SCHEME 1. Benzothiazine Synthesis
Benzothiazines in Synthesis. Further Studies of
the Intramolecular, Stereoselective Addition of
Sulfonimidoyl Carbanions to r,ꢀ-Unsaturated
Functional Groups
Michael Harmata,* Kanok-on Rayanil, Vinson R. Espejo,
and Charles L. Barnes
Department of Chemistry, UniVersity of Missouri-Columbia,
Columbia, Missouri 65211
SCHEME 2. Stereospecific Conjugate Addition
ReceiVed January 23, 2009
and the antitubercular agents erogorgiaene and pseudopterox-
azole, among others.4,5
A variety of alkenes substituted by electron-withdrawing
groups serve as competent electrophiles for the stereoselec-
tive, intramolecular nucleophilic addition of sulfonimidoyl
carbanions to form benzothiazines. This reaction generally
proceeds with complete stereoselectivity within the limits
of our detection. In some cases, benzothiazine formation
occurs in a single pot at relatively high temperatures during
N-arylation of the simple sulfoximine used in this study. Yet,
the process occurs with the same direction and extent of
stereoselectivity as that seen when the Michael addition is
performed at very low temperatures.
In principle, the process is quite general, and we wondered
the extent to which changing the electron-withdrawing group
would affect the yield and stereochemical outcome of the
intramolecular Michael addition reaction. This report details our
first examination of this question.
Our initial goal was not to be exhaustive, but to survey a
reasonable number of electron-withdrawing groups and build a
database of reactivity and stereoselectivity that could be used
as a basis for further studies and applications.
A series of substrates was prepared from o-bromobenzalde-
hyde with standard methods and details are provided in the
Supporting Information. These compounds were coupled with
(S)-3 under our standard coupling conditions to afford N-aryl
sulfoximines in high yield.2,6 The results are summarized in
Table 1. In general this reaction proceeded quite smoothly.
However, in the case of 27, when the reaction was conducted
under standard conditions, the only product isolated in low yield
was benzothiazine 2. We assumed that this outcome arose via
the mechanism shown in Scheme 3.
Nucleophilic attack of hydroxide on 27 afforded the 1,6-
conjugate addition product 8. This compound underwent a
vinylogous retro-Claisen condensation to afford 1, which then
coupled with (S)-3 as shown in Scheme 1. It is likely that other
decomposition problems also intervened, given the low yield
of 28. Nevertheless, we hoped that by excluding water we could
improve the reaction outcome. Indeed, performing the coupling
in the presence of molecular sieves afforded 28 in 79% yield,
The use of heterocyclic templates in organic synthesis has a
long and honored history.1 Whether for simple bond formation
or those including the generation of stereogenic centers,
heterocycles have played a key role in organic synthesis, in
addition to serving as targets themselves.
As part of our ongoing interest in this area, a number of years
ago we reported the synthesis of benzothiazines in a one-pot
process via the reaction of o-halobenzaldehydes with certain
enantiomerically pure N-H sulfoximines using the Buchwald-
Hartwig reaction (Scheme 1).2 We extended this process to the
synthesis of benzothiazines beginning with o-bromocinnamates
in which an initial C-N bond forming event was generally
followed by an intramolecular Michael addition that was
completely stereoselective and stereospecific (Scheme 2).3 This
led to several applications, including the synthesis of curcumene
(1) Eicher, T.; Haputmann, S.; Suschitzky, H. The Chemistry of Heterocycles:
Structure, Reactions, Syntheses and Applications, 2nd ed.; Wiley: Chichester,
UK, 2003.
(2) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419–2422.
(3) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754–5756.
(4) (a) Harmata, M.; Hong, X.; Schreiner, P. R. J. Org. Chem. 2008, 73,
1290–1296. (b) Harmata, M.; Hong, X. Tetrahedron Lett. 2005, 46, 3847–3849.
(5) (a) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581. (b) Harmata, M.;
Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201.
(6) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731–5734.
3214 J. Org. Chem. 2009, 74, 3214–3216
10.1021/jo900151d CCC: $40.75 2009 American Chemical Society
Published on Web 03/13/2009