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Communication

Copper-Promoted Intramolecular Oxidative Dehydrogenation for Synthesizing Dihydroisocoumarins and Isocoumarins

1
Shaanxi Key Laboratory of Catalysis, School of Chemistry and Environmental Science, Shaanxi University of Technology, Hanzhong 723001, China
2
Key Laboratory of Syngas Conversion of Shaanxi Province, Key Laboratory for Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi’an 710062, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2023, 28(17), 6319; https://doi.org/10.3390/molecules28176319
Submission received: 29 June 2023 / Revised: 16 August 2023 / Accepted: 18 August 2023 / Published: 29 August 2023
(This article belongs to the Special Issue Advances in Transition-Metal-Catalyzed Synthesis)

Abstract

:
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.

1. 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 synthesizing isocoumarins mainly depended on the coupling of carboxyl groups and unsaturated compounds, which involved metal-catalyzed reactions as well as various intramolecular and intermolecular cyclization reactions [6,7,8]. In 1998, Miura’s group [9] firstly employed palladium as a catalyst to synthesize isocoumarins (Figure 1a). In 2009 and 2014, Obushak’s group [10,11] reported the one-pot synthesis of dihydroisocoumarin derivatives and 3-substituted methyl 3,4-dihydroisocoumarin-6-carboxylates under Meerwein’s arylation conditions (Figure 1b). In 2017, Shen’s group [12] discolsed a Fe(NO3)3-catalyzed synthesis of dihydroisocoumarin derivatives (Figure 1c). In 2018, Oh’s group [13] demonstrated A rhodium-catalyzed decarbonylative aerobic oxidation of cyclic α-diketones for the formations of isocoumarins. Among these reactions, transition metal complexes, such as palladium [14,15,16,17,18,19,20], rhodium [21,22,23,24,25,26,27,28,29,30,31], ruthenium [32,33,34], iridium [35], nickel [36], and silver [37], are commonly used catalysts. Moreover, these protocols have the disadvantages of requiring expensive catalysts and halogenated raw materials, and low atomic utilization, etc.
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.
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.

2. Results

2.1. 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.

2.2. 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 through a short silica gel column. The crude product was purified using preparative thin-layer chromatography to give the corresponding product.

3. Materials and Methods

Experimental Reagents and Instruction

1H NMR and 13C 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.

4. 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 CuF2. Other bivalent coppers, such as CuO, Cu(OAc)2, and CuBr2, 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).
When CuO was added, an isocoumarin product 3a in 25% yield was observed (Table 2, entry 1). 16% and 12% yields of 3a were observed in nitrogen and oxygen atmospheres, respectively (Table 2, entries 2, 3). When the solvents were screened (Table 2, entries 4–8), only DMAc gave a slight increase yield (32%, Table 2, entry 4). The yield was 33% when CuCl was replaced by CuCl2·2H2O (Table 2, entry 9). Other copper salts, such as Cu(OH)2, CuCl2, and CuBr, also can deliver 3a (Table 2, entries 10–12). The yields was found to be 50%, 46% and 26% using Cu(OTf)2, AgOTf and AgOAc, respectively (Table 2, entries 13–15). The yield was enhanced to 59% with 3.0 eq. Cu(OTf)2 and 0.5 eq. CuCl2·2H2O at 150 °C for 2.5 h (Table 2, entry 16). It is pleased to find that 65% yield of 3a was observed when the amount of 1a was increased to 0.2 mmol (Table 2, entry 17).
With the optimum reaction conditions in hand, the application of this method was investigated with a series of substituted 2-(3-oxobutyl) benzoic acids. The results are listed in Figure 2 and Figure 3. As can be seen from Figure 2, substituted 2-(3-oxo-amyl) benzoic acids bearing electron-donating groups at ortho-position of carboxyl such as ethyl, phenyl, benzyl, and ethylphenyl delivered moderate yields (2b2e, 49–57%), and the yield was 74% when there was no substituted group in the benzene ring. Meta- and para-substituted 2-(3-oxamyl) benzoic acids such as 3-methyl, 3-methoxy, 4-methyl, and 4-ethyl, afforded good to excellent yields of cyclization products (2g2l). 3-Cl-substituted 2-(3-oxamyl) benzoic acid also produced the targeted product (2i) in a 46% yield. Disubstituted 2-(3-oxopentyl) benzoic acids were also compatible, giving rise to moderate to good yields (2m2u, 44–68%). 3,4,5-Trimethoxy-2-(3-oxamyl) benzoic acid gave 68% yield of 2v. When the benzene ring was substituted by thiophene, the yield was 42% (2w). Employing 3-(3-oxo-amyl)-2-naphthylformic acid and 2-(3-oxo-amyl)-2-naphthylformic acid as substrates, the cyclization products were 72% and 40%, respectively (2x and 2y). 5-Methyl-2-(3-oxobutyl) benzoic acid and 5-methyl-2-(3-oxooctyl) benzoic acid generated 85% and 65% desired products, respectively (2z and 2aa).
As can be seen from Figure 3, the oxidative dehydrogenation of 2-(3-oxopentyl) benzoic acids bearing different substituents produced isocoumarins in moderate to good yields. Similar to the formation of dihydroisocoumarins, donating groups at the ortho, meta, and para-position of carboxyl, 2,3-disubstituted 2-(3-oxo-amyl) benzoic acid, 2,4-disubstituted 2-(3-oxo-amyl) benzoic acid, 3,4-disubstituted 2-(3-oxo-amyl) benzoic acid worked well, and moderate to good yields were obtained (3b3n). 3,4,5-Trimethoxy-2-(3-oxamyl) benzoic acid delivered 77% yield of targeted product. For heterocyclic 3-(3-oxopentyl) thiophene-2-carboxylic acid, 54% of product was observed. 76% and 51% of the isocoumarins were obtained from 3-methyl-2-(3oxobutyl) benzoic acid and 3-methyl-2-(3oxo-octyl) benzoic acid, respectively.
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).
Based on the above results and radical studies [44,45,46], a plausible mechanism for forming dihydroisocoumarin was given in 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).

5. Conclusions

In summary, the divergent syntheses of isocoumarins and 3,4-dihydroisocoumarins were achieved by intramolecular dehydrogenative cyclization of 2-(3-oxobutyl) benzoic acids via Csp3–H bonds and O–H bonds coupling in air using copper salts. The advantages of this protocol include simple operation, air atmosphere, short reaction time, broad substrate scope, and cheap copper salts. The reactions may undergo free radical process.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28176319/s1, characterization data of compounds, the conversions of acids and NMR spectra of compounds.

Author Contributions

Conceptualization, Q.Z. and X.-Y.S.; methodology, X.-Y.S. investigation, Q.Z. and L.-Y.Z.; resources, X.-Y.S.; data curation, L.-Y.Z.; writing—original draft preparation, Q.Z.; writing—review and editing, Q.Z. and X.-Y.S.; supervision, X.-Y.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

All procedures were approved by the Committee of Shaanxi University of Technology.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the authors.

Acknowledgments

The authors are grateful to the support of the Shaanxi Normal University experimental testing platform in the process of characterizing compounds.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. The works for the synthesis of isocoumarins and dihydroisocoumarins. (a) Miura’s, work; (b) Obushak’s works; (c) Shen’s work.
Figure 1. The works for the synthesis of isocoumarins and dihydroisocoumarins. (a) Miura’s, work; (b) Obushak’s works; (c) Shen’s work.
Molecules 28 06319 g001
Figure 2. The synthesis of dihydroisocoumarins. Reaction conditions: substituted benzoic acid (0.1 mmol), CuCl (0.1 mmol), DMF (0.6 mL), 140 °C, 20 min, air, isolated yield.
Figure 2. The synthesis of dihydroisocoumarins. Reaction conditions: substituted benzoic acid (0.1 mmol), CuCl (0.1 mmol), DMF (0.6 mL), 140 °C, 20 min, air, isolated yield.
Molecules 28 06319 g002
Figure 3. The synthesis of isocoumarins. Reaction conditions: substituted benzoic acid (0.2 mmol), Cu(OTf)2 (0.6 mmol), CuCl2·2H2O (0.1 mmol), DMAc (0.6 mL), 150 °C, 4 h, air, isolated yield.
Figure 3. The synthesis of isocoumarins. Reaction conditions: substituted benzoic acid (0.2 mmol), Cu(OTf)2 (0.6 mmol), CuCl2·2H2O (0.1 mmol), DMAc (0.6 mL), 150 °C, 4 h, air, isolated yield.
Molecules 28 06319 g003
Figure 4. Exploration of possible free radical reactions.
Figure 4. Exploration of possible free radical reactions.
Molecules 28 06319 g004
Figure 5. A plausible mechanism.
Figure 5. A plausible mechanism.
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Table 1. Selected results for optimizing reaction conditions a.
Table 1. Selected results for optimizing reaction conditions a.
Molecules 28 06319 i001
EntryAdditiveSolventConversion (%)Yield (%) b
1CuIDMF804
2 cCuIDMF--ND
3 dCuIDMF--ND
4CuClDMF9128
5CuBrDMF7118
6CuF2DMF841
7CuODMF--ND
8Cu(OAc)2DMF--ND
9CuBr2DMF--ND
10CuClDMAc9314
11CuClDMSO8218
12CuClTHF784
13CuCltert-pentanol405
14CuCltoluene--ND
15CuCl1,4-dioxane--ND
16 eCuClDMF8335
17 fCuClDMF8561
18 gCuClDMF9849
19 hCuClDMF10053
20 iCuClDMF10050
a Reaction conditions: 1a (0.1 mmol), additive (0.5 eq.) solvent (0.6 mL), 150 °C, 24 h, air. b 1,3,5-Trimethoxybenzene was used as internal standard, and the yield was calculated by 1H NMR characterization of the crude product. ND means not detected. c N2; d O2; e CuCl (1.0 eq.); f CuCl (1.0 eq.), 140 °C, 20 min; g CuCl (1.0 eq.), 150 °C,10 min; h CuCl (1.0 eq.), 150 °C, 20 min; i CuCl (1.0 eq.), 150 °C, 30 min.
Table 2. Selected results for optimizing reaction conditions a.
Table 2. Selected results for optimizing reaction conditions a.
Molecules 28 06319 i002
EntryOxidantAdditiveSolventConversion (%)Yield (%) b
1CuOCuClDMF8625
2 cCuOCuClDMF8416
3 dCuOCuClDMF9112
4CuOCuClDMAc--32
5CuOCuClDCE9310
6CuOCuCl CH3CN 21
7CuOCuCltoluene--ND
8CuOCuCl1,4-dioxane--ND
9CuOCuCl2·2H2ODMAc8933
10CuOCu(OH)2DMAc10024
11CuOCuCl2DMAc9425
12CuOCuBr DMAc7325
13Cu(OTf)2CuCl2·2H2O DMAc8250
14AgOTfCuCl2·2H2ODMAc9046
15AgOAcCuCl2·2H2O DMAc6326
16 eCu(OTf)2CuCl2·2H2ODMAc8759
17 fCu(OTf)2CuCl2·2H2O DMAc9565
a Reaction conditions: 1a (0.1 mmol), oxidant (2.0 eq.), additive (1.0 eq.), solvent (0.6 mL), 150 °C, 12 h, air. b 1,3,5-Trimethoxybenzene (0.1 mmol) was used as the internal standard, and the yield was calculated by 1H NMR characterization of the crude product. ND means not detected. c N2; d O2; e Cu(OTf)2 (3.0 eq.), CuCl2·2H2O (0.5 eq.), 150 °C, 2.5 h; f 1a (0.2 mmol), Cu(OTf)2 (3.0 eq.), CuCl2·2H2O (0.5 eq.), DMAc (0.6 mL), 150 °C, 4 h, air.
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Zhang, Q.; Zhang, L.-Y.; Shi, X.-Y. Copper-Promoted Intramolecular Oxidative Dehydrogenation for Synthesizing Dihydroisocoumarins and Isocoumarins. Molecules 2023, 28, 6319. https://doi.org/10.3390/molecules28176319

AMA Style

Zhang Q, Zhang L-Y, Shi X-Y. Copper-Promoted Intramolecular Oxidative Dehydrogenation for Synthesizing Dihydroisocoumarins and Isocoumarins. Molecules. 2023; 28(17):6319. https://doi.org/10.3390/molecules28176319

Chicago/Turabian Style

Zhang, Qiang, Lin-Yan Zhang, and Xian-Ying Shi. 2023. "Copper-Promoted Intramolecular Oxidative Dehydrogenation for Synthesizing Dihydroisocoumarins and Isocoumarins" Molecules 28, no. 17: 6319. https://doi.org/10.3390/molecules28176319

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