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Turkish Journal of Chemistry logoLink to Turkish Journal of Chemistry
. 2020 Oct 26;44(5):1303–1313. doi: 10.3906/kim-2003-23

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

Sait SARI 1, Mehmet YILMAZ 1,*
PMCID: PMC7751941  PMID: 33488231

Abstract

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.

Keywords: Piperazine, dihydrofuran, Mn(OAc) 3, radical cyclization

1. Introduction

Heterocycles are important compounds and have gathered much attention due to their biological properties, and many synthetic drugs contain heterocyclic scaffolds [1,2]. Piperazine is considered a privileged scaffold in medicinal chemistry [3], and there are many biological activity studies in the literature for piperazine-bearing compounds such as antibacterial [4], anticonvulsant [5], antituberculosis [6], antiviral [7], anticancer [8], and acetylcholinesterase inhibition [9,10]. Piperazinecan be found in active drug ingredients such as imatinib [11], sildenafil [12], indinavir [13], and gatifloxacin[14]. In addition, there have been anticonvulsant activity [15], monacylglyserine lipase inhibition [16], antimicrobial [17], and antiinflammatory activity studies [18]for cinnamylpiperazines and antimycobacterial [19], antiischemic [20], and antiparasitic activity studies [21] for acrylamide piperazine derivatives.

Dihydrofurans have gathered much attention due to their biological activities and have great potential as building blocks for pharmaceutical agents. Sarcophytoxide [22], clerodin [23], fercoprolone [24], and austocystin [25] are natural bioactive compounds that carry dihydrofuran moieties. Dihydrofurans can be obtained via transition metal salts which are capable of transferring single electrons (Mn 3+ , Ce 4+ , Co 3+ , etc.) to active methylene compounds to form α-carbon radicals. The addition of these radicals to unsaturated systems is used to generate new C-C bonds [26–28]. Manganese (III) acetate [29–33] and cerium(IV) ammonium nitrate (CAN) [34–38] are widely used in these reactions. Our research group has reported radical addition and cyclization reactions with CAN [39–42] and radical cyclization reactions of 1,3-dicarbonyl derivatives with various unsaturated systems, such as conjugated amide derivatives [43–47]and heteroaromatic conjugated alkenes [48–51].

In this work we report new dihydrofuran-containing piperazine compounds (3a-n) viaMn(OAc) 3 mediated radical cyclization in medium to high yields. All new compounds were characterized by 1 HNMR, 13 C NMR, HRMS, and FTIR spectroscopy.

2. Results and discussion

In our previous work [52] diacyl and alkyl-acylpiperazine derivatives were obtained; in this work these compounds (1a-h) were used as starting reagents to synthesize piperazine-containing dihydrofuran molecules.

Novel piperazine–dihydrofuran compounds (3a-n) were synthesized via Mn(OAc) 3 mediated oxidative radical cyclization reactions of unsaturated diacyl (1a-d) and alkyl-acyl (1e-h) piperazine derivatives ,as well as 1,3-dicarbonyl compounds such as dimedone (2a), acetylacetone (2b), and ethylacetoacetate (2c). All radical cyclizations were carried out at 1.2:1:2 molar ratios [piperazine derivative:1,3-dicarbonyl:Mn(OAc) 3 ].

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-to-good 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).

Table 1.

Radical cyclizations of 1a-d with 2a-c.

Entry Piperazine 1,3-dicarbonyl Product Yield (%) a
1 graphic file with name turkjchem-44-1303-fig_t1_11.jpg graphic file with name turkjchem-44-1303-fig_t1_12.jpg graphic file with name turkjchem-44-1303-fig_t1_13.jpg 81
2 graphic file with name turkjchem-44-1303-fig_t1_21.jpg graphic file with name turkjchem-44-1303-fig_t1_22.jpg graphic file with name turkjchem-44-1303-fig_t1_23.jpg 50
3 graphic file with name turkjchem-44-1303-fig_t1_31.jpg graphic file with name turkjchem-44-1303-fig_t1_32.jpg graphic file with name turkjchem-44-1303-fig_t1_33.jpg 64
4 graphic file with name turkjchem-44-1303-fig_t1_41.jpg graphic file with name turkjchem-44-1303-fig_t1_42.jpg graphic file with name turkjchem-44-1303-fig_t1_43.jpg 73
5 graphic file with name turkjchem-44-1303-fig_t1_51.jpg graphic file with name turkjchem-44-1303-fig_t1_52.jpg graphic file with name turkjchem-44-1303-fig_t1_53.jpg 52
6 graphic file with name turkjchem-44-1303-fig_t1_61.jpg graphic file with name turkjchem-44-1303-fig_t1_62.jpg graphic file with name turkjchem-44-1303-fig_t1_63.jpg 31
7 graphic file with name turkjchem-44-1303-fig_t1_71.jpg graphic file with name turkjchem-44-1303-fig_t1_72.jpg graphic file with name turkjchem-44-1303-fig_t1_73.jpg 60
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a) Isolated yield based on 1,3-dicarbonyl compounds.

Figure.

Figure

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Proposed mechanism of Mn(OAc) 3 mediated radical cyclization.

The results of the reactions of 1e-hwith 2a are given in Table 2. From the reactions of ally piperazine derivatives (1e-g) with 2a, dihydrofurans 3h (30%), 3i (32%), and 3j (20%) were obtained in low yields. By comparing the yields of 3a (81%) with 3i (32%) and yields of 3c (64%) with 3j (20%) it can be deduced that yields of methacryloyl-piperazine–substituted dihydrofurans are higher than yields of allyl-piperazine–substituted dihydrofurans. Additionally, reactions of 1e-g with 2c formed 3k (25%), 3l (40%), and 3m (20%) in low yields, respectively. Reactions of ally-methacryloyl piperazine (1h) with 2c formed 3n (20%) in low yields.

Table 2.

Radical cyclizations of 1e-h with 2a and 2c.

Entry Piperazine 1,3-dicarbonyl Product Yield (%) a
1 graphic file with name turkjchem-44-1303-fig_t2_11.jpg graphic file with name turkjchem-44-1303-fig_t2_12.jpg graphic file with name turkjchem-44-1303-fig_t2_13.jpg 30
2 graphic file with name turkjchem-44-1303-fig_t2_21.jpg graphic file with name turkjchem-44-1303-fig_t2_22.jpg graphic file with name turkjchem-44-1303-fig_t2_23.jpg 32
3 graphic file with name turkjchem-44-1303-fig_t2_31.jpg graphic file with name turkjchem-44-1303-fig_t2_32.jpg graphic file with name turkjchem-44-1303-fig_t2_33.jpg 20
4 graphic file with name turkjchem-44-1303-fig_t2_41.jpg graphic file with name turkjchem-44-1303-fig_t2_42.jpg graphic file with name turkjchem-44-1303-fig_t2_43.jpg 25
5 graphic file with name turkjchem-44-1303-fig_t2_51.jpg graphic file with name turkjchem-44-1303-fig_t2_52.jpg graphic file with name turkjchem-44-1303-fig_t2_53.jpg 40
6 graphic file with name turkjchem-44-1303-fig_t2_61.jpg graphic file with name turkjchem-44-1303-fig_t2_62.jpg graphic file with name turkjchem-44-1303-fig_t2_63.jpg 20
7 graphic file with name turkjchem-44-1303-fig_t2_71.jpg graphic file with name turkjchem-44-1303-fig_t2_72.jpg graphic file with name turkjchem-44-1303-fig_t2_73.jpg 20
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a) Isolated yield based on 1,3-dicarbonyl compounds.

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) [45,46,48,49,53–56], 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 Mn2+. 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 1H-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.

Summarily, reactions of methacryloyl- and 3-arylacryloyl–substituted piperazines (1a-d) with 1,3-dicarbonyls (2a-c) occurs on 3-arylacryloyl sides, regioselectively. However, in reactions of allyl- and acryloyl-substituted (methacryloyl or 3-arylacryloyl) piperazines (1e-h)with 2a or 2c, cyclization occurs at acryloyl moiety, regioselectively, and thus, relevant dihydrofurans (3h-n) were formed. No cyclization occurred on allyl moiety at any reaction.

3. Experimental design

3.1. Chemicals and equipment

Melting points were determined on a Gallenkamp capillary melting point apparatus (Gallenkamp & Co., London, UK) and IR spectra (ATR, PerkinElmer, Inc. Waltham, MA, USA) were obtained with a Bruker Tensor27 spectrophotometer (Bruker Optics GmbH, Ettlingen, Germany) in the 400–4000 cm -1 range with 2 cm -1 resolutions. The 1 H NMR and 13 C NMR spectra were recorded on a Varian Mercury-400 high-performance digital FT-NMR and Varian Oxford NMR300 spectrometers (Varian Medical Systems, Inc., Palo Alto, CA, USA). High resolution mass time-of-flight spectra (TOF) were measured on an Agilent 1200/6210 LC/MS spectrophotometer (AgilentTechnologies, Inc., SantaClara, CA, USA). Thin layer chromatography (TLC) was performed on Merck aluminum-packed silica gel plates (Merck&Co., Inc., Kenilworth, NJ, USA). Purification of products was by column chromatography on silica gel (Merck silica gel 60, 40–60 mm), and preparative TLC was on silica gel from Merck (PF 254-366nm ) (Kenilworth, NJ, USA). All reagents, 1,3-dicarbonyl compounds, and solvents were commercially purchased. Radical oxidant Mn(OAc) 3 was synthesized by electrochemical method [57]. Please note that 1 H NMR, 13 C NMR, and HRMS spectra for all novel compounds can be found as supplementary information.

3.2. 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.

Trans -3-(4-Methacryloylpiperazine-1-carbonyl)-6,6-dimethyl-2-(5-methylfuran-2-yl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3a)

It was obtained as a yellow oil; yield: 81% (0.345 g); IR (ATR) υmax 3000, 2957, 2926, 1720 (C=O), 1618 (C=O), 1606 (C=C), 1197, 1022, 748 (arom. CH) cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 6.30 (1H, d, J = 3.2 Hz, arom. CH), 6.00 (1H, d, J = 5.6 Hz, H-2), 5.96 (1H, d, J = 3.2 Hz, arom. CH), 5.21 (1H, s, H olef. ), 5.04 (1H, s, H olef. ), 4.51 (1H, d, J = 5.6 Hz, H-3), 4.07-3.27 (8H, m), 2.43 (1H, d, J = 17.6 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.33 (1H, d, J = 16.4 Hz), 2.28 (3H, s, -CH 3 ), 2.19 (1H, d, J = 16.4 Hz), 1.95 (3H, s, -CH 3 ), 1.13 (3H, s, -CH 3 ), 1.11 (3H, s, -CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm):193.9 (C=O), 177.3 (C=C, C-7a), 171.3 (C=O), 169.9 (C=O), 154.0, 148.6, 140.0 (C=C), 115.9 (C=C), 112.3, 111.1,106.7(C=C, C-3a), 83.6 (C-2), 51.1, 46.6, 45.0 (C-3), 42.2, 37.9, 34.4, 28.9 (-CH 3 ), 28.2 (-CH 3 ), 20.4 (-CH 3 ), 13.6 (-CH 3 );HRMS (ESI)(m/z) Calcd for C 24 H 30 N 2 O 5 427.22275 found 427.22472 (M+H) + .

3-(4-Methacryloylpiperazine-1-carbonyl)-2,6,6-trimethyl-2-(5-methylfuran-2-yl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3b)

It was obtained as a yellow oil; yield: 50% (0.220 g); IR (ATR) υmax3093, 2956, 2925, 1721 (C=O), 1635 (C=O), 1610 (C=C), 1194, 1020, 728 (arom. CH) cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm):6.24 (1H, d, J = 3.2Hz, arom. CH), 5.94 (1H, d, J = 3.2 Hz), 5.22 (1H, s, H olef ), 5.03 (1H, s, H olef ), 4.58 (1H, s, H-3), 3.79-3.52 (8H, m), 2.40 (1H, d, J = 17.6 Hz), 2.35 (1H, d, J = 17.6 Hz), 2.32 (1H, d, J = 16.0 Hz), 2.20 (1H, d , J = 16.0 Hz), 2.30 (3H, s, -CH 3 ), 1.94 (3H, s, -CH 3 ), 1.68 (3H, s, -CH 3 ), 1.20 (3H, s, -CH 3 ), 1.11 (3H, s, -CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm): 194.1 (C=O), 175.4 (C=C, C-7a), 171.3 (C=O), 167.8 (C=O), 153.2, 152.8, 139.8 (C=C), 116.1 (C=C), 112.9, 112.5, 106.5 (C=C, C-3a), 88.1 (C-2), 50.7, 49.0 (C-3), 45.9, 42.5, 37.8, 34.6, 28.6 (-CH 3 ), 28.5 (-CH 3 ), 21.1 (-CH 3 ), 20.4 (-CH 3 ), 13.6 (-CH 3 );HRMS (ESI)(m/z) Calcd forC 25 H 32 N 2 O 5 441.23840 found 441.23896 (M+H) + .

Trans -3-(4-Methacryloylpiperazine-1-carbonyl)-6,6-dimethyl-2-(thiophen-2-yl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3c)

It was obtained as a yellow oil; yield: 64% (0.274 g); IR (ATR) υmax3085, 2956, 2930, 1732 (C=O), 1639 (C=O), 1615 (C=C), 1197, 1026, 726 (arom. CH)cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 7.34 (1H, d, J = 5.2 Hz, arom. CH), 7.06 (1H, d, J = 3.6 Hz, arom. CH), 7.00 (1H, dd, J = 5.2, 3.6 Hz, arom. CH), 6.32 (1H, d, J = 5.2 Hz, H-2), 5.21 (1H, s, H olef ), 5.04 (1H, s, H olef ), 4.36 (1H, d, J = 5.2 Hz, H-3), 4.03-3.28 (8H, m), 2.47 (1H, d, J = 17.6 Hz), 2.35 (1H, d, J = 17.6 Hz), 2.32 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 1.94 (3H, s, -CH 3 ), 1.14 (3H, s, -CH 3 ), 1.12 (3H, s, -CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm): 193.9 (C=O), 177.0 (C=C, C-7a), 171.2 (C=O), 169.8 (C=O), 141.9, 140.0 (C=C), 115.9 (C=C), 127.1, 126.6, 126.3, 111.9 (C=C, C-3a), 86.1 (C-2), 51.1, 50.0 (C-3), 46.5, 42.2, 37.9, 34.4, 28.9 (-CH 3 ), 28.1 (-CH 3 ), 20.4 (-CH 3 ); HRMS (ESI) (m/z) Calcd for C 23 H 28 N 2 O 4 S429.18425 found 429.18588 (M + H) + .

Trans -1-(4-(4-Acetyl-5,5’-dimethyl-2,3-dihydro-[2,2’-bifuran]-3-carbonyl)piperazin-1-yl)-2-methylprop-2-en-1-one (3d)

It was obtained as a yellow oil; yield: 73% (0.282 g); IR (ATR) υmax3009, 2956, 2930, 1732 (C=O), 1652 (C=O), 1612 (C=C), 1193, 1020, 746 (arom. CH)cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 6.29 (1H, d, J = 3.2 Hz, arom. CH), 5.95 (1H, d, J = 3.2 Hz, arom. CH), 5.52 (1H, d, J = 6.4 Hz, H-2), 5.20 (1H, s, H olef ), 5.02 (1H, s, H olef ), 4.69 (1H, d, J = 6.4 Hz, H-3), 3.80-3.66 (8H, m), 2.31 (3H, s, -CH 3 ), 2.30 (3H, s, -CH 3 ), 2.29 (3H, s, -CH 3 ), 1.93 (3H, s, -CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm): 192.8 (C=O), 171.3 (C=C, C-7a), 171.2 (C=O), 167.6 (C=O), 155.5, 153.8, 140.0 (C=C), 116.7 (C=C), 115.9, 110.9, 106.7 (C=C, C-3a), 79.9 (C-2), 49.1 (C-3), 46.2, 42.7, 28.8 (-CH 3 ), 20.4 (-CH 3 ), 15.6 (-CH 3 ), 13.6 (-CH 3 );HRMS (ESI)(m/z) Calcd for C 21 H 26 N 2 O 5 387.19145 found 387.19223 (M+H) + .

Trans -1-(4-(4-Acetyl-5-methyl-2-(thiophen-2-yl)-2,3-dihydrofuran-3-carbonyl)piperazin-1-yl)-2-methylprop-2-en-1-one (3e)

It was obtained as a yellow oil; yield: 52% (0.202g); IR (ATR) υmax3085, 2998, 2917, 1714 (C=O), 1639 (C=O), 1610 (C=C), 1194, 1020, 724 (arom. CH)cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 7.33 (1H, d, J = 5.2 Hz, arom. CH), 7.05 (1H, d, J = 3.6 Hz, arom. CH), 7.00 (1H, dd, J = 5.2, 3.6 Hz, arom. CH), 5.86 (1H, d, J = 6.4 Hz, H-2), 5.20 (1H, s, H olef ), 5.02 (1H, s, H olef ), 4.54 (1H, d, J = 6.4 Hz, H-3), 3.81-3.39 (8H, m), 2.34 (3H, s, -CH 3 ), 2.33 (3H, s, -CH 3 ), 1.93 (3H, s, -CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm): 192.8 (C=O), 171.3 (C=C, C-7a), 171.1 (C=O), 167.6 (C=O), 144.6, 140.0 (C=C), 127.1, 126.4, 126.1, 116.6 (C=C), 115.9 (C=C, C-3a), 82.6 (C-2), 53.5 (C-3), 46.5, 42.4, 28.9 (-CH 3 ), 20.4 (-CH 3 ), 15.6 (-CH 3 )192.9HRMS (ESI)(m/z) Calcd for C 20 H 24 N 2 O 4 S389.15295found 389.15460 (M+H) + .

1-(4-(4-Acetyl-2,5-dimethyl-2-(thiophen-2-yl)-2,3-dihydrofuran-3-carbonyl)piperazin-1-yl)-2-methylprop-2-en-1-one (3f)

It was obtained as a yellow oil; yield: 31% (0.125 g); IR (ATR) υmax3117, 2953, 2918, 1734 (C=O), 1648 (C=O), 1615 (C=C), 1191, 1022, 724 (arom. CH)cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 7.27 (1H, d, J = 6.4 Hz, arom. CH), 6.97-6.95 (2H, m, arom. CH), 5.22 (1H, s, H olef ), 5.04 (1H, s, H olef ), 4.54 (1H, s, H-3), 3.68-3.32 (8H, m), 2.35 (3H,s, -CH 3 ), 2.30 (3H,s, -CH 3 ), 1.94 (3H,s, -CH 3 ), 1.74 (3H,s, -CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm): 192.9 (C=O), 171.3 (C=C, C-7a), 168.9 (C=O), 166.5 (C=C, C-3a), 149.6, 139.9 (C=C), 126.9, 125.0, 123.0, 116.3 (C=C), 116.0 (C=C, C-3a), 86.4 (C-2), 56.6 (C-3), 46.3, 42.6, 28.7 (-CH 3 ), 24.0 (-CH 3 ), 20.4 (-CH 3 ), 15.4 (-CH 3 );HRMS (ESI)(m/z) Calcd for C 21 H 26 N 2 O 4 S403.16860 found 403.16968 (M+H) + .

Trans -Ethyl 3-(4-methacryloylpiperazine-1-carbonyl)-5,5’-dimethyl-2,3-dihydro-[2,2’-bifuran]-4-carboxylate (3g)

It was obtained as a yellow oil; yield: 60% (0.250 g); IR (ATR) υmax3080, 2980, 2922, 1701 (C=O), 1641 (C=O), 1619 (C=C), 1194, 1020, 730 (arom. CH)cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 6.30 (1H, d, J = 3.2 Hz, arom. CH), 5.95 (1H, d, J = 3.2 Hz, arom. CH), 5.55 (1H, d, J = 5.6 Hz, H-2), 5.21 (1H, s, H olef ), 5.02 (1H, s, H olef ), 4.67 (1H, d, J = 5.6 Hz, H-3),4.16 (2H, q, J = 7.2 Hz, -OCH2CH 3 ), 3.57-3.40 (8H, m), 2.30 (3H, s, -CH 3 ), 2.25 (3H, s, -CH 3 ), 1.93 (3H, s, -CH 3 ), 1.27 (3H, t, J = 7.2 Hz, -OCH2CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm): 171.3 (C=O), 171.2 (C=C, C-7a), 168.8 (C=O), 165.0 (C=O), 153.7, 148.6, 139.9 (C=C), 116.0 (C=C), 110.8, 106.7, 103.8 (C=C, C-3a), 80.2 (C-2), 59.9, 48.7 (C-3), 46.4, 42.6, 20.4 (-CH 3 ), 14.5 (-CH 3 ), 14.4 (-CH 3 ), 13.6 (-CH 3 );HRMS (ESI)(m/z) Calcd for C 22 H 28 N 2 O 6 417.20201 found 417.20397 (M+H) + .

3.3. 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.

Trans -3-(4-Allylpiperazine-1-carbonyl)-6,6-dimethyl-2-phenyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3h)

It was obtained as a yellow oil; yield: 30% (0.118 g); IR (ATR) υmax3067, 2961, 2868, 1730 (C=O), 1632 (C=O), 1612 (C=C), 1197, 1020, 754, 701 (arom. CH)cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm):7.39-7.31 (3H, m, arom. CH), 7.24-7.22 (2H, m, arom. CH), 6.04 (1H, d, J = 5.6 Hz, H-2), 5.83 (1H, ddt, J = 16.8, 10, 6.4 Hz, H olef. ), 5.18 (1H, dd, J = 16.8, 1.2 Hz, H olef. ), 5.14 (1H, dd, J = 10.0, 1.2 Hz, H olef. ), 4.23 (1H, d, J = 5.6 Hz, H-3), 3.96-3.84 (2H, m), 3.50-3.39 (2H, m), 3.00 (2H, d, J = 6.4 Hz), 2.56-2.44 (4H, m), 2.31 (2H, d, J = 16.0 Hz), 2.18 (2H, d, J = 16.0 Hz), 1.27 (3H, s, -CH 3 ), 1.16 (3H, s, -CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm):193.7(C=O), 177.4 (C=C, C-7a), 169.9 (C=O), 139.9, 134.3 (C=C), 129.0, 128.8, 125.5, 118.5 (C=C), 112.2 (C=C, C-3a), 90.5 (C-2), 61.4,53.1, 52.6, 51.1, 49.7, 46.2, 42.4 (C-3), 34.3, 28.9 (-CH 3 ), 28.2(-CH 3 );HRMS (ESI)(m/z) Calcd for C 24 H 30 N 2 O 3 395.23292 found 395.23361 (M+H) + .

Trans -3-(4-Allylpiperazine-1-carbonyl)-6,6-dimethyl-2-(5-methylfuran-2-yl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3i)

It was obtained as a yellow oil; yield: 32% (0.127 g); IR (ATR) υmax30171, 2961, 2930, 1732 (C=O), 1641 (C=O), 1617 (C=C), 1197, 1002, 734 (arom. CH)cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm):6.28 (1H, d, J = 3.2 Hz, arom. CH), 5.94 (1H, d, J = 6.0 Hz, H-2), 5.93 (1H, d, J = 3.2 Hz, arom. CH), 5.83 (1H, ddt, J = 16.8, 10, 6.8 Hz, H olef ), 5.18 (1H, dd, J = 16.8, 1.6 Hz, H olef ), 5.14 (1H, dd, J = 10.0, 1.6 Hz, H olef ), 4.49 (1H, d, J = 6.0 Hz, H-3), 3.99-3.89 (2H, m), 3.49-3.37 (2H, m), 2.99 (2H, d, J = 6.8 Hz), 2.59-2.49 (4H, m), 2.40 (1H, d, J = 17.6 Hz), 2.30 (1H, d, J = 17.6 Hz), 2.29 (1H, d, J = 16.0 Hz), 2.26 (3H, s, -CH 3 ), 2.17 (1H, d, J = 16.0 Hz), 1.12 (3H, s, -CH 3 ), 1.08 (3H, s, -CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm):193.8 (C=O), 176.8 (C=C, C-7a), 169.5 (C=O), 153.8, 148.9, 134.3 (C=C), 118.5 (C=C), 112.5, 110.8, 106.6 (C=C, C-3a), 83.5 (C-2), 61.4, 53.0, 52.5, 51.1, 46.2, 45.5, 42.3 (C-3), 37.8, 34.4, 28.9(-CH 3 ), 28.1(-CH 3 ), 13.6(-CH 3 );HRMS (ESI)(m/z) Calcd for C 23 H 30 N 2 O 4 399.22783 found 399.22924 (M+H) + .

Trans -3-(4-Allylpiperazine-1-carbonyl)-6,6-dimethyl-2-(thiophen-2-yl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3j)

It was obtained as a yellow oil; yield: 20% (0.080 g); IR (ATR) υmax3076, 2955, 2924, 1731 (C=O), 1628 (C=O), 1617 (C=C), 1137, 1000, 750 (arom. CH)cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 7.32 (1H, d, J = 5.2 Hz, arom. CH), 7.06 (1H, d, J = 3.6 Hz, arom. CH), 6.99 (1H, dd, J = 5.2, 3.6 Hz, arom. CH), 6.28 (1H, d, J = 5.2 Hz, H-2), 5.85 (1H,ddt, J =16.8, 10.0,6.8 Hz, H olef ), 5.20 (1H, dd, J = 16.8, 1.6 Hz, H olef ), 5.18 (1H, dd, J = 10.0, 1.6 Hz, H olef ), 4.37(1H,d, J =5.2 Hz, H-3), 4.00-3.96 (2H,m), 3.54-3.42 (2H, m), 3.04 (2H,d, J =6.8 Hz), 2.58 (4H, s), 2.46 (1H, d, J = 17.6 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.32 (1H, d, J = 16.0 Hz), 2.20 (1H, d, J = 16.0 Hz), 1.14 (3H, s, -CH 3 ), 1.11 (3H, s, -CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm):193.8 (C=O), 176.7 (C=C, C-7a), 169.3 (C=O), 143.7, 133.9 (C=C), 128.4, 127.0, 126.4, 116.6 (C=C), 112.1 (C=C, C-3a), 86.1 (C-2), 61.3, 53.0, 52.5, 51.1, 49.8, 46.1, 42.2 (C-3), 37.9, 34.4, 28.9 (-CH 3 ), 28.1 (-CH 3 );HRMS (ESI)(m/z) Calcd for C 22 H 28 N 2 O 3 S400.23319 found 401.1894 (M+H) + .

Trans -Ethyl 4-(4-allylpiperazine-1-carbonyl)-2-methyl-5-phenyl-4,5-dihydrofuran-3-carboxylate (3k)

It was obtained as a yellow oil; yield: 25% (0.096g); IR (ATR) υmax3080, 2978, 2930, 1701 (C=O), 1659 (C=O), 1619 (C=C), 1203, 969, 730, 692 (arom. CH) cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 7.40-7.27 (5H, m, arom. CH), 5.81 (1H, ddt, J =17.2, 10.4, 6.4 Hz, H olef ), 5.61 (1H, d, J = 7.2 Hz, H-2), 5.17 (1H, dd, J = 16.8, 1.6 Hz, H olef ), 5.15 (1H, dd, J = 10.4, 1.6 Hz, H olef ), 4.33 (1H, d, J = 7.2 Hz, H-3), 4.13 (2H, q, J = 7.2 Hz, -OCH2CH 3 ), 3.84-3.79 (1H, m), 3.64-3.58 (1H, m), 3.48-3.34(2H, m), 2.97 (2H, d, J = 6.8 Hz), 2.53-2.36 (4H, m), 2.35 (3H, s, -CH 3 ), 1.24 (3H, t, J = 7.2 Hz, -OCH2CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm):171.2 (C=O), 169.6 (C=C, C-7a), 164.9 (C=O), 140.3, 134.4 (C=C), 128.9, 128.6, 125.4, 118.4 (C=C), 103.6 (C=C, C-3a), 87.3 (C-2), 61.4, 59.7, 53.1, 52.9, 52.8, 42.4 (C-3), 14.4 (-CH 3 ), 14.3 (-CH 3 );HRMS (ESI)(m/z) Calcd for C 22 H 28 N 2 O 4 385.21218 found 385.21370 (M+H) + .

Trans -Ethyl 3-(4-allylpiperazine-1-carbonyl)-5,5’-dimethyl-2,3-dihydro-[2,2’-bifuran]-4-carboxylate (3l)

It was obtained as a yellow oil; yield: 40% (0.155 g); IR (ATR) υmax3067, 2982, 2907, 1708 (C=O), 1663 (C=O), 1626 (C=C), 1199, 1100, 732 (arom. CH) cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 6.26 (1H, d, J = 3.2 Hz, arom. CH), 5.92 (1H, d, J = 3.2 Hz, arom. CH), 5.80 (1H, ddt, J = 16.8, 10.0, 6.4 Hz, H olef ), 5.48 (1H, d, J = 7.6 Hz, H-2), 5.14 (1H, dd, J = 16.8, 1.6 Hz, H olef ), 5.13 (1H, dd, J = 10.0, 1.6 Hz, H olef ), 4.62 (1H, d, J = 7.6 Hz, H-3), 4.12 (2H, q, J = 7.2 Hz, -OCH2CH 3 ), 3.76-3.71 (1H, m), 3.58-3.49 (2H, m), 3.45-3.40 (1H, m), 2.94 (2H, d, J = 6.4 Hz), 2.49-2.13 (4H, m), 2.27 (3H, s, -CH 3 ), 2.23 (3H, s, -CH 3 ), 1.22 (3H, t, J = 7.2 Hz, -OCH2CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm):170.7 (C=O), 168.7 (C=C, C-7a), 164.9 (C=O), 153.5, 148.9, 134.4 (C=C), 118.4 (C=C), 110.5, 106.5, 103.8 (C=C, C-3a), 80.2 (C-2), 61.4, 59.7, 53.0, 52.6, 48.6, 46.0, 42.3 (C-3), 14.4(-CH 3 ), 14.3(-CH 3 ), 13.6(-CH 3 );HRMS (ESI)(m/z) Calcd for C 21 H 28 N 2 O 5 389.20710 found 389.20877 (M+H) + .

Trans -Ethyl 4-(4-allylpiperazine-1-carbonyl)-2-methyl-5-(thiophen-2-yl)-4,5-dihydrofuran-3-carboxylate (3m)

It was obtained as a yellow oil; yield: 20% (0.078 g); IR (ATR) υmax3075, 2978, 2923, 1701 (C=O), 1652 (C=O), 1628 (C=C), 1197, 1040, 728 (arom. CH) cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 7.32 (1H, dd, J = 5.2 Hz, arom. CH), 7.05 (1H, d, J = 3.2 Hz, arom. CH), 6.98 (1H, dd, J = 5.2, 3.2 Hz, arom. CH), 5.84 (1H, d, J = 6.8 Hz, H-2), 5.81 (1H, ddt, J = 16.8, 10.0, 6.4 Hz, H olef ), 5.18 (1H, dd, J = 16.8, 1.6 Hz, H olef ), 5.15 (1H, dd, J = 10.0, 1.6 Hz, H olef ), 4.48 (1H,d, J = 6.8 Hz, H-3), 4.15 (2H, q, J = 7.2 Hz, -OCH2CH 3 ), 3.83-3.45 (4H, m), 2.98 (2H, d, J = 6.4 Hz), 2.52-2.18 (4H, m), 2.29 (3H, s, -CH 3 ), 1.25 (3H, t, J = 7.2 Hz, -OCH2CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm):170.6 (C=O), 168.9 (C=C, C-7a), 164.8 (C=O), 142.5, 134.3 (C=C), 126.9, 126.1, 125.8, 118.5 (C=C), 103.7 (C=C, C-3a), 82.9 (C-2), 61.4, 59.8, 53.1, 53.0, 52.7, 46.1, 42.4 (C-3), 14.5 (-CH 3 ), 14.4 (-CH 3 );HRMS (ESI)(m/z) Calcd for C 20 H 26 N 2 O 4 S391.16860 found 391.16985 (M+H) + .

Ethyl 5-(4-allylpiperazine-1-carbonyl)-2,5-dimethyl-4,5-dihydrofuran-3-carboxylate(3n)

It was obtained as a yellow oil; yield: 20% (0.065 g); IR (ATR) υmax3076, 2983, 2930, 1701 (C=O), 1657 (C=O), 1630 (C=C), 1190, 1040cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) d (ppm): 5.84 (1H, ddt, J = 16.8, 10, 6.8 Hz, H olef ), 5.20 (1H, dd, J = 16.8, 1.6 Hz, H olef ), 5.17 (1H, dd, J = 10.0, 1.6 Hz, H olef ), 4.15 (2H, q, J = 7.2 Hz, -OCH2CH 3 ), 3.81-3.62 (4H, m), 3.58 (1H, d, J = 15.2 Hz, Ha-3), 3.00 (2H, d, J = 6.8 Hz), 2.70 (1H, d, J = 15.2 Hz, Hb-3), 2.44 (4H, m), 2.18 (3H, s, -CH 3 ), 1.55 (3H, s, -CH 3 ), 1.26 (3H, t, J = 7.2 Hz, -OCH2CH 3 ); 13 C NMR(100 MHz, CDCl 3 ) d (ppm):170.1 (C=O), 165.7 (C=C, C-7a), 164.8 (C=O), 134.3 (C=C), 118.5 (C=C), 102.1 (C=C, C-3a), 88.4 (C-2), 61.5, 59.6, 53.1, 52.8, 46.2, 43.2, 41.1 (C-3), 26.0(-CH 3 ), 14.3(-CH 3 ), 14.1(-CH 3 );HRMS (ESI)(m/z) Calcd for C17H26N2O4323.19653 found 323.19805 (M+H) + .

4. Conclusion

Summarily, novel piperazines containing dihydrofuran compounds (3a-n) were synthesized by the Mn(OAc) 3 mediated radical cyclization from unsaturated diacyl (1a-d) and alkyl-acyl (1e-h) piperazine compounds with 1,3-dicarbonyls (2a-c) in low to high yields for the first time. All compounds were characterized by 1 HNMR, 13 C NMR, HRMS, and FTIR spectroscopy.

Acknowledgments

This study was financially supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK) (TBAG-116Z455). Sait SARI thanks TÜBİTAK for the doctoral fellowship.

References

  1. Dua R Shrivastava S Sonwane SK Shrivastava SK Pharmacological Significance of Synthetic Heterocycles Scaffold: A Review. Advances in Biological Research. 2011;5:120–144. [Google Scholar]
  2. Rachakonda V Alla M Kotipalli SS Ummani R. European Journal of Medicinal Chemistry. u2193;70:536–547. doi: 10.1016/j.ejmech.2013.10.034. [DOI] [PubMed] [Google Scholar]
  3. Szabo M Herenbrink CK Christopoulos A Lane JR Capuano B Structure−Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D2 Receptor. Journal of Medicinal Chemistry2014; 57:4924–4939. doi: 10.1021/jm500457x. [DOI] [PubMed] [Google Scholar]
  4. Chaudhary P Kumar R Verma AK Singh D Yadav V Synthesis and antimicrobial activity of N-alkyl and N-aryl piperazine derivatives. Bioorganic and Medicinal. Chemistry2006:14–14. doi: 10.1016/j.bmc.2005.10.032. [DOI] [PubMed] [Google Scholar]
  5. Harish KP Mohana KN Mallesha L Kumar BNP European Journal of Medicinal Chemistry. u2194;65:276–283. doi: 10.1016/j.ejmech.2013.04.054. [DOI] [PubMed] [Google Scholar]
  6. Patel KN Telvekar VN European Journal of Medicinal Chemistry. 2014;75:43–56. doi: 10.1016/j.ejmech.2014.01.024. [DOI] [PubMed] [Google Scholar]
  7. Wang T Kadow JF Zhang Z Yin Z Gao Q Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives. Bioorganic and Medicinal Chemistry Letters. 2009;19:5140–5145. doi: 10.1016/j.bmcl.2009.07.076. [DOI] [PubMed] [Google Scholar]
  8. Tuğrak M Gül HI Bandow K Sakagami H Gülçin I Synthesis and biological evaluation of some new mono Mannich bases with piperazines as possible anticancer agents and carbonic anhydrase inhibitors. Bioorganic Chemistry. 2019;90:103095. doi: 10.1016/j.bioorg.2019.103095. [DOI] [PubMed] [Google Scholar]
  9. Meena P Nemaysh V Khatri M Manral A Luthra PM Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer’s disease. Bioorganic and Medicinal Chemistry. 2015;23:1135–1148. doi: 10.1016/j.bmc.2014.12.057. [DOI] [PubMed] [Google Scholar]
  10. Piemontese L Tomás D Hiremathad A Capriati Vi Candeias E Donepezil structurebased hybrids as potential multifunctional anti-Alzheimer’s drug candidates. Journal of Enzyme Inhibition and Medicinal Chemistry. 2018;33:1212–1224. doi: 10.1080/14756366.2018.1491564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Stegmeier F Warmuth M Sellers WR Dorsch M. Targeted Cancer Therapies in the Twenty-First Century: Lessons From Imatinib. Clinical Pharmacology&Therapautics. 2010;87:543–552. doi: 10.1038/clpt.2009.297. [DOI] [PubMed] [Google Scholar]
  12. Lue TF Erectile dysfunction. New England Journal of Medicine. 2000;342:1802–1813. doi: 10.1056/NEJM200006153422407. [DOI] [PubMed] [Google Scholar]
  13. Vacca JP Dorsey BD Schleif WA Levin RB McDaniel SL : an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proceedings of the national academy of sciences. 524;735:4096–4100. doi: 10.1073/pnas.91.9.4096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Burka JM Bower KS Vanroekel RC Stutzman RD Kuzmowych CP The effect of fourth-generation fluoroquinolones gatifloxacin and moxifloxacin on epithelial healing following photorefractive keratectomy. American Journal of Ophthalmology . 2005;140:83–87. doi: 10.1016/j.ajo.2005.02.037. [DOI] [PubMed] [Google Scholar]
  15. Hu C Sun ZG Wei CX Quan ZS Synthesis and anticonvulsant activity of some cinnamylpiperazine derivatives. Letters in Drug Design & Discovery. 2010;7:661–664. [Google Scholar]
  16. Kapanda CN Masquelier J Labar G Muccioli GG Poupaert JH Synthesis and Pharmacological Evaluation of 2,4-Dinitroaryldithiocarbamate Derivatives as Novel Monoacylglycerol Lipase Inhibitors. Journal of Medicinal Chemistry. 2012;55:5774–5783. doi: 10.1021/jm3006004. [DOI] [PubMed] [Google Scholar]
  17. Srikanth RT Suryakiran N Narasimhulu M Ramesh D Chinni MK Semi-synthesis and bio-evaluation of polybrominated diphenyl ethers from the sponge Dysidea herbacea. Bioorganic & Medicinal Chemistry Letters. 2012;22:4900–4906. doi: 10.1016/j.bmcl.2012.04.133. [DOI] [PubMed] [Google Scholar]
  18. Hatnapure GD Keche AP Rodge AH Birajdar SS Tale RH Synthesis and biological evaluation of novel piperazine derivatives of flavone as potent anti-inflammatory and antimicrobial agent. Bioorganic & Medicinal Chemistry Letters. 2012;22:6385–6390. doi: 10.1016/j.bmcl.2012.08.071. [DOI] [PubMed] [Google Scholar]
  19. Kakwani MD Suryavanshi P Ray M Rajan MGR Majee S Design, synthesis and antimycobacterial activity of cinnamide derivatives: A molecular hybridization approach. Bioorganic & Medicinal Chemistry Letters. 2011;21:1997–1999. doi: 10.1016/j.bmcl.2011.02.022. [DOI] [PubMed] [Google Scholar]
  20. Zhong Y Xu Z Wang Y Xu Y Li P et al. Synthesis, Crystal Structure and Anti-ischaemic Activity of (E)-1-{4-[Bis(4-methoxy-phenyl) methyl]piperazin-1-yl}-3-(4-chlorophenyl)-prop-2-en-1-one. South African Journal of Chemistry. 2014;67:214–217. [Google Scholar]
  21. Saadeh HA Mosleh IM Mubarak MS Synthesis of novel hybrid molecules from precursors with known antiparasitic activity. Molecules. 2009;14:1483–1494. doi: 10.3390/molecules14041483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Chen SP Chen BW Dai CF Sung PJ Wu YC New Dihydrofuranocembranoids from a Dongsha Atoll Soft Coral Sarcophyton sp. Bulletin of Chemical Society of Japan. 2012;85:920–922. [Google Scholar]
  23. Lallemand JY Six Y Ricard LA Concise Synthesis of an Advanced Clerodin Intermediate through a Vaultier Tandem Reaction. European Journal of Organic Chemistry. 2002;3:503–513. [Google Scholar]
  24. Appendino G Cravotto G Palmisano G Annunziata R Synthesis of fercoprolone, a degraded prenylated coumarin. Tetrahedron. 1998;54:10819–10826. [Google Scholar]
  25. Kornsakulkarn J Saepua S Srichomthong K Supothina S Thongpanchang C New mycotoxins from the scale insect fungus Aschersonia coffeae Henn. BCC 28712. Tetrahedron. 2012;68:8480–8486. [Google Scholar]
  26. Melikyan GG Manganese(III) Mediated Reactions of Unsaturated Systems. Synthesis. 1993;9:833–850. [Google Scholar]
  27. Snider BB Manganese(III) Mediated Reactions of Unsaturated Systems. Chemical Reviews. 1996;96:339–363. doi: 10.1021/cr950026m. [DOI] [PubMed] [Google Scholar]
  28. Mondal M Bora U Recent advances in manganese(iii) acetate mediated organic synthesis. RSC Advances. 2013;3:18716–18754. [Google Scholar]
  29. Castro S Fernandez JJ Fananas FJ Vicente R Rodriguez F. Manganese-Mediated C-H Alkylation of Unbiased Arenes Using Alkylboronic Acids. Chemistry A European Journal. 2016;22:9068–9071. doi: 10.1002/chem.201601482. [DOI] [PubMed] [Google Scholar]
  30. Lofstrand VA Matsuura BS Furst L Narayanam JMR Stephenson JRC Formation and trapping of azafulvene intermediates derived from manganese-mediated oxidative malonate coupling. Tetrahedron. 2016;72:3775–3780. doi: 10.1016/j.tet.2016.03.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hyunh TT Nguyen VH Nishino H One-pot synthesis of 2-oxa-7-azaspiro[4.4]nonane-8,9-diones using Mn(III)-based oxidation of 4-acylpyrrolidine-2,3-diones. Tetrahedron Letters. 2017;58:3619–3622. [Google Scholar]
  32. Aslan H Öktemer A Dal H Hökelek T. Synthesis of ferrocene substituted dihydrofuran derivatives via manganese(III) acetate mediated radical addition-cyclization reactions. Tetrahedron. 2017;73:7223–7232. [Google Scholar]
  33. Zhang PZ Zhang L Li JA Shoberu A Zou JP Phosphinoyl Radical Initiated Vicinal Cyanophosphinoylation of Alkenes. 2017;Orgamic Letters19:5537–5540. doi: 10.1021/acs.orglett.7b02621. [DOI] [PubMed] [Google Scholar]
  34. Chuang CP Wu YL Oxidative free radical reactions of enamino esters. Tetrahedron. 2004;60:1841–1847. [Google Scholar]
  35. Kobayashi K Nagase K Morikawa O Konishi H Convenient Synthesis of Furopyranopyrandione Derivatives by the CAN-mediated Furan Ring Formation. Heterocycles. 2003;60:939–946. [Google Scholar]
  36. Nair V Mohanan K Suja TD Suresh E Stereoselective synthesis of 3,4-trans-disubstituted pyrrolidines and cyclopentanes via intramolecular radical cyclizations mediated by CAN. Tetrahedron Letters. 2006:2803–2806. [Google Scholar]
  37. Sridharan V Menendez JC Cerium(IV) Ammonium Nitrate as a Catalyst in OrganicSynthesis. 2010;110:3805–3849. doi: 10.1021/cr100004p. [DOI] [PubMed] [Google Scholar]
  38. Nair V Deepthi A Cerium(IV) Ammonium NitrateA Versatile Single-Electron Oxidant Chemical Reviews. 2007;107:1862–1891. doi: 10.1021/cr068408n. [DOI] [PubMed] [Google Scholar]
  39. Yılmaz M. Studies on the Radical Cyclization of 3-Oxopropanenitriles and Alkenes withCerium(IV) Ammonium Nitrate in Ether Solvents. Helvetica Chimica Acta. 2011;94:1335–1342. [Google Scholar]
  40. Yılmaz M Ustalar A Synthesis of 2-(2-phenylethenyl) substituted 4,5-dihydrofurans byregioselective addition of 1,3-dicarbonyl compounds to dienespromoted by cerium(IV) ammonium nitrate. Arkivoc. 2016:202–213. [Google Scholar]
  41. Ustalar A Yılmaz M Osmani A Keçeli SA Synthesis and antifungal activity of new dihydrofurocoumarins anddihydrofuroquinolines. Turkish Journal of Chemistry. 2017;41:80–88. [Google Scholar]
  42. Hocaoğlu B Yılmaz M. Regioselective radical addition of 3-oxopropanenitriles with terminal dienespromoted by cerium(IV) ammonium nitrate andmanganese(III) acetate. Synthetic Communications. 2019;49:1938–1946. [Google Scholar]
  43. Yilmaz M Pekel AT Regioselective Synthesis of 5-Carbamoyl-Dihydrofurans Mediated Manganese (III) Acetate in Acetic Acid. Synthetic Communications. 31:2189–2194. [Google Scholar]
  44. Yilmaz M Pekel AT Synthesis of benzofuran derivatives using manganese (III) acetate mediated addition of β-dicarbonyl compounds to alkyne and alkenes – a comparative study. Synthetic Communications. 2001;31:3871–3876. [Google Scholar]
  45. Burgaz EV Yılmaz M Pekel AT Öktemer A Oxidative cyclization of 3-oxopropanenitriles with a,b-unsaturated amides by manganese(III) acetate. Regio- and stereoselective synthesis of 4-cyano-2,3-dihydrofuran-3-carboxamides. Tetrahedron. 2007;63:3–3. [Google Scholar]
  46. 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. Arkivoc. 2016. pp. 79–91.
  47. Yılmaz EVB Yılmaz M Öktemer A Radical cyclizations of conjugated esters and amides with3-oxopropanenitriles mediated by manganese(III) acetate. Arkivoc. 2011;63:363–376. [Google Scholar]
  48. Yılmaz M Uzunalioglu N Pekel AT Manganese(III) acetate based oxidative cyclizations of 3-oxopropanenitriles with conjugated alkenes and synthesis of 4,5-dihydrofuran-3-carbonitriles containing heterocycles. Tetrahedron. 2005;61:8860–8867. [Google Scholar]
  49. Yilmaz M. Synthesis of dihydrofurans containing trifluoromethyl ketone and heterocycles by radical cyclization of fluorinated 1,3-dicarbonyl compounds with 2-thienyl and 2-furyl substituted alkenes. Tetrahedron. 2011;67:8255–8263. [Google Scholar]
  50. Özgür M Yılmaz M Nishino H Avar EÇ Dal H Efficient syntheses and antimicrobial activities of new thiophene containing pyranone and quinolinone derivatives using manganese(III) acetate: the effect of thiophene on ring closure–opening reactions. New Journal of Chemistry. 2019;43:5737–5751. [Google Scholar]
  51. Yilmaz M Bicer E Ustalar A Pekel AT Synthesis of furan-substituted dihydrofuran compounds by radicalcyclization reactions mediated by manganese(III) acetate. Arkivoc. 2014:225–236. [Google Scholar]
  52. Sarı S Ünalan S Yılmaz M. Synthesis Synthesis and characterization of unsaturated diacyl and alkyl-acyl piperazinederivatives. Turkish Journal of Chemistry. 2019;43:1656–1671. [Google Scholar]
  53. Hagiwara H Sato K Nishino D Hoshi T Suzuki T Ando M. Domino Michael–O-alkylation reaction: one-pot synthesis of 2,4-diacylhydrofuran derivatives and its application to antitumor naphthofuran synthesis. Journal of the Chemical Society, Perkin Transactions 1. 2001;22:2946–2957. [Google Scholar]
  54. Vinoshaa B Perumal S Renugaa S Almansour AI. A facile domino protocol for the stereoselective synthesis of trans-2,3-dihydrobenzofurans and cis-5,6-dihydrofuro[2,3-d]pyrimidines. Tetrahedron Letters. 2012;53:962–966. [Google Scholar]
  55. Yu H Han J Chen J Deng H Shao M Zhang H Cao W Preparation of (E )-4-Aryl-1,1,1-trifluoro-3-tosylbut-3-en-2‐ones as Fluorinated Building Blocks and Their Application in Ready and Highly Stereoselective Routes to trans ‐2,3‐Dihydrofurans Substituted with Trifluoromethyl and Sulfonyl Groups. European Journal of Organic Chemistry. 2012;16:3142–3150. [Google Scholar]
  56. Martinet S Mou, A Brun P 1H and 13C chemical shifts for some tetrasubstituted 2,5‐diaryl di‐ and tetrahydrofuran derivatives. Magnetic Resonance in Chemistry. 2007;45:182–184. doi: 10.1002/mrc.1933. [DOI] [PubMed] [Google Scholar]
  57. Yılmaz M Yılmaz EVB Pekel AT Radical Cyclization of Fluorinated 1,3-Dicarbonyl Compounds with Dienes Using Manganese(III) Acetate and Synthesis of Fluoroacylated 4,5-Dihydrofurans. Helvetica Chimica Acta. 2011;94:3–3. [Google Scholar]

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