Novel indole syntheses by ring transformation of b-lactam-condensed 1,3-benzothiazines into indolo[2,3-b][1,4]benzothiazepines and indolo[3,2-c]isoquinolines Lajos Fodor a, b, c, * ,P  eter Csom  os a, b, c , Antal Cs  ampai d ,P  al Soh  ar d, * a Institute of Health Care and Environmental Sanitation Studies, Szent Istv an University, H-5700 Gyula, Szent Istv an st. 17e19, Hungary b Central Laboratory, County Hospital, H-5701 Gyula, POB 46, Hungary c Institute of Pharmaceutical Chemistry, University of Szeged, and Research Group of Stereochemistry of the Hungarian Academy of Sciences, H-6720, Szeged, E€ otv€ os u. 6, Hungary d Institute of Chemistry, E€ otv€ os Lor and University, H-1518 Budapest, POB 32, Hungary article info Article history: Received 13 September 2011 Received in revised form 24 October 2011 Accepted 14 November 2011 Available online 19 November 2011 Keywords: Indole synthesis b-Lactam 1,3-Benzothiazine Ring transformation Indolo-1,4-benzothiazepine Indolo[3,2-c]isoquinoline IR, 1 H and 13 C NMR abstract ortho-Nitrophenyl-substituted condensed 1,3-benzothiazines proved to be a useful core unit in indole syntheses under non-reductive conditions. Thus, the treatment of ortho-nitro-2-aryl-2a-chloro-4H-azeto [2,1-b][1,3]benzothiazin-1-ones with sodium methoxide in methanol provided indolo-1,4- benzothiazepines via a novel rearrangement. Through the sulfur extrusion reaction of indolo[2,3-b] [1,4]benzothiazepines, further alkaloid-type indole derivatives, indolo[3,2-c]isoquinolines, were ob- tained. The structures of the new ring systems were determined by means of NMR spectroscopy. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Because of their privileged role in nature and medicine, indole compounds are of continuously increasing research interest. 1 Al- though basic synthetic pathways for the preparation of indoles have long been known, 2 several modifications of named indole syntheses have been published to provide a variety of substitution pattern and more efficient reactions, which occur under mild conditions. 1 On the other hand, new indole synthetic strategies, such as the CeH amination of azides, 3 Pd-catalysed CeH func- tionalization, 4 Nb-promoted CeF functionalization 5 and rear- rangement reactions, 6 have also been developed. Among the most widely used practical methods of indole syn- thesis, such as those of Bartoli 7 and Cadogan-Sundberg, 8 reductive N-heterocyclization utilizes the ortho-nitro group of a phenyl moiety for the construction of an indole nitrogen. In contrast, there are only rare examples (not even mentioned in main indole re- views) in which an ortho-nitroaryl compound under basic condi- tions furnishes an N-hydroxy-indole ring without the addition of any reducing agent. Reactions of this type were investigated by Wrobel et al., 9 and some earlier examples can also be found in the literature. 10 By means of these methods, N-hydroxyindoles have been obtained. 9,10 During our recent investigations of the ring-enlargement re- actions of 2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]benzothiazin-1- ones to 1,4-benzothiazepines, 11 we observed that the reaction of ortho-nitro-2-phenyl-substituted b-lactam with sodium methoxide in methanol gave an indole compound. 12 Somewhat surprisingly, treatment with a large excess of sodium methoxide led to the for- mation of indolo-1,4-benzothiazepines via a novel rearrange- ment. 12 As a continuation of that work, we set out to extend this novel indole synthesis to different derivatives and to investigate the substituent-reactivity pattern. On the other hand, these com- pounds in our view promise the possibility of rearrangement to indenoisoquinolines, which have been described as pharmacolog- ically interesting compounds. 13 2. Results and discussion The starting 4H-1,3-benzothiazines were obtained from aroy- lamide thioethers 1aee through an acid-catalysed intermolecular rearrangement with phosphorus oxychloride (Scheme 1). 14 * Corresponding authors. Tel.: þ36 66 463763; fax: þ36 66 526539 (L.F.); tel.: þ36 1 3722911; fax: þ36 1 3722592 (P.S.); e-mail addresses: fodor@pandy.hu (L. Fodor), sohar@chem.elte.hu (P. Soh ar). Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.11.036 Tetrahedron 68 (2012) 851e856