Benzothiazines in organic synthesis. the preparation of enantiomerically pure 4-substituted quinolones

Article abstract of DOI:10.1021/ol0710358

Equation Presented 3,4-Dihydroquinolin-2(1H)-ones have potential biological and pharmacological significance. Enantiomerically pure benzothiazines, readily available via an intramolecular addition of a sulfoximine-stabilized carbanion to an α,β-unsaturate

Full text of DOI:10.1021/ol0710358

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2701-2704
Benzothiazines in Organic Synthesis.
The Preparation of Enantiomerically
Pure 4-Substituted Quinolones
Michael Harmata* and Xuechuan Hong
Department of Chemistry, UniVersity of Missouri-Columbia,
Columbia, Missouri 65203
harmatam@missouri.edu
Received May 3, 2007
ABSTRACT
3,4-Dihydroquinolin-2(1H)-ones have potential biological and pharmacological significance. Enantiomerically pure benzothiazines, readily available
via an intramolecular addition of a sulfoximine-stabilized carbanion to an -unsaturated ester, could be used as templates for making a
series of enantiomerically pure 3,4-dihydroquinolin-2(1H)-ones under mild conditions.
r,â
Quinolin-2(1H)-ones are ubiquitous structural motifs that can
be found in many naturally and non-naturally occurring
compounds (Figure 1).1 Many of these heterocycles possess
interesting biological properties and have been developed
as drugs that are antibiotics,1b HIV-1 reverse transcriptase
inhibitors,1c NMDA antagonists,1d and 5-HT3 receptor
antagonists.1e Their importance in medicinal chemistry has
stimulated considerable attention from organic chemists and
encouraged the development of new synthetic pathways to
prepare these compounds.
syntheses of quinolin-2(1H)-ones give racemic compounds
or low enantiomeric excesses under relatively harsh reaction
A number of syntheses of quinolin-2(1H)-ones have been
reported that rely on radical cyclizations of a secondary
amide,2a,b solid-phase synthesis,2c asymmetric cyclocarbo-
nylation of 2-vinylanilines by palladium2d-h or rhodium
catalysts,2i Friedlander-type methods or Friedel-Crafts
cyclization,2j-l and multicomponent reactions.2m Most of the
(1) (a) Jones, G. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, UK,
1996; p 167. (b) Uchida, R.; Imasato, R.; Shiomi, K.; Tomoda, H.; Omura,
S. Org. Lett. 2005, 7, 5701. (c) Patel, M.; McHugh, R. J.; Cordova, B. C.;
Klabe, R. M.; Bacheler, L. T.; Erickson-Viitanen, S.; Rodgers, J. D. Bioorg.
Med. Chem. Lett. 2001, 11, 1943. (d) Carling, R. W.; Leeson, P. D.; Moore,
K. W.; Smith, J. D.; Moyes, C. R.; Mawer, I. M.; Thomas, S.; Chan, T.;
Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R.;
Tricklebank, M. D.; Saywell, K. L. J. Med. Chem. 1993, 36, 3397. (e)
Hayashi, H.; Miwa, Y.; Miki, I.; Ichikawa, S.; Yoda, N.; Ishii, A.; Kono,
M.; Suzuki, F. J. Med. Chem. 1992, 35, 4893.
Figure 1. Examples of tetrahydroquinolone-containing natural and
non-natural products.
10.1021/ol0710358 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/08/2007

conditions. The use of radical cyclization to build six-
membered rings has some limitations as well, often resulting
in very low yields.
In our continuing efforts to expand the utility of 2,1-
benzothiazine chemistry, we thought that our enantiopure
2,1-benzothiazines3 would be ideal to construct enatiomeri-
cally pure 3,4-dihydroquinolin-2(1H)-ones. We anticipated
that reductive desulfurization with sodium amalgam would
result in a transient metal amide that would condense
intramolecularly with the ester functional group to produce
a lactam (Scheme 2). Indeed, reductive desulfurization of 9
We recently reported the stereoselective, intramolecular
Michael addition of sulfoximine carbanions to R,â-unsatur-
ated esters as exemplified in Scheme 1.3 The preparation of
Scheme 1
Scheme 2
would yield 3,4-dihydroquinolin-2(1H)-one 10 in a concise
and especially straightforward way. Herein we reported the
first synthesis of enantiopure 3,4-dihydroquinolin-2(1H)-ones
under mild conditions.
Our initial evaluation of the reductive desulfurization of
benzothiazines was carried out using a simple system (Table
1). Treatment of benzothiazines 11a-d3 with excess sodium
amalgam in methanol/tetrahydrofuran at room temperature
sulfoximine 7 was conducted by using the methodology
introduced by Bolm and co-workers.4 Subsequent treatment
of sulfoximine 7 with LDA afforded 8 as a single stereo-
isomer in high yield. The reaction is stereospecific and offers
a way of establishing benzylic stereocenters with high
fidelity. We are interested in using these benzothiazines as
useful synthons in a variety of ways.
Benzothiazines that we have prepared have been directly
converted to indoles,5a allylanilines,5b 2-alkylanilines,5b-d and
2-alkenylanilines.5e Further, we have demonstrated that the
C2-symmetric bis-benzothiazines could be used as chiral
ligands in asymmetric allylic alkylations.5f We also applied
benzothiazines to the total syntheses of (+)-curcuphenol, (+)-
curcumene,6 erogorgiaene,7 and pseudopteroxazole.8
Table 1. Conversion of Benzothiazines 11 to
4-Methyl-3,4-dihydroquinolin-2(1H)-ones 12
(2) (a) Binot, G.; Zard, S. Z. Tetrahedron Lett. 2005, 46, 7503. (b) Clark,
A. J.; Jones, K.; McCarthy, C.; Storey, J. M. D. Tetrahedron Lett. 1991, 3,
2829. (c) Turner, K. L.; Baker, T. M.; Islam, S.; Procter, D. J.; Stefaniak,
M. Org. Lett. 2006, 8, 329. (d) Touzani, R.; Alper, H. J. Mol. Catal. A:
Chem. 2005, 227, 197. (e) Dong, C.; Alper, H., Tetrahedron: Asymmetry
2004, 15, 35. (f) Okuro, K.; Kai, H.; Alper, H. Tetrahedron: Asymmetry
1997, 8, 2307. (g) El Ali, B.; Okuro, K.; Vasapollo, G.; Alper, H. J. Am.
Chem. Soc. 1996, 118, 4264. (h) Manley, P. J.; Bilodeau, M. T. Org. Lett.
2004, 6, 2433. (i) Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto K.;
Yamaguchi, R. Org. Lett. 2004, 6, 2785. (j) Jones G. In ComprehensiVe
Heterocyclic Chemistry; Boulton, A. J., McKillop, A., Eds.; Pergamon
Press: Oxford, UK, 1984; Vol. 2 (8). (k) Li, K.; Foresee, L. N.; Tunge, J.
A. J. Org. Chem. 2005, 70, 2881. (l) Kadnikov, D. V.; Larock, R. C. J.
Org. Chem. 2004, 69, 6772. (m) Marcaccini, S.; Pepino, R.; Pozo, M. C.;
Basurto, S.; Garc´ıa-Valverde, M.; Torroba, T. Tetrahedron Lett. 2004, 45,
3999.
(3) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754.
(4) (a) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731.
(b) Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000, 65, 169.
(5) (a) Harmata, M.; Herron, B. F. Tetrahedron 1991, 47, 8855. (b)
Harmata, M.; Jones, D. E. Tetrahedron Lett. 1995, 36, 4769. (c) Harmata,
M.; Herron, B. F. Tetrahedron 1991, 47, 8855. (d) Harmata, M.; Claassen,
R. J., II; Barnes, C. L. J. Org. Chem. 1991, 56, 5059. (e) Harmata, M.;
Kahraman, M. Synthesis 1994, 142. (f) Harmata, M.; Ghosh, S. K. Org.
Lett. 2001, 3, 3321.
(6) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003, 44,
7261.
(7) Harmata, M.; Hong, X. Tetrahedron Lett. 2005, 46, 3847.
(8) (a) Harmata, M.; Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201.
(b) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581.
2702
Org. Lett., Vol. 9, No. 14, 2007

Scheme 3
for several hours resulted in the formation of 4-methyl-3,4-
with the methyl on the R position of the sulfoximine 11f in
81% yield as a 16.3:1 mixture of isomers. The mixture of
these two isomers of 17a was treated with Na/Hg to provide
4-ethyl-3,4-dihydroquinolin-2(1H)-one 18a in 63% yield via
a reductive desulfurization/condensation process (entry 1).
dihydroquinolin-2(1H)-ones 12a-d in excellent yields with
high enantiopurity (entries 1-4). Benzothiazines 11e,f
displayed similar reactivity to 11b,c, giving 4-methyl-3,4-
dihydroquinolin-2(1H)-ones 12b and 12c in 83% and 78%
yields, respectively. Enantiomerically pure bis-benzothiazine
15 was prepared as per our published procedures3 involving
the reaction of sulfoximine 14 with LDA. Compound 15
could be reduced and condensed to 16 in 65% yield (Scheme
3).
Our efforts were subsequently directed at metalation of
the benzothiazines 11f and their reaction with electrophiles.
The products of such reactions would place substituents other
than a methyl group at the 4-position of the 4-alkyl-3,4-
dihydroquinolin-2(1H)-ones obtained upon reduction (Table
2). In the initial attempt, deprotonation of 11f with 1.1 equiv
of LiHMDS at -50 °C for 1 h followed by reaction with
4.0 equiv of CH3I for 1 h provided exclusively the product
Encouraged by these preliminary results, we considered
applying these methods toward the installation of a range of
other groups at the 4-position of the 3,4-dihydroquinolin-
2(1H)-ones. Pleasingly, a variety of substituents could be
installed in good yields. An ethyl, allyl, benzyl, or MEM
group could be placed on the R position of the sulfoximine
11f with the corresponding electrophiles in 44-83% yields
with high diastereoselectivity.9 As expected, benzothiazines
17b-d were readily converted to 3,4-dihydroquinolin-2(1H)-
ones 18b-d with different substituents at the 4-position.
However, benzothiazine 17e was converted to 4-vinyl-3,4-
dihydroquinolin-2(1H)-one 18e, instead. The formation of
18e could be explained by assuming the formation of a
negative charge adjacent to the alkoxy group during the
course of the reduction. Elimination of the alkoxy group then
resulted in the formation of the vinyl group. A related
Table 2. Conversion of Benzothiazine 11f to
4-Alkyl-3,4-dihydroquinolin-2(1H)-ones 18
Table 3. Conversion of Thiazines 19 to Ring-Fused
Pyridin-2(1H)-ones 20
yield ratio (17, time,
yield
product (%)
entry
RX
product (%,17) cis:trans)a
h
1
2
3
MeI
17a
17b
17c
80
44
83
16.3:1
28.8:1
5.1:1
36
72
48
18a
18b
18c
63
65
51
EtBr
allyl
bromide
benzyl
bromide
MEM-Cl
4
5
17d
17e
79
48
16.4:1
24.1:1
72
72
18d
18e
60
72
1
a Determined by H NMR analysis of the crude reaction mixture.
Org. Lett., Vol. 9, No. 14, 2007
2703

sequence to introduce substituted alkenes is a potentially
general process.
In summary, we have developed a new, convenient route
for the synthesis of enatiomerically pure 3,4-dihydroquinolin-
2(1H)-ones10,11 under mild conditions. Further investigations
regarding the scope of the reaction presented and their appli-
cation in organic synthesis will be reported in due course.
We were also curious to see if heterocyclic ring-fused
thiazines 19a-d could be used for the synthesis of ring-
fused pyridin-2(1H)-ones. Gratifyingly, good results were
obtained when thiophene, furan, and indole thiazines 19a-d
were treated with a similar reaction sequence (Table 3).
Acknowledgment. This work was supported by the NIH
(1R01-AI59000-01A1) to whom we are grateful.
(9) Allylation of 11f resulted in only a 5.1:1 mixture of the isomers of
17c (entry 3, Table 2).
Supporting Information Available: Experimental pro-
cedures, as well as characterization and copies of proton and
carbon spectra for all previously unreported compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) We are assuming the dihydroquinolones are as enantiomerically pure
as the sulfoximine 6, which is used to prepare the benzothiazine precursors
of the quinolones. The resolution of 6 is performed according to Gais11
and the enantiomeric purity of the sulfoxime is checked by chiral column
chromatography. We prepared enantiomerically pure 12a and compared it
to racemic material by chiral HPLC to validate this assumption.
(11) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
OL0710358
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