Application of metalation reactions for synthesis of sulfur/selenium-containing heterocyclic compounds

This thesis deals mainly with the synthesis of various sulfur/selenium-containing heterocyclic compounds, many of which include structural features present in several biologically active molecules, with particular emphasis on compounds of synthetic importance, such as indoles, as well as other heteroaromatic species.

In the first part, an efficient procedure toward synthesis of new 3-(arylthio)indoles based on reactions of aryl Grignard reagents or lithiated heteroaromatics with protected 3,3′-dithiobisindoles is described. In addition, the heterocyclic core of the marine alkaloid echinosulfone A, namely 3,3′-bis(indolyl) sulfone, was obtained by treatment of a 3-lithioindole derivative with bis(phenylsulfonyl) sulfide. These methodologies offer convenient synthetic routes toward a wide range of 3-(arylthio)indoles in good yields. In an extension, the sulfonation of 1-(phenylsulfonyl)indoles and pyrroles using chlorosulfonic acid in acetonitrile has been studied, leading to development of a simple and clean protocol for synthesis of the corresponding 1-phenylsulfonyl-1H-indole-3-sulfonyl chlorides and 1-phenylsulfonyl-1H-pyrrole-3-sulfonyl chlorides.

In the second part, a new practical approach is described toward the synthesis of several biologically active indolothiopyrans and related selenopyrans, as analogues of indolocarbazoles. The target compounds were accessed via treatment of C-2 metalated indoles with bis(phenylsulfonyl) sulfide or selenide, followed by cyclization of the intermediate 2,2′-di(indolyl) sulfide/selenides, involving for example triethyl orthoformate under acidic conditions.

The final section of this thesis describes a new method for synthesis of dibenzo[b,f]thiepins and related fused systems via ortho-metalation of aromatic acetals, followed by treatment with bis(phenylsulfonyl) sulfide, initially giving symmetrical diaryl-sulfides, which were subjected to deacetalization, and finally McMurry coupling. The method could also be extended to preparation of thiepin analogues such as 1-sila-, 1-germa- and 1-selenacyclohepta-2,4,6-trienes containing two fused aromatic or heterocyclic units.

List of scientific papers

I. Shirani H, Stensland B, Bergman J, Janosik T (2006). New routes to 3-(arylthio)indoles: Application to the synthesis of the 3,3-bis(indolyl)sulfone core of the marine alkaloid echinosulfone A. Synlett. 2459-2463

II. Shirani H, Janosik T (2007). Synthesis of 3-(arylthio)indoles and related compounds by reactions of metalated aromatics or heterocycles with protected 3,3-dithiobisindoles. Synthesis. 2690-2698

III. Janosik T, Shirani H, Wahlström N, Malky I, Stensland B, Bergman J (2007). Efficient sulfonation of 1-phenylsulfonyl-1H-pyrroles and 1-phenylsulfonyl-1H-indoles using chlorosulfonic acid in acetonitrile. Tetrahedron. 62: 1699-1707

IV. Wincent E, Shirani H, Bergman J, Rannug U, Janosik T (2009). Synthesis and biological evaluation of fused thio- and selenopyrans as new indolocarbazole analogues with aryl hydrocarbon receptor affinity. Bioorg Med Chem. 17(4): 1648-53. Epub 2009 Jan 15
https://pubmed.ncbi.nlm.nih.gov/19186062

V. Shirani H, Janosik T (2007). A new concise strategy for synthesis of dibenzo[b,f]thiepins and related fused symmetrical thiepin derivatives. J Org Chem. 72(23): 8984-6. Epub 2007 Oct 12
https://pubmed.ncbi.nlm.nih.gov/17929979

VI. Shirani H, Janosik T (2008). Synthesis of fused 1-sila-, 1-germa-, and 1-selenacyclohepta-2,4,6-trienes. Organometallics. 27: 3960-3963

VII. Shirani H, Janosik T (2009). New syntheses of unsymmetrical thiepins and their selenium analogues. [Manuscript]