Ethyl methylthioacetate

Chloro-4-(triHuoromethyl)phenoxy)-3- methylthio 1 CI2. Ethyl methylthioacetate 2 4-[2-Chloro-4-(trifluoromethyl)phcnoxyl]aniline 3 Et,N 49, [16]... 

Methoxy-4,7-hi.s-(methoxymethyl)-6-niethyl- 3-mcthylthio 1 CI2, Ethyl methylthioacetate 2 4-Methoxy-2,5-6/.s-(methoxvmethyl)-3-methylaniline 3 EtjN 4 Xylene, 120 C 74. [17]... 

The sulfur analogue of the Hauser ortho-substitution rearrangement provides access to an arylacet-ic NSAID. Reaction of the aminobenzophenone 176 with ethyl methylthioacetate and tert-butyl hypochlorite gives the intermediate 178. The reaction probably proceeds by way of formation of the S-chlorinated sulfonium derivative 177 displacement on sulfur will lead to the salt 178. Treatment with triethylamine leads initially to the betaine 179. Electrocyelic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid 180. Internal ester-amine interchange leads then to indolone 181 [45]. The thiomethyl group is then removed with Raney niekel. Saponifieation of intermediate 182 affords bromfenac (183) [46J. 

The chlorosulfonium compounds can also be used for the synthesis of oxindoles, the stable tautomeric form of 2-hydroxyindoles. The a -methylthio ketone is replaced by ethyl methylthioacetate and the products of the Sommelet-Hauser rearrangement are cyclized to 3-methylthiooxindoles. The methylthiooxindoles are reductively desulfurized with Raney nickel (equation 102) (74JA5508). 

Use of ethyl methylthioacetate converts the method to an oxindole synthesis (Scheme 23). This is probably the smoothest oxindole synthesis presently available. 

Recently Wright and co-workers have described a modified Gassman oxindole synthesis. They point out the problem associated with the preparation of the chlorosulfonium salt (reagent for Method 2) from chlorine gas and ethyl methylthioacetate, and demonstrated a modified procedure that makes use of a sulfoxide as a synthetic equivalent of a sulfenyl halide48 (Scheme 11). The Gassman procedure can also be applied to AZ-alkyl anilines43. 

From an experimental perspective, the reaction proceeds with the addition of a stoichiometric amount of tert-butyl hypochlorite (dissolved in CH2CI2) to a stirred solution of the aniline in dichloromethane at -65 °C. After a few minutes, a solution of ethyl methylthioacetate (stoichiometric amount, dissolved in CH2CI2) is added. The sulfonium salt usually does not precipitate out of solution. After an hour at -65 "C, a stoichiometric amount... 

The preparation of 3-substituted oxindoles can be readily achieved by using alkylated derivatives of ethyl methylthioacetate." For example, reaction of aniline with compound 18 gave oxindole derivative 19 in 64% yield. Reduction of 19 with Raney nickel gave oxindole 20 in 70% yield, while reduction with LiAlH4 gave the corresponding indole 21 in 76% yield. The two-step route to indoles eomplements the Gassman indole synthesis. 

Applications of the Gassman oxindole synthesis in total synthesis are uncommon. Savall and McWhorter prepared a 6,7-dihydroxyindole derivative, part of the potent antihelmintic compound paraherquamide A, by using a chlorosulfonium ion (15) obtained from ethyl methylthioacetate and sulfuryl chloride.The intermediate oxindole 23 was obtained in 80% crude yield. The starting aniline was obtained in good yield from 2,3-dimethoxybenzoic acid via a modified Curtius rearrangement. Removal of the thiomethyl functionality with Raney nickel gave the final product in 62% yield. 

A 2 L CH2CI2 solution of 98 g (0.5 mol) of aniline 27 and 74 g (0.5 mol) of ethyl methylthioacetate was cooled to -70 °C and treated dropwise with 56 g (0.5 mol) of 95% fert-butyl hypochlorite at such a rate that the temperature did not exceed -65 °C 1 h after the addition was complete, 51 g (0.5 mol) of Et3N was added, and the mixture was allowed to warm to ambient temperature. The solution was diluted with 800 mL of 3 N HCl, and the mixture was stirred for 1 h. The layers were separated, and the organic layer was dried (Na2S04) and evaporated under reduced pressure at 50 °C to give a gummy solid residue. The residue was triturated with Et20, and the powder was collected by filtration. The solid was recrystallized from absolute EtOH to yield 92 g (62%) of compound 28 as a white powder, mp 135-137 °C. 

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