Synthesis and characterization of piperazine-substituted dihydrofuran derivatives viaMn(OAc) 3 mediated radical cyclizations

The aim of this study is to synthesize novel piperazine-containing dihydrofuran compounds (3a-n)from radical additions and cyclizations of diacyl and alkyl-acyl piperazine derivatives (1a-h) with 1,3-dicarbonyl compounds (2a-c) mediated by Mn(OAc) 3 for the first time. From the reactions of 1a-c with dimedone (2a);1a, 1c, and 1d with acetylacetone (2b); and 1a with ethylacetoacetate(2c) ,the dihydrofuran-piperazine compounds 3a-c, 3d-f, and 3g were obtained in medium to high yields (31%–81%), respectively. In addition, dihydrofuran-piperazine compounds 3h-j and 3k-n were prepared at low to medium yields (20%–40%) from the reactions of 1e-g with 2a and 1e-h with 2c , respectively.

The results of the reactions of 1a-d with 2a-care given in Table 1. The treatment of 1a-c with dimedone (2a) gave dihydrofurans3a (81%), 3b (50%), and 3c (64%), respectively, in moderate-to-good yields. Although compounds 1a and 1b are similar, there is a significant difference in product yields obtained from them (3aand 3b, respectively). The steric hindrance originated through methyl substitution on alkene moiety of 1b caused the relatively low yield of 3b. Compounds 3d (73%), 3e (52%), and 3f (31%) were obtained as a result of reactions between 1a, 1c, and 1d with 2b in moderate-togood yields, respectively. Through the reaction of 1a with 2c, compound 3g was isolated at a 60% yield. All cyclizations occurred at the aromatic-ring-carrying sides of the piperazines. This is because radical intermediates formed adjacent to aromatic rings have greater stability than those formed adjacent to methacryloyl alpha carbons on carbon atoms (Figure, Intermediate C and F).
Radical cyclizations of unsaturated diacyl and allyl-acyl piperazine compounds (except 1h) occurred regioselectively through 3-arylpropenoyl moiety. However, no cyclization product that formed over ally or methacryloyl moiety was isolated (except 3n). This is due to the fact that radical intermediates formed adjacent to the aromatic rings are much more stable than those formed on allyl or methacryloyl moieties. Similarly, since the radical intermediates formed on methacrylic moiety are much more stable than those formed on the ally group, radical cyclization of 1h and 2c occurred through methacryloyl group to form dihydrofuran-piperazine (3n). The 1 H NMR spectra of obtained compounds 3a, 3c-e, and 3g-m show that vicinal dihydrofuran couplings are J trans = 5.2-7.6 Hz (in the literature J trans = 2.5-7.6 Hz and J cis = 8-11 Hz) [45,46,48,49,[53][54][55][56], thus it was determined that these molecules are trans compounds.
The proposed mechanism for the formation of dihydrofuransis is explained in Figure. According to this mechanism, the enol form of dimedone (A) reacts with Mn(OAc) 3 , and an alpha carbon radical B is formed, while Mn 3+ reduces to Mn 2+ . There are two possible pathways for this alpha carbon radical to attach to 1a. Radical intermediate C can be formed by following pathway-i, and radical intermediate F can be formed by following pathway-ii. On pathway-i, oxidation of C to carbocation D with Mn(OAc) 3 and intramolecular cyclization of D forms the product E. Similarly, by following pathway-ii, product H is formed. However, on the 1 H-NMR spectra of the obtained products, the chemical shifts of two terminal alkene peaks of methacryl group were observed in the range of 5.25-5.00 ppm. Additionally, two vicinal proton peaks of dihydrofurans around 6.00 and 4.51 ppm (J trans = 5.2-6.4 Hz) were observed. According to this information, it was determined that the radical cyclization of 1a-d with 2a-c followed the pathway-i, and products 3a-g formed; however, the other possible products (H) were not isolated.

General synthesis procedure and spectroscopic data of diacyl (3a-g) piperazine-dihydrofuran compounds
A solution of Mn(OAc) 3 (2mmol, 0.53 g) in 15 mL of glacial acetic acid was heated to 80 °C until dissolved. Then, the solution temperature was set to 65 °C. A solution of the corresponding 1,3-dicarbonyl compound (2a-c) (1mmol) and suitable unsaturated piperazine compound (1a-d)(1.2 mmol) in 2 mL of acetic acid was added to Mn(OAc) 3 solution.
The mixture was stirred, and the disappearance of the dark brown color indicated that the reaction was finished (15-60 min). Water was added, and the crude product was extracted with chloroform (20×3 mL). Combined organic phases were neutralized with saturated NaHCO 3 solution, dried over anhydrous Na 2 SO 4 , and evaporated. The residue was purified with column chromatography (silica gel 60, 40-60 mm) using chloroform-acetone (85:15) as eluent. All compounds were further purified by preparative TLC (PF 254-366nm ) before spectroscopic analyses.

General synthesis procedure and spectroscopic data of alkyl-acyl (3h-n) piperazines-dihydrofuran compounds
A solution of Mn(OAc) 3 (2mmol, 0.53 g ) in 15 mL of glacial acetic acid was heated to 80 °C until dissolved. Then, the solution temperature was set to 65 °C. A solution of the corresponding 1,3-dicarbonyl compound (2a or 2c) (1mmol) and the suitable unsaturated piperazine compound (1e-h) (1.2 mmol) in 2 mL of acetic acid was added to Mn(OAc) 3 solution. The mixture was stirred, and the disappearance of the dark brown color indicated that the reaction was finished (15-60 min). Water was added, and the crude product was extracted with chloroform (20 × 3 mL). Combined organic phases were neutralized with saturated NaHCO 3 solution, dried over anhydrous Na 2 SO 4 , and evaporated. The residue was purified with column chromatography (silica gel 60, 40-60 mm) using chloroform-acetone (85:15) as eluent. All compounds were further purified by preparative TLC (PF 254-366nm ) before spectroscopic analyses.