Oxindoles, synthesis

Another indole/oxindole synthesis achieves the critical ortho-substitution by Sommelet-Hauser rearrangement of an anilinosiilfonium ion intermediate. Use of P-thioketones (G = R, an alkyl group) generates 2-substituted indoles, whereas P-thioesters (G = OR) lead to oxindoles. In each case, a 3-thio substituent must be removed by desulfuri2ation. 

B A E Y E R Oxindole Synthesis Synthesis of oxindole from o-nitrophenylacetates. 

G A S S M A N Oxindole Synthesis Synthesis ol oxindoles Irom anilines... 

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. 

Reductive cyclization of o-nitrophenylacetic acids is a very general method of oxindole synthesis (see Section 3.06.2.1.1 for the application of this method to indoles in general). The main problem is efficient construction of the desired phenylacetic acid. One method involves base-catalyzed condensation of substituted nitrotoluenes with diethyl oxalate followed by oxidation of the 3-arylpyruvate (equation 200) (63CB253). Nucleophilic substitution of o-nitrophenyl trifluoromethanesulfonate esters, which are readily prepared from phenols, by dimethyl malonate provides another route (equation 201) (79TL2857). 

Intramolecular nucleophilic substitution by the anions of o-haloanilides is another viable oxindole synthesis. This is a special example of the category Ic process described in Section 3.06.2.3. The reaction is photo-stimulated and the mechanism is believed to be of the electron-transfer type SRN1 rather than a classical addition-elimination mechanism. The reaction is effective when R = H if 2 equivalents of the base are used to generate the dianion (equation 202) (80JA3646). 

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

A unique oxindole synthesis is the addition of diphenylketene to the mono-A-phenylimine of benzoquinone the resulting spiro-P-lactam (18) rearranges to give a 62% overall yield of 5-hydroxy-l,3,3-triphenyloxindole (19), which can be methylated to the 5-methoxy compound,35 which in turn could be converted to the Fischer s base. 

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. 

HINSBERQ - STOLLfi Indole-Oxindol Synthesis Indole synthesis Irom anilines and glyoxal (Hinsberg), oj haioacyihaKdes(Stoiie). 

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

The oxindole construction mentioned above is a variation of an oxindole synthesis developed by Jones. An application of this method to the synthesis of horsfi-line is outlined in Eq. (11) [21], It is notable that whereas the cyclization of 37 is quite efficient, attempts to cyclize amide 38 gave only reduction of the aryl bromide. This is a common problem in radical cyclizations involving secondary amides as the ii-geometry of the amide precludes cyclization. This general problem was first... 

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