Anilines Gassman oxindole synthesis

A convenient modification of the Gassman oxindole synthesis was reported using ethyl (methylsulfinyl)acetate (101) activated by oxalyl chloride to generate the same chlorosulfonium salt 102 normally generated from ethyl (methylthio)acetate 100 and elemental chlorine <96TL4631>. Thus, treatment of the sulfoxide 101 with oxalyl chloride, followed by the addition of the desired aniline, triethylamine, and finally acid cyclization of 103 affords the oxindoles 104. This procedure is particularly convenient for reactions carried out on smaller scales and for anilines that ate susceptible to electrophiUc halogenation. 

Generally, the reaction works well for electron-deficient anilines. A modified approach using in situ prepared chlorosulfonium salts is preferred for more electron-rich anilines. Substituted thiol derivatives can be used to produce 3-oxindoles, which can be further reduced to 3-indole derivatives that are not available via the Gassman indole synthesis. The reaction is equally useful for the preparation of isatin derivatives vide infra). Historically, the Gassman oxindole synthesis has found applications in the preparation of heterocycles with medical or insecticidal properties. The reaction also has potential applications for the synthesis of oxindole containing natural products. ... 

The proposed mechanisms for the two main variations of the Gassman oxindole synthesis are shown below. The A -chloroaniline starting material 6 is prepared from an aniline and tert-butyl hypochlorite. 

In the second variation of the Gassman oxindole synthesis, the nucleophile-electrophile pairing is reversed and the aniline 10 attacks a positively charged chlorosulfonium ion to produce sulfonium ion 7. After that, the reaction proceeds along the same mechanistic route as the one proposed for the original Gassman oxindole 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. 

The Gassman indole synthesis has one serious limitation. Attempts to use anilines with an ortho/para- methoxy moiety failed to indolize. One means to overcome this was synthesis of the corresponding oxindoles followed by reduction to the indoles. ... 

GASSMAN Oxmdote Synthesis Synthesis of oxindoles from anilines... 

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. 

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