Indanone chiral phase-transfer

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

Figure 5. Variations of the chiral phase transfer methylation of indanone 5.

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°. 

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). ... 

Asymmetric Michael additions can also be performed under phase-transfer conditions with an achiral base in the presence of a chiral quaternary ammonium salt as a phase-transfer agent. Conn and coworkers conducted the Michael addition of 2-propyl-l-indanone (13) to methyl vinyl ketone under biphasic conditions (aq 50% NaOH/toluene) using the cinchonine/cinchonidine-derived chiral phase-transfer catalysts (PTCs), 14a and 14b, as a catalyst (Scheme 9.5). However, only low to... 

A conceptually different approach to interligand asymmetric induction uses chiral phase transfer catalysts. Scheme 3.26 illustrates two examples of such a process using an A -benzylcinchonium halide catalyst. The first is an indanone methylation [150] and the second is a glycine alkylation [151]. Hughes et al. reported a detailed kinetic study of the indanone methylation which revealed a mechanism significantly more complicated than a simple phase-transfer process the reaction is 0.55 order in catalyst and 0.7 order in methyl chloride, deprotonation of the indanone occurs at the interface, and methylation of the enolate (not deprotonation) is rate-determining [150]. Nevertheless, the rationale for the... 

This synthesis, which was reported by a group of development chemists, represents a remarkably efficient application of asymmetric alkylation by chiral phase transfer catalysis (PTC) (see section 6.1.1). Reaction of indanone (77) and allylic halide (78) under PTC conditions in the presence of only a few per cent of chiral cinchonidine derivative... 

The stereoselectivity of the methylation of ketone enolates is determined by the structure of the substrate. Stereoselective methylation of cyclic ketone enolates has been examined in detail and current models reliably predict the stereochemical outcome (eqs 9-11). Diastereoselective methylation of acyclic ketone and ester enolates has been accomplished employing a variety of chiral auxiliaries (eq 12). Efficient catalytic enantioselective methylation of 6,7-dichloro-5-methoxy-l-indanone has been accomplished via a chiral phase-transfer catalyst (eq 13). An enantiomeric excess of 92% was observed when employing Chloromethane as the methylating agent, whereas... 

A variety of chiral phase-transfer catalysts have been developed and successfully used in asymmetric syntheses of a-amino acids [19. 23, 24]. In 1984, researchers at Merck described the methylation of indanone 74 in the presence of the quaternized cinchona salt 75 as a chiral phase-transfer catalyst (Scheme 10.12) [66]. The alkylation product 76 was isolated in 92% ee and 95 % yield and subsequently elaborated into (-H)-indacrinone (77), which had previously only been prepared by resolution techniques. 

Cinchona Alkaloid-Derived Quaternary Ammonium Salts The first successful application of cinchona-based quaternary ammonium salts as chiral phase-transfer catalysts was conducted by the Merck research group in 1984 [16]. Dolling and coworkers reported the N-p-trifluoromethylbenzylcinchoninium bromide 11a for the highly enantioselective alkylation of indanone derivatives imder phase-transfer conditions (Figure 12.3). 

These observations showed that the reaction can be simplified by preformation of the indanone enolate in toluene/50% NaOH and subsequent addition of catalyst and CH3CI (Figure 12). This eliminates the "induction period and most importantly the high sensitivity of rate and ee to the catalyst/indanone ratio. Detailed kinetic measurements on this preformed enolate methylation in toluene/50% NaOH determined that the reaction is 0.55 order in catalyst. This is consistent with our finding that the catalyst goes into solution as a dimer which must dissociate prior to com-plexation with the indanone anion. If the rate has a first order dependence on the monomer, the amount of monomer is very small, and the equilibration between dimer and monomer is fast, then the order in catalyst is expected to be 0.5. The 0.5 order in catalyst is not due to the preformation of solid sodium indanone enolate but is a peculiarity of this type of chiral catalyst. Vlhen Aliquat 336 is used as catalyst in this identical system the order in catalyst is 1. Finally, in the absence of a phase transfer catalyst less than 2% methylation was observed in 95 hours. 

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... 

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