New Synthesis of Thioflavones by the Regioselective Cyclization of 1-(2-Benz-ylthio)phenyl-3-phenylprop-2-yn-1-ones Using Hydrobromic Acid

Journal of the Korean Chemical Society 2020, Vol. 64, No. 4

Printed in the Republic of Korea https://doi.org/10.5012/jkcs.2020.64.4.239

-239-

Note

New Synthesis of Thioflavones by the Regioselective Cyclization of 1-(2-Benz- ylthio)phenyl-3-phenylprop-2-yn-1-ones Using Hydrobromic Acid

Jae In Lee

Department of Chemistry, College of Science and Technology, Duksung Women’s University, Seoul 01369, Korea.

*E-mail: [email protected]

(Received April 10, 2020; Accepted May 8, 2020) Key words: Thioflavones, Condensation, Acylation, 6-Endo cyclization

Thioflavones are thio analogs of naturally occurring fla- vones 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 anti- fungal 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 vaso- relaxation through activation of the epidermal growth fac- tor (EGF) receptor.⁵

Several types of reactions for the synthesis of thiofla- vones have been described.⁶ In general, thioflavones were synthesized by the cyclic condensation of thiophenols with ethyl benzoylacetates using polyphosphoric acid at 90 ^oC 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-mercaptophe- nyl)-3-phenylpropan-1,3-diones, which were prepared from 2’-mercaptoacetophenone and N-methoxy-N-methyl ben- zamides using sulfuric acid in CH3CN afforded the thio- flavones 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 Wit- tig 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)ace-

Scheme 1. Several methods for the synthesis of thioflavones.

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240 Jae In Lee

tophenones using NaOH, with 3 equiv. of iodine in the presence of NaHCO₃ in refluxing EtCN afforded the thio- flavones (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 oxi- dation with sulfuric acid at 80 ^oC to give the thioflavones (Scheme 2(b)).¹⁴ Tandem substitution-S_NAr reaction of β- chlorochalcones, which had been prepared by the iron- catalyzed addition of aryl chlorides to arylacetylene, with sodium hydrosulfide in the presence of 2 equiv. of Cs2CO3 in DMSO at 140^oC afforded thioflavones (Scheme 2(c)).¹⁵ The addition of sodium hydrosulfide¹⁶ or sodium sulfide¹⁷ to 2’-bromoalkynones produced the thiolate adducts rap- idly, 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 ary- lacetylenes 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 reac- tion 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 ary- laldehydes furnished the enones, which were then depro- tected 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-dimethylhydroxyl- amine hydrochloride in THF and 2 was obtained in 84%

yield after the usual acidic work-up (Scheme 3).TheS-ben- zylation of 2 was carried out by the treatment of 2 with sodium hydride in THF for 1 h at room temperature, fol- lowed by the addition of benzyl chloride and stirring for 1.5 h between 0^oC and room temperature. After the usual aqueous work-up and purification by silica gel column Scheme 2. Several methods for the synthesis of thioflavones.

Scheme 3. Reagents and conditions: (a) CH3(CH₃O)NH₂Cl, 3 equiv. iso-PrMgCl, THF, -10-0 ^oC, 0.5 h; 1N HCl; (b) NaH, THF, rt, 1 h;

PhCH₂Cl, 0 ^oC-rt, 1.5 h; (c) THF, 0 ^oC-rt, 0.5 h; 1 N HCl; (d) 2 equiv. 48 wt.% HBr, HOAc, rt or 60 ^oC, 1-3 h.

New Synthesis of Thioflavones by the Regioselective Cyclization of 1-(2-Benzylthio)phenyl-3-phenylprop-2-yn-1-ones Using Hydrobromic Acid 241

2020, Vol. 64, No. 4

chromatography, N-methoxy-N-methyl (2-benzylthio)ben- zamide (3) was obtained in 91% yield.

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 gen- erated from arylacetylenes and CH₃Li at 0^oC, in THF for 0.5 h between 0^oC 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 chromatog- raphy to give 4a-l in 84-91% yields.

The optimal conditions for the debenzylation and cycliza- tion of 1-(2-benzylthio)phenyl-3-phenylprop-2-yn-1- one (4b) were determined by screening different acids and sol- vents (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 tem- perature (entries 5, 6).

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 lib- eration of benzyl bromide to produce the corresponding 1- (2-mercapto)phenyl-3-phenylprop-2-yn-1-one intermedi- ates, which underwent rapid 1,4-addition to give thiofla- vones (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 com- pleted in 1-3 h at 60^oC, 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 dia- magnetic shielding due to the rotation of C_1’-C₂ single bonds.

As listed in Table 2, various thioflavones were synthe- sized 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-ben- zothiopyran-4-one (5l) in 93% and 86% yields, respec- tively.

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 hyd- robromic acid in HOAc in high yields.

Table 1. Effect of acids and solvents for the cyclization of 1-(2- benzylthio)phenyl-3-phenylprop-2-yn-1-one (4b)^a

Entry Acids^b 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.

Table 2. Synthesis of thioflavones from 4 using hydrobromic acid^a

5a (93%) 5b (85%) 5c^b (91%)

5d (87%) 5e (85%) 5f^b (93%)

5g (88%) 5h^b (84%) 5i (92%)

5j (90%) 5k^b (86%) 5l (86%)

aThe conversion of 4 to 5 was carried out using 2 equiv. of 48 wt.% HBr in HOAc at room temperature for 1-3 h. ^bThe reaction was completed for 1-3 h at 60^oC.

S

O

S O

S O

Br

S

O

Br S O

Cl S

O Me

S O

Me

S O

OMe

S O

OMe

S O

Cl

Cl S

O Me

OMe

S

O S

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242 Jae In Lee

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 ^oC. The reaction mixture was stirred for 0.5 h between 0 ^oC 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 concen- trated residue was purified by silica gel column chroma- tography using 30% EtOAc/n-hexane as an eluting solvent to give 4b (887 mg, 90%). mp 120-121^oC; 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 ^oC; 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 andspectral data for the thio- flavones associated with this article can be found in the Supporting Information.

Supporting Information. Additional supporting infor- mation may be found online in the Supporting Informa- tion section at the end of the article.

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