Copper-Promoted Intramolecular Oxidative Dehydrogenation for Synthesizing Dihydroisocoumarins and Isocoumarins

Isocoumarins and dihydroisocoumarins are important skeletons with a wide range of biological activities, such as anti-bacterial, anti-allergy, anti-fungal, anti-tumor, and anti-HIV properties. Herein, we demonstrated divergent syntheses of isocoumarins and 3,4-dihydroisocoumarins by intramolecular dehydrogenative cyclization of 2-(3-oxobutyl) benzoic acids. This transformation undergoes Csp3–H bonds and O–H bonds coupling in air using copper salt. The reactions may undergo free radical process.


Introduction
In recent years, oxygen-containing heterocyclic compounds have emerged as the mainstream in drug research and development because of their unique structural characteristics and physiological activities.Compounds with isocoumarins and dihydroisocoumarins, which are important skeletons of many natural products, bioactive substances, and agricultural chemicals, have a wide range of biological activities, such as anti-bacterial and anti-allergy, anti-fungal, anti-tumor, and anti-HIV, and can be used to make herbicides [1][2][3][4][5].
The synthesis of dihydroisocoumarins is rarely reported.The methods reported in the literature are mainly constructed via the oxidation of methylene groups.Oxygen [12], iridium [35,38], iron [12,39,40], ruthenium [32][33][34]41], manganese [42] can oxidize methylene in isochroman to synthesize dihydroisocoumarins.However, this kind of reaction is not suitable for isocoumarin substrates.Metal-catalyzed intramolecular and intermolecular cyclization reactions, coupling of carbon monoxide with alcohols, and palladium-catalyzed carbonyl insertion have also been used for the synthesis of dihydroisocoumarins.The synthesis of dihydroisocoumarins is rarely reported.The methods reported in the literature are mainly constructed via the oxidation of methylene groups.Oxygen [12], iridium [35,38], iron [12,39,40], ruthenium [32][33][34]41], manganese [42] can oxidize methylene in isochroman to synthesize dihydroisocoumarins.However, this kind of reaction is not suitable for isocoumarin substrates.Metal-catalyzed intramolecular and intermolecular cyclization reactions, coupling of carbon monoxide with alcohols, and palladiumcatalyzed carbonyl insertion have also been used for the synthesis of dihydroisocoumarins.
Our previous study [43] displayed that 2-(3-oxobutyl) benzoic acid can be generated from aromatic carboxylic acids and 1-penten-3-one in one pot via rhodium-catalyzed carboxyl-directed conjugate addition of C-H bonds to α,β-unsaturated ketones in air and water.We envision that whether 2-(3-oxobutyl) benzoic acid can undergo intramolecular cyclization reaction and oxidative dehydrogenation to yield dihydroisocoumarins and isocoumarins in one pot.Herein, we illuminated copper-promoted intramolecular oxidative dehydrogenation of 2-(3-oxoalkyl) benzoic acid for synthesizing dihydroisocoumarins and isocoumarins in a step in air.

General Method for the Synthesis of Dihydroisocoumarins
CuCl (9.9 mg, 0.1 mmol), 0.6 mL of N,N-dimethylformamide, substituted benzoic acid (0.1 mmol) were added in sequence to a microwave reactor.The reaction tube was directly sealed and reacted at 140 °C (oil bath temperature) for 20 min.Then, the mixture was cooled to room temperature and diluted with ethyl acetate, and the salt was removed through a short silica gel column.The crude product was purified using preparative thinlayer chromatography to give the corresponding product.

General Method for the Synthesis of Isocoumarins
Cu(OTf)2 (217.0 mg, 0.6 mmol), CuCl2•2H2O (17 mg, 0.1 mmol), 0.6 mL of N,N-dimethylacetamide, and substituted benzoic acid (0.2 mmol) were added in the microwave reactor.The mixture reacted at 150 °C (oil bath temperature) for 4 h.After cooling to room temperature, the mixture was diluted with ethyl acetate, and the salt was removed Our previous study [43] displayed that 2-(3-oxobutyl) benzoic acid can be generated from aromatic carboxylic acids and 1-penten-3-one in one pot via rhodium-catalyzed carboxyl-directed conjugate addition of C-H bonds to α,β-unsaturated ketones in air and water.We envision that whether 2-(3-oxobutyl) benzoic acid can undergo intramolecular cyclization reaction and oxidative dehydrogenation to yield dihydroisocoumarins and isocoumarins in one pot.Herein, we illuminated copper-promoted intramolecular oxidative dehydrogenation of 2-(3-oxoalkyl) benzoic acid for synthesizing dihydroisocoumarins and isocoumarins in a step in air.

General Method for the Synthesis of Dihydroisocoumarins
CuCl (9.9 mg, 0.1 mmol), 0.6 mL of N,N-dimethylformamide, substituted benzoic acid (0.1 mmol) were added in sequence to a microwave reactor.The reaction tube was directly sealed and reacted at 140 • C (oil bath temperature) for 20 min.Then, the mixture was cooled to room temperature and diluted with ethyl acetate, and the salt was removed through a short silica gel column.The crude product was purified using preparative thin-layer chromatography to give the corresponding product.

General Method for the Synthesis of Isocoumarins
Cu(OTf) 2 (217.0 mg, 0.6 mmol), CuCl 2 •2H 2 O (17 mg, 0.1 mmol), 0.6 mL of N,N-dimethylacetamide, and substituted benzoic acid (0.2 mmol) were added in the microwave reactor.The mixture reacted at 150 • C (oil bath temperature) for 4 h.After cooling to room temperature, the mixture was diluted with ethyl acetate, and the salt was removed through a short silica gel column.The crude product was purified using preparative thin-layer chromatography to give the corresponding product.

Experimental Reagents and Instruction
1 H NMR and 13 C NMR spectra were measured on a Bruker spectrometer, using CDCl 3 as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature.High-resolution mass spectrometry was determined using a compass-maxis high-resolution mass spectrometer from Bruker Company, Germany.All solvents used in the experiment were dried using activated molecular sieves, and the other reagents used in the experiment were all analytically pure without any other treatment.Chemical shifts are given in δ relative to TMS, and the coupling constants J are given in Hz.Characterization data of compounds, the conversions of acids and NMR spectra of compounds, See Supplementary Materials.

Discussion
2-methyl-6-(3-oxopentyl)benzoic acid was selected as substrate to screen the reaction conditions (Table 1).To our delight, 4% yield of the dihydroisocoumarin product 2a was observed at 150 • C for 24 h with CuI.The 2a were not observed in the atmosphere of nitrogen and oxygen.Using CuCl or CuBr instead of CuI, the yields were increased to 28% and 18% (Table 1, entries 4, 5), only 1% yield was detected using CuF 2 .Other bivalent coppers, such as CuO, Cu(OAc) 2 , and CuBr 2 , failed to generate cyclization product (Table 1, entries 7-9).Lower yields were detected in DMAc, DMSO, THF or tert-pentanol (Table 1, entries 10-13).No 2a were observed in toluene and 1,4-dioxane (Table 1, entries 14,15).The yield increased to 35% when the amount of CuCl was doubled.It was found that increasing reaction temperature to 140 • C and shortening reaction time to 20 min, the yield of 2a was enhanced to 61% (Table 1, entry 17).Then, the effects of reaction time on the yield were investigated.A reaction time of 20 min was the best among 10 min, 20 min, and 30 min (Table 1, entries 18-20).

Experimental Reagents and Instruction
1 H NMR and 13 C NMR spectra were measured on a Bruker spectrometer, using CDCl3 as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature.High-resolution mass spectrometry was determined using a compass-maxis high-resolution mass spectrometer from Bruker Company, Germany.All solvents used in the experiment were dried using activated molecular sieves, and the other reagents used in the experiment were all analytically pure without any other treatment.Chemical shifts are given in δ relative to TMS, and the coupling constants J are given in Hz.Characterization data of compounds, the conversions of acids and NMR spectra of compounds, See Supplementary Materials.
To make an insight on the mechanism, free radical scavenger TEMPO was added to the reaction mixture.The addition of TEMPO depressed the formation of dihydroisocoumarin, and 21% of isocoumarin was detected, which suggesting that the reaction may undergo a radical process (Figure 4).

Figure 4 .
Figure 4. Exploration of possible free radical reactions.

Figure 4 .
Figure 4. Exploration of possible free radical reactions.Figure 4. Exploration of possible free radical reactions.

Figure 4 .
Figure 4. Exploration of possible free radical reactions.Figure 4. Exploration of possible free radical reactions.

Figure 5 .
Firstly, Cu(I) is oxidized by air to afford Cu(II), which reacts with 2-(3-oxopentyl) benzoic acid to form the intermediate (B).Then the free radical intermediate (C) is formed via homolysis of the O-Cu bond.The carbon radical intermediate (D) is obtained via hydrogen transfer from α-H of carbonyl to oxygen free radical.The final product is formed via the copper-catalyzed single-electron intermediate and intramolecular cyclization (F).

Table 1 .
Selected results for optimizing reaction conditions a .

Table 1 .
Selected results for optimizing reaction conditions a .

Table 2 .
Selected results for optimizing reaction conditions a .

Table 2 .
Selected results for optimizing reaction conditions a .