Microwave assisted synthesis of novel 4,5,6,7-tetrahydro-1,3-thiazepines, 5,6-dihydro-4H-1,3-thiazines and 2-thiazolines

MARÍA CRUZ MOLLO; JUAN A. BISCEGLIA; NATALIA B. KILIMCILER; LILIANA R. ORELLI

San Pablo

Congreso; 46th World Chemistry Congress; 2017

Sociedade Brasileira de Química

Microwave assisted synthesis of novel 4,5,6,7-tetrahydro-1,3-thiazepines, 5,6-dihydro-4H-1,3-thiazines and 2-thiazolines.María C. Mollo, Juan A. Bisceglia, Natalia B. Kilimciler, Liliana R. OrelliUniversidad de Buenos Aires. CONICET. FFyB. Departamento de Química Orgánica. Junín 956, (1113) Buenos Aires, Argentina.mcmollo@ffyb.uba.arS,N-heterocycles are compounds of great interest because of their biological and industrial importance. They are present in natural and synthetic biologically active products as anti-HIV, antifungals, antineoplastics, and deferrating agents, among others.1 In addition, chiral thiazolines and bis-thiazolines are widely employed as ligands in asymmetric catalysis.2 Because of the importance of 2-thiazolines, a large number of methods have been developed for their synthesis. Current methods rely on condensation of nitriles, carboxylic acids and esters withbeta-amino thiols or beta-amino alcohols (with the inclusion of a sulfuration step).1 Concerning the 6-membered homologues (thiazines) the usual synthetic approaches for their preparation are an extension of those developed for 2-thiazolines.3 In contrast to their five and six-membered homologues, 4,5,6,7-tetrahydro-1,3-thiazepines have remained almost unexplored, probably due to the lack of suitable methods for their synthesis. There is only one derivative reported in the literature which was obtained with modest yield and long reaction time.4Polyphosphoric acid (PPA) ethyl and trimethylsilyl esters (PPE and PPSE, respectively) find application in a variety of organic reactions, acting as mild irreversible dehydrating agents of the Lewis acid type that activate oxygen and nitrogen functionalities toward nucleophilic attack and, at the same time, react chemically with water. We have previously demonstrated their efficiency in the microwave-assisted synthesis of various diaza heterocycles. More recently, we have investigated their use in the heterocyclization of amidoalcohols leading to 2-oxazolines and their 6 and 7-membered homologues.5In this work, we present a general method for the synthesis of 4,5,6,7-tetrahydro-1,3-thiazepines, 2-thiazolines and 5,6-dihydro-4H-1,3-thiazines (1). We have explored two alternative synthetic approaches relying on microwave assisted heterocyclizations promoted by PPE/PPSE. After careful optimization of each individual step, Path B turned out to be the most efficient route for the synthesis of the S,N-heterocyles affording good to high yields of the desired heterocycles in remarkably short reaction times. The successful results obtained on seven membered heterocycles are of particular relevance, as no general methods are available for their preparation. Additionally, this method represents a new application of polyphosphate esters.References1 Gaumont, A.C.; Gulea, M.; Levillain, J.; Chem. Rev. 2009, 109, 1371, and references therein.2 Mellah, M.; Voiturez, A.; Schultz, E.; Chem. Rev. 2007, 107, 5133.3 Nishio, T.; Konno, Y.; Ori, M.; Sakamoto, M.; Eur. J. Org. Chem. 2001, 3553.4 Wipf, P.; Hayes, G.B, Tetrahedron, 1998, 54, 6987.5 Mollo, M. C.; Orelli, L.R.; Org. Lett. 2016, 18, 6116.AcknowledgementsThis work was supported by the University of Buenos Aires (Grant 20020130100466).