Esters indoline-3-carboxylic acid

The methyl and benzyl esters of proline were also used as chiral auxiliaries in respective acrylamides, but the isoxazoline cycloadducts were obtained with only poor to modest stereoselectivity (189,190). The related indoline-2-carboxylic acid derivative 33, however, showed excellent ability to direct nitrile oxide attack, favoring one rotamer (Scheme 6.37), and thereby leading to 3-phenylisoxazoline-5-carboxamide... 

Therefore better methods for the chiral reduction of indole-2-carboxylic acid derivatives would provide an elegant synthesis of this intermediate. A study by Kuwano and Kashiwabara of the reduction of indole derivatives into the corresponding indohnes found that a range of the more common ligand systems gave almost no enantioselectivity but the TRAP ligand gave the chiral indolines in up to 95 % ee for reduction of the methyl ester (B, R=Me, R =H). Further developments are awaited. 

The 2H-and 3//-pyrroles and -indoles are considerably more basic than the corresponding H-isomers and they readily undergo alkylation to give the quaternary salts, which are then highly susceptible to nucleophilic attack. Thus, for example, methylation of the trialkyl-3//-indole (507), followed by reaction with aqueous base, yields the indolin-2-ol (508). A similar reaction sequence results from the acylation of (507) under Schotten-Baumann conditions to give (509 X = OH). When the benzoylation is conducted in benzene in the absence of the base, the 2-chloroindoline (509 X = C1) is formed and acylation of (507) with a carboxylic acid anhydride produces the ester (509 X = OCOR) (79HC(25-3)l). 

Amino acids with side chains containing the benzyl and indoline groups usually show good performance in the esterification. In general, the higher yield is obtained for ethyl esters compared with isopropyl esters. One exception is indoline-2-carboxylic acid, where the yield of isopropyl ester is much higher that the ethyl ester. It is also believed that the N-acetyl ethyl esters are more stable than the N-unprotected ethyl esters and butyl esters (16), which implies that the N-acetyl ethyl esters studied are very valuable for further applications. 

Sol and Serrano [108] employed a palladium/triphenylphosphane-based catalyst system in the intramolecular a-arylation of fl-(2-iodoanilino) esters, tiffording the corresponding indoline products in low to good yields (Scheme 8.60). [Pd(PPh3) j and potassium phenoxide as base were the conditions applied to obtain indoline-3-carboxylic acid derivatives. 

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