Oxindole alkylation, phase-transfer

Asymmetric Alkylation. 7Y-[4-(Trifluoromethyl)benzyl]-cinchoninium bromide (1) has been used as chiral phase-transfer catalyst in the alkylation of indanones (eq 1). For the alkylation of a-aryl-substituted carbonyl compounds the diastere-omeric 7Y-[4-(trifluoromethyl)benzyl]cinchonidinium bromide (2) was used to obtain the opposite stereochemistry (eqs 2 and 3). The asymmetric alkylation of oxindoles was used as the key step in an asymmetric synthesis of (—)-physostigmine (eq 4). ... 

The stereochemistry of alkylation of chiral phosphorus-stabilised carbanions (138) has been investigated and shown to be highly sensitive to the nature of the nitrogen substituent. Phase-transfer catalysed alkylation of 2-(diethoxyphosphinyl)cyclohexanone (139) gives bothO-(140) and C-(141) alkylated products. The latter predominate when reactive, non-sterically demanding alkyl halides are used. a-Arylphosphonates (142) have been synthesised in good yields by the copper(l) salt-mediated arylation of phosphonate carbanions. Under similar conditions A-(2-iodophenyl)-substituted phosphonates provide benzoxazole-(143) and oxindole-(144) substituted phosphonates. 

Scheme 86 Phase-transfer catalyzed oxindole alkylation...

Scheme 8.11 The ablation followed by alkylation of 2-oxindoles in a toluene potassium hydroxide biphasic system catalyzed by a palladium precatalyst and a phase-transfer catalyst TBAB.

Takabe et al. [90] described a Cj-symmetric quaternary ammonium salt 57 and applied it to the asymmetric benzylation of N-(diphenyhnethylene) glycine tert-butyl ester. A much lower enantioselectivity was obtained by using the mono- or di-OH group-containing phase-transfer catalyst instead of (R,R,R)-57, which clearly illustrated the importance of a second coordination site to achieve reasonable selectivities. Starting from readily accessible a-amino acids, Ooi and coworkers recently designed and prepared a series of chiral 1,2,3-triazolium 58, and their potential as phase-transfer catalysts was demonstrated through application to the asymmetric alkylation of 3-substituted oxindoles [91]. 

Oxindoles are the structural motifs frequently found in many natural products and biologically active molecules. Many of them feature a chiral quaternary stereocenter at the C3 position of the heterocycHc ring. In the presence of suitable phase-transfer catalysts (Q X ), 3-substituted oxindoles could proceed to form the intermediary chiral ion pair, which was trapped by electrophihc substrates (E) such as alkylating reagents [91, 123], molecular oxygen [124], imines [95], and Michael acceptors [76, 125] to give the corresponding products (Scheme 12.17). 

The phase-transfer-catalyzed alkylation strategy was successfully appHed to the asymmetric cyanomethylation of oxindole 92 by the use of catalyst Hi [123]. This reaction allowed a simple and stereoselective synthesis of (—)-esermethole, a precursor to the clinically useful anticholinesterase agent (—)-physostigmine... 

Scheme 12.18 Asymmetric total synthesis of (-)-esermethole by a phase-transfer catalytic alkylation of oxindole 92.

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