Table 1. Evaluation of the solvent and reaction times; oxidant = 1 mol. eq. m CPBA - PowerPoint PPT Presentation

amelia
table 1 evaluation of the solvent and reaction times oxidant 1 mol eq m cpba n.
Skip this Video
Loading SlideShow in 5 Seconds..
Table 1. Evaluation of the solvent and reaction times; oxidant = 1 mol. eq. m CPBA PowerPoint Presentation
Download Presentation
Table 1. Evaluation of the solvent and reaction times; oxidant = 1 mol. eq. m CPBA

play fullscreen
1 / 1
Download Presentation
Table 1. Evaluation of the solvent and reaction times; oxidant = 1 mol. eq. m CPBA
106 Views
Download Presentation

Table 1. Evaluation of the solvent and reaction times; oxidant = 1 mol. eq. m CPBA

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. CONVENIENT ONE-POT FORMATION OF HIGHLY FUNCTIONALIZED 5-HALOTHIAZOLES Eduard Dolušić, Sara Modaffari, Lionel Pochet, Johan Wouters, Bernard Masereel and RaphaëlFrédérick NAmurMEDIcine Center (NAMEDIC), NARILIS, 61 rue de Bruxelles, B-5000 Namur, Belgium NAMEDIC 1. Introduction Thiazoles are an important class of heterocycles. They are present in many natural products possessing biological activity.1A growing body of medicinal chemistry literature reports thiazole derivatives in the treatment of various pathologies.2 These heteroaromatics have also found applications in materials science, e. g. as liquid crystals.3 • Halogenated thiazoles are useful synthetic intermediates for introducing this scaffold into more complex molecules. Older methods for thiazole halogenation in the 5-position, which rely on the use of elemental halogens,4a,b are still in use today4c despite halogen toxicity and low atom economy of the transformation. Some recent alternatives include the application of N-halosuccinimides,5a copper(II) halides5b or metalations of the thiazole ring followed by quenching the reactive intermediates with electrophiles.5c However, all these methods are based on transformations of pre-formed 1,3-thiazoles and often include relatively lengthy reaction times or silylated starting thiazoles. In attempted preparations of substituted thiazole N-oxides in our laboratory, treatment of 2-aminothiazoles with m-chloroperoxybenzoicacid (mCPBA) in dichloromethane did not afford the desired products (Scheme 1). Spectral analyses (NMR, not shown; LC/MS, Figure 1) proved that corresponding 5-bromothiazoles were formed instead in very good yields. This can be explained by the fact that the starting compounds had, in fact, been obtained as hydrobromide salts. Rapid oxidative bromination mediated by mCPBA then occurred in the 5-position of the thiazole ring. We decided to explore this interesting transformation in more detail. Scheme 1. mCPBA-mediated 5-bromothiazole formation 2. Synthesis and its scope Scheme 2. General synthetic scheme for (5-bromo-4-phenyl-thiazol-2-yl)-phenylamineand its 5-H derivative Figure 1. LC/MS chromatogram of 5-bromothiazole 1 We next aimed at exploring an one-pot operation, i. e. adding mCPBA directly to the thiazole forming reaction mixture (Scheme 2). The ‘5-Br’ / ‘5-H’ was chosen as the model system and the absolute yields of the two thiazoles were determined by LC/MS analysis. Ethanol and DMF worked best as solvents, with reaction times as short as 5 min at room temp. per step (Table 1). However, adding mCPBA simultaneously with the a-bromoketone and thiourea (entry 3’’) caused a sharp drop in the 5-Br yield. Being more practical to handle than DMF, ethanol was chosen for most subsequent experiments. All other oxidants investigated were inferior to mCPBA in terms of 5-Br yield (Table 2), including Oxone® in MeCN, a system working fine in a number of other oxidative halogenations.6a Adding more than 1 equivalent mCPBA could improve the bromination yield up to a certain extent, but increasing its quantity further caused the yields to drop again (Table 3; acetone was chosen as solvent because the formation of both 5-Br and 5-H could clearly be observed). Table 3. Evaluation of the mCPBA quantity; solvent = acetone; rt = 10’ + 10’ Finally, the chosen conditions (0.3 M of all reagents in ethanol) were applied to probe the syntheses of a range of brominated thiazoles (Table 4). mCPBA was added upon completion of the first (Hantzsch) step as judged by TLC. In some cases, the Hantzsch step required extended reaction times or microwave heating. In most cases, max. 10 min with mCPBA at room temperature was enough for the completion of the oxidative bromination reaction. The final products were typically obtained by trituration with cyclohexane, filtration and drying. No chromatography on silica was usually necessary. The ratio of the brominated vs. non-brominated compound was determined by LC/MS. The reaction scope was successfully extended to 5-chlorination in a model reaction (Scheme 3). The exact reaction mechanism is not completely clear at this point, although in situ formationof the active halogenating species by oxidation of X- with mCPBAcan be assumed with great probability. Table 1. Evaluation of the solvent and reaction times; oxidant = 1 mol. eq. mCPBA Table 2. Evaluation of the oxidant (1 mol. eq.); rt = 10’ + 10’; *) urea hydrogen peroxide; **) 2 KHSO5·KHSO4·K2SO4 • Table 4. Reaction conditions and outcomes of syntheses of (bromo)thiazoles with various substitution patterns. • ƞ = overall yield of the thiazole products, followed by the relative yield of the 5-brominated product; • N. D. = not done Scheme 3. One-pot 5-chlorothiazole synthesis 3. Conclusions and perspectives Highly functionalized 5-halothiazoles could be prepared quickly and efficiently in an one-pot operation from simple starting materials and without using catalysts and harsh conditions or reagents. This methods fits into the modern developments of environmentally friendly and biomimetic methods of oxyhalogenations, which have so far only been described for a limited range of aromatic substrates.6 Attempts are in progress to further functionalize these 5-halothiazoles by known chemical methods to give rise to pharmacologically interesting products (e. g. Scheme 4). Scheme 4. Envisaged synthesis of anti-Alzheimer's compound 4.7 4. References • 1) (a) Jin, Zh. Nat. Prod. Rep. 2006,23, 464; (b) Turner, G. L. et al, Angew. Chem. Int. Ed. 2007, 46, 7996; (c) Bagley, M. C. et al, Chem. Rev. 2005,105, 685; (d) Altmann, K.-H. et al, ChemMedChem2007, 2, 396. • 2) (a) Huang, W. H. et al, Curr. Med. Chem. 2009,16, 1806; (b) Matulenko, M. A. et al, Curr. Top. Med. Chem. 2009, 9, 362; (c) McInnes, C., Drug Discov. Today2008,13, 875; (d) Cabrera, D. G. et al, J. Med. Chem. 2011, 54, 7713. • 3) (a) Kiryanov, A. A., et al, J. Org. Chem.2001, 66, 7925; (b) Mori, A., et al, J. Am. Chem. Soc. 2003, 125, 1700. • 4) (a) Kaye, P. T., et al, J. Chem. Soc. Perkin Trans. 1, 1981, 2335; (b) Begtrup, M. and Hansen, L. B. L., Acta Chem. Scand. 1992, 46, 372; (c) Grubb, A. M., et al, Synthesis2012, 44, 1026. • 5) (a) Altman, M. D., et al, 2011, WO2011075515 (A1); (b) Siméon, F. G., et al, J. Org. Chem. 2009, 74, 2578; (c) Dunst, C. and Knochel, P., J. Org. Chem. 2011, 76, 6972. • 6) (a) Krishna Mohan Kandepi, V. V. and Narender, N., Synthesis 2012, 44, 15; (b) Rothenberg, G. andClark, J. H.; Green Chemistry 2000, 2, 248. • 7) Lagoja, I., et al, Eur. J. Pharm. Sci.2011, 43, 386. • This work is supported by the FNRS and the Walloon Region (BioWin project CANTOL: Convention n° 5678).