Novel Synthesis of Thioflavones and Their Pyridyl Analogs from 2-Mercaptobenzoic(nicotinic) Acid

Thioflavones have the skeleton of a thiochromen-4-one ring, which serves as a building block for biologically active molecules. Thioflavones have drawn much attention because of their various pharmacological activities such as antimalarial,¹ antiviral,² and antimicrobial activity.³ They also inhibit the proliferation of tumor cells⁴ while thioflavonoids, such as 3’,4’-dimethoxythioflavone, relax vascular contraction by activation of the EGF receptor.⁵

Several types of synthetic reactions for thioflavones and their heterocyclic analogs have been described in the literature.⁶ Among them, a tandem reaction using 2’-substituted chalcones and ynones allows for the efficient synthesis of thioflavones and their heterocyclic analogs. Three types of 2’-substituted chalcones, which were prepared from the condensation of arylaldehydes and 2’-substituted acetophenones, were converted to thioflavones by the following methods (Scheme 1(a)): (i) Treatment of 3-aryl-1-[2-(t-butyl-sulfanyl) phenyl]prop-2-en-1-ones with 3 equiv. iodine and NaHCO₃ at reflux in EtCN.⁷ (ii) Cyclization of 2’-tosyloxy-chalcones with 5 equiv. sulfur in the presence of Et₃N in DMSO at 80 °C.⁸ This method produced thioflavones together with (Z)-thioaurones as byproducts. (iii) Cu-catalyzed cyclization of 2’-iodo(bromo)chalcones using 2 equiv. potassium ethyl xanthogenate followed by the sequential oxidation of thioflavanone intermediates using H₂SO₄ in DMSO at 80 °C.⁹

The coupling of 2-(methylthio)benzoyl chlorides and arylacetylenes with 2.5 equiv. AlCl₃ in CH₂Cl₂, followed by the addition of chloride, afforded the 2’-(methylthio)-β-chlorochalcone intermediates. These intermediates underwent sequential 1,4-addition of sulfur atom and demethylation by chloride anion to yield the thioflavones (Scheme 1(b)).¹⁰ Similarly, sequential addition of NaSH-elimination-S_NAr reaction to 2’-halo-β-chlorochalcones, in the presence of 2 equiv. Cs₂CO₃ in DMSO at 140 °C, also afforded the thioflavones (Scheme 1(b)).¹¹

On the other hand, the 1,4-addition of 1-(2-methoxyphenyl)-3-phenylprop-2-yn-1-ones with sodium sulfide nonahydrate produced 3-mercapto-1-(2-methoxyphenyl)-3-phenylprop-2-en-1-ones in DMSO at 80 °C, which underwent cycloaddition to yield thioflavones after re-aromatization (Scheme 1(c)).¹² The heterocyclic analogs of thioflavones were also prepared by the addition of 1-(2-haloheteroaryl)-3-phenylprop-2-yn-1-ones to sodium hydrosulfide through sequential aromatic substitution at reflux in EtOH (Scheme 1(d)).¹³

A carbonylative coupling of 2-iodofluorobenzenes and arylacetylenes in CH₃CN in the presence of 4 mol% Pd(OAc)₂ and 8 mol% t-Bu₃P·HBF₄ under CO (5 bar), followed by the conjugate addition of sodium sulfide and S_NAr substitution, afforded the thioflavones by a four-component reaction (Scheme 1(e)).¹⁴ Similarly, 1-bromo-2-fluorobenzenes were coupled with phenylacetylenes and tert-butyl isocyanide as a carbonyl source, in the presence of 3 mol% Pd(OAc)₂ and 6 mol% bis[(2-diphenylphosphino)phenyl] ether (DPEPhos), in DMF at 100 °C to give the imino alkyne intermediates. These intermediates then underwent sodium sulfide nonahydrate addition, followed by hydrolysis with oxalic acid at reflux in THF, to yield the thioflavones (Scheme 1(e)).¹⁵ Thioflavones and their heterocyclic analogs were also synthesized by the three-component coupling of o-halo(hetero)aroyl chlorides with arylacetylenes, addition of sodium sulfide nonahydrate or sodium hydrosulfide, and subsequent cyclization at reflux in EtOH (Scheme 1(f)).¹⁶

Previous work

Scheme1.

Several methods for the synthesis of thioflavones and their heterocyclic analogs.

Although several types of synthetic reactions for thioflavones have been reported, some of these methods have drawbacks including lack of regioselectivity during cyclization, byproducts, and harsh conditions. Recently, we reported that thioflavones were synthesized via 6-endo cyclization of 1-(2-benzylthio)phenyl-3-phenylprop-2-yn-1-ones derived from methyl 2-mercaptobenzoate.¹⁷ As an extension of our studies on the synthesis of thioflavones,^13b,17,18 we report herein that thioflavones and their pyridyl analogs can be synthesized by 6-endo cyclization of 1-[(2-methylthio)phenyl]-3-phenylprop-2-yn-1-ones and 1-[(2-methylthio)pyridine-3-yl]-3-phenylprop-2-yn-1-ones using hydrobromic acid (Scheme 2).

This work

Scheme2.

Our approach for the synthesis of thioflavones and their pyridyl analogs.

The treatment of 2-mercaptobenzoic acid (1) with 2 equiv. NaH in THF for 6 h at room temperature, followed by the addition of methyl iodide, afforded 2-(methylthio)benzoic acid (2) in 92% yield by selective S-methylation (Scheme 3). N-Methoxy-N-methyl 2-(methylthio)benzamide (5) was prepared by treating 2 with N-methoxy-N-methylcarbamoyl chloride and Et₃N in the presence of 0.02 equiv. 4-(dimethylamino) pyridine (DMAP) in CH₃CN. The reaction proceeded via carboxylic-carbamic anhydrides with the evolution of carbon dioxide for 1 h at room temperature, yielding 5 in 80% yield after a basic work-up and chromatographic separation. Thus, the synthesis of 5 from 1 was more effective than previous method¹⁷ by reducing reaction step.

Scheme3.

Reagents and conditions: (a) 2 equiv. NaH, rt, 6 h, THF; CH₃I, overnight; (b) ClCON(OCH₃)CH₃, Et₃N, 0.02 equiv. DMAP, CH₃CN, rt, 1 h; (c) CH₃OH (excess), 0.2 equiv. H₂SO₄, reflux, 48 h; (d) CH₃(CH₃O)NH₂Cl, 2 equiv. iso-PrMgCl, THF, -10-0 °C, 1 h; (e) THF, 0 °C-rt, 1 h; (f) X = C: 2 equiv. 48 wt.% HBr, AcOH, rt, 1.5-2 h; rt, 24 h for 7b; 60 °C, 2 h for 7f; X = N: 3 equiv. 48 wt.% HBr, AcOH, 100 °C, 6-10 h.

Methyl 2-(methylthio)nicotinate (4) was prepared by the reaction of 2-mercaptonicotinic acid (3) with an excess of CH₃OH in the presence of 0.2 equiv. H₂SO₄ for 48 h at reflux. The esterification occurred together with the S-methylation of the thiol group under this condition.¹⁹ The S-methylation seemed to proceed by the nucleophilic substitution of the sulfur atom to a protonated methyloxonium cation. Thus, the two methyl groups of 4 were observed at δ 3.93/2.54 in ¹H NMR and δ 52.3/13.9 ppm in ¹³C NMR spectra. The conversion of 3 to 4 has the advantage of avoiding additional S-methylation. Original attempt to S-methylation of 3 with methyl iodide using 2 equiv. of sodium hydride or lithium diisopropylamide was fruitless.

N-Methoxy-N-methyl 2-(methylthio)nicotinamide (6) was prepared by the slow addition of 2 equiv. iso-PrMgCl to a slurry solution of 4 and Me(OMe)NH₂Cl in THF. The methoxy group of 4 was substituted by in situ Me(OMe)NMgCl for 1 h between -10 and 0 °C, yielding 6 in 90% yield after an acidic work-up and chromatographic separation. The acylation of 5 and 6 with (hetero) arylethynyllithiums in THF proceeded smoothly for 1 h between 0 °C and room temperature. After quenching with a 1 N HCl solution and an acidic work-up, the residue was purified by silica gel column chromatography to give 7 and 8 in 88-92% and 85-93% yields, respectively.

The 6-endo cyclization of 7 was carried out using 2 equiv. HBr in AcOH. The reaction proceeded smoothly for 1.5-2 h at room temperature and the competitive 5-exo cyclization was not observed. In contrast, the cyclization of 1-(2-methylthio)phenyl-3-(2-methoxyphenyl)prop-2-yn-1-one (7b) proceeded sluggishly for 24 h at room temperature, reflecting the steric effect of the o-methoxy group. After the evaporation of AcOH and a basic work-up, the residue was purified by silica gel column chromatography to give 9 in 80-88% yields. The cyclization of 1-[(2-methylthio)pyridine-3-yl]-3-phenylprop-2-yn-1-one (8a) was briefly screened with different acids and solvents. The reaction of 8a with 3 equiv. HCl, HBr, and HI in AcOH at 100 °C afforded 2-phenyl-4H-thiopyrano[2,3-b]pyridin-4-one (10a) in 72, 89, and 81% yield, respectively, after 24, 10, and 7 h, respectively. The cyclization of 8a with 3 equiv. HBr in CH₃CN proceeded for 24 h at 80 °C to give 10a in 74% yield. Thus, the 6-endo cyclization of 8 was carried out using 3 equiv. HBr in AcOH at 100 °C and afforded 10 in 41-90% yields.

As shown in Table 1, various thioflavones and their pyridyl analogs were synthesized by the cyclization of 7 and 8 using HBr in AcOH. The regioselective cyclization of 7 and 8 worked well with both electron-donating (CH₃, OCH₃) and electron-withdrawing groups (Cl, Br) of the 2-substituted ring. Furthermore, the cyclization of 7 and 8 containing 3-pyridyl (7g) and 3-thienyl (8h) worked equally well to give 2-(3-pyridyl)-4H-1-benzothiopyran-4-one (9g) and 2-(3-thienyl)-4H-thiopyrano[2,3-b]pyridin-4-one (10h) in 80% and 88% yield, respectively.

Table1.

Synthesis of thioflavones (9) and 2-phenyl-4H-thiopyrano[2,3-b]pyridin-4-ones (10) from 7 and 8^a

^a The reaction was carried out using 2 or 3 equiv. 48 wt.% HBr in AcOH.

In conclusion the present method provides a regioselective synthesis of thioflavones and their pyridyl analogs by 6-endo cyclization of 7 and 8, derived from 2-mercaptobenzoic(nicotinic) acid, using HBr in AcOH in high yields.