HETEROCYCLES

Short Paper | Regular issue | Vol. 91, No. 11, 2015, pp. 2172-2179
Received, 29th August, 2015, Accepted, 13th October, 2015, Published online, 27th October, 2015.
DOI: 10.3987/COM-15-13311

■ Synthesis of Isocoumarins: Rhenium Complex-Catalyzed Cyclization of 2-Ethynylbenzoic Acids

Rui Umeda, Shunya Yoshikawa, Kouji Yamashita, and Yutaka Nishiyama*

Faculty of Chemistry and Materials Engineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan

Abstract

When 2-ethynylbenzoic acids were treated with a catalytic amount of a rhenium complex, such as ReCl(CO)5, 6-endo cyclization of 2-ethynylbenzoic acids proceeded with a high selectivity to give the corresponding isocoumarins in moderate to good yields.

Isocoumarin (1H-2-benzopyran-1-one) is one of the important structural subunits in numerous natural products that exhibit a wide range of biological properties1 and is a useful intermediate for the preparation of hetero- and carbocyclic compounds including isocarbostyrils, isochromenes and isoquinolines.2 Therefore, the development of synthetic methods of the isocoumarins has significantly contributed to organic and medicinal chemistries.3
We and some groups showed that ReX(CO)5 (X = Cl or Br) can be used as a catalyst for organic reactions instead of various Lewis acid complexes.4,5 Recently, Hou reported that the rhenium complex-catalyzed addition of carboxylic acids to terminal alkynes proceeded with a high regioselectivity affording the anti-Markovnikov adduct, i.e., α,β-unsaturated carboxylic acids, in moderate to good yields.6 Based on these results, it is expected that the treatment of 2-ethynylbenzoic acids in the presence of rhenium catalyst would provide the one of the preparation methods of cyclic esters, isocoumarins or vinylphthalides, via the intramolecular cyclization of 2-ethynylbenzoic acids.７ We now wish to report the successful example of the rhenium-catalyzed 6-endo intramolecular cyclization of 2-ethynylbenzoic acids for the synthesis of isocoumarins (Scheme 1).

When 2-(phenylethynyl)benzoic acid (1a) was stirred in the presence of a catalytic amount of ReCl(CO)5 (5 mol%) in a hexane at 80 °C for 5 h, the 6-endo cyclization of 1a smoothly proceeded with a high selectivity to give 3-phenyl-1H-isochromen-1-one (2a) in 80% yield with a small amount of the 5-exo cyclized product, 3-(1-benzylidene)phthalide (3a) (1%) (Entry 1 in Table 1). No reaction took place in the absence of the rhenium complex (Entry 2). The yield of 2a was improved by the extended reaction time (10 h) (Entry 3). At a lower reaction temperature (60 °C), the yield and selectivity of 2a decreased (Entry 4). To explore the effect of the solvents and rhenium complexes, the reaction of 1a was carried out in various solvents and rhenium complex catalysts. In the toluene solvent, a decrease in both the yield and selectivity of 2a were observed (Entry 5). In the cases of THF and acetonitrile, which were coordinated solvents to metals, the yields of 2a dramatically decreased (Entries 6 and 7).

The use of 1,2-dichloroethane, which is often used for the rhenium-catalyzed reaction, led to the good yield of 2a (80%), but the selectivity slightly decreased (Entry 8). When ReBr(CO)5 was used instead of ReCl(CO)5 as the catalyst, both the yield and selectivity of 2a were lower than those of ReCl(CO)5 (Entry 9). Other rhenium complexes, such as Re2(CO)10, ReCl5 and (C5H5)Re(CO)3, did not show any high catalytic activity (entries 10-12).8
To clear the scope and limitation of the rhenium complex catalytic system, various 2-(arylethynyl)benzoic acids were treated with a catalytic amount of rhenium complex. These results are shown in Table 2. The 6-endo cyclization of 2-(arylethynyl)benzoic acids bearing electron-donating groups on the aromatic ring, such as the 2-((4-methylphenyl)ethynyl)- and 2-((4-methoxyphenyl)ethynyl)benzoic acid, proceeded with excellent selectivity to give the corresponding 3-aryl-1H-isochromen-1-one, 2b,c, in 96 and 87% yields, respectively (Entries 2 and 3). For the reaction of 2-((4-chlorophenyl)ethynyl)benzoic acid, in which the electron withdrawing group was substituted on the aromatic ring, the yield of 3-(4-chlorophenyl)-1H-isochromen-1-one (2d) decreased (Entry 4). In the case of the 2-((3-methoxyphenyl)ethynyl)benzoic acid, the yield of 3-(3-methoxyphenyl)-1H-isochromen-1-one (2e) decreased due to the decreasing selectivity (Entry 5). For the sterically hindered 2-(arylethynyl)benzoic acids, 2-((2-methoxyphenyl)- and 2-((2-methylphenyl)ethynyl)benzoic acid, the yields of products decreased (Entries 6 and 7). The preparation of the naphthyl and alkyl substituted 1H-isochromen-1-ones 2 was successfully achieved using the rhenium catalytic system (Entries 8-12).

We cannot fully explain the reaction pathway for the reaction, however, one of the plausible reaction pathways for the rhenium-catalyzed reaction is shown in Scheme 2. First, the decarbonylation of ReCl(CO)5 to form ReCl(CO)4, which is the coordinatively unsaturated 16-electron complex, is the first step of the catalytic reaction.9 The carbon-carbon triple bond of the 2-ethynylbenzoic acids 1 is activated by the coordination of the rhenium species. The nucleophilic addition of the carboxy group to the carbon-carbon triple bond activated by the rhenium complex followed by the protonation then gave the 1H-isochromen-1-ones 2.

We developed a new synthetic method of isocoumarins by the rhenium complex-catalyzed 6-endo cyclization of 2-ethynylbenzoic acids. The application of the reaction and determining the reaction mechanism are now in progress.

EXPERIMENTAL
Reagents. ReBr(CO)5, ReCl(CO)5, (C5H5)ReO3, Re2(CO)10, and ReCl5 were commercially available and were used without further purification. 2-(Arylethynyl)benzoic acids were prepared by the hydoration of corresponding methyl esters, which were prepared by the Sonogashira coupling of methyl 2-iodobenzoate and arylethyny, 1-pentyne, 1-hexyne, ethynylcyclohexane or 3,3-dimethyl-1-butyne. Other chemical agents were obtained commercially and were purified if necessary by distillation.
General procedure for rhenium-catalyzed cyclization of 2-ethynylbenzoic acids. A hexane (2.0 mL) solution of 2-ethynylbenzoic acid (0.3 mmol) and ReCl(CO)5 (5 mol%) was stirred under an atmosphere of nitrogen at 80 ºC for 10 h. After the reaction was complete, H2O was added to the reaction mixture and extracted with EtOAc. The organic layer was dried with MgSO4. The resulting mixture was filtered, and the filtrate was concentrated. Purification of the residue by silica gel column chromatography afforded isocoumarins. The structures of the products were assigned by their 1H and 13C-NMR, and mass spectra. The products were characterized by comparing its spectral data with those of authentic samples or previous reports 2a,3e 2b,3e 2c,3e 2d,3e 2e,10 2f,3e 2g,7b 2h,3e 2i,7b,11 2j,3e 2k,12 2l,13 3a,14 3b,14 3d,15 and 3g.7b The structures of the products (3e and 3f) were assigned by their 1H and 13C NMR, IR and mass spectrum.

ACKNOWLEDGEMENTS
This work was financially supported by the Grant-in-Aid for Scientific Research and the Kansai University Research Grants: Grant-in-Aid for Encouragement of Scientists.

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