has been accomplished via Ag-catalyzed cyclization. But none
of these investigations has explored the possibility of accessing
benzothiazines (or benzoisothiazoles) via regiocontrolled addi-
tion of the sulfonamide moiety toward the triple bond in the
presence of a silver or copper salt.
A Remarkable Accelerating Effect of Ag-Salt on
Intramolecular Cyclization of
o-(1-Alkynyl)benzenesulfonamides†
Deepak Kumar Barange, T. C. Nishad, N. Kumara Swamy,
Venkanna Bandameedi, Dinesh Kumar,
Bukkapattanam R. Sreekanth, K. Vyas, and Manojit Pal*
Benzothiazines, a widely studied family of heterocycles, have
a privileged framework found in a number of anti-inflammatory
agents,4,5 some of which, particularly oxicams (e.g., Meloxicam,
Piroxicam, etc.), have already been marketed. As a consequence
of their biological significance, continued effort has been
devoted for the development of newer synthetic methods to
construct the 2H-benzo[e][1,2]thiazine ring.6,7 Recently, a new
Pd-mediated one-step synthesis of benzothiazines involving
Sonogashira coupling of bromosulfoximine with terminal alkynes
has been developed8 where a substantial number of isomeric
1,2-benzoisothiazoles were isolated as side products. More
recently, we have reported a convenient synthesis of benzo-
thiazines that required an additional step to remove the C-4
iodo group.9a In this Note, we describe our recent findings
on direct and one-step regioselective synthesis of 2H-benzo[e]-
[1,2]thiazine-1,1-dioxides using a transition metal-catalyzed
intramolecular cyclization of 2-alkynyl benzenesulfonamide
(Scheme 1) addressing several issues, e.g., (i) reactivity of the
-SO2NH- moiety toward transition metal-activated alkynes,
(ii) regioselectivity, and (iii) the optimal catalyst system. To
the best of our knowledge synthesis of the benzothiazine ring
Chemistry-DiscoVery Research, Dr. Reddy’s Laboratories Ltd.,
Bollaram Road, Miyapur, Hyderabad 500049, India
ReceiVed July 16, 2007
Herein, we report transition metal-catalyzed intramolecular
cyclization of o-(1-alkynyl)benzenesulfonamides to afford
3-substituted benzothiazines regioselectively via a C-N bond
forming reaction and Cu-catalyzed sequential C-N and C-C
bond formation leading to the corresponding 3,4-disubstituted
derivatives.
(3) (a) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005, 70,
4531. (b) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69, 5139. (c)
Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett.
2002, 4, 4727. (d) Peng, A.-Y.; Ding, Y.-X. J. Am. Chem. Soc. 2003, 125,
15006. (e) Liang, Y.; Xie, Y.-X.; Li, J.-H. Synthesis 2007, 400. (f) Peng,
A.-Y.; Ding, Y.-X. Org. Lett. 2005, 7, 3299. (g) van Esseveldt, B. C. J.;
Vervoort, P. W. H.; van Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem.
2005, 70, 1791. (h) Agarwal, S.; Knolker, H.-J. Org. Biomol. Chem. 2004,
2, 3060. (i) Dalla, V.; Pale, P. New J. Chem. 1999, 23, 803. (j) Patil, N. T.;
Pahadi, N. K.; Yamamoto, Y. J. Org. Chem. 2005, 70, 10096.
(4) Lombardino, J. G.; Wiseman, E. H. Med. Res. ReV. 1982, 2, 127.
(5) Lazer, E. S.; Miao, C. K.; Cywin, C. L.; Sorcek, R.; Wong, H.-C.;
Meng, Z.; Potocki, I.; Hoermann, M.; Snow, R. J.; Tschantz, M. A.; Kelly,
T. A.; McNeil, D. W.; Coutts, S. J.; Churchill, L.; Graham, A. G.; David,
E.; Grob, P. M.; Engel, W.; Meier, H.; Trummlitz, G. J. Med. Chem. 1997,
40, 980 and references cited therein.
(6) Layman, W. J., Jr.; Greenwood, T. D.; Downey, A. L.; Wolfe, J. F.
J. Org. Chem. 2005, 70, 9147.
(7) (a) Sianesi, E.; Redaelli, R.; Magistretti, M. J.; Massarani, E. J. Med.
Chem. 1973, 16, 1133. (b) Lombardino, J. G.; Wiseman, E. H. J. Med.
Chem. 1971, 14, 973. (c) Catsoulacos, P. J. Heterocycl. Chem. 1971, 8,
947. (d) Hauser, C. R.; Wantanabe, H.; Mao, C.-L.; Barnish, I. T. J. Org.
Chem. 1969, 34, 919.
Reactions catalyzed by silver and copper salts have attracted
remarkable attention in recent years.1,2 In particular, these salts
have been demonstrated to be exceptional and versatile reagents
for the formal addition of an X-H bond (where X ) O, N)
across a C-C triple bond. Thus Cu- or Ag-mediated activation
of the triple bond and then prompting the nearest nucleophilic
substituent to attack the coordinated alkynyl moiety in an
intramolecular fashion offers an attractive and atom-economical
route for the synthesis of functionalized heterocycles. For
example, furans,3a cyclic alkenyl ethers,3b benzofurans,3c
phosphaisocoumarins,3d isocoumarins and R-pyrones,3e etc. are
among the compounds for which highly regioselective syntheses
have been demonstrated via Cu-catalyzed reactions. On the other
hand, synthesis of 2H-1,2-oxaphosphorin 2-oxides,3f 5-substi-
tuted proline derivatives,3g pyrroles,3h and other heterocycles3i,j
(8) Harmata, M.; Rayanil, K.-o.; Gomes, M. G.; Zheng, P.; Calkins, N.
L.; Kim, S.-Y.; Fan, Y.; Bumbu, V.; Lee, D. R.; Wacharasindhu, S.; Hong,
X. Org. Lett. 2005, 7, 143.
† DRL publication no. 661.
(9) Because of its cheap availability and high catalytic activity, Pd/C
has been used in Sonogashira coupling by us and several other groups, see
for example: (a) Barange, D. K.; Batchu, V. R.; Gorja, D.; Pattabiraman,
V. R.; Tatini, L. K.; Babu, J. M.; Pal, M. Tetrahedron 2007, 63, 1775. (b)
Batchu, V. R.; Subramanian, V.; Parasuraman, K.; Swamy, N. K.; Kumar,
S.; Pal, M. Tetrahedron 2005, 61, 9869. (c) Subramanian, V.; Batchu, V.
R.; Barange, D.; Pal, M. J. Org. Chem. 2005, 70, 4778. (d) Pal, M.; Batchu,
V. R.; Swamy, N. K.; Padakanti, S. Tetrahedron Lett. 2006, 47, 3923. (e)
For a review, see: Yin, L. X.; Liebscher, J. Chem. ReV. 2007, 107, 133.
On several occasions it has been observed that the use of Pd/C provided
normal Sonogashira products where homogenous palladium catalysts either
failed or yielded unexpected products, see for example: (f) Yin, L.;
Erdmann, F.; Liebscher, J. J. Heterocycl. Chem. 2005, 42, 1369. (g)
Marrison, L. R.; Dickinson, J. M.; Ahmed, R.; Fairlamb, I. J. Tetrahedron
Lett. 2002, 43, 8853. (h) Pal, M.; Parasuraman, K.; Gupta, S.; Yeleswarapu,
K. R. Synlett 2002, 1976.
(1) (a) Antoniotti, S.; Genin, E.; Michelet, V.; Geneˆt, J.-P. J. Am. Chem.
Soc. 2005, 127, 9976. (b) Genin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour,
C.; Geneˆt, J.-P.; Michelet, V. J. Am. Chem. Soc. 2006, 128, 3112. (c)
Hashimi, A. S. K.; Schwarz, L.; Choi, J. H.; Frost, T. M. Angew. Chem.,
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Org. Lett. 2005, 7, 5409. (e) Harkat, H.; Weibel, J.-M.; Pale, P. Tetrahedron
Lett. 2007, 48, 1439. (f) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489.
(g) Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4907. (h) Yao, T.;
Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679.
(2) The use of copper in the synthesis of an array of heterocycles was
first demonstrated by Castro et al., see: (a) Castro, C. E.; Gaughan, E. J.;
Owsley, D. C. J. Org. Chem. 1966, 31, 4071. (b) Castro, C. E.; Havlin, R.;
Honwad, V. K.; Malte, A. M.; Moje, S. W. J. Am. Chem. Soc. 1969, 91,
6464. This procedure usually requires the use of a stoichiometric amount
of the preformed cuprous acetylide and refluxing pyridine.
10.1021/jo701470h CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/02/2007
J. Org. Chem. 2007, 72, 8547-8550
8547