Journal of the Korean Chemical Society 2021, Vol. 65, No. 2
Printed in the Republic of Korea https://doi.org/10.5012/jkcs.2021.65.2.166
-166-
Note
Novel Synthesis of Thioflavones and Their Pyridyl Analogs from 2-Mercaptobenzoic(nicotinic) Acid
Jae In Lee
Department of Chemistry, College of Science and Technology, Duksung Women’s University, Seoul 01369, Korea.
E-mail: [email protected]
Key words: Thioflavones, 2-Phenyl-4H-thiopyrano[2,3-b]pyridin-4-ones, Acylation, 6-endo Cyclization
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 anti- malarial,1 antiviral,2 and antimicrobial activity.3 They also inhibit the proliferation of tumor cells4 while thioflavonoids, such as 3’,4’-dimethoxythioflavone, relax vascular contrac- tion by activation of the EGF receptor.5
Several types of synthetic reactions for thioflavones and their heterocyclic analogs have been described in the lit- erature.6 Among them, a tandem reaction using 2’-substi- tuted 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 acetophe- nones, 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-cat- alyzed 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 under- went sequential 1,4-addition of sulfur atom and demeth- ylation by chloride anion to yield the thioflavones (Scheme 1(b)).10 Similarly, sequential addition of NaSH-elimina- tion-SNAr reaction to 2’-halo-β-chlorochalcones, in the pres- ence 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-methoxyphe- nyl)-3-phenylprop-2-yn-1-ones with sodium sulfide nona- hydrate produced 3-mercapto-1-(2-methoxyphenyl)-3-
Scheme 1. Several methods for the synthesis of thioflavones and their heterocyclic analogs.
Previous work
Novel Synthesis of Thioflavones and Their Pyridyl Analogs from 2-Mercaptobenzoic(nicotinic) Acid 167
2021, Vol. 65, No. 2
phenylprop-2-en-1-ones in DMSO at 80 °C, which under- went cycloaddition to yield thioflavones after re-aroma- tization (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 hydro- sulfide 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 SNAr sub- stitution, afforded the thioflavones by a four-component reaction (Scheme 1(e)).14 Similarly, 1-bromo-2-fluoroben- zenes 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, addi- tion of sodium sulfide nonahydrate or sodium hydrosulfide, and subsequent cyclization at reflux in EtOH (Scheme 1(f)).16 Although several types of synthetic reactions for thio- flavones 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 thiofla- vones,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).
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-(dime- thylamino)pyridine (DMAP) in CH3CN. The reaction pro- ceeded 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.
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-methyla- tion of the thiol group under this condition.19 The S-meth- ylation 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/
Scheme 2. Our approach for the synthesis of thioflavones and their pyridyl analogs.
This work
Scheme 3. 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.
Journal of the Korean Chemical Society
168 Jae In Lee
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 addi- tional 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 chromato- graphic separation. The acylation of 5 and 6 with (het- ero)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 cycliza- tion 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)pyr- idine-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, respec- tively. 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 pyr- idyl 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.
In conclusion the present method provides a regiose- lective synthesis of thioflavones and their pyridyl analogs by 6-endo cyclization of 7 and 8, derived from 2-mer-
captobenzoic(nicotinic) acid, using HBr in AcOH in high yields.
EXPERIMENTAL Preparation of Thioflavone (9a)
To a solution of 1-[(2-methylthio)phenyl]-3-phenylprop- 2-yn-1-one (7a, 252 mg, 1.0 mmol) in AcOH (15 mL) was added hydrobromic acid (48 wt.% in H2O, 227 μL, 2.0 mmol) and stirred for 1.5 h at room temperature. After evaporation of AcOH, the mixture was poured into a sat- urated NaHCO3 solution (20 mL) and extracted with meth- ylene chloride (3×15 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The concentrated residue was purified by silica gel column chromatography with 30% EtOAc/n-hexane to give 9a (203 mg, 85%). mp 125- 126 °C; 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 7.5 Hz, 1H), 7.62-7.71 (m, 4H), 7.55-7.61 (m, 1H), 7.48-7.55 (m, 3H), 7.24 (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).
Preparation of 2-phenyl-4H-thiopyrano[2,3-b]pyridin- 4-one (10a)
To a solution of 1-[(2-methylthio)pyridine-3-yl]-3-phen- Table 1. Synthesis of thioflavones (9) and 2-phenyl-4H-thiopy- rano[2,3-b]pyridin-4-ones (10) from 7 and 8a
9a (85%) 9b (86%) 9c (81%)
9d (88%) 9f (86%) 9g (80%)
10a (89%) 10b (60%) 10c (41%)
10e (87%) 10f (90%) 10h (88%)
a The reaction was carried out using 2 or 3 equiv. 48 wt.% HBr in AcOH.
S O
S O
OMe
S O
Cl
S
O
Br S
O
OMe
S
O N
N S
O
N S
O
OMe
N S
O
Cl
N S
O
Me
N S
O
OMe
N S
O S
Novel Synthesis of Thioflavones and Their Pyridyl Analogs from 2-Mercaptobenzoic(nicotinic) Acid 169
2021, Vol. 65, No. 2
ylprop-2-yn-1-one (8a, 253 mg, 1.0 mmol) in AcOH (15 mL) was added hydrobromic acid (48 wt.% in H2O, 341 μL, 3.0 mmol) and the reaction mixture was heated at 70 °C to yield an homogeneous solution. The mixture was further stirred for 10 h at 100 °C and AcOH was then evaporated under reduced pressure. The mixture was poured into a saturated Na2CO3 solution (20 mL) and extracted with meth- ylene chloride (3×15 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
The product was isolated by silica gel column chromatog- raphy with 50% EtOAc/n-hexane to give 10a (213 mg, 89%).
mp 121-123 °C; 1H NMR (300 MHz, CDCl3) δ 8.82 (dd, J = 4.5, 1.9 Hz, 1H), 8.77 (dd, J = 8.1, 1.9 Hz, 1H), 7.68-7.74 (m, 2H), 7.49-7.52 (m, 4H), 7.27 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 181.3, 159.1, 154.8, 152.8, 136.8, 136.3, 131.1, 129.4, 128.1, 127.0, 123.6, 123.0; FT-IR (KBr) 1617 (C=O) cm-1; Ms m/z (%) 239 (M+, 100).
Supporting Information. Additional supporting infor- mation may be found online in the Supporting Information section at the end of the article.
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