Journal Information
Journal ID (publisher-id): chemical
Title: Journal of the Korean Chemical Society
Translated Title (ko): 대한화학회지
ISSN (print): 1017-2548
ISSN (electronic): 2234-8530
Publisher: Korean Chemical Society대한화학회
Thioaurones belong to the family of thioflavonoids and are interesting compounds due to their photoswitchable property depending upon the scale of wavelength.1 They possess pharmacological activities such as an anticancer property2 against human tumor cells and a liphophilic drug characteristic3 that plays an important role in their biological action.
Several methods for synthesizing (Z)-thioaurones have been reported.4 The base-catalyzed condensation of benzothiophen-3-ones with arylaldehydes using NaOH/t-BuOH5 or BaO-KF6 under microwave irradiation afforded (Z)-thioaurones (Scheme 1, eq. 1). Similarly, the condensation of 3-acetoxybenzothiophenes with arylaldehydes using NaOH afforded (Z)-thioaurones (eq. 2).7 The intramolecular cyclization through lithiation of methyl (2-methylthio)benzoates8 or N,N-diethyl (2-methylthio)benzamides9 in the presence of 2.5 equiv of lithium diisopropylamide (LDA) also led to benzothiophen-3-ones in situ, followed by an aldol condensation with arylaldehydes to give (Z)-thioaurones (eq. 3).
The cyclization of 2'-methylthiochalcones using 0.5 equiv of iodine afforded (Z)-thioaurones with demethylation of their methylthio groups in DMSO at 150 °C, together with thioflavones as side products.10 Furthermore, the incorporation of sulfur atoms into 2'-nitrochalcones with 5 equiv of sulfur in the presence of 5 equiv of Et3N in DMSO and the successive nucleophilic substitution of the nitro group gave (Z)-thioaurones (eq. 4).11 Recently we developed method for synthesizing (Z)-thioaurones through 5-exo cyclization of 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-ones using formic acid in THF at 65 °C (eq. 5).12
Among the methods reported for synthesizing (Z)-thioaurones, some suffer from lack of regioselectivity during cyclization, the use of excess reagent, and harsh conditions. As an extension of our studies on the syntheses and biological activities of thioflavonoids,13 we report the efficient synthesis of (Z)-thioaurones from N-methoxy-N-methyl 2-mercaptobenzamide and arylethynyllithiums in a one-pot operation.
Methyl 2-mercaptobenzoate (2) was prepared from 2-mercaptobenzoic acid (1) using 20 mol% H2SO4 in CH3OH at reflux according to a similar method described by Unelius et al.14 (Scheme 2). The esterification proceeded sluggishly for 48 h at 65 °C, presumably due to the resonance and steric effect of o-thiol on COOH group. The usual basic work-up after evaporation of CH3OH and purification by vacuum distillation gave 2 as a yellow liquid in 94% yield.
Scheme2.
Reagents and conditions: (a) CH3OH, 20 mol% H2SO4, reflux, 48 h; (b) CH3(CH3O)NH2Cl, 3 equiv i-PrMgCl, THF, -10~0 °C, 0.5 h; 1 N HCl; (c) LDA, THF, 0 °C, 10 min; (d) THF, 0 °C~rt, 2~3 h; 0.1 N HCl.
N-Methoxy-N-methyl 2-mercaptobenzamide (3) was prepared by the slow addition of 3 equiv of isopropylmagnesium chloride to a slurry solution of 2 and N,O-dimethylhydroxylamine hydrochloride for 0.5 h between -10 °C and 0 °C. The resulting N-methoxy-N-methylmagnesium chloride, generated from CH3(CH3O)NH2Cl and 2 equiv of i-PrMgCl, smoothly substituted for the methoxy group in 2. The reaction mixture was quenched with 1 N HCl solution, followed by evaporation of THF. The usual acidic work-up and purification by silica gel column chromatography gave 3 in 84% yield.
Initially the synthesis of (Z)-thioaurone (4a) was carried out by the direct addition of 2 equiv of LDA to a mixture solution of N-methoxy-N-methyl 2-mercaptobenzamide (3) and phenylacetylene in THF at 0 °C, but 4a was obtained in only 18% yield. However, (Z)-thioaurones (4) could be synthesized by the nucleophilic acyl substitution of 3 with arylethynyllithiums and the successive intramolecular cyclization. For example, the treatment of 3 with LDA in THF for 10 min at 0 °C afforded the resulting lithium thiophenolate intermediate, the N-methoxy-N-methyl group of which was then substituted by phenylethynyllithium. The successive one-pot 5-exo cyclization by sulfur anion in the resulting lithiothiolate alkynone produced (Z)-thioaurone (4a) by kinetic control for 2.5 h between 0 °C and room temperature in 58% yield. Upon employing this process, various (Z)-thioaurones (4) could be obtained in yields ranging from 43−66% after the usual acidic work-up and purification by silica gel column chromatography. Although (Z)-thioaurone was synthesized by the reaction of the magnesium thiophenolate intermediate, generated from 3 and t-BuMgCl, and phenylethynylmagnesium chloride for 4.5 h between 0 °C and room temperature, the yield was decreased to 35% yield.
The IR spectra of the C=O band in the synthesized (Z)-thioaurones appeared in the range of 1669−1683 cm-1 as the conjugated form. The configuration of C=C in 4 appeared to be (Z), judging from the value of chemical shifts of vinyl protons and the corresponding (E)-isomers were not obtained. The 1H NMR spectra of vinyl protons in 4 appeared in the range of 7.85−7.97 ppm, which indicated the presence of thioaurones in the (Z)-form. In the case of the (E)-form, the vinyl proton was shifted about 0.6−0.8 ppm upfield.9b However, in the cases of 2'-substituted (Z)-thioaurones with methoxy (4b) and methyl (4i) groups, the vinyl protons appeared at 8.43 and 8.18 ppm, respectively, and the downfield shift was tentatively attributed to the anomeric “ortho effect”.
As shown in Table 1, various (Z)-thioaurones were efficiently synthesized from N-methoxy-N-methyl 2-mercaptobenzamide and arylethynyllithiums in one-pot operation. The conversion of 3 to 4 worked well with both electron-donating (4b, 4e, 4f, 4i, 4j) and electron-withdrawing (4c, 4d) operating on the phenyl ring of arylethynyllithiums. Furthermore, the reaction of 3 and the two heteroarylethynyl-lithiums containing the heteroaromatic group, 3-thienyl (4g) and 2-pyridyl (4h), proceeded well to give the corresponding (Z)-thioaurones in 47% and 43% yield, respectively
In conclusion, we have described a highly regioselective method for synthesizing (Z)-thioaurones from N-methoxy-N-methyl 2-mercaptobenzamide and arylethynyllithiums in a one-pot procedure.
EXPERIMENTAL▼
General
All chemicals were purchased from Aldrich Chemical Co., Tokyo Chemical Co., and used without further purification. Tetrahydrofuran was refluxed over sodium-benzophenone ketyl under argon atmosphere and distilled prior to use. 1H NMR and 13C NMR spectra were recorded with Bruker Avance 300 (300 MHz) spectrometer in CDCl3 as a solvent. FT-IR spectra were recorded with Bruker vector 22 spectrometer. Low-resolution mass spectra were measured with Agilent Gc/Ms (6890 Gc/5933 Ms). Melting points were measured with Mel-temp II (Aldrich) and were uncorrected.
Preparation of Methyl 2-mercaptobenzoate (2)
To a solution of 2-mercaptobenzoic acid (1, 3.08 g, 20.0 mmol) in CH3OH (40 mL) was added sulfuric acid (213 μL, 4.0 mmol) and the reaction mixture was refluxed for 48 h. After evaporating the CH3OH, the residue was dissolved in methylene chloride (30 mL) and poured into a saturated NaHCO3 solution (50 mL). After extraction with methylene chloride (3×30 mL), the organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by vacuum distillation using Kugelrohr apparatus to give 2 (3.16 g, 94%) as a yellow liquid. bp 90−95 °C/1.5 mmHg; 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 1H), 7.28−7.33 (m, 2H), 7.11−7.19 (m, 1H), 4.69 (s, 1H), 3.92 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.1, 138.3, 132.5, 131.7, 130.9, 125.8, 124.6, 52.2; FT-IR (film) 1709 (C=O) cm−1 ; Ms m/z (%) 168 (M+, 34), 136 (100), 108 (46).
Preparation of N-Methoxy-N-methyl 2-mercaptobenzamide (3)
To a slurry solution of 2 (2.52 g, 15.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.61 g, 16.5 mmol) in THF, isopropylmagnesium chloride (2.0 M in THF, 24 mL, 48.0 mmol) was slowly added during 0.5 h by syringe while the temperature of the mixture was kept between -10 °C and 0 °C. After stirring for 0.5 h, the mixture was quenched with 1 N HCl solution (5 mL) and the THF was evaporated. The mixture was poured into 0.5 N HCl solution (50 mL) and extracted with methylene chloride (3×25 mL). The concentrated residue was purified by silica gel column chromatography using 30% EtOAc/n-hexane as an eluent to give 3 (2.49 g, 84%). mp 59−61 °C; 1H NMR (300 MHz, CDCl3) δ 7.37 (dd, J = 7.7, 1.2 Hz, 1H), 7.28−7.34 (m, 1H), 7.25 (dd, J = 7.6, 1.8 Hz, 1H), 7.16−7.22 (m, 1H), 3.89 (s, 1H), 3.57 (s, 3H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.0, 135.3, 131.2, 129.7, 129.0, 127.6, 125.6, 61.2, 33.5; FT-IR (KBr) 1642 (C=O) cm−1; Ms m/z (%) 197 (M+, 7), 165 (46), 137 (100), 109 (46).
Preparation of (Z)-4'-Methoxythioaurone (4f)
To a solution of 3 (395 mg, 2.0 mmol) in THF (4 mL) was added LDA (1.8 M in THF, 1.1 mL, 2.0 mmol) at 0 °C and stirred for 10 min. 4-Methoxyphenylethynyllithium, prepared from 1-ethynyl-4-methoxybenzene (317 mg, 2.4 mmol) and methyllithium (1.5 M in Et2O, 1.6 mL, 2.4 mmol) in THF (4 mL) for 15 min between 0 °C and room temperature, was added to the above solution at 0 °C. The reaction mixture was stirred for 3 h between 0 °C and room temperature and then the resulting tan-color solution was quenched with 0.1 N HCl solution (5 mL). After evaporating the THF, the mixture was poured into 0.1 N HCl solution (30 mL) and extracted with methylene chloride (3×20 mL). The concentrated residue was separated by silica gel column chromatography using EtOAc/n-hexane/CH2Cl2 (v/v/v=1/1/1) as an eluent to give 4f (338 mg, 63%) as a yellow solid. mp 162−163 °C; 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.93 (d, J = 7.1 Hz, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.52−7.59 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.24−7.31 (m, 1H), 6.99 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 188.5, 161.3, 146.0, 134.9, 133.7, 133.0, 130.8, 127.8, 127.1, 126.9, 125.5, 123.9, 114.7, 55.5; FT-IR (KBr) 1669 (C=O) cm-1; Ms m/z (%) 268 (M+, 100), 267 (93), 237 (41).
(Z)-Thioaurone (4a): mp 131−133 °C; 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.54−7.60 (m, 1H), 7.39−7.51 (m, 4H), 7.26−7.32 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 188.6, 146.1, 135.3, 134.4, 133.5, 131.0, 130.5, 130.3, 130.1, 129.0, 127.1, 125.6, 123.9; FT-IR (KBr) 1675 (C=O) cm−1; Ms m/z (%) 238 (M+, 59), 237 (100).
(Z)-2'-Methoxythioaurone (4b): mp 153−154 °C; 1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 7.94 (d, J = 7.1 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.46−7.60 (m, 2H), 7.36−7.44 (m, 1H), 7.24−7.32 (m, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 188.6, 159.2, 146.2, 135.1, 131.9, 130.8, 130.2, 129.9, 128.6, 127.0, 125.4, 123.9, 123.5, 120.7, 111.0, 55.6; FT-IR (KBr) 1677 (C=O) cm−1; Ms m/z (%) 268 (M+, 25), 237 (100).
(Z)-3'-Chlorothioaurone (4c): mp 162−163 °C; 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 7.7 Hz, 1H), 7.85 (s, 1H), 7.66 (s, 1H), 7.52−7.62 (m, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.34−7.44 (m, 2H), 7.24−7.33 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 188.5, 145.8, 136.1, 135.6, 135.1, 131.6 (overlapped), 130.5, 130.2 (overlapped), 130.0, 129.0, 127.2, 125.9, 124.0; FT-IR (KBr) 1683 (C=O) cm−1; Ms m/z (%) 274 (M++2, 27), 273 (47), 272 (M+, 73), 271 (100), 237 (93), 208 (14).
(Z)-4'-Bromothioaurone (4d): mp 168−169 °C; 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 7.7 Hz, 1H), 7.86 (s, 1H), 7.55−7.63 (m, 5H), 7.48−7.54 (m, 1H), 7.28−7.34 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 188.5, 145.7, 135.5, 133.2, 132.3, 132.2, 132.0, 130.9, 130.3, 127.2, 125.8, 124.6, 124.0; FT-IR (KBr) 1681 (C=O) cm−1; Ms m/z (%) 318 (M++2, 63), 316 (M+, 62), 237 (100), 208 (20).
(Z)-4'-Methylthioaurone (4e): mp 138−139 °C; 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.89−7.93 (m, 1H), 7.51−7.62 (m, 3H), 7.45−7.51 (m, 1H), 7.23−7.31 (m, 3H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 188.7, 146.1, 140.9, 135.2, 133.8, 131.5, 131.1, 130.6, 129.9, 129.2, 127.0, 125.5, 123.9, 21.6; FT-IR (KBr) 1671 (C=O) cm−1; Ms m/z (%) 252 (M+, 60), 251 (69), 237 (100).
(Z)-2-(3-Thienylmethylene)benzo[b]thiophen-3(2H)-one (4g): mp 169−170 °C; 1H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.73−7.78 (m, 1H), 7.53−7.60 (m, 1H), 7.40−7.51 (m, 3H), 7.24−7.32 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 188.7, 145.6, 136.7, 135.2, 130.9, 130.4, 129.6, 128.7, 127.0, 126.9, 126.8, 125.6, 124.0; FT-IR (KBr) 1673 (C=O) cm−1; Ms m/z (%) 244 (M+, 92), 243 (100), 171 (13).
(Z)-2-(2-Pyridylmethylene)benzo[b]thiophen-3(2H)-one (4h): mp 154−155 °C; 1H NMR (300 MHz, CDCl3) δ 8.82 (d, J = 4.7 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.87 (s, 1H), 7.72−7.79 (m, 1H), 7.53−7.60 (m, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.23−7.31 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 189.6, 152.9, 149.7, 149.5, 136.7, 135.5, 134.8, 130.3, 129.3, 127.6, 126.8, 125.4, 124.1, 123.2; FT-IR (KBr) 1679 (C=O) cm−1; Ms m/z (%) 239 (M+, 100), 238 (68), 210 (57).
(Z)-4'-Methoxy-2'-methylthioaurone (4i): mp 139−141 °C; 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 7.94 (d, J = 7.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.45−7.59 (m, 2H), 7.24−7.32 (m, 1H), 6.86 (d, J = 6.7 Hz, 1H), 6.81 (s, 1H), 3.85 (s, 3H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 188.4, 161.0, 146.3, 142.3, 134.9, 131.1, 131.0, 130.8, 128.8, 127.0, 125.9, 125.4, 123.9, 116.6, 111.8, 55.4, 20.5; FT-IR (KBr) 1671 (C=O) cm−1; Ms m/z (%) 282 (M+, 75), 267 (100), 265 (73), 250 (27).
(Z)-3',5'-Dimethoxythioaurone (4j): mp 167−168 °C; 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 7.7 Hz, 1H), 7.86 (s, 1H), 7.54−7.61 (m, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.26−7.33 (m, 1H), 6.85 (d, J = 2.2 Hz, 2H), 6.52 (t, J = 2.2 Hz, 1H), 3.85 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 188.6, 161.0, 146.1, 136.0, 135.4, 133.7, 130.8, 130.4, 127.1, 125.7, 123.9, 108.7, 102.8, 55.5; FT-IR (KBr) 1674 (C=O) cm−1; Ms m/z (%) 298 (M+, 56), 297 (28), 267 (100), 224 (13).