Cinchoninium

Interestingly, phase-transfer catalysts including crown ethers have been used to promote enantioselective variations of Darzens condensation. Toke and coworkers showed that the novel 15-crown-5 catalyst derived from d-glucose 33 could promote the condensation between acetyl chloride 31 and benzaldehyde to give the epoxide in 49% yield and 71% A modified cinchoninium bromide was shown to act as an effective phase transfer catalyst for the transformation as well. ... 

Catalysis of the C-alkylation of 5-methyoxy-l,3-dimethyloxindole with chloroacetonitrile by A-(3,4-dichlorobenzyl)cinchoninium or quininium chloride leads in good yield to the (5)-3-alkylatcd derivative (78% ee), which provides an efficient stereospecific route to the anticholinesterase agent, (-)-physostigmine [9]. Other analogous alkylation reactions have been reported [10]. 

Attempts to produce chiral cyanhydrins under phase-transfer catalytic conditions (3.3.9) using ephedrinium or cinchoninium catalysts has been singularly unsuccessful [21,22]. Optical purities varying from 0 to 60% have been recorded [22], but verification of the reproducibility of the higher values is needed. Similarly, nucleophilic attack on a carbonyl group by the trichloromethyl anion under phase-transfer catalytic conditions (see Section 7.4) in the presence of benzylquininium chloride produces a chiral product, but only with an enantiomeric excess of 5.7% [23]. The veracity of this observation has also been questioned [24],... 

Poor stereoselectivity (<30% ee) is recorded for the Michael addition of 1,3-di-ketones with nitroalkenes using cinchona bases [50] and early work recorded <25% ee using N-methylquininium and quinidinium hydroxides [51, 52], In contrast, indanones have been reported to react with methyl vinyl ketone in the presence of a cinchoninium salts to produce a chiral (S)-product in >95% yield (80% ee) [7]. Surprisingly, the (R)-isomer is obtained less readily (ee 40-60%) using cinchoni-dinium salts. Both isomers are obtained in high optical purity (>80% ee) via alkylation with 1,3-dichlorobut-2-ene and subsequent ring closure yields the Robinson... 

Diastereomeric excesses of up 56% have been claimed for the preparation of a-amino-P-hydroxy acids via the aldol condensation of aldehydes with f-butyl N-(diphenylmethylene)glycinate [63]. It might be expected that there would be thermodynamic control of the C-C bond formation influenced by the steric requirements of the substituents, but the use of cinchoninium and cinchonidinium salts lead to essentially the same diastereoselectivity. The failure of both tetra-n-butylammo-nium and benzyltriethylammonium chloride to catalyse the reaction is curious. 

Asymmetric induction has been noted [64] when ethyl glycine, protected as its imine by (S)-menthone, is allowed to react with ethyl acrylate under phase-transfer catalytic conditions using tetra-n-butylammonium bromide. An overall yield of 43% was achieved with 46% ee. The stereoselectivity of the reaction was not enhanced when A-benzylquininium or cinchoninium chloride were used and, unlike reactions catalysed by chiral catalysts, the enantiomeric excess increased, when a more polar solvent was used. 

Attempts to control the stereochemistry of the addition of chlorine to alkenes using ephedrinium and cinchoninium salts give only low optical activity [31]. 

Epoxidation of cycloalk-2-enones by oxygen in the presence of 9-n-hexylfluorene and a quaternary ammonium salt [17, 21, 22] has been shown to proceed via the intermediate formation of the 9-hydroperoxyfluorene [21]. The catalytic use of cinchoninium salts produces the 2(S),3(S)-oxiranes in high yields with enantiomeric excesses of up to 63% [17,21,22]. 

There are only a few reports on chiral phase transfer mediated alkylations". This approach, which seems to offer excellent opportunities for simple asymmetric procedures, has been demonstrated in the catalytic, enantioselective alkylation of racemic 6,7-dichloro-5-methoxy-2-phenyl-l-indanone (1) to form ( + )-indacrinone (4)100. /V-[4-(tnfluoromethyl)phenylmethyl]cinchoninium bromide (2) is one of the most effective catalysts for this reaction. The choice of reaction variables is very important and reaction conditions have been selected which afford very high asymmetric induction (92% cc). A transition state model 3 based on ion pairing between the indanone anion and the benzylcinchoninium cation has been proposed 10°. 

The indanone substrate was methylated in 94% enantiomeric excess, by the use of a chiral catalyst, N-(/>-(trifluoromethyl)benzyl)cinchoninium bromide, under phase transfer conditions.1468 In another method enantioselective alkylation can be achieved by using a chiral base to form the enolate.1469... 

For another example of the use of chiral phase-transfer catalysts in synthesis, see N-(p-Trifluoromethylbenzyl)cinchoninium bromide (this volume). 

N-(/7-Trifluoromethylbenzyl)cinchoninium bromide (1). The phase-transfer catalyst is available from Chemical Dynamics Corp., South Plainfield, N.J. 

Lithium diisopropylamide, 163 Sodium hydroxide-N-(p-Trifluoro-methylbenzyl)cinchoninium bromide, 325... 

Potassium r-butoxide-Hexamethyl-phosphoric triamide, 252 Potassium r-butoxide-Xonotlite, 254 Potassium hydroxide, 258 Potassium hydroxide-18-Crown-6, 258 Potassium hydroxide-Tricaprylyl-methylammonium chloride, 258 Sodium hydroxide-Methyltrioctyl-ammonium chloride, 192 Sodium hydroxide-Triethyl(2-methyl-butyl)ammonium bromide, 239 Sodium hydroxide-N-(p-Trifluoro-methylbenzyl)cinchoninium bromide, 325... 

N-(p-Trifluoromethylbenzyl)-cinchonidinium bromide, 325 N-(p-Trifluoromethylbenzyl)-cinchoninium bromide, 325 Tris[2-(2-methoxyethoxy)ethyl]amine, 336... 

The first example of the use of an alkaloid-based chiral phase-transfer catalyst as an efficient organocatalyst for enantioselective alkylation reactions was reported in 1984 [3, 4]. Researchers from Merck used a cinchoninium bromide, 8, as a catalyst... 

A complementary approach to similar products involved the asymmetric Darzens reaction of a-chloro ketones such as 29 with aldehydes. The cinchoninium salt 2f allowed the epoxide 30 to be prepared with reasonably high enantiomeric excess (Scheme 11) [19]. 

The reaction of carbonyl substrates with oxygen in basic media has been utilized by Shioiri and co-workers to generate optically active a-hydroxy carbonyl compounds when a quaternary ammonium salt such as /V-(4-trifluoromethylphenylmethyl)cinchoninium bromide (2) is employed as a chiral catalyst102. Enantiomeric excesses up to 74% have been realized by using this simple methodology (Table 10). 

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). ... 

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