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
Thioflavones are thio analogs of naturally occurring flavones and have the skeleton of a thiochroman-4-one ring with 2-substituted aryl groups. They exhibit a variety of pharmacological activities, such as antibacterial and antifungal effects,1 antiviral activity2 against enterovirus and coxsackievirus, and antiproliferative activity3 on human breast cancer. They also display inhibitory action against tumor cells4 and induced endotherium-dependent vasorelaxation through activation of the epidermal growth factor (EGF) receptor.5
Several types of reactions for the synthesis of thioflavones have been described.6 In general, thioflavones were synthesized by the cyclic condensation of thiophenols with ethyl benzoylacetates using polyphosphoric acid at 90 ℃ in low yields (Scheme 1(a)).7 The condensation of methyl 2-mercaptobenzoate with N-benzoylhydrazones with an excess of LDA gave the C-acylated intermediates, which underwent subsequent addition and hydrolysis with 3 N HCl under reflux to produce thioflavones (Scheme 1(b)).8 The condensation of 2’-haloacetophenones and methyl phenyldithioesters using a 1.5 equiv. of sodium hydride in DMF also afforded thioflavones in low to moderate yields (Scheme 1(c)).9 The cyclodehydration of 1-(2-mercaptophenyl)-3-phenylpropan-1,3-diones, which were prepared from 2’-mercaptoacetophenone and N-methoxy-N-methyl benzamides using sulfuric acid in CH3CN afforded the thioflavones in high yields (Scheme 1(d)).10
Alternatively, the intramolecular Friedel-Crafts acylation of 3-(arylthio)-3-phenylpropanoic acids, which were derived from the 1,4-addition of thiophenols to trans-cinnamic acid using sulfuric acid, afforded thioflavanones, which were dehydrogenated further with DDQ in refluxing benzene to give the thioflavones in moderate yields (Scheme 1(e)).11 The reaction of S-aroyl derivatives of 2-mercaptobenzoic acid with N-phenyl(triphenylphosphoranylidene)ethenimine or (trimethylsilyl)methylenetriphenylphosphorane produced the corresponding acylphosphoranes, which underwent Wittig type cyclization in refluxing THF to give thioflavones (Scheme 1(f)).12
On the other hand, tandem reactions using chalcone or alkynone intermediates allowed the convenient synthesis of thioflavones. The treatment of 3-aryl-1-(2-tert-butylthio) phenylprop-2-en-1-ones, which had been prepared from the condensation of arylaldehydes with 2’-(tert-butylthio)acetophenones using NaOH, with 3 equiv. of iodine in the presence of NaHCO3 in refluxing EtCN afforded the thioflavones (Scheme 2(a)).13 The reaction of 2’-iodochalcones and potassium O-ethyl dithiocarbonate as a sulfur source in the presence of 10 mol% Cu(OAc)2 afforded the thio-flavanones in situ, which then underwent sequential oxidation with sulfuric acid at 80 ℃ to give the thioflavones (Scheme 2(b)).14 Tandem substitution-SNAr reaction of β-chlorochalcones, which had been prepared by the ironcatalyzed addition of aryl chlorides to arylacetylene, with sodium hydrosulfide in the presence of 2 equiv. of Cs2CO3 in DMSO at 140 ℃ afforded thioflavones (Scheme 2(c)).15
The addition of sodium hydrosulfide16 or sodium sulfide17 to 2’-bromoalkynones produced the thiolate adducts rapidly, which then underwent intramolecular nucleophilic substitution in refluxing EtOH to give thioflavones (Scheme 2(d)). Similarly, the reaction of 2’-methoxyalkynones with 2 equiv. of sodium sulfide in DMF afforded the thioflavones via 1,4-addition and subsequent substitution (Scheme 2(e)).18 The reaction of 2-(methylthio)benzoyl chloride and arylacetylenes in the presence of 2.5 equiv. of AlCl3 afforded the α,β-unsaturated β-chlorovinyl ketones in situ, which underwent acylation to give thioflavones (Scheme 2(f)).19 A palladium-catalyzed carbonylative four-component reaction was effective in the synthesis of thioflavones. Thus, the treatment of 2-iodofluorobenzene and arylacetylenes using sodium sulfide in the presence of 4 mol% Pd(OAc)2, 8 mol% t-Bu3P·HBF4, and 3 equiv. of Et3N under five bar of CO afforded the thioflavones (Scheme 2(g)).20
Although several types of reactions for the synthesis of thioflavones have been reported, some suffer from a lack of regioselectivity during cyclization, multiple steps, low yields, and harsh conditions. Previously, the condensation of S-(p-methoxybenzylthio) β-ketosulfoxides, derived from the protection of methyl 2-mercaptobenzoate and acyl substitution by sodium methylsulfinylmethide, with arylaldehydes furnished the enones, which were then deprotected and eliminated thermally to give the thioflavones, but it required five steps.21 This article describes the new synthesis of thioflavones by the regioselective cyclization of 1-(2-benzylthio)phenyl-3-phenylprop-2-yn-1-ones using hydrobromic acid.
N-Methoxy-N-methyl 2-mercaptobenzamide (2) was prepared using a previously reported method.22 Briefly, 3 equiv. of iso-PrMgCl were added to a mixture solution of methyl 2-mercaptobenzoate (1) and N,O-dimethylhydroxylamine hydrochloride in THF and 2 was obtained in 84% yield after the usual acidic work-up (Scheme 3). The S-benzylation of 2 was carried out by the treatment of 2 with sodium hydride in THF for 1 h at room temperature, followed by the addition of benzyl chloride and stirring for 1.5 h between 0 ℃ and room temperature. After the usual aqueous work-up and purification by silica gel column chromatography, N-methoxy-N-methyl (2-benzylthio)benzamide (3) was obtained in 91% yield.
Scheme3.
Reagents and conditions: (a) CH3(CH3O)NH2Cl, 3 equiv. iso-PrMgCl, THF, -10-0 ℃, 0.5 h; 1N HCl; (b) NaH, THF, rt, 1 h; PhCH2Cl, 0 ℃-rt, 1.5 h; (c) THF, 0 ℃-rt, 0.5 h; 1 N HCl; (d) 2 equiv. 48 wt.% HBr, HOAc, rt or 60 ℃, 1-3 h.
The synthesis of 1-(2-benzylthio)phenyl-3-phenylprop-2-yn-1-ones (4a-l) was accomplished by the acyl substitution of 3 with arylethynyllithium compounds, which were generated from arylacetylenes and CH3Li at 0 ℃, in THF for 0.5 h between 0 ℃ and room temperature. After quenching the mixture with a 1 N HCl solution and the usual work-up, the residue was purified by silica gel column chromatography to give 4a-l in 84-91% yields.
The optimal conditions for the debenzylation and cyclization of 1-(2-benzylthio)phenyl-3-phenylprop-2-yn-1-one (4b) were determined by screening different acids and solvents (Table 1). The reaction of 4b with 2 equiv. of 48 wt.% HBr in HOAc at room temperature proceeded well to give thioflavone (5b) in 85% yield (entry 1). When CH3CN, DME, ClCH2CH2Cl were used as solvents, 5b was obtained in 91, 68, and 51% yield, respectively, after 6, 24, and 24 h, respectively, at room temperature (entries 2-4). On the other hand, the cyclization of 4b using 57 wt.% HI and 37 wt.% HCl in HOAc afforded 5b in 87 and 85% yields, respectively, after 1 and 24 h, respectively, at room temperature (entries 5, 6).
Table1.
Effect of acids and solvents for the cyclization of 1-(2-benzylthio)phenyl-3-phenylprop-2-yn-1-one (4b)a
| Entry | Acidsb | Solvents | Time, h | Yields of 5b, %c |
|---|---|---|---|---|
| 1 | HBr | HOAc | 1.5 | 85 |
| 2 | HBr | CH3CN | 6 | 91 |
| 3 | HBr | DME | 24 | 68 (25) |
| 4 | HBr | ClCH2CH2Cl | 24 | 51 (38) |
| 5 | HI | HOAc | 1 | 87 |
| 6 | HCl | HOAc | 24 | 85 |
a The reaction was carried at room temperature. b 2 equiv. was used. c The numbers in parentheses indicate the recovery yields of 4b.
Thus, the regioselective 6-endo cyclization of 4a-l was carried out using 2 equiv. of 48 wt.% HBr in HOAc and the competitive 5-exo cyclization products were not observed in isolable amounts. The cyclization of 4a-l appeared to proceed through the debenzylation by HBr with the liberation of benzyl bromide to produce the corresponding 1-(2-mercapto)phenyl-3-phenylprop-2-yn-1-one intermediates, which underwent rapid 1,4-addition to give thioflavones (5a-l). In general, the 6-endo cyclization of 4 using 2 equiv. of 48 wt.% HBr was completed within 3 h at room temperature. In contrast, the cyclization of alkynones with o-substituted aryl groups in the 3-position in 4 was completed in 1-3 h at 60 ℃, reflecting the steric effect. The characteristic chemical shifts of the vinyl protons in 5 were generally observed in the range of δ 7.18-7.25 ppm. On the other hand, the chemical shifts of the vinyl protons of 2’-substituted thioflavones (5c, 5f, 5h, 5k) were observed in the range of δ 6.19-7.17 ppm by the effect of diamagnetic shielding due to the rotation of C1’-C2 single bonds.
As listed in Table 2, various thioflavones were synthesized from 1-(2-benzylthio)phenyl-3-phenylprop-2-yn-1-ones using 48 wt.% HBr in HOAc in high overall yields (57-65%). The regioselective 6-endo cyclization of 4 worked well regardless of the types and positions of the electron-withdrawing (5c-e, 5j) and electron-donating (5f-i, 5k) substituents on the 2-substituted phenyl rings to give the corresponding thioflavones under the present conditions. Furthermore, the reaction of 4 containing n-butyl and 3-thienyl groups proceeded equally well to give 2-(n-butyl)-4H-benzothiopyran-4-one (5a) and 2-(3-thienyl)-4H-benzothiopyran-4-one (5l) in 93% and 86% yields, respectively.
Table2.
Synthesis of thioflavones from 4 using hydrobromic acida
a The conversion of 4 to 5 was carried out using 2 equiv. of 48 wt.% HBr in HOAc at room temperature for 1-3 h. b The reaction was completed for 1-3 h at 60 ℃.
In conclusion, the present method provides a highly regioselective synthesis of thioflavones via 6-endo cyclization of 1-(2-benzylthio)phenyl-3-phenylprop-2-yn-1-ones, derived from methyl 2-mercaptobenzoate, using 2 equiv. of hydrobromic acid in HOAc in high yields.
EXPERIMENTAL▼
Preparation of 1-(2-benzylthio)phenyl-3-phenylprop-2-yn-1-one (4b)
To a solution of N-methoxy-N-methyl (2-benzylthio) benzamide (3, 862 mg, 3.0 mmol) in THF (6 mL) was added lithium phenylacetylide, which had been generated from phenylacetylene (368 mg, 3.6 mmol) and CH3Li (1.5 M in Et2O, 2.4 mL, 3.6 mmol) in THF at 0 ℃. The reaction mixture was stirred for 0.5 h between 0 ℃ and room temperature and quenched with a 1 N HCl solution (3 mL). After evaporating the solvents, the mixture was poured into a 0.1 N HCl solution (30 mL) and extracted with dichloromethane (3 × 20 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The concentrated residue was purified by silica gel column chromatography using 30% EtOAc/n-hexane as an eluting solvent to give 4b (887 mg, 90%). mp 120-121 ℃; 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J = 7.8 Hz, 1H), 7.64-7.70 (m, 2H), 7.38-7.52 (m, 7H), 7.23-7.38 (m, 4H), 4.19 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 177.7, 143.7, 135.9, 134.6, 133.4, 133.3, 133.0, 130.7, 129.2, 128.7 (overlapped), 127.4, 125.3, 123.7, 120.3, 92.9, 87.2, 37.1; FT-IR (KBr) 2200 (C≡C), 1623 (C=O) cm-1.
Preparation of thioflavone (5b)
Hydrobromic acid (48 wt.% in H2O, 453 μL, 4.0 mmol) was added to a solution of 4b (575 mg, 2.0 mmol) in HOAc (10 mL) and stirred for 1.5 h at room temperature. After evaporating of the HOAc, the reaction mixture was poured into a saturated NaHCO3 solution (30 mL) and extracted with dichloromethane (3 × 20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Benzyl bromide was evaporated further under a high vacuum, and the residue was recrystallized twice in 15% EtOAc/n-hexane to give 5b (405 mg, 85%). mp 125-126 ℃; 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 7.9 Hz, 1H), 7.62-7.72 (m, 4H), 7.55-7.61 (m, 1H), 7.48-7.54 (m, 3H), 7.25 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 180.9, 153.1, 137.7, 136.6, 131.6, 130.9, 130.8, 129.3, 128.6, 127.8, 127.0, 126.5, 123.5; FT-IR (KBr) 1615 (C=O) cm-1; Ms m/z (%) 238 (M+, 100). The physical and spectral data for the thio-flavones associated with this article can be found in the Supporting Information.