Facile Synthesis of 2-Aryl or β,γ–Unsaturated Esters via 1,2-Migration from Aryl or α,β-Unsaturated Ketones Using Thallium(III) p-Tosylate

The 2-arylpropanoic acids have drawn interest because they exhibit nonsteroidal anti-inflammatory activities.¹ 2-Arylpropanoates as precursors of them have generally been synthesized by Friedel-Crafts alkylation of aromatic compounds with alkyl 2-(mesyloxy)propanoates using aluminum chloride² and mono-methylation of methyl arylacetates with dimethyl carbonate in the presence of potassium carbonate at 220°C.³ Methylation of methyl arylacetates with methyl iodide proceeded under mild conditions using bases such as sodium hydride⁴ and tetrabutylammonium fluoride,⁵ but the success of methylation depended on the nature of substituents in the aryl group. Cross-coupling of 2-bromopropanoates and transmetalated aryl Grignard reagents with zinc chloride also afforded 2-arylpropanoates in moderate yields.⁶

The synthesis of 2-aryl esters was improved by involving 1,2-migration from aryl ketones. The reaction of propiophenones with 2 equiv of iodine in trimethyl orthoformate afforded corresponding iodo ketal intermediates that underwent 1,2-aryl migration to give methyl 2-arylpropanoates after 24 h at room temperature.⁷ Treatment of acetophenones with iodine in the presence of silver nitrate also afforded methyl 2-arylacetates in methanol containing trimethyl orthoformate.⁸ Furthermore, oxidative 1,2-aryl migration of aryl alkyl ketones was accomplished using (diacetoxyiodo)benzene⁹ or iodic acid¹⁰ in trimethyl orthoformate or methanol containing trimethyl orthoformate, respectively, to give the corresponding methyl arylacetates. However, reaction of acetophenones with 1H-1-hydroxy-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide (HMBI) afforded methyl phenylacetates together with 2-methoxyacetophenones side products in cases of acetophenones bearing electron-withdrawing groups.¹¹

The reaction of acetophenones and lead(IV) acetate with boron trifluoride etherate or perchloric acid in methanol or trimethyl orthoformate, respectively, yielded methyl 2-arylacetates.¹² This method was further expanded for the synthesis of β,γ–unsaturated esters and cyclopropyl acetates from α,β–unsaturated ketones and cyclopropyl methyl ketones, respectively.¹³ Alkyl 2-arylpropanoates were prepared by treating of 1-halogenoethyl aryl ketones with thallium(III) trinitrate and 2 equiv of perchloric acid in trimethyl orthoformate.¹⁴ 1-Aryl-2-halo-1-alkanones were also converted to 1-aryl-1,1-dimethoxy-2-propanols by sodium methoxide, treated with sulfuryl chloride or sulfonyl chloride, and followed by 1,2-aryl migration to give 2-arylalkanoic esters in three steps.¹⁵

Although several methods have been reported for synthesizing 2-aryl esters, some require multiple steps, trimethyl orthoformate solvent, and vigorous or long reaction conditions. The present paper reports that 2-aryl esters can be efficiently synthesized via 1,2-aryl migration from aryl ketones using thallium(III) p-tosylate in high yields. Previously, thallium(III) p-tosylate was used to convert flavanones to isoflavones and tetrahydroquinolones to quinolones by 2,3-aryl rearrangement.¹⁶ However, it has not been utilized for direct conversion of aryl ketones to 2-aryl esters.

To determine optimum conditions for conversion of aryl ketones to 2-aryl esters, the effects of solvents were examined. An initial reaction of 4’-methoxypropiophenone and perchloric acid using thallium(III) p-tosylate in ethanol afforded ethyl 2-(4-methoxyphenyl)propanoate in only 10% yield after 24 h at room temperature. However, the corresponding reaction in ethanol/triethyl orthoformate (4/1) was completed in 1 h between 0 °C and room temperature to give ethyl 2-(4-methoxyphenyl)propanoate in 94% yield. The presence of triethyl orthoformate induced rapid ketalization of enol intermediate and facilitated 1,2-migration of the 4-methoxyphenyl group. The relative effectiveness of several metal salts was also examined for conversion of 2’,4’-dimethoxypropiophenone to ethyl 2-(2,4-dimethoxyphenyl)propanoate. Reaction of 2’,4’-dimethoxy-propiophenone and perchloric acid in ethanol/triethyl orthoformate (4/1) using Tl(OCOCF₃)₃, Tl(NO₃)₃·3H₂O, Pb(OAc)₄, and PhI(OAc)₂ at room temperature yielded ethyl 2-(2,4-dimethoxyphenyl)propanoate in 70%, 67%, 58%, and 27% yield after 5 h, 10 h, 24 h, and 12 h, respectively. However, the corresponding reaction using thallium(III) p-tosylate was completed after 1.5 h between 0 °C and room temperature to give ethyl 2-(2,4-dimethoxyphenyl)propanoate in 82% yield.

Thus, conversion of aryl ketones (1) to 2-aryl esters (4) was carried out by the addition of thallium(III) p-tosylate to pretreated 1 with perchloric acid in alcohols/trialkyl orthoformates. The plausible mechanism is represented in Scheme 1. 1 was enolized by perchloric acid to give enol intermediates (2), which were ketalized by alcohols and trialkyl orthoformates to give tetrahedral intermediates (3) together with the addition of thallium(II) p-tosylate. These intermediates then underwent facile 1,2-rearrangement of the aryl group by electron participation of the hydroxyl group. This was followed by elimination of Tl(OTs)₂ to produce 4. After reaction completion, alcohols and trialkyl orthoformates were evaporated off, and the residue was dissolved in methylene chloride. The resulting white precipitate was filtered off, and the extracted residue was purified by vacuum distillation to give 4.

Scheme1.

As shown in Table 1, various 2-aryl or β,γ–unsaturated esters were efficiently synthesized by this method in high yields (62-94%). The rapidity of 1,2-aryl migration in 3 was affected by the type of substituents on the phenyl ring. When substituents were electron-donating groups such as methyl (4e) and methoxy (4f-4i), the reaction was completed within 2 h between 0 °C and room temperature. Furthermore, the presence of a hydroxyl group (4c, 4d) did not affect the facile conversion of 1 to 4 regardless of substitution position under the present reaction conditions. However, the reaction of 3’-chloropropiophenone with an electron-withdrawing group on the phenyl ring proceeded sluggishly in methanol/trimethyl orthoformate (4/1). Thus, the reaction was carried out in trimethyl orthoformate to give methyl 2-(3-chlorophenyl)propanoate (4b) in 93% yield after 4h at room temperature. With (3E)-4-phenyl-3-buten-2-one, conversion to the corresponding β,γ–unsaturated esters was less effective in the presence of perchloric acid. The reaction was carried out by treating (3E)-4-phenyl-3-buten-2-one with 2 equiv of boron trifluoride etherate and 10 equiv of alcohols in THF to give methyl (3E)-4-phenyl-3-butenoate (4j) and ethyl (3E)-4-phenyl3-butenoate (4k) in 73% and 62% yield, respectively, at room temperature.

Table1.

Synthesis of 2-aryl or β,γ–unsaturated esters (4) from 1

^a The reaction was carried out in trimethyl orthoformate. ^bThe reaction was carried out using 2 equiv of BF₃ · Et₂O and 10 equiv of CH₃OH in THF.