New synthesis of benzothiazines and benzoisothiazoles containing a sulfoximine functional group

Article abstract of DOI:10.1021/ol047781j

(Chemical Equation Presented) The reaction of S-2-bromophenyl-S- methylsulfoximine with terminal alkynes in the presence of a palladium catalyst resulted in the formation of both 1,2-benzothiazines and 1,2-benzoisothiazoles. A preference for the former was seen with alkylalkynes, while the latter were preferentially formed with alkynylarenes.

Full text of DOI:10.1021/ol047781j

ORGANIC
LETTERS
2005
Vol. 7, No. 1
143-145
New Synthesis of Benzothiazines and
Benzoisothiazoles Containing a
Sulfoximine Functional Group
Michael Harmata,* Kanok-on Rayanil, Maria G. Gomes, Pinguan Zheng,
Nathan L. Calkins, Soo-Yeun Kim, Yimin Fan, Valentina Bumbu,
Dong Reyoul Lee, Sumrit Wacharasindhu, and Xuechuan Hong
Department of Chemistry, UniVersity of Missouri-Columbia,
Columbia, Missouri 65211
harmatam@missouri.edu
Received October 28, 2004
ABSTRACT
The reaction of S-2-bromophenyl-S-methylsulfoximine with terminal alkynes in the presence of a palladium catalyst resulted in the formation
of both 1,2-benzothiazines and 1,2-benzoisothiazoles. A preference for the former was seen with alkylalkynes, while the latter were preferentially
formed with alkynylarenes.
Very recently, there have been a number of new reactions
reported involving the cyclization of alkynylarenes bearing
a nucleophilic ortho substituent.1 These reactions have
included variations that involve the synthesis of a variety of
heterocycles.2 On certain occasions, the initial products were
intermediates that could undergo further reaction (e.g.,
cycloaddition) to produce the isolated products.3
We have had a longstanding interest in the synthesis of
2,1-benzothiazines represented by structures 1 and 2. These
can be prepared by the annulation reaction of either alkynes
or alkenes with sulfonimidoyl chlorides4 or by a domino
sequence involving a Buchwald-Hartwig reaction5 followed
by ring formation.6 These benzothiazines can also be
described as cyclic sulfoximines.7
A general description of these reactions is shown in
Scheme 1. In principle, the approach is a very general one,
Scheme 1
and virtually any nucleophilic group might be expected to
participate in the key ring-forming step.
In keeping with our interest in benzothiazines and sul-
foximine chemistry in general, we were intrigued by the
(1) For reviews, see: (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104,
2285. (b) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127.
(2) For some recent examples, see: (a) Dai, G.; Larock, R. C. Org. Lett.
2001, 3, 4035. (b) Ohtaka, M.; Nakamura, H.; Yamamoto, Y. Tetrahedron
Lett. 2004, 45, 7339. (c) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004,
69, 5139.
(3) (a) Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem. Soc. 2001,
123, 5814. (b) Kusama, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc.
2002, 124, 11592. (c) Zhu, J.; Germain, A. R.; Porco, J. R., Jr. Angew.
Chem., Int. Ed. 2004, 43, 1239. (d) Sato, K.; Salprima, Y. S.; Asao, N.;
Yamamoto, Y. Synthesis 2004, 1409. (e) Asao, N.; Aikawa, H.; Yamamoto,
Y. J. Am. Chem. Soc. 2004, 126, 7458.
10.1021/ol047781j CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/15/2004

possibility of forming 1,2-benzothiazines 3 (or benzoisothia-
zoles 4) using the chemistry illustrated in Scheme 1.8 1,2-
Benzothiazines are of pharmaceutical interest, and a new
general procedure for their synthesis opens the door for the
creation of libraries of diversely functionalized compounds
that may prove to be of value as leads in drug develop-
ment.9,10 From a more fundamental perspective, the nucleo-
philicity of the sulfoximine nitrogen atom is of general
interest and further exploration of its reactivity is needed.11
This Letter describes our successful initial exploration of the
synthesis of 1,2-benzothiazines and 1,2-benzoisothiazoles
using chemistry represented in Scheme 1.
Scheme 2
In the course of our studies of the Sonogashira coupling,
we found that treatment of 8 with terminal alkynes in the
presence of Pd(PPh3)2Cl2, CuI, and triethylamine in warm
DMF afforded 1,2-benzothiazines directly and in good yield,
along with 1,2-benzoisothiazoles resulting from a 5-exo-dig
cyclization.
The results of our study are shown in Table 1. Alkyl-
substituted terminal alkynes afforded benzothiazines 9 in 53-
Our approach was inspired by the work of Snieckus and
Lane, who showed that ortho-iodosulfonamide 5 could
undergo a Sonogashira coupling to form 6, which could be
converted to benzoisothiazole 7 upon exposure to sodium
hydride (Scheme 2).12 We began our studies with the racemic
bromosulfoximine 8, easily prepared from 2-bromothio-
phenol using literature procedures (see Supporting Informa-
tion). We planned to conduct a Sonogashira coupling with
8 and then attempt an electrophile-mediated cyclization to
afford 1,2-benzothiazines 3, hoping that the sulfoximine
nitrogen was sufficiently nucleophilic to intercept any
electrophilic species produced by activation of the alkyne.13
Table 1. Synthesis of 1,2-Benzothiazines and
1,2-Benzoisothiazoles
(4) Harmata, M.; Kahraman, M.; Jones, D. E.; Pavri, N.; Weatherwax,
S. E. Tetrahedron 1998, 54, 9995 and references cited therein.
(5) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731.
(6) (a) Harmata, M.; Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201.
(b) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754-5756. (c)
Harmata, M.; Ghosh, S. K.; Barnes, C. L. J. Supramol. Chem. 2003, 2,
349. (d) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003, 44,
7261. (e) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3, 3321. (f) Harmata,
M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419.
(7) (a) Bosshammer, S.; Gais, H.-J. Synthesis 1998, 6, 919. (b) Hwang,
K. J.; Logusch, E. W.; Brannigan, L. H.; Thompson, M. R. J. Org. Chem.
1987, 52, 3435. (c) Schaffner-Sabba, K.; Tomaselli, H.; Henrici, B.; Renfroe,
H. B. J. Org. Chem. 1977, 42, 952.
entry
Ra
products
% (9)b
% (10)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
propyl
butyl
pentyl
hexyl
9a/10a
9b/10b
9c/10c
9d/10d
9e/10e
9f/10f
9g/10g
9h/10h
9i/10i
9j/10j
9k/10k
9l/10l
9m/10m
9n/10n
70
73
60
58
54
53
56
50
0c
52
56
0
21
16
20
27
19
16
18
13
19
18
0c
-(CH2)3OBn
-(CH2)3Ph
-(CH2)3CCH
cyclohexyl
tert-butyl
(8) A limited number of cyclic sulfoximines related to 3 are known.
See: (a) Williams, T. R.; Cram, D. J. J. Org. Chem. 1973, 38, 20. (b)
Stoss, P.; Satzinger, G. Chem. Ber. 1972, 105, 2575. (c) Williams, T. R.;
Cram, D. J. J. Am. Chem. Soc. 1971, 93, 7333.
1-cyclohexenyl
cyclopropyl
phenyl
4-methylphenyl
4-tert-butylphenyl
d
19
81
73
69
(9) Lombardino, J. G.; Kuhla, D. E. AdV. Heterocycl. Chem. 1981, 28,
73.
(10) (a) Bihovsky, R.; Tao, M.; Mallamo, J. P.; Wells, G. J. Bioorg.
Med. Chem. Lett. 2004, 14, 1035. (b) Del Tacca, M.; Colucci, R.; Fornai,
M.; Blandizzi, C. Clin. Drug InVest. 2002, 22, 799. (c) Pandey, V. K.;
Pathak, Seema R. Ind. J. Chem, Sect. B 2002, 41, 1749. (d) Davies, Neal
M.; Skjodt, Neil M. Clin. Pharmacokinet. 1999, 36, 115. (e) Pairet, M.;
Van Ryn, J.; Schierok, H.; Mauz, A.; Trummlitz, G.; Engelhardt, G.
Inflammation Res. 1998, 47, 270.
a Between 2 and 10 equiv of alkyne was used. Further optimization to
reduce the amount of alkyne must be performed. b Yields are for isolated
products. c Only coupling product was formed. See text. d Product could
not be isolated in pure form.
(11) (a) Hackenberger, C. P. R.; Raabe, G.; Bolm, C. Chem.sEur. J.
2004, 10, 2942. (b) Bolm, C.; Hackenberger, C. P. R.; Simic, O.; Verrucci,
M.; Muller, D.; Bienewald, F. Synthesis 2002, 7, 879. (c) Johnson, C. R.;
Lavergne, O. M. J. Org. Chem. 1993, 58, 1922. (d) Raguse, B.; Ridley, D.
D. Aust. J. Chem. 1986, 39, 1655. (e) Schmidbaur, H.; Kammel, G. Chem.
Ber. 1971, 104, 3234. (f) Johnson, C. R.; Rigau, J. J.; Haake, M.; McCants,
D., Jr.; Keiser, J. E.; Gertsema, A. Tetrahedron Lett. 1968, 9, 3719.
(12) (a) Lane, C.; Snieckus, V. Synlett 2000, 1294. But see also: (b)
Kundu, N. G.; Khan, M. W. Tetrahedron 2000, 56, 4777. (c) Asao, N.;
Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,
764.
73% yield along with 13-27% yields of the corresponding
benzoisothiazoles 10 (Table 1, entries 1-8). Steric effects
(13) At the suggestion of a referee, we conducted a reaction with 8 and
an internal alkyne. The reaction of 8 with 4-octyne under our reported
reaction conditions afforded recovered starting material (50%) as well as a
small amount of an unidentified product that did not incorporate 4-octyne
and was not a benzothiazine or isobenzothiazole.
144
Org. Lett., Vol. 7, No. 1, 2005

can preclude the formation of any heterocyclic product. For
example, the reaction of 8 with tert-butylacetylene resulted
only in the formation of the Sonogashira coupling product
11 with no evidence for the formation of either possible
heterocycle (Table 1, entry 9). As might be expected,
alkynylarenes preferentially cyclized to benzoisothiazoles,
the aryl group activating the alkyne toward 5-exo-dig ring
closure (Table 1, entries 12-14). Other potentially activating
groups such as the cyclopropyl and cyclohexenyl did not
change the course of the reaction vis-a`-vis that observed for
simple alkynes.
tert-butylbenzaldehyde, as evidenced by proton NMR analy-
sis of the crude reaction mixture.16 The mechanism of this
process is presently not clear, and the temptation to consider
a dioxetane intermediate is offset by the expectation that the
generation of such an intermediate would require the
presence of singlet oxygen.17
In summary, we have established a new approach to 1,2-
benzothiazines possessing a sulfoximine functional group.
In certain cases, 1,2-benzoisothiazoles can be selectively
produced. Learning how to control the regiochemistry of the
cyclization, expanding the scope of the reaction, and
developing the chemistry of the “enamine” double bond of
both heterocycles will be pursued. Developments will be
reported in due course.
The structures of 9 and 10 were easily established on the
basis of NMR analysis. The stereochemistry of benzoisothia-
zoles 10 was assigned on the basis of a NOESY experiment
performed on 10b.
Acknowledgment. This work was funded by the Petro-
leum Research Fund, administered by the American Chemi-
cal Society, to whom we are grateful. N.L.C. and V.B. thank
the Department of Chemistry at the University of Missouri-
Columbia for a summer Stevens’ Research Fellowship. We
thank Dr. Charles L. Barnes for the X-ray data.
The compounds produced in this reaction are N-vinyl
sulfoximines, cyclic version of N-vinyl sulfoximines, a
relatively unstudied class of compounds.14 Benzothiazines
9 appear to be stable compounds. Indeed, resonance delo-
calization should stabilize these compounds.
On the other hand, benzoisothiazoles 10 do not appear to
be very stable. Attempted isolation of 10e after several days
on the benchtop resulted in the isolation of 12 via recrys-
tallization.15 Its structure was confirmed by spectroscopic
analysis and single-crystal X-ray analysis. Furthermore,
exposure of 10n to an oxygen atmosphere for 12 h resulted
in significant decomposition and the formation of 12 and
Supporting Information Available: X-ray structure data
1
for 12, detailed experimental procedures, and copies of H
and 13C NMR and other characterization data for all new
compounds (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL047781J
(14) (a) Dehli, J. R.; Bolm, C. J. Org. Chem. 2004, 69, 8518. (b)
Bonacorso, H. G.; Bittencourt, S. R. T.; Lourega, R. V.; Flores, A. F. C.;
Zanatta, N.; Martins, M. A. P. Synthesis 2000, 1431. (c) Ikeda, M.;
Tsubouchi, H.; Tsunekawa, M.; Kondo, H.; Tamura, Y. Chem Pharm. Bull.
1984, 32, 3028. (d) Ikeda, M.; Tsubouchi, H.; Tsunekawa, M.; Kondo, H.;
Tamura, Y. Heterocycles 1983, 20, 2185. (e) Tamura, Y.; Bayomi, S. M.;
Tsunekawa, M.; Ikeda, M. Chem Pharm. Bull. 1979, 27, 2137.
(16) After 12 h of stirring in CDCl3 under an oxygen atmosphere, proton
NMR analysis suggested the formation of a 25% yield of 12. After 36 h,
tert-butylbenzaldehyde was isolated in 20% yield along with 61% of
recovered 10n. Compound 12 did not elute from the silica column, even
after flushing with polar solvents.
(15) Stoss, P.; Satzinger, G. Angew. Chem., Int. Ed. Engl. 1971, 10, 76.
(17) Ando, W.; Saiki, T.; Migita, T. J. Am. Chem. Soc. 1975, 97, 5028.
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