One-Pot Synthesis of 3,4-Dihydrocoumarins via C-H Oxidation/Conjugate Addition/Cyclization Cascade Reaction

Dae Young Kim

doi:10.3390/molecules28196853

. 2023 Sep 28;28(19):6853. doi: 10.3390/molecules28196853

One-Pot Synthesis of 3,4-Dihydrocoumarins via C-H Oxidation/Conjugate Addition/Cyclization Cascade Reaction

Dae Young Kim ¹

Editor: Gilbert Kirsch¹

PMCID: PMC10574682 PMID: 37836696

Abstract

The 3,4-dihydrocoumarin derivatives were obtained from 2-alkyl phenols and oxazolones via C–H oxidation and cyclization cascade in the presence of silver oxide (Ag₂O) and p-toluenesulfonic acid as a Brønsted acid catalyst. This approach provides a one-pot strategy to synthesize the multisubstituted 3,4-dihydrocoumarins with moderate to high yields (64–81%) and excellent diastereoselectivity (>20:1).

Keywords: organocatalysis, one-pot reaction, ortho-quinone methides, dihydrocoumarins, oxazolones

1. Introduction

The dihydrocoumarin core is present as a characteristic structural motif to possess a broad range of biological activities [1,2]. Particularly, 3,4-dihydrocoumarins have attracted considerable attention due to their various pharmacological properties, such as antiviral, anti-inflammatory, and anticancer effects [3,4]. Therefore, various novel methods for the synthesis of 3,4-dihydrocoumarins have been developed [5,6,7,8,9,10,11]. The most general protocol for the synthesis of 3,4-dihydrocoumarins is the [4 + 2] cycloaddition of ortho-quinone methides (o-QMs) [12,13,14,15,16]. ortho-Quinone methides are synthetic intermediates widely used in organic synthesis [17,18]. A variety of useful reactions of ortho-quinone methides with several dipoles have been reported using transition metal catalysts [19,20] or organic catalysts [21,22]. Oxazolone derivatives have been recognized as well-known precursors of α-amino acids, are versatile building blocks in organic synthesis, and are often used in the synthesis of α,α-disubstituted α-amino acids [23].

Many studies have been reported to synthesize 6-membered oxacyclic compounds through [4 + 2] cycloaddition by reacting o-QM with various 1,2-dipoles [24,25]. Recently, the synthesis of 3,4-dihydrocoumarin derivatives by cycloaddition reaction between o-QM and oxazolones using a metal complex or hydrogen bonding organocatalyst has been reported (Scheme 1a) [26,27]. Additionally, the [4 + 2] ring addition of o-QM precursor and oxazolone using an organic catalyst has been reported (Scheme 1b) [28,29]. Despite this progress, the development of new and efficient synthetic methods for the synthesis of 3,4-dihydrocoumarin is still highly desirable. Cascade cyclization reactions have attracted much attention in the past few decades, providing practical protocols for the synthesis of heterocyclic molecules with the convenience afforded by shortening the reaction steps [29,30]. To the best of our knowledge, the single-pot synthesis of dihydrocoumarins from the in situ generation of o-QMs via C–H oxidation of benzyl phenol has not been reported. Therefore, we envisioned a one-pot synthesis of 3,4-dihydrocoumarin derivatives via C–H oxidation and ring closure cascade of 2-benzyl phenol with oxazolone under Brønsted acid conditions (Scheme 1c). In connection with our work on conjugate addition reactions, [31,32], we reported the Michael-type addition/ring closure sequences of o-QM with dipoles [33]. Herein, we describe the one-pot synthesis of 3,4-dihydrocoumarin derivatives from 2-benzyl phenol via C–H oxidation and acid-catalyzed ring closure cascade.

Scheme 1 — Methods for the asymmetric synthesis of dihydrocoumarins.

2. Results and Discussion

We commenced our study with 6-(4-methoxybenzyl)benzo[d][1,3]dioxol-5-ol (1a) and 4-benzyl-2-phenyloxazol-5(4H)-one (2a) as model substrates in the presence of oxidant and Brønsted acid catalyst, which was previously validated as the suitable catalysts for conjugate addition reactions [34,35].

The initial study was conducted with Ag₂CO₃ as an oxidant for the in situ generation of ortho-quinone methide intermediate via C-H oxidation. The desired 3,4-dihydrocoumarin (3a) was obtained in a 35% yield with 10 mol% of p-toluenesulfonic acid (Table 1, entry 1). To further improve the yield, organic and metallic oxidants, such as Ag₂O, AgOAc, AgOTf, AgBF₄, AgNO₃, MnO₂, Mn(OAc)₃, Mn(acac)_3, K₂S₂O₈, Oxone, TBHP (tert-butyl hydroperoxide), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), (diacetoxyiodo)benzene, and PIFA ([bis(trifluoroacetoxy)iodo]benzene) were evaluated for their potential impact on this reaction. Silver oxide (Ag₂O) proved to be a suitable oxidant with regard to yield (Table 1, entry 2). Ag₂O has the advantage of excellent thermal stability and is commercially available in various forms (e.g., powder, pellets, flakes, etc.). Next, we examined the evaluation of the efficiency of selected Brønsted acids, including methanesulfonic acid, 2,4-dinitroebenzene sulfonic acid, acetic acid, trifluoroacetic acid, and diphenyl phosphate (DPP) (Table 1, entries 2 and 16–20). Diphenyl phosphate was the optimal catalyst for the oxidative cyclization cascade reaction (81% yield, Table 1, entry 20). Then, other common solvents such as methylene chloride, 1,2-dichloroethane (DCE), ethyl acetate, diethyl ether, tetrahydrofuran (THF), dioxane, benzene, toluene, and p-xylene were tested in the reaction (Table 1, entries 2 and 21–29). Chloroform was confirmed as the optimum solvent in terms of yield (Table 1, entry 20).

Table 1.

Optimization of the reaction conditions ^[a,c].

graphic file with name molecules-28-06853-i001.jpg

Entry	Oxidant	Catalyst	Solvent	Yield ^[b] (%)
1	Ag₂CO₃	p-TsOH	CHCl₃	35
2	Ag₂O	p-TsOH	CHCl₃	63
3	AgOAc	p-TsOH	CHCl₃	25
4	AgOTf	p-TsOH	CHCl₃	33
5	AgBF₄	p-TsOH	CHCl₃	28
6	AgNO₃	p-TsOH	CHCl₃	18
7	MnO₂	p-TsOH	CHCl₃	41
8	Mn(OAc)₃	p-TsOH	CHCl₃	29
9	Mn(acac)₃	p-TsOH	CHCl₃	61
10	K₂S₂O₈	p-TsOH	CHCl₃	trace
11	Oxone	p-TsOH	CHCl₃	trace
12	TBHP	p-TsOH	CHCl₃	trace
13	DDQ	p-TsOH	CHCl₃	trace
14	PhI(OAc)₂	p-TsOH	CHCl₃	trace
15	PIFA	p-TsOH	CHCl₃	trace
16	Ag₂O	MsOH	CHCl₃	61
17	Ag₂O	DNBS	CHCl₃	57
18	Ag₂O	AcOH	CHCl₃	15
19	Ag₂O	TFA	CHCl₃	45
20	Ag₂O	DPP	CHCl₃	81
21	Ag₂O	DPP	CH₂Cl₂	72
22	Ag₂O	DPP	DCE	70
23	Ag₂O	DPP	EtOAc	46
24	Ag₂O	DPP	EtOEt	38
25	Ag₂O	DPP	THF	58
26	Ag₂O	DPP	dioxane	47
27	Ag₂O	DPP	benzene	38
28	Ag₂O	DPP	toluene	45
29	Ag₂O	DPP	p-xylene	42

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^[a] Reaction conditions: benzyl phenol 1a (0.2 mmol), oxazolone 2a (0.2 mmol), oxidant (0.24 mmol), and catalyst (0.02 mmol) in solvent (3 mL) at room temperature for 24 h under N₂ atmosphere. ^[b] Isolated yield. ^[c] The relative configuration of the indicated diastereomer was determined by ¹H-NMR analysis. PMP = para-methoxyphenyl, TBHP = tert-butyl hydroperoxide, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, Hacac = acetylacetone, PIFA = [bis(trifluoroacetoxy)iodo]benzene.

After establishing the optimized conditions, the substrate range of oxazolone derivative 2 was investigated. In reactions with various oxazolone derivatives (2), the corresponding 3,4-dihydrocoumarin derivatives 3 were obtained in reasonable yields (Scheme 2). The reactions of 5-(4H)oxazolones (2) with either electron-donating (4-OMe, 4-Me, 3-Me, and 3,5-di-Me₂) or electron-withdrawing (4-CF₃, 4-Cl, and 2-Cl) substituents on the phenyl ring in the C2 position yielded the corresponding 3,4-dihydrocoumarins (3b–3h) in high yields (Table 2, 68–77% yields). In addition, when there are p-halo-substituted (F, Cl) benzyl and (methylthio)ethyl groups instead of the benzyl group in the C4 position of 5-(4H)oxazolone (2), the corresponding 3,4-dihydrocoumarins (3i–3k) were processed in reasonable yields and (Table 2, 64–72 yields). In all cases, the diastereoselectivity of the products (3) was excellent (over 20:1). The relative configuration of the indicated diastereomer was determined by ¹H-NMR analysis compared with reported works [26,27].

Scheme 2 — The gram-scale synthesis of dihydrocoumarin 3a.

Table 2.

Substrate scope ^[a,b,c].

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graphic file with name molecules-28-06853-i003.jpg

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^[a] Reaction conditions: benzyl phenol 1 (0.2 mmol), oxazolone 2 (0.2 mmol), Ag₂O (0.24 mmol), and diphenyl phosphate (0.01 mmol) in chloroform (3 mL) at room temperature for 24–36 h under N₂ atmosphere. ^[b] Isolated yield. ^[c] The relative configuration of the indicated diastereomer was determined by ¹H-NMR analysis.

In order to demonstrate the synthetic utility of this transformation, the gram-scale synthesis of 3,4-dihydrocoumarin (3a) was conducted. As shown in Scheme 2, when 2-benzyl phenol (1a) was treated with 4-benzyl-2-phenyloxazol-5(4H)-one (2a) under optimal reaction conditions, the reaction proceeded well to afford the chiral 3,4-dihydrocoumarin (3a) with a 78% yield. To achieve the asymmetric version of this reaction, the reaction was conducted with a chiral phosphoric acid catalyst (4) instead of diphenyl phosphate under standard reaction conditions (Scheme 3). The chiral 3,4-dihydrocoumarin (3a) obtained a 63% yield with 86% enantioselectivity. It is necessary to further investigate the structure of the catalyst and optimize reaction conditions suitable for asymmetric reactions, and further research is still being carried out in our laboratory.

Scheme 3 — Asymmetric synthesis of 3,4-dihydrocoumarins 3a.

Based on the experimental results, a plausible reaction pathway and activation mode were proposed (Figure 1). The ortho-quinone methide intermediate A was generated in situ from benzylphenol (1) in the presence of Ag₂O as an oxidant. Then, diphenyl phosphate simultaneously generated two hydrogen bonds with both the ortho-quinone methide intermediate and enol-form of oxazolone (2a). The subsequent conjugate addition of the C4 of oxazolone enolate to ortho-quinone methide leads to the Michal-type adduct (C). The intermediate (C) would undergo an annulation (lactonization) reaction with a concomitant opening of the azlactone ring to produce cyclic α-acylaminolactone (3).

3. Materials and Methods

All chemicals were purchased from commercial suppliers and used without further purification unless otherwise specified. Solvents for extractions and chromatography were of technical grade and were distilled prior to use. Extracts were dried over technical-grade anhydrous Na₂SO₄. Anhydrous solvents were deoxygenated by sparging with N₂ and dried by passing through activated alumina columns of a Pure Solv solvent purification system (Innovative Technology). Reactions were monitored by analytical thin-layer chromatography (TLC) using silica gel 60 F₂₅₄ pre-coated glass plates (0.25 mm thickness) and visualized using UV light (254 nm and 365 nm), I₂, p-anisaldehyde, ninhydrin, and phosphomolybdic acid solution as an indicator. Flash chromatography was carried out on E. Merck silica gel (230–400 mesh). ¹H NMR, ¹³C NMR, and ¹⁹F NMR spectra were recorded at 400 MHz, 100 MHz, and 376 MHz, respectively, on a Jeol ECS 400 MHz NMR spectrometer. Chemicals shift values (δ) are reported in parts per million and referenced in relation to the following standards: Me₄Si as the internal references for the ¹H- and ¹³C-NMR signals in chloroform and PhCF₃ as the external references for the ¹⁹F-NMR signal. The peak information is described as s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. Mass spectra (MS-EI, 70 eV) were conducted on a GC-MS Shimadzu QP2010. High-resolution mass spectra were measured on a Jeol HX110/110A using the electrospray ionization technique. The enantiomeric excesses (EEs) were determined by HPLC. HPLC analysis was performed on a Shimadzu prominence 20, measured at 254 nm using the indicated chiral column. Optical rotations were measured on a JASCO-DIP-1000 digital polarimeter with a sodium lamp. Infrared spectra were recorded on a Thermo Fisher Scientific Nicolet iS5 FT-IR spectrometer. The elemental analysis was carried out on a Perkin-Elmer 2400 Series II Elemental Analyzer.

General procedure for the one-pot synthesis of 3,4-dihydrocoumarins 3: To a stirred solution of 2-benzylphenol 1 (0.2 mmol), oxazolone 2 (0.2 mmol), and Ag₂O (0.24 mmol) in chloroform (3 mL), diphenyl phosphate (0.02 mmol) was added at room temperature under an N₂ atmosphere. The reaction mixture was stirred for 24–36 h at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc/hexane = 1:5) to afford 3,4-dihydrocoumarins 3.

N-(7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide (3a), 81% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.41 (m, 2H), 7.20–7.16 (m, 3H), 7.05–7.02 (m, 4H), 6.82 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 6.69–6.68 (m, 3H), 6.64 (s, 1H), 5.99 (dd, J = 16.0, 1.6 Hz, 2H), 5.27 (s, 1H), 4.13 (d, J = 14.0 Hz, 1H), 3.67 (s, 3H), 3.13 (d, J = 14.1 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 168.0, 159.0, 148.1, 144.4, 135.2, 135.0, 131.7, 130.2, 129.9, 129.0, 128.7, 128.5, 127.4, 126.8, 117.8, 114.2, 108.7, 102.1, 98.5, 77.4, 77.1, 76.8, 66.0, 55.2, 49.2, 38.2; IR: 3356, 2970, 1764, 1666, 1502, 1481, 1324, 1128 cm⁻¹; HRMS (ESI): m/z calcd for C₃₁H₂₅NNaO₆ [M + Na]⁺: 530.1580; found 530.1585; Elemental Analysis for C₃₁H₂₅NO₆: C, 73.36; H, 4.96; N, 2.76; O, 18.91. Found: C, 73.34; H, 4.98; N, 2.75; O, 18.93.

N-(7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)-4-methoxybenzamide (3b), 74% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.46–7.40 (m, 2H), 7.23–7.16 (m, 3H), 7.05–6.98 (m, 4H), 6.52 (d, J = 8.8 Hz, 2H), 6.71–6.69 (m, 3H), 6.64 (s, 1H), 5.99 (dd, J = 16.0, 1.6 Hz, 2H), 5.28 (s, 1H), 4.35 (d, J = 14.0 Hz, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 3.14 (d, J = 14.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 167.4, 162.4, 159.0, 148.0, 145.3, 144.4, 135.1, 130.3, 130.0, 129.0, 128.7, 128.4, 127.4, 127.4, 117.9, 114.1, 113.8, 108.7, 102.1, 98.5, 65.9, 55.5, 55.2, 49.2, 38.2; IR: 3342, 2971, 1762, 1675, 1501, 1491, 1324, 1129 cm⁻¹; HRMS (ESI): m/z calcd for C₃₂H₂₇NNaO₇ [M + Na]⁺: 560.1685; found 560.1681; Elemental Analysis for C₃₂H₂₇NO₇: C, 71.50; H, 5.06; N, 2.61; O, 20.83. Found: C, 71.47; H, 5.08; N, 2.60; O, 20.85.

N-(7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)-4-methylbenzamide (3c), 77% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J = 6 Hz, 2H), 7.20–7.10 (m, 3H), 7.05 (d, J = 8.7 Hz, 4H), 6.80 (s, 1H), 6.70 (s, 4H), 5.98 (s, 2H), 6.02 (d, J = 17.2, 4H) 5.30 (s, 1H), 4.15 (d, J = 14.0 Hz, 1H), 3.68 (s, 3H), 3.17 (d, J = 14.4 Hz, 1H), 2.40 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 167.9, 159.0, 148.0, 145.3, 144.4, 142.1, 135.1, 132.4, 130.2, 130.0, 129.3, 129.0, 128.4, 127.4, 126.8, 117.9, 114.2, 108.7, 102.1, 98.5, 65.9, 55.2, 49.2, 38.2, 21.5; IR: 3352, 2971, 1764, 1668, 1502, 1481, 1332, 1130 cm⁻¹; HRMS (ESI): m/z calcd for C₃₂H₂₇NNaO₆ [M + Na]⁺: 544.1736; found 544.1733; Elemental Analysis for C₃₂H₂₇NO₆: C, 73.69; H, 5.22; N, 2.69; O, 18.41. Found: C, 73.67; H, 5.23; N, 2.68; O, 18.42.

N-(7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)-4-(trifluoromethyl)benzamide (3d), 71% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.23–7.21 (m, 3H), 7.05–7.03 (m, 4H), 6.82 (s, 1H), 6.62–6.70 (m, 4H), 5.97 (d, J = 16.8 Hz, 2H), 5.23 (s, 1H), 4.11 (d, J = 16 Hz, 1H), 3.70 (s, 3H), 3.20 (d, J = 14 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 166.7, 159.1, 148.2, 145.5, 144.2, 138.3, 134.8, 130.1, 129.9, 128.9, 128.6, 127.6–, 127.2, 125.8, 125.8, 117.5, 114.2, 108.6, 102.1, 98.6, 66.0, 55.3, 49.3, 38.3; ¹⁹F NMR (376 MHz, CDCl₃) δ -62.9; IR: 3347, 2981, 1758, 1667, 1502, 1481, 1326, 1130 cm⁻¹; HRMS (ESI): m/z calcd for C₃₂H₂₄F₃NNaO₆ [M + Na]⁺: 598.1453; found 598.1455; Elemental Analysis for C₃₂H₂₄FNO₆: C, 66.78; H, 4.20; N, 2.43; O, 16.68. Found: C, 66.76; H, 4.21; N, 2.43; O, 16.67.

N-(7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)-4-chlorobenzamide (3e), 76% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.37 (m, J = 1.8, 4H), 7.20–7.19 (m, J = 3.2, 3H), 7.04 (dd, J = 8.4, 4H), 6.81 (s, 1H), 6.70–6.86 (m, 4H), 6.02 (dd, J = 14.8, 2H), 5.24 (s, 1H), 4.15 (d, J = 14.0, 1H), 3.69 (s, 3H), 3.20 (d, J = 13.6, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 166.8, 159.1, 148.1, 145.4, 144.3, 138.0, 134.9, 133.4, 130.1, 129.9, 129.0, 128.5, 128.2, 127.5, 117.7, 114.2, 108.7, 102.1, 98.6, 66.0, 55.2, 49.2, 38.3, 25.5; IR: 3355, 2972, 1762, 1666, 1502, 1481, 1332, 1129 cm⁻¹; HRMS (ESI): m/z calcd for C₃₁H₂₄ClNNaO₆ [M + Na]⁺: 564.1190; found 564.1196; Elemental Analysis for C₃₁H₂₄ClNO₆: C, 68.70; H, 4.46; N, 2.58; O, 17.71. Found: C, 68.69; H, 4.46; N, 2.58; O, 17.72.

N-(7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)-3-methylbenzamide (3f), 75% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, J = 10.4 Hz, 2H), 7.21– 7.19 (m, 5H), 7.06 (dd, J = 14, 6.8 Hz, 4H), 6.80 (s, 1H), 6.70 (dd, J = 6.8, 3.2 Hz, 4H), 5.98 (dd, J = 16.8, 1.2 Hz, 2H), 5.28 (s, 1H), 4.15 (d, J = 15.2 Hz, 1H), 3.68 (s, 3H), 3.17 (d, J = 14.0 Hz, 1H), 2.33 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 168.2, 159.0, 148.1, 145.4, 144.3, 138.6, 135.2, 135.1, 132.4, 130.3, 130.0, 129.0, 128.5, 128.5, 127.4, 123.9, 117.9, 114.2, 108.7, 102.1, 98.5, 65.9, 55.2, 49.2, 38.2, 21.4; IR: 3358, 2972, 1774, 1666, 1514, 1476, 1320, 1128 cm⁻¹; HRMS (ESI): m/z calcd for C₃₂H₂₇NNaO₆ [M + Na]⁺: 544.1736; found 544.1734; Elemental Analysis for C₃₂H₂₇NO₆: C, 73.69; H, 5.22; N, 2.69; O, 18.41. Found: C, 73.68; H, 5.23; N, 2.68; O, 18.42.

N-(7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)-2-chlorobenzamide (3g), 68% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.40 (m, 2H), 7.20–7.17 (m, 3H), 7.05–7.01 (m, 4H), 6.82 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 6.69–6.68 (m, 3H), 6.64 (s, 1H), 5.99 (dd, J = 16.0, 1.6 Hz, 2H), 5.27 (s, 1H), 4.13 (d, J = 14.0 Hz, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 3.13 (d, J = 14.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.3, 166.3, 159.2, 148.1, 145.4, 144.1, 134.8, 134.6, 131.6, 130.7, 130.4, 130.2, 129.6, 129.2, 128.5, 127.5, 126.9, 117.8, 114.4, 108.6, 102.1, 98.6, 66.1, 55.4, 49.6, 38.6; IR: 3359, 2971, 1764, 1666, 1502, 1482, 1324, 1130 cm⁻¹; HRMS (ESI): m/z calcd for C₃₁H₂₄ClNNaO₆ [M + Na]⁺: 564.1190; found 564.1187; Elemental Analysis for C₃₁H₂₄ClNO₆: C, 68.70; H, 4.46; N, 2.58; O, 17.71. Found: C, 68.69; H, 4.46; N, 2.58; O, 17.72.

N-(7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)-3,5-dimethylbenzamide (3h), 69% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.30–7.22 (m, 3H), 7.06–6.86 (m, 7H), 6.81 (s, 1H), 6.69 (dd, J = 46.8, 2.8 Hz, 4H), 5.99 (d, J = 15.6 Hz, 2H), 5.28 (s, 1H), 4.12 (d, J = 14.0 Hz, 1H), 3.70 (s, 3H), 3.17 (d, J = 13.6 Hz, 1H), 2.28 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 168.3, 159.0, 148.0, 145.4, 144.4, 138.4, 135.2, 135.1, 133.3, 130.3, 130.0, 129.0, 128.4, 127.4, 124.5, 117.9, 114.2, 108.7, 102.1, 98.5, 65.9, 55.2, 49.2, 38.2, 21.3; IR: 3357, 2973, 1764, 1666, 1502, 1481, 1345, 1142 cm⁻¹; HRMS (ESI): m/z calcd for C₃₃H₂₉NNaO₆ [M + Na]⁺: 558.1893; found 558.1895.

N-(7-(4-fluorobenzyl)-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide (3i), 72% yield; ¹H NMR (400 MHz, CDCl₃) 7.40 (dd, J = 34.6, 6.5 Hz, 5H), 7.16–6.46 (m, 11H), 5.99 (d, J = 15.1 Hz, 2H), 5.26 (s, 1H), 4.12 (d, J = 14.0 Hz, 1H), 3.67 (s, 3H), 3.14 (d, J = 14.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 167.9, 159.0, 148.0, 145.4, 144.2, 134.9, 131.7, 131.4, 131.3, 130.7, 130.0, 128.9, 128.7, 126.7, 117.6, 115.4, 115.2, 114.2, 108.6, 102.0, 98.4, 65.8, 49.1, 37.4, 25.4; ¹⁹F NMR (376 MHz, CDCl₃) δ -114.9; IR: 3360, 2971, 1758, 1672, 1500, 1480, 1322, 1123 cm⁻¹; HRMS (ESI): m/z calcd for C₃₁H₂₄FNNaO₆ [M + Na]⁺: 548.1485; found 548.1489.

N-(7-(4-chlorobenzyl)-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide (3j), 71% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 6.7 Hz, 3H), 7.36 (d, J = 6.7 Hz, 2H), 7.16 (d, J = 7.4 Hz, 2H), 7.05 (dd, J = 19.2, 8.8 Hz, 4H), 6.80 (s, 1H) 6.68 (m, 4H), 5.98 (d, J = 15.6 Hz, 2H), 5.25 (s, 1H), 4.14 (d, J = 14.4 Hz, 1H), 3.68 (s, 3H), 3.15 (d, J = 13.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.3, 168.0, 159.1, 148.1, 145.5, 144.3, 134.9, 133.5, 133.4, 131.8, 131.2, 130.0, 129.0, 128.8, 128.7, 126.7, 117.6, 114.2, 108.7, 102.1, 98.5, 65.8, 55.2, 49.1, 37.6; IR: 3348, 2976, 1764, 1666, 1502, 1480, 1324, 1102 cm⁻¹; HRMS (ESI): m/z calcd for C₃₁H₂₄ClNNaO₆ [M + Na]⁺: 564.1190; found 564.1187; Elemental Analysis for C₃₁H₂₄ClNO₆: C, 68.70; H, 4.46; N, 2.58; O, 17.71. Found: C, 68.69; H, 4.46; N, 2.58; O, 17.72.

N-(8-(4-methoxyphenyl)-7-(2-(methylthio)ethyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide (3k), 65% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.53 (m, 2H), 7.51–7.47 (m, 1H), 7.41–6.37 (m, 2H), 7.00–6.97 (m, 2H), 6.92 (s, 1H), 6.71–6.68 (m, 3H),6.63 (s, 1H), 5.99 (d, J = 15.4 Hz, 2H), 5.09 (s, 1H), 3.69 (s, 3H), 3.25–3.17 (m, 1H), 2.51 (td, J = 12.7, 5.0 Hz, 1H), 2.35 (td, J = 12.4, 4.9 Hz, 1H), 2.18–2.09 (m, 1H), 2.01 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.2, 167.4, 159.1, 148.0, 145.4, 144.3, 134.6, 131.9, 130.0, 128.9, 128.8, 126.9, 117.4, 114.2, 108.6, 102.1, 98.5, 64.2, 55.3, 49.1, 32.6, 29.0, 15.7; IR: 3362, 2972, 1724, 1663, 1502, 1481, 1324, 1104 cm⁻¹; HRMS (ESI): m/z calcd for C₂₇H₂₅NNaO₆S [M + Na]⁺: 514.1300; found 514.1305.

N-(7-isobutyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide (3l), 66% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.48–7.56 (m, 3H), 7.40 (t, J = 7.4 Hz, 2H), 6.98–7.01 (m, 2H), 6.93 (s, 1H), 6.68–6.71 (m, 3H), 6.64 (s, 1H), 6.00 (dd, J = 14.7, 1.4 Hz, 2H), 5.09 (s, 1H), 3.70 (s, 3H), 3.49 (d, J = 4.8 Hz, 2H), 2.20–2.11 (m, 1H), 0.90 (dd, J = 7.2, 20.8 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 169.5, 167.6, 159.3, 148.3, 145.6, 144.5, 134.9, 132.1, 130.2, 129.2, 129.0, 127.1, 117.6, 114.5, 108.8, 102.3, 98.8, 64.4, 55.5, 41.04, 21.82, 20.18; IR: 3349, 2970, 1766, 1660, 1500, 1485, 1324, 1102 cm⁻¹; HRMS (ESI): m/z calcd for C₂₈H₂₇NNaO₆ [M + Na]⁺: 496.1736; found 496.1740.

N-(8-(4-methoxyphenyl)-6-oxo-7-phenyl-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide (3m), 67% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.52 (m, 3H), 7.29–7.34 (m, 2H), 7.13–7.22 (m, 7H), 7.04–7.09 (m, 2H), 6.82 (s, 1H), 6.70 (d, J = 6.4 Hz, 2H), 6.01 (dd, J = 16.7, 1.1 Hz, 2H), 5.32 (s, 1H), 3.69 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.7, 168.5, 148.5, 145.7, 144.8, 138.6, 135.6, 135.3, 132.0, 130.4, 129.3, 129.0, 128.9, 128.2, 127.8, 127.1, 117.9, 109.1, 102.5, 99.0, 60.1, 50.5, 38.7; IR: 3344, 2975, 1760, 1660, 1500, 1485, 1324, 1092 cm⁻¹; HRMS (ESI): m/z calcd for C₃₀H₂₃NNaO₆ [M + Na]⁺: 516.1423; found 516.1427.

N-(7-benzyl-6-oxo-8-phenyl-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide (3n), 64% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.47–7.43 (m, 3H), 7.36–7.32 (m, 2H), 7.21–7.19 (m, 3H), 7.07–7.04 (m, 4H), 6.81 (s, 1H), 6.71–6.68 (m, 4H), 6.01 (d, J = 15.4 Hz, 2H), 4.13 (d, J = 14.0 Hz, 1H), 3.16 (d, J = 14 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.3, 168.1, 148.2, 145.4, 144.4, 138.3, 135.2, 134.9, 131.6, 130.0, 128.9, 128.6, 128.5, 127.9, 127.5, 126.7, 117.5, 108.7, 102.1, 98.6, 65.7, 50.1, 38.3; IR: 3354, 2974, 1762, 1626, 1508, 1488, 1324, 1120 cm⁻¹; HRMS (ESI): m/z calcd for C₃₀H₂₃NNaO₅ [M + Na]⁺: 500.1474; found 500.1471.

N-(7-benzyl-8-((E)-4-methoxystyryl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide (3o), 72% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.65–7.61 (m, 2H), 7.51–7.46 (m, 1H), 7.41–7.37 (m, 2H), 7.22–7.20 (m, 3H), 7.15–7.11 (m, 2H), 7.04–7.00 (m, 2H), 6.77 (d, J = 5.6 Hz, 2H), 6.74–6.72 (m, 2H), 6.35 (d, J = 16 Hz, 1H), 6.04 (d, J = 4.4 Hz, 2H), 5.89 (dd, J = 15.6, 8.0 Hz, 1H), 3.91 (d, J = 14 Hz, 1H), 3.74 (s, 3H), 3.06 (d, J = 14.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 167.4, 159.3, 148.0, 145.2, 144.1, 134.8, 132.8, 131.7, 129.9, 129.1, 128.7, 128.4, 127.7, 127.4, 126.8, 123.0, 116.6, 113.8, 108.6, 102.0, 98.6, 64.9, 53.5, 47.1, 37.7; IR: 3386, 2978, 1784, 1672, 1500, 1481, 1332, 1135 cm⁻¹; HRMS (ESI): m/z calcd for C₃₃H₂₇NNaO₆ [M + Na]⁺: 556.1736; found 556.1731.

The gram-scale synthesis of dihydrocoumarin 3a: To a stirred solution of 2-benzylphenol (1, 0.517 g, 2.0 mmol), 4-benzyl-2-phenyloxazol-5(4H)-one (2, 0.503 g, 2.0 mmol), and Ag₂O (0.556 g, 2.4 mmol) in chloroform (30 mL), diphenyl phosphate (50.0 mg, 0.2 mmol) was added at room temperature under an N₂ atmosphere. The reaction mixture was stirred for 62 h at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure. After extraction with ethyl acetate (90 mL) three times and drying with anhydrous sodium sulfate, the resulting solution was concentrated by an evaporator and purified by silica gel column chromatography (EtOAc/hexane = 1:5) to afford N-(7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide 3a (0.721 g, 78%).

The typical procedure for the asymmetric synthesis of 3,4-dihydrocoumarins 3a: To a stirred solution of 2-benzylphenol (1, 25.8 mg, 0.1 mmol), 4-benzyl-2-phenyloxazol-5(4H)-one (2, 25.1 mg, 0.1 mmol), and Ag₂O (27.8 mg, 0.12 mmol) in chloroform (2 mL), (11bR)-2,6-di(anthracen-9-yl)-4-hydroxydinaphtho [2,1-d:1’,2’-f][1–3]dioxaphosphepine 4-oxide (4, 7.0 mg, 0.01 mmol) was added at room temperature under an N₂ atmosphere. The reaction mixture was stirred for 42 h at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc/hexane = 1:5) to afford N-((7S,8S)-7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3]dioxolo [4,5-g]chromen-7-yl)benzamide 3a (31.9 mg).

63% yield; [α $]_{D}^{25}$ = +8.01 (c = 0.20, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.41 (m, 2H), 7.20–7.16 (m, 3H), 7.05–7.02 (m, 4H), 6.82 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 6.69–6.68 (m, 3H), 6.64 (s, 1H), 5.99 (dd, J = 16.0, 1.6 Hz, 2H), 5.27 (s, 1H), 4.13 (d, J = 14.0 Hz, 1H), 3.67 (s, 3H), 3.13 (d, J = 14.1 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 168.0, 159.0, 148.1, 144.4, 135.2, 135.0, 131.7, 130.2, 129.9, 129.0, 128.7, 128.5, 127.4, 126.8, 117.8, 114.2, 108.7, 102.1, 98.5, 77.4, 77.1, 76.8, 66.0, 55.2, 49.2, 38.2; IR: 3356, 2970, 1764, 1666, 1502, 1481, 1324, 1128 cm⁻¹; Elemental Analysis for C₃₁H₂₅NO₆: C, 73.36; H, 4.96; N, 2.76; O, 18.91. Found: C, 73.34; H, 4.98; N, 2.75; O, 18.93; HRMS (ESI): m/z calcd for C₃₁H₂₅NNaO₆ [M + Na]⁺: 530.1580; found 530.1585; The EE value was 93%, tR (major) = 36.40 min, tR (minor) = 30.45 min (Daicel chiralcel IA, λ = 254 nm, n-hexane/i-PrOH 97/3, 1.0 mL/min).

4. Conclusions

In summary, we have developed an efficient synthesis of 3,4-dihydrocoumarin derivatives via C–H oxidation between 2-alkyl substituted phenol derivatives and 5-(4H)oxazolones and cyclization cascade under acid-catalyzed conditions. This approach provides a one-pot strategy to synthesize multisubstituted 3,4-dihydrocoumarins in moderate to high yields (64–81%) and excellent diastereoselectivity (>20:1).

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28196853/s1. The experimental procedures and ¹H NMR, and ¹³C NMR spectra of products can be found in the supporting information. References are cited from [36,37,38,39,40,41,42].

Click here for additional data file.^{(6.1MB, zip)}

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article or Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

Funding Statement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2021-R1I1A3044807, 2021R1A6A1A03039503) and Soonchunhyang University Research Fund (2023-4).

Footnotes

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Data Availability Statement

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PERMALINK

One-Pot Synthesis of 3,4-Dihydrocoumarins via C-H Oxidation/Conjugate Addition/Cyclization Cascade Reaction

Dae Young Kim

Roles

Abstract

1. Introduction

Scheme 1.