Synthesis of trifluoromethylated dihydrofurans by addition of 1,3-dicarbonyl compounds to alkenes promoted by manganese(III) acetate

Radical addition reaction of trifluoromethyl-1,3-dicarbonyl compounds (1a-e) with various alkenes (2a-f) was investigated in the presence of manganese(III) acetate. As a result of these reactions trifluoromethyl ketone substituted dihydrofuran and bicyclic enol ether derivatives were obtained. A formation of dihydrofuran’s mechanism was proposed for all compounds. Radical addition reactions with 1,1-disubstituted alkenes were obtained in good yields, however with cyclic alkenes were shown poor yields.


Introduction
The use of organofluorine compounds has been attracted significant attention due to the unique influence of a fluorine substituent on the chemical, physical and physiological properties of these compounds.Thus, organofluorine chemistry impacts many areas of everyday life and technology. 1 These compounds show a large number of industrial uses in lubricants, fire extinguisher agents, surfactants, pharmaceuticals and agrochemicals. 2 Since the fluorine atom is highly reactive and difficult to control, the synthesis of organic fluorine compounds is an ongoing area of research in synthetic organic chemistry. 3raditional methods for the synthesis of organofluorine compounds are direct fluorination 4 and fluoroalkylation. 5Manganese(III) mediated oxidative radical addition has become a valuable method for the formation of C-C bonds in the last three decades.Since manganese(III) acetate is effective for the formation of C-C bonds within the intramolecular addition to form lactones, 6 dihydrofurans, 7 furans, 8 and lactams. 9Another way of obtaining organofluorine compounds is addition of the corresponding fluorinated 1,3-dicarbonyl compounds with unsaturated systems mediated transition metal salts such as Mn 3+ , Ce 4+ , Ag + etc. 10 Trifluoromethyl substituted dihydrofuran compounds may be achieved by using this method.
In order to obtain highly functionalized dihydrofuran compounds, 1,1-disubstituted alkenes (2c-f) were also used with trifluoromethyl-1,3-dicarbonyl compounds (1a-e) in the presence of manganese(III) acetate (Table 2).Treatment of 1c with 4-fluorophenyl bearing alkene 2c and 2d, gave the adduct products 3h and 3k in 75% and 73% yields, respectively.Similarly, the addition reactions of alkenes 2c and 2d with the 2-naphthyl-1,3-dicarbonyl compound 1d afforded 3i and 3l with 73% and 69% yields.On the other hand, when the yields of 3k-n were compared, 3k (73%) and 3l (69%) had better yields than the ones of 3m (37%) and 3n (50%) due to the phenyl group is better stabilizer than methyl.The characterization of the obtained compounds was realized by 1 H-NMR spectra.H-4 protons of the 3f-l are appeared in the range of 3.73-4.06ppm as singlet.But, an AB system with 2 JAB 14.4-14.8Hz was found for the diastereotopic H-4 protons of 3m and 3n.
As a result of these reactions, we propose a mechanism depicted in Scheme 1.According to the mechanism, while Mn 3+ is reduced to Mn 2+ a C-radical A is formed.Then, addition of A to alkene forms radical intermediate B, meanwhile radical B is oxidized to the carbocation C by an equivalent amount of manganese(III) acetate.Eventually, addition of C can occur with two pathways i and ii.When the reaction follows pathway i, product E is formed while with pathway ii forms product G.Consequently, we only observed E and differentiated the compounds E and G by using 13 C-NMR.Scheme 1. Mechanism for the radical addition reaction of trifluoromethyl-1,3-dicarbonyl compounds with alkenes in the presence of manganese(III) acetate.
According to the reaction mechanism proposed in Scheme 2, it is possible to afford compounds A or B depended on the addition of 1,3-dicarbonyl compound to alkene resulting in the substituon of CF3 group to carbonyl carbon and C2 carbon of dihydrofuran.11m But a single product was obtained.So, the exact structure of the compound was determined by 13 C-NMR spectra.In the spectrum of 3a, carbonyl carbon gives a quartet at 174.8 ppm ( 2 JC-F 34. 3 Hz)  while the C2 carbon gives singlet at 166.5 ppm.If CF3 substituted to C2 carbon, it would appear as quartet at about 150 ppm.The reason of obtaining only single isomer A is due to the cyclization of the most stable form of 1,3-dicarbonyl compound 14 (Scheme 1, product E).Also, it is observed that carbonyl carbon split into quartet at 173.3-176.5 ppm ( 2 JC-F 33.6-35.5 Hz) in all resulting compounds (3a-o).This shows that the CF3 is substituted to carbonyl carbon not C2 on the dihydrofuran.Scheme 2. Two possible product A and B after the radical addition of 1,3-dicarbonyl compounds 1a-e to corresponding alkenes 2a-f.

Conclusions
In this paper, we easily obtained highly useful intermediates for the pharmaceutically important trifluoromethyl ketone containing dihydrofuran compounds.In addition, a synthetic approach in the presence of manganese(III) acetate with radical addition reaction has been investigated for the synthesis of trifluoromethyl substituted dihydrofuran compounds apart from the fluoroalkylation and direct fluorination to obtain trifluoromethyl ketone compounds.
General procedure for the synthesis of dihydrofurans (3a-o).Manganese(III) acetate dihydrate (0.83 g, 3 mmol) in 20 mL of glacial acetic acid was heated under nitrogen atmosphere to 80 °C until it dissolved.After the solution cooled down to 60 °C, a solution of 1,3-dicarbonyl compound (2 mmol) and alkene (1 mmol) in 5 mL acetic acid was added to this mixture.The reaction was completed when the initial dark brown color of the solution disappeared.Water (20 mL) was added to this solution and extracted with CHCl3 (3x20 mL).The combined organic phases were neutralized with saturated NaHCO3 solution, dried over anhydrous Na2SO4 and evaporated.The crude products were purified by column chromatography on silica gel or preparative TLC using n-hexane/EtOAc as eluent.