Regio-and diastereoselective synthesis of trans -dihydrofuran-3- carboxamides by radical addition of 1,3-dicarbonyl compounds to acrylamides using manganese(III) acetate and determination of exact configuration by X-ray crystallography

In this study, we investigated the radical addition of 1,3-dicarbonyl compounds to acrylamide derivatives including phenyl, 2-thienyl and 5-methyl-2-furyl groups mediated by manganese(III) acetate. trans -3-Carboxamide-dihydrofurans were obtained in modarate to good yields, as well as regio-and diastereoselectievly. Structural analyses of these compounds were made by NMR techniques such as HMBC and NOSY spectra. Also, exact configuration and structures of these ( 7b , 7i and 7j ) compounds were determined by X-ray crystallography.


Results and Discussion
Treatments of (2E)-3-phenylacrylamide 5a with dimedone 6a and 1,3-cyclohexandione 6b in the presence of Mn(OAc)3 in HOAc in a 2:1:3 molar ratio (1,3-dicarbonyl : acrylamide : Mn(OAc)3) at 70 °C gave 2-phenyl-3-carboxamide-dihydrobenzofurans 7a in 68% and 7b in 55% yields (Table 1).In the 1 H NMR spectra of these compounds, the H-2 and H-3 (C8-H and C7-H in the x-ray graphic for 7b, respectively) protons of the dihydrobenzofurans 7a and 7b appeared as two doublets with a vicinal coupling constant of J 6.0 Hz.The H-2 protons (δ 6.14 and 6.27 ppm) resonate at low field due to inductive effect of neighbouring etheric oxygen atom.Since the HMBC spectra of 7a shows that the H-2 proton correlates with the ortho-carbon of phenyl resonates at 125.3 ppm, phenyl group attached to the C-2 carbon in the dihydrobenzofuran ring.Also, we verified absolute configuration and the assignment of regioand diastereoselectivity through X-ray analysis of 7b (2R, 3R) in Figure 2.
Related unsaturated amides used in radical reactions regained with column chromatography from each crude products in 15-25 % yields.To accurately understand if there are any possible compounds (especially cis-isomers) formed in this type of radical addition reactions , the crude products from experiments 7a and 7e were analysed with LC-MS (without purification).The results from these analyses showed that there are no isomers with same masses formed beside the trans-products.A : Yield of isolated product based on the conjugated amides 5b and 5c.Moreover, structural assignment of compounds 7i (2S, 3S) and 7j (2R, 3R) were further characterized by x-ray single crystal analysis (Figs 3 and 4), as a result of this, we can conclude that these vicinal protons are definitely in trans-configuration.

Conclusions
We obtained 3-carboxamide-dihydrofurans in good yields as diastereoselectively by the manganese(III) acetate mediated reaction of acrylamide derivatives and 1,3-dicarbonyl compounds.It is seen that coupling constants of vicinal protons of the dihydrofurans in this work are 1-1.5 Hz less than that of 3-cyano-carboxamides.These results show that the substituents attached on the C=C double bond in the dihydrofuran rings significantly effect on the coupling constants of vicinal protons.Our studies based on the X-ray analyses continue to determine substituent effects on the coupling constant of vicinal protons and definite configurations of some dihydofurans whose structure is open to debate.

Experimental Section
General.Melting points were determined on an electrothermal capillary melting point apparatus.IR spectra (ATR) were obtained with a Bruker Tensor-27 400-4000 cm -1 range with 2 cm -1 resolution. 1 H NMR, 13 C NMR, HMBC, NOSY, spectra were recorded on a Bruker Avance DPX-400 MHz and Varian Mercury-400 High performance Digital FT-NMR spectrophotometers.High Resolution Mass Time-of-Flight spectra (TOF) were measured on a Agilent 1200/6210 LC/MS spectrophotometer.Unit cell measurements and intensity data collection was performed on an Bruker APEX II QUAZAR three-circle diffractometer using monochromatized Mo Kα microfocus sealed-tube (λ = 0.71073 Å) using φ and ω technique at 120 K. Thin layer chromatography (TLC) was performed on Merck aluminum-packed silica gel plates.Purification of the products was performed by column chromatography on silica gel (Merck silica gel 60, 40-63 mm) or preparative TLC on silica gel of Merck (PF254-366nm).

General procedure for dihydrofuran-carboxamides (7).
A solution of manganese(III) acetate dihydrate (3 mmol, 0.804 g) in 10 mL of glacial acetic acid was heated on oil bath under a nitrogen atmosphere at 80 °C until it dissolved.After Mn(OAc)3 dissolved completely, the solution was cooled down to 60 °C.A solution of 1,3-dicarbonyl compound (2 mmol) and acrylamide (1 mmol) in 5 mL of acetic acid was added to this mixture and the temperature was raised to 70 °C.The reaction was complete when the dark brown color of the solution disappeared (monitoring by TLC).30 mL water was added to the solution and extracted by CHCl3 (3x20 mL).The combined organic extracts were neutralized with 10 mL of satd NaHCO3 solution, and dried over anhydrous Na 2 SO 4 and evaporated.The crude products were purified by column chromatography or preparative TLC (20x20 cm plates, 2 mm thickness) using nhexane/EtOAc (1:1) as eluent.

Figure 2 .
Figure 2. Molecular structure of the compound 7b.

Figure 3 .
Figure 3. Molecular structure of the compound 7i.

Figure 4 .
Figure 4. Molecular structure of the compound 7j.Displacement ellipsoids are drawn at the 50 % probability level.H-atoms are shown as small spheres of arbitrary radii.

Table 1 .
The