The goal of the present study was the synthesis of bis-heterocyclic compounds starting with L-prolinol and arylglyoxals 1. The initial formation of bis-heterocycles 2 was in line with the results of a similar study already described in the literature [4]. However, we found that they are labile compounds and smoothly undergo diastereoselective isomerisation in the presence of an acidic catalyst yielding bicyclic morpholinones 3.

The latter were used for nucleophilic trifluoromethylation reaction via treatment with (trifluoromethyl)trimethylsilane TMS-CF₃ (Ruppert-Prakash reagent) in the presence of cesum fluoride CsF as a catalyst. Trifluoromethylated morpholinols 4 with trans orientation of the CF₃ and Ar groups were formed in a complete stereoselective manner. 

The mechanism of the aroyl 1,2-migration leading to the formation of bicyclic morpholinones 3 and the influence of the para-substituent on the rate of isomerisation will be discussed.

References:

[1] a) B. N. Balasubramanian, et al., Bioorg. Med. Chem. Lett., 2003, 13, 1419; b) A. P. Kourounakis, A. N. Matralis, A. Nitikatis, Bioorg. Med. Chem., 2010, 18, 7402.

[2] a) V. A. Petrov, Ed., Fluorinated Heterocylic Compounds: Synthesis, Chemistry, and Applications, J. Wiley & Sons, Inc., Hoboken, NJ, 2009; b) V. G. Nenajdenko, Ed., Fluorine in Heterocyclic Chemistry, Springer Verlag, Berlin, 2013; c) G. Mlostoń, E. Obijalska, H. Heimgartner, J. Fluorine Chem., 2010, 131, 829 (and references cited therein).

[3] J.-P. Begue, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, Wiley & Sons, Hoboken, NJ. 2008.

[4] Y. Ukaji, K. Yamamoto, M. Fukui, T. Fujisawa, Tetrahedron Lett., 1991, 32, 2919.

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1. On the border line of concerted and non-concerted mechanisms in the [2+3]-cycloaddition reactions 
2. Studies on Flash Vacuum Thermolysis of Thiones of Selected N-, O-, and S-heterocycles