Process for making 2-(trihaloacetyl)-3-(substituted amino)-2-propenoates

#This invention relates to a new and convenient one step process for the preparation of 2-(trihaloacetyl)-3-(substituted amino)-2-propenoates and related derivatives thereof. These compounds are useful intermediates in the synthesis of trihalomethyl substituted heterocycles for pharmaceutical and agricultural applications.

#It is known that N,N-dimethylamino derivatives are useful intermediates in organic synthesis, for example Burnett et al., Heterocycles, 45 (1997) and Kralj et al., J. Heterocyclic Chem., 34, 247 (1997). In particular, N,N-dimethylamino-methylene derivatives (1) of β-ketoesters have been utilized in the synthesis of substituted heterocyclic compounds, many of which have important pharmaceutical and agricultural applications, for example Gelin et al., Synthesis, 566 (1983) and Mosti et al., Farmaco, 47, 427 (1992).

#It also has been recognized that trifluoromethyl (CF3) groups can significantly modify the physico-chemical properties and the biological activities of compounds on which they are substituted, for example Banks et al., editors, “Organofluorine Chemistry, Principles and Applications”, Plenum Press, New York, N.Y. (1994) and Welch et al., editors, “Fluorine in Bioorganic Chemistry”, John Wiley and Sons, New York, N.Y. (1991). Therefore, the availability of the N,N-dimethylaminomethylene derivative (2) of ethyl trifluoroacetoacetate (3) would serve as a simple, but key intermediate for the construction of trifluoromethyl substituted heterocycles for pharmaceutical and agricultural applications.

#Reaction of Ethyl Trifluoroacetoacetate with DMF Dimethyl Acetal in the Presence of Acetic Acid

#To a stirred mixture of ethyl trifluoroacetoacetate (4.6 g, 0.025 mol) and acetic acid (3.0 g, 0.05 mol) in 20 ml of dry tetrahydrofuran (THF), DMF dimethyl acetal (6.2 g, 0.05 mol) was added dropwise at such a rate that the reaction temperature did not exceed 35° C. After the addition, the mixture was stirred for additional 30 minutes to complete the reaction as monitored by thin layer chromatography (TLC). The yellow reaction mixture was poured into water and then extracted with CH2Cl2. The organic extract was washed with water, brine solution, and dried (MgSO4). The solvent was removed by evaporation to give a yellow oil which was column-chromatographed (silica gel; Et2O:Hexanes/7:3) to separate the products.

#Ethyl 2-trifluoroacetyl-3-(N,N-dimethylamino)-2-propenoate (Compound 2; Rf:0.3) was obtained as an oil which solidified on standing; 3.7 g (61.8%). The compound was recrystallized from hexanes/EtOAc mixture to give an off-white solid; mp: 43-45° C.; 1H NMR (CDCl3) δ 1.3 (t, 3H); 2.9 (s, 3H); 3.3 (s, 3H); 4.4 (q, 2H); 7.3 (s, 1H). 19F NMR (CDCl3)-72 ppm.