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Digyaindoleacid A: 2-(1-(4-Hydroxyphenyl)-3-oxobut-1-en-2-yloxy)-3-(1H-indol-3-yl)propanoic Acid, a Novel Indole Alkaloid

Molbank 2019, 2019(3), ; https://doi.org/10.3390/M1081

Short Note
(E)-4-(3-Phenylisoxazol-5-yl)but-3-en-2-one
1
Department of Chemistry and Pharmacy, Institute of Organic Chemistry I, University of Erlangen-Nuremberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany
2
Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 Stachki St., Rostov on Don 344090, Russia
*
Author to whom correspondence should be addressed.
Received: 19 August 2019 / Accepted: 17 September 2019 / Published: 18 September 2019

Abstract

:
(E)-4-(3-Phenylisoxazol-5-yl)but-3-en-2-one was synthesized via the oxidative ring opening reaction of 2-(5-methylfuran-2-yl)-1-phenylethanone oxime, followed by the iodine mediated isomerization.
Keywords:
oxazole; furan; RORC reaction; (E,Z)-isomerization

1. Introduction

The isoxazole ring is a structural motif of numerous bioactive compounds, including several marketed drugs [1]. Substituted isoxazoles are known as promising anticancer [2,3,4,5], antifungal [6], antidepressant [7], antioxidant [8], and antituberculous agents [9]. Additionally, some of the isoxazoles demonstrate herbicidal [10] and insecticidal [11] properties.
In 2017, Pinho e Melo et al. described a new synthesis of isoxazoles from tetrahydrofurooxazines via the intermediate formation of oximes (Scheme 1) [12]. Main products of this acid-catalyzed reaction were substituted 4-(isoxazol-5-yl)butan-2-ones 3. On the other hand, minor isoxazolylvinyl ketones (E)-4 are of special interest, due to an active enone fragment, which can be utilized for the construction of linked isoxazoles [13] and other new complex structures containing an isoxazole subunit [14].
Herein, we describe an easy approach to (E)-4-(3-phenylisoxazol-5-yl)but-3-en-2-one 4c, and its characterization by 1D and 2D NMR spectroscopy.

2. Results and Discussion

Oxime 2c was synthesized via the reaction of furfuryl ketone 5 with hydroxylamine hydrochloride, and sodium acetate in ethanol. The subsequent furan ring opening–isoxazole ring closure reaction of 2c under oxidative conditions [15,16] provided the target 4-(3-phenylisoxazol-5-yl)but-3-en-2-one 4c in high yield as a mixture of (E,Z)-isomers (Scheme 2).
Isoxazole (E)-4c was obtained in a pure form through iodine-mediated isomerization [17] and fully characterized (Scheme 3).
The structure of compound 4c was confirmed by 1H and 2D nuclear magnetic resonance spectroscopy: 1H-1H correlation spectroscopy (COSY), 1H-13C heteronuclear single-quantum correlation spectroscopy (HSQC), and 1H-13C heteronuclear multiple-bond correlation spectroscopy (HMBC) (Figure 1, Figure 2 and Figure 3). In the 1H NMR spectrum of (E)-4c, signals of the vinyl protons α-H and β-H are observed at δH = 6.95 and 7.40 ppm, respectively, and have a coupling constant of 16.2 Hz, which indicates a (E)-configuration (Figure S1). In the 1H-13C HMBC spectrum, there are cross-peaks between the α-H proton and C-atom of the methyl group (δC 28.5 ppm) and isoxazole C(5) atom (δC 166.3 ppm). The β-H proton correlates with carbonyl carbon atom at δC 197.0 ppm and isoxazole C(4) atom at δC 104.5 ppm. Cross-peaks between the proton H(4) at δH 6.80 ppm and β-C atom of the acetyl vinyl fragment at δC 125.4 ppm, and between protons of the methyl group at δH 2.41 ppm and α-C atom of the acetyl vinyl fragment at δC 130.8 ppm are observed as well. All key cross-peaks are presented in Table 1.
In summary, we have suggested an effective route to (E)-4-(3-phenylisoxazol-5-yl)but-3-en-2-one employing oxidative RORC reaction of furfuryl ketone oxime. The exploration of the reaction scope is underway in our laboratory.

3. Materials and Methods

All commercial products and solvents were used without further purification (Fisher Scientific, Loughborough, UK). All reactions were run under the air unless noted otherwise.
The reactions under microwave irradiation were conducted in Microwave Synthesis Reactor «Biotage® Robot Eight» (Biotage AB, Uppsala, Sweden) using sealed microwave reaction vessels. TLC analyses were performed on Merck 60 F254 aluminum plates in combination with UV detection (254 nm). Flash chromatography was performed on silica gel 200–300 mesh (Merck, Darmstadt, Germany) using mixture EtOAc/i-hexane as eluents. Melting points were determined on a Mel-Temp II Laboratory Devices apparatus (Triad Scientific Manasquan, Manasquan, NJ, USA); the values are uncorrected. NMR spectra were recorded on a Bruker AV-600 (1H NMR at 600 MHz and 13C NMR at 151 MHz,) and Bruker AV-400 (1H NMR at 400 MHz and 13C NMR at 101 MHz) spectrometers (Bruker GmbH, Mannheim, Germany). Proton chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), with the solvent resonance employed as the internal standard (CDCl3 δ = 7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets), coupling constants (J) and integration. Coupling constants (J) are reported in Hertz (Hz). Carbon chemical shifts are reported in ppm from tetramethylsilane (TMS), with the solvent resonance as the internal standard (CDCl3 δ = 77.16 ppm).
IR spectra were measured on PerkinElmer Spectrum BX spectrophotometer (NaCl plates, PerkinElmer LAS GmbH, Rodgau, Germany). HRMS-ESI spectra were recorded at The Mass Spectroscopy Laboratory, Chair of Organic Chemistry, Friedrich-Alexander University of Erlangen-Nuremberg.
Starting furfuryl ketone 5 was obtained according to the published procedure [18].
2-(5-Methylfuran-2-yl)-1-phenylethan-1-one oxime (2c)
Hydroxylamine hydrochloride (2 mmol) and anhydrous NaOAc (4 mmol) were added to a solution of furfuryl ketone 5 (2 mmol) in ethanol (5 mL), and the mixture was stirred for 24 h at 80 °C (TLC and LC-MS control). Then, the reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (4 × 25 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography using EtOAc/i-Hex as eluents.
Yield 0.61 g (100%). White solid. M.p. 90–92 °C. 1H NMR (600 MHz, CDCl3): δ = 7.69–7.67 (m, 2H), 7.37–7.36 (m, 3H), 5.92 (d, J = 3.0 Hz, 1H), 5.83 (m, 1H), 4.13 (s, 2H), 2.24 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.2, 150.9, 147.9, 135.3, 129.4, 128.5, 126.4, 107.5, 106.3, 25.5, 13.6 ppm. IR (NaCl): 3241, 2922, 1568, 1495, 1461, 1321, 1168, 1016, 960 cm−1. HRMS (ESI): m/z calcd. for C13H13NO2 [M-H]+: 214.0868; found: 214.0862.
(E,Z)-4-(3-Phenylisoxazol-5-yl)but-3-en-2-one ((E,Z)-4c)
m-CPBA (77% w/w, 0.135 g, 0.6 mmol) was added to a solution of oxime 2c (0.5 mmol) in DCM (2 mL) at 0 °C. The reaction mixture was stirred at the same temperature for 1 h. Then TFA (0.038 mL, 0.05 mmol) was added. The reaction mixture was allowed to reach room temperature and stirred for 20 h. Once the reaction was complete, the mixture was washed with Na2S2O3 solution three times, and then with brine. DCM was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give a pure (E,Z)-4.
(Z)-4-(3-Phenylisoxazol-5-yl)but-3-en-2-one ((Z)-4c)
In a mixture with (E)-isomer. 1H NMR (600 MHz, CDCl3): δ = 7.87–7.86 (m, 2H), 7.69 (s, 1H), 7.48–7.44 (m, 3H), 6.74 (d, J = 12.8 Hz, 1H), 6.43 (d, J = 12.8 Hz, 1H), 2.37 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 197.8, 166.0, 163.2, 130.8, 130.4, 130.1, 128.9, 126.8, 123.5, 106.0, 31.5 ppm.
Isomerization (E,Z)-4→(E)-4
Microwave reaction vessel was charged with (E,Z)-4c (0.2 mmol), I2 (0.0034 g, 0.013 mmol), and toluene (5 mL). The reaction mixture was stirred at 140 °C in a microwave reactor for 2 h. After completion of the reaction, toluene and iodine were removed under reduced pressure to afford pure (E)-3a.
(E)-4-(3-Phenylisoxazol-5-yl)but-3-en-2-one) (E)-4c)
Yield 0.034 g (80%). White solid. M.p. 130–132 °C. 1H NMR (600 MHz, CDCl3): δ = 7.83–7.81 (m, 2H), 7.49–7.47 (m, 3H), 7.40 (d, J = 16.2 Hz, 1H), 6.95 (d, J = 16.2 Hz, 1H), 6.80 (s, 1H), 2.41 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 197.0, 166.3, 163.1, 130.8, 130.4, 129.1, 128.4, 126.8, 125.4, 104.5, 28.5 ppm. IR (NaCl): 1664 (C=O), 1560, 1439, 1268, 983, 952, 769 cm−1. HRMS (ESI): m/z calcd. for C13H11NO2 [M + H]+: 214.0868; found: 214.0861.

Supplementary Materials

The following are available online, Figure S1: 1H NMR spectrum of compound 2c, Figure S2: 13C NMR spectrum of compound 2c, Figure S3: 1H NMR spectrum of compound (E)-4c, Figure S4: 13C NMR spectrum of compound (E)-4c, Figure S5: 1H NMR spectrum of compound (Z)-4c, Figure S6: 13C NMR spectrum of the compound (Z)-4c.

Author Contributions

N.S.—synthesis, A.A.K.—NMR data analysis, writing the manuscript, O.V.S.—conceptualization, supervision, data analysis, writing the manuscript, funding acquisition. All authors read and approved the final manuscript.

Funding

This research was funded by the program “Promotion of Equal Opportunities for Women in Research and Teaching” (FFL) Bayern, Germany.

Acknowledgments

We thank Peter Gmeiner, Department of Chemistry and Pharmacy, University of Erlangen-Nuremberg, for his kind support.

Conflicts of Interest

The authors declare no conflict of interest.

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Scheme 1. Acid-catalyzed formation of isoxazolylvinyl ketones as minor products.
Scheme 1. Acid-catalyzed formation of isoxazolylvinyl ketones as minor products.
Molbank 2019 m1081 sch001
Scheme 2. Synthesis of compound 4c.
Scheme 2. Synthesis of compound 4c.
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Scheme 3. Isomerization (E,Z)-4c→(E)-4c.
Scheme 3. Isomerization (E,Z)-4c→(E)-4c.
Molbank 2019 m1081 sch003
Figure 1. Data of 1H-1H correlation spectroscopy for compound (E)-4c (CDCl3).
Figure 1. Data of 1H-1H correlation spectroscopy for compound (E)-4c (CDCl3).
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Figure 2. Data of 1H-13C heteronuclear multiple-bond correlation spectroscopy for compound (E)-4c (CDCl3).
Figure 2. Data of 1H-13C heteronuclear multiple-bond correlation spectroscopy for compound (E)-4c (CDCl3).
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Figure 3. Data of 1H-13C heteronuclear single-quantum correlation spectroscopy for compound (E)-4c (CDCl3).
Figure 3. Data of 1H-13C heteronuclear single-quantum correlation spectroscopy for compound (E)-4c (CDCl3).
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Table 1. Cross-peaks in heteronuclear single-quantum correlation and heteronuclear multiple-bond correlation spectra of compound (E)-4c.
Table 1. Cross-peaks in heteronuclear single-quantum correlation and heteronuclear multiple-bond correlation spectra of compound (E)-4c.
Molbank 2019 m1081 i001
1H, δ, ppm13C, δ, ppm
HMQCHMBC
7.40 (β-H)125.4104.5, 130.8, 166.3, 197.0 (C=O)
6.95 (α-H)130.828.5, 125.4, 166.3, 197.0 (C=O)
6.80 (HIso)104.5125.4, 163.1, 166.3
2.41 (CH3)28.5130.8, 197.0 (C=O)

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