The intramolecular, stereoselective addition of sulfoximine carbanions to α,β-unsaturated esters

Article abstract of DOI:10.1021/ja034744z

ortho-Bromocinnamates can be coupled with methyl phenylsulfoximine to afford N-arylsulfoximines in excellent yield. Treatment of these products with an amide base results in a completely stereoselective cyclization to afford enantiomerically pure benzothiazines. This reaction is stereospecific.

Full text of DOI:10.1021/ja034744z

Published on Web 04/19/2003
The Intramolecular, Stereoselective Addition of Sulfoximine
Carbanions to r,â-Unsaturated Esters
Michael Harmata* and Xuechuan Hong
Contribution from the Department of Chemistry, UniVersity of Missouri-Columbia,
Columbia, Missouri 65211
Received February 18, 2003; E-mail: harmatam@missouri.edu
Abstract: ortho-Bromocinnamates can be coupled with methyl phenylsulfoximine to afford N-arylsulfoximines
in excellent yield. Treatment of these products with an amide base results in a completely stereoselective
cyclization to afford enantiomerically pure benzothiazines. This reaction is stereospecific.
Introduction
One motivation for this study centered on the idea that the
method, if general, could be used to introduce a stereogenic
center adjacent to an aromatic ring, that is, at the benzylic
position. The natural and man-made pharmacopoeia is replete
with interesting and important structures bearing such a stereo-
genic center.4 While to say any methodology can definitively
be applied to such a broad range of compounds may be
unrealistic, the potential exists for a significant contribution if
the initial steps in a methodological development indicate high
yields and high levels of stereocontrol.
As part of our program concerning the synthesis and
chemistry of 2,1-benzothiazines,1 we recently reported the one-
pot synthesis of enantiomerically pure benzothiazines via the
reaction of enantiomerically pure N-H sulfoximines and ortho-
bromobenzaldehydes, as shown in eq 1.2 This process involves
Results and Discussion
It is important to mention that our work made use of
sulfoximine 6, whose privileged status arises from the fact that
it is extremely easy to prepare in enantiomerically pure form.5
At the outset of this study, it was not clear if we would have to
optimize the structure of the sulfoximine to achieve high
stereoselection in the conjugate addition step of the process.
That this was unnecessary means that this reaction is more than
interesting; it is useful.
the Buchwald-Hartwig reaction,3 followed by an intramolecular
condensation. In that report, we also demonstrated a single
example of a reaction involving an intramolecular addition of
a sulfoximine carbanion to an R,â-unsaturated ester (eq 2). This
reaction was completely stereoselective, but it was not clear if
the process would be general, nor were any mechanistic details
about the reaction known. The study reported herein establishes
that such a reaction is general, stereoselective, and stereospecific
and can, under the appropriate circumstances, be conducted as
a one-pot process involving both carbon-nitrogen and carbon-
carbon bond formation.
In coupling sulfoximine 6 to various ortho-bromocinnamates,
we made use of the Buchwald-Hartwig reaction as modified
by Bolm for coupling sulfoximines to bromoarenes.6 In general,
this involved refluxing a toluene solution of the bromocinnamate
with 5 mol % Pd(OAc)2 in the presence of 7.5 mol % racemic
BINAP, 1.4 equiv of Cs2CO3, and 1.2 equiv of 6. This procedure
(4) Consider, as examples, some compounds seen on perusal of the Merck
Index: the Aspidosperma alkaloids, estrone and its congeners, tetrahydro-
cannabinols, podophyllotoxin, morphinoids, calycanthine, chimonanthine,
turmerone, viridin, mitomycins, vindoline, teleocidin B4, pranoprufen,
pentazocine, lycoramine, naproxen, and ibuprofen. For a recent reference
on the generation of benzylic stereocenters, see: Paras, N. A.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 7894.
(5) Brandt, J.; Gais, H. Tetrahedron: Asymmetry 1997, 6, 909.
(6) (a) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 37, 5731. (b) Bolm,
C.; Hildebrand, J. P. J. Org. Chem. 2000, 65, 169.
(1) Harmata, M.; Kahraman, M.; Jones, D. E.; Pavri, N.; Weatherwax, S. E.
Tetrahedron 1998, 54, 9995 and references therein.
(2) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 16, 2419.
(3) (a) Hartwig, J. F. Palladium-Catalyzed Amination of Aryl Halides and
Related Reactions. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley: Hoboken, 2002; pp 1051-96. (b) Yang,
B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
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10.1021/ja034744z CCC: $25.00 © 2003 American Chemical Society

Addition of Sulfoximine Carbanions
A R T I C L E S
Table 1. Reaction of (R)- or (S)-6 with Various
ortho-Bromocinnamates
Our rationalization for the outcome of these reactions is based
on minimization of steric interactions in the transition state
leading to carbon-carbon bond formation. Models suggest that
the transition state leading to the observed products is sterically
less encumbered than the diastereomeric transition state.
In the course of this work, we discovered that certain ortho-
bromocinnamates reacted with sulfoximine 6 to give products
of both carbon-carbon and carbon-nitrogen bond formation.
This was first observed with 19, whose reaction with 6 afforded
a 53% yield of 20 as well as a 36% yield of benzothiazine 21,
with complete stereoselectivity (eq 3). We ascribed the formation
of 21 to a buttressing effect, which biased 20 toward a
conformation which placed the methyl group of its sulfoximine
functionality near the â-carbon of the R,â-unsaturated ester.
Equilibrium deprotonation of the sulfoximine to form the
corresponding carbanion resulted in some cyclization, due to
this proximity effect.
generally afforded high yields of N-arylated sulfoximine using
either enantiomer of 6 (Table 1).
Most gratifyingly, we found that treatment of the sulfoximines
with an amide base resulted in the formation of benzothiazines
with complete diastereoselectivity (Table 2). Typical reaction
conditions involved adding a THF solution of 2 equiv of LDA
or LiHMDS in THF to the sulfoximine at -78 °C. Some
variation in temperature was explored to assess the effect of
this variable on selectivity. None was found. Two substrates
could not be cyclized under these conditions. While thiophene
9 afforded benzothiazine 15 in good yield, furan 11 appeared
to polymerize when base was added. This problem was
circumvented by simply adding the furan to a solution in base,
thereby keeping its concentration relatively low. Similarly,
pyridine 12 gave either decomposition or side products when
treated with base. Inverse addition coupled with rigorous
degassing solved this problem, and the desired benzothiazine
was obtained in high yield.
This idea was tested with two other substrates. The reaction
of both 22 and 24 with 6 under standard reaction conditions
afforded only benzothiazines 23 and 25, respectively, in a one-
pot procedure in good yield (eqs 3 and 4). Thus, it appears that
a buttressing effect may be used to create benzothiazines in a
single operation. Other effects may also be important, however.
For example, the reaction of 26 with 6 gave not only the
sulfoximine 27 in 60% yield, but the benzothiazine 28 as well
(eq 6). Clearly, no buttressing effect is possible with this system.
All of the benzothiazines were formed as single stereoisomers.
Stereochemical assignments were based on X-ray data obtained
for 5.2 Other assignments were made on the basis of analogy,
based on spectroscopic comparison to 5.
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A R T I C L E S
Harmata and Hong
Table 2. Reaction of Sulfoximines 7-12 with an Amide Base
LDA (eq 7). Benzothiazine 13 was obtained as the sole product
in 89% yield, suggesting that the reaction was stereospecific.
Conclusion
In summary, we have demonstrated that the intramolecular
conjugate addition of sulfoximine carbanions to R,â-unsaturated
esters is a powerful method for establishing a stereogenic center
at a benzylic position. This methodology has the potential for
application to natural product synthesis, especially because a
procedure for the reductive removal of the sulfur functionality
from benzothiazines is known.7 The synthesis of molecular
scaffolds, establishing the formation of chiral quaternary centers,
and exploration of the chemistry of certain chiral benzothiazines
themselves are among our immediate goals in further exploring
this methodology. Finally, this chemistry is only beginning to
be explored. Extensions to other nonbenzenoid systems, using
the results obtained thus far as guiding principles, should make
possible the synthesis of a wide variety of enantiomerically pure
compounds. Further results will be reported in due course.
Acknowledgment. This work was supported by the Petroleum
Research Fund, administered by the American Chemical Society,
to whom we are grateful. We thank FMC Lithium for a generous
gift of the alkyllithium reagents used in this study.
Supporting Information Available: Experimental procedures
1
and copies of the H and 13C NMR spectra of 7-12, their
a Prepared by addition of base to sulfoximine. b Prepared by addition of
sulfoximine to base.
precursors, and 13-28 (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
To obtain more information about the base-mediated cycliza-
tion step with those substrates requiring two steps to achieve
benzothiazine formation, we treated the (Z)-cinnamate 7 with
JA034744Z
(7) Harmata, M.; Kahraman, M. Synthesis 1994, 142-144.
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