds to a growing family of easy-to-prepare hydroxylamine
reagents of broad synthetic utility.8 We are currently
developing an asymmetric variant of this reagent and will
report on our findings shortly.
Acknowledgment. The authors thank the EPSRC for
financial support and the Mass Spectrometry Service,
Swansea for high-resolution spectra.
Supporting Information Available: Analytical data and
experimental details for the preparation of reagent 5, the
R-functionalized products (Tables 1 and 2), and the hetero-
cycles 20-23. This material is available free of charge via
the Internet at http://pubs.acs.org.
(18) Wasserman, H. H.; Glazer, E. A.; Hearn, M. J. Tetrahedron Lett.
1973, 14, 4855-4858.
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