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. 

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. 

GAREGG - SAMUELSSON Olelmation 141 GASSMAN Oxindole synthesis 142 GASTALDI Pyrazme synthesis 143 Gettermann 332... 

Scheme 8.10 Modified Gassman oxindole synthesis in the presence of Proton Sponge (1)...

This reaction is closely related to the Gassman Reaction and Gassman Oxindole Synthesis. 

Other references related to the Gassman oxindole synthesis are cited in the literature. ... 

Gassman Oxindole Synthesis Daniel P. Christen 3.6.1 Description... 

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. 

Larger-scale applications of the Gassman oxindole synthesis are possible. Reactions in the 100 g plus range have been reported for all of the common synthetic approaches. For example, Walsh and co-workers reported the synthesis of oxindole 22 in 92 g yield using the original Gassman procedure. ... 

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. 

As mentioned in the introduction, the Gassman oxindole synthesis is a good way to gain access to isatins. Historically, the isolated oxindoles were oxidized to the corresponding isatin using red mercuric oxide and boron trifluoride.These harsh and environmentally unfriendly conditions have been replaced by an air oxidation approach in which an in situ generated anion reacts with oxygen to make an intermediate peroxo radical that... 

In 1981, Wierenga first introduced a modification of Gassman oxindole synthesis for the synthesis of indole derivative 34, part of the left-hand segment of the antitumor agent CC-1065. In accordance to that, addition of derivative 30 in a equimolar amount of the hindered base, [1,8-bis(dimethylamino)naphthylene (R3N), to the chloride complex of ethyl-a-(mercaptomethyl)propionate 31, followed by a triethylamine catalyzed Sommelet-Hauser rearrangement and an acid-induced cyclization gave oxindole 32. Treatment of 32 with excess BH3 SMei at room temperature afforded 33 in 95% yield. 

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