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

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).

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.
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.
Table 1.Optimization of the reaction conditions [a,c] .
Table 1.Optimization of the reaction conditions [a,c] .
Scheme 1. Methods for the asymmetric synthesis of dihydrocoumarins.
In order to demonstrate the synthetic utility of this transformation, the gra synthesis of 3,4-dihydrocoumarin (3a) was conducted.As shown in Scheme 2, w benzyl phenol (1a) was treated with 4-benzyl-2-phenyloxazol-5(4H)-one (2a) und mal reaction conditions, the reaction proceeded well to afford the chiral 3,4-dihy marin (3a) with a 78% yield.To achieve the asymmetric version of this reaction, t tion was conducted with a chiral phosphoric acid catalyst (4) instead of dipheny Scheme 2. The gram-scale synthesis of dihydrocoumarin 3a.Table 2. Substrate scope [a,b,c] .
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 2benzyl 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.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 2benzyl 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.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 phos-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 Ag 2 O 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).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).

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 technicalgrade 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

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 Na 2 SO 4 .Anhydrous solvents were deoxygenated by sparging with N 2 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 F 254 pre-coated glass plates (0.25 mm thickness) and visualized using UV light (254 nm and 365 nm), I 2 , p-anisaldehyde, ninhydrin, and phosphomolybdic acid solution as an indicator.Flash chromatography was carried out on E. Merck silica gel (230-400 mesh). 1 H NMR, 13 C NMR, and 19 F 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: Me 4 Si as the internal references for the 1 H-and 13 C-NMR signals in chloroform and PhCF 3 as the external references for the 19 F-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.
Methods for the asymmetric synthesis of dihydrocoumarins.

Table 1 .
Optimization of the reaction conditions[a,c].