Regioselective construction of six-membered fused heterocyclic rings via Pd/C-mediated C–C coupling followed by iodocyclization strategy: a new entry to 2H-1,2-benzothiazine-1,1-dioxides * Deepak Kumar Barange, Venkateswara Rao Batchu, Dhillirao Gorja, Vijaya Raghavan Pattabiraman, Lakshmi Kumar Tatini, J. Moses Babu and Manojit Pal * Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, Andhra Pradesh, India Received 20 September 2006; revised 4 December 2006; accepted 14 December 2006 Available online 17 December 2006 Abstract—We describe a practical and elegant method of constructing a thiazine ring fused with benzene under mild reaction conditions. A variety of 4-iodo-2H-benzo[e][1,2]thiazine-1,1-dioxides were prepared with high regioselectivity via a two-step process involving Pd/ C-mediated C–C coupling of o-halobenzenesulfonamides with terminal alkynes, followed by iodocyclization of the resulting o-(1-alkynyl)- arenesulfonamide using elemental iodine in acetonitrile. The coupling reaction was carried out using 10% Pd/C–PPh 3 –CuI as a catalyst sys- tem in the presence of Et 3 N. The process worked well for bromides and iodides, and a wide array of terminal alkynes containing alkyl and aryl substituents were employed. The iodocyclization step tolerated a variety of functional groups such as hydroxy, chloro, cyano, and methoxy, producing the six-membered heterocyclic ring selectively. The resulting 4-iodo-2H-benzo[e][1,2]thiazine-1,1-dioxides participated in Sono- gashira, Heck, and Suzuki reactions producing a wide range of functionally substituted benzothiazines in good yields. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction Transition metal mediated coupling–cyclization processes, of which many rely on palladium catalysis and involve in situ generation of acetylenic compounds bearing a nucleo- philic substituent in close proximity to the triple bond, have proven to be an efficient and versatile way of construct- ing carbocyclic and heterocyclic structures. 1 Generally, the electrophilic cyclization of ortho-functionalized aryl (or het- eroaryl) alkynes takes place in the same pot in a tandem fash- ion. However, the efficiency of the cyclization step largely depends on the reaction conditions employed and the nature of the nucleophilic substituent present in the o-(1-alkynyl)- aryl (or heteroaryl) derivatives produced. On several occa- sions, the uncyclized acetylenic compounds have been isolated, and then cyclized separately to afford the desired products. 2 For instance, coupling of N-ethyl-2-iodo-4- methyl-benzenesulfonamide with trimethylsilyl acetylene under Sonogashira conditions afforded the corresponding ethynyl substituted product which, on treatment with NaH, yielded benzoisothiazole. 2c Recently, iodocyclization of C–C triple bond with a wide variety of nucleophiles, includ- ing N, O, and S nucleophiles, has been studied extensively 3 and proved to be an efficient method for intramolecular cy- clization. This approach is particularly attractive as it offers the advantage of further transformation of the iodide func- tional group of the resulting compound into other substitu- ents that is not often feasible via organometallic tandem coupling–cyclization method in a single pot. This has been well exemplified by the recent synthesis of a wide array of heterocycles. 4–13 Notably, the nucleophilicity of the sulfon- amide nitrogen of the o-(1-alkynyl)benzenesulfonamide moiety towards the electrophilic species produced as a result of activation of the triple bond under the conditions of iodo- cyclization has not been studied well. 13f In conjunction with our new drug discovery research, we have had a longstanding interest in the synthesis of acyclic and cyclic derivatives of the benzenesulfonamide class, 14 e.g., 1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl substituted pyrazoles 14b,c 2 (Fig. 1). In a further continuation of the above investigation, we became interested in the 2H-benzo[e][1,2]- thiazine-1,1-dioxide ring system (3, Fig. 1), a common structural subunit prevalent in numerous pharmaceutically important anti-inflammatory agents, 15,16 particularly oxicams. Earlier syntheses of 2H-benzo[e][1,2]thiazines, represented by structure 3, involve heteroannulation of 2-iodobenzene- sulfonamide with ketone enolates under photostimulated * DRL publication no. 604A. Keywords:2H-Benzo[e][1,2]thiazine-1,1-dioxides; o-Halobenzenesulfon- amide; Palladium catalyst; Terminal alkynes. * Corresponding author. Tel.: +91 40 23045439; fax: +91 40 23045438/ 23045007; e-mail: manojitpal@drreddys.com 0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2006.12.040 Tetrahedron 63 (2007) 1775–1789