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Short Note

2,3,4,9-Tetrahydro-9-(3-hydroxy-1,4-dioxo-1H-dihydro-naphthalen-2-yl)-8-methoxy-3,3-dimethyl-1H-xanthen-1-one

School of Pharmacy, Hyogo University of Health Sciences, 1-3-6, Minatojima, Chuo-ku, Kobe, 650-8530, Japan
*
Author to whom correspondence should be addressed.
Molbank 2015, 2015(1), M841; https://doi.org/10.3390/M841
Submission received: 16 December 2014 / Revised: 23 January 2015 / Accepted: 27 January 2015 / Published: 30 January 2015

Abstract

:
The title compound 2,3,4,9-tetrahydro-9-(3-hydroxy-1,4-dioxo-1H-dihydro-naphthalen-2-yl)-8-methoxy-3,3-dimethyl-1H-xanthen-1-one (5) was obtained by the nucleophilic addition of 2-hydroxy-1,4-naphthoquinone (4) to 2H-chromene derivative 3, which was prepared by the domino three-component coupling reaction of aryne precursor 1 with DMF and the active methylene compound dimedone (2). The one-pot synthesis of the title compound 5 from aryne precursor 1 was also achieved.

Graphical Abstract

Arynes are highly reactive and kinetically unstable intermediates for constructing multisubstituted arenes with structural diversity and complexity [1,2]. In particular, the recent aryne-based chemistry has made great advances in synthetic chemistry [3,4,5,6,7,8,9,10,11,12,13,14]. Our laboratory is interested in developing domino reactions using arynes. We have recently developed the efficient insertion of arynes, generated in situ from ortho-(trimethylsilyl)aryl triflates and the fluoride ion, into the C=O π–bond of DMF [15,16,17,18,19,20].
Synthetic strategies involving domino processes offer the advantage of multiple carbon-carbon and/or carbon-heteroatom bond formations in a single operation [21,22]. In this paper, we report two synthetic methods for preparing the title compound 5 via a domino multicomponent coupling reaction starting from the generation of an aryne. Moreover, this molecule 5 has a pharmaceutically important structure, because a similar type of compound was studied as a neuropeptide Y Y5 receptor antagonist by Merck-Banyu researchers [23].
First, the 2H-chromene derivative 3 was prepared according to our reported method (Scheme 1) [17]. To suppress the competitive reaction of aryne A with dimedone (2), N,N-dimethylformamide (DMF) was employed as a solvent. In the presence of anhydrous TBAF (3 equiv.), treatment of triflate 1 with dimedone (2) in DMF at room temperature for 3 h gave the desired 2H-chromene 3 in 53% yield. This transformation proceeds via the insertion of aryne A, generated from ortho-(trimethylsilyl)aryl triflate 1, into the C=O of DMF and the nucleophilic addition of dimedone (2) to benzoxetene B or ortho-quinone methide C.
For the synthesis of the title compound 5, 2-hydroxy-1,4-naphthoquinone (4) was employed as a nucleophile (Scheme 2). In the presence of anhydrous TBAF (3 equiv.), we allowed 2H-chromene 3 to react with 1.1 equiv. of 2-hydroxy-1,4-naphthoquinone 4 in DMF. As expected, the title compound 5 was obtained in 67% yield. We were gratified to observe that 2-hydroxy-1,4-naphthoquinone 4 acts as a nucleophilic active methylene compound with the sufficient reactivity toward 2H-chromene 3.
As an alternative convenient approach to title compound 5, we next directed our attention to the direct one-pot synthesis of 5 from aryne precursor 1 (Scheme 3). The two-step preparation was successfully applied in the convenient one-pot synthesis. At first, triflate 1 in DMF was treated with dimedone (2) in the presence of anhydrous TBAF. After being stirred for 3 h, 2-hydroxy-1,4-naphthoquinone (4, 2.1 equiv.) was added to the reaction mixture. After the purification, the desired title compound 5 was isolated in 40% yield.

Experimental

General Information

Infrared spectra were measured on a FT/IR-4100 instrument (JASCO, Hachioji-city, Tokyo, Japan). 1H-NMR (400 MHz) and 13C-NMR (101 MHz) spectra were measured on a ECX-400 PSK (JEOL, Akishima-city, Tokyo, Japan) with CDCl3 as an internal standard (77.0 ppm). Mass spectra (ESI-MS) were obtained by use of a Thermo Fisher Scientific Exactive LC/MS spectrometer (Bremen-city, Germany). For silica gel column chromatography, SiliCycle Inc. (Quebec-city, QC, Canada) SiliaFlash F60 was used.

2,3,4,4a-Tetrahydro-4a-hydroxy-8-methoxy-3,3-dimethyl-1H-xanthen-1-one (3)

To a solution of 3-methoxy-2-(trimethylsilyl)phenyl triflate (1, 105 µL, 0.40 mmol) and dimedone (2, 56 mg, 0.40 mmol) in DMF (3.4 mL) was added a solution of anhydrous TBAF (314 mg, 1.20 mmol) in DMF (0.60 mL) under argon atmosphere at room temperature. After being stirred at room temperature for 3 h, silica gel (1.0 g) was added to the reaction mixture, and then it was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography (AcOEt:hexane = 1:8–1:0 with 2% CH2Cl2) afforded 2H-chromene 3 (58 mg, 53%). Colorless crystals. Sublimated decomposition 118–120 °C (CH2Cl2-iso-Pr2O). IR (KBr) 3417 (br), 2957, 1671, 1603, 1566, 1467 cm−1. 1H-NMR (C6D6) δ 8.21 (1H, s), 6.94 (1H, t, J = 8.0 Hz), 6.73 (1H, d, J = 8.0 Hz), 6.03 (1H, d, J = 8.0 Hz), 3.20 (3H, s), 2.39 (1H, br s), 2.32 (1H, dd, J = 16.0, 1.5 Hz), 2.13 (1H, dd, J = 14.0, 1.0 Hz), 2.03 (1H, br d, J = 14.0 Hz), 1.91 (1H, br d, J = 16.0 Hz), 0.94 (3H, s), 0.69 (3H, s). 13C-NMR (C6D6) δ 196.1, 158.2, 153.9, 132.2, 128.7, 124.7, 111.0, 110.3, 103.4, 96.7, 55.2, 52.6, 48.7, 31.4, 30.3, 27.8. HRMS (ESI+) calcd for C16H18O4Na (M+Na+): 297.1097, Found: 297.1095.

2,3,4,9-Tetrahydro-9-(3-hydroxy-1,4-dioxo-1H-dihydronaphthalen-2-yl)-8-methoxy-3,3-dimethyl-1H-xanthen-1-one (5)

To a solution of 2H-chromene 3 (16 mg, 0.060 mmol) and 2-hydroxy-1,4-naphthoquinone (4, 12 mg, 0.066 mmol) in DMF (600 µL) was added a solution of anhydrous TBAF (47 mg, 0.18 mmol) in DMF (90 µL) under argon atmosphere at room temperature. After being stirred at room temperature for 1 h, silica gel (0.1 g) was added to the reaction mixture, and then it was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography (acetone/chloroform = 1:50–1:2) afforded compound 5 (17 mg, 67%). Dark red solid. 1H-NMR (CDCl3) δ 8.07 (1H, br s), 8.01 (1H, dd, J = 7.5, 1.2 Hz), 7.68 (1H, br t, J = 7.3 Hz), 7.61 (1H, td, J = 7.5, 1.2 Hz), 7.15 (1H, t, J = 8.2 Hz), 6.70 (1H, d, J = 8.2 Hz), 6.53 (1H, d, J = 8.2 Hz), 5.44 (1H, br s), 3.67 (3H, s), 2.53 (2H, br s), 2.30 (1H, d, J = 16.5 Hz), 2.20 (1H, d, J = 16.5 Hz), 1.11 (3H, s), 1.01 (3H, s). 13C-NMR (CDCl3) δ 197.4 (br), 182.0, 157.6, 153.0 (br), 151.2, 134.6, 132.8, 132.5, 129.5, 128.0, 126.9 (br), 125.8, 111.5, 110.3, 108.6, 106.2, 55.7, 50.7, 41.5, 32.1, 29.3, 27.2, 24.4; Three carbon peaks were missing due to overlapping. HRMS (ESI+) calcd for C26H23O6 (M+H+): 431.1489, Found: 431.1473; Anal. calcd for C26H22O6: C, 72.55; H, 5.15. Found: C, 71.77; H, 5.15.

Procedure for One-Pot Synthesis

To a solution of 3-methoxy-2-(trimethylsilyl)phenyl triflate (1, 158 µL, 0.60 mmol) and dimedone (2, 56 mg, 0.40 mmol) in DMF (5.1 mL) was added a solution of anhydrous TBAF (472 mg, 1.8 mmol) in DMF (0.90 mL) under argon atmosphere at room temperature. After being stirred at room temperature for 3 h, 2-hydroxy-1,4-naphthoquinone (4, 151 mg, 0.84 mmol) was added to the reaction mixture. After being stirred at room temperature for 1 h, silica gel (1.5 g) was added to the reaction mixture, and then it was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography (acetone/chloroform = 1:50–1:2) afforded compound 5 (69 mg, 40%).

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3

Acknowledgments

This work was partially supported by JSPS KAKENHI Grant-in-Aid for Young Scientists (B) Grant Number 24790032.

Author Contributions

E. Yoshioka performed experiments and analyzed the data. S. Kohtani carried out part of the data analysis. H. Miyabe contributed to design of the study and manuscript writing.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Scheme 1. Preparation of 2H-chromene derivative 3.
Scheme 1. Preparation of 2H-chromene derivative 3.
Molbank 2015 m841 sch001
Scheme 2. Synthesis of title compound 5.
Scheme 2. Synthesis of title compound 5.
Molbank 2015 m841 sch002
Scheme 3. One-pot synthesis of title compound 5.
Scheme 3. One-pot synthesis of title compound 5.
Molbank 2015 m841 sch003

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MDPI and ACS Style

Yoshioka, E.; Kohtani, S.; Miyabe, H. 2,3,4,9-Tetrahydro-9-(3-hydroxy-1,4-dioxo-1H-dihydro-naphthalen-2-yl)-8-methoxy-3,3-dimethyl-1H-xanthen-1-one. Molbank 2015, 2015, M841. https://doi.org/10.3390/M841

AMA Style

Yoshioka E, Kohtani S, Miyabe H. 2,3,4,9-Tetrahydro-9-(3-hydroxy-1,4-dioxo-1H-dihydro-naphthalen-2-yl)-8-methoxy-3,3-dimethyl-1H-xanthen-1-one. Molbank. 2015; 2015(1):M841. https://doi.org/10.3390/M841

Chicago/Turabian Style

Yoshioka, Eito, Shigeru Kohtani, and Hideto Miyabe. 2015. "2,3,4,9-Tetrahydro-9-(3-hydroxy-1,4-dioxo-1H-dihydro-naphthalen-2-yl)-8-methoxy-3,3-dimethyl-1H-xanthen-1-one" Molbank 2015, no. 1: M841. https://doi.org/10.3390/M841

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