Indanones, asymmetric alkylation

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. 

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). ... 

Hughes, D. L. Dolling, U.-H. Ryan, K. M. Schoenewaldt,E. F. Grabowski, E.J.J., Efficient Catalytic Asymmetric Alkylations. 3. A Kinetic and Mechanistic Study of the Enantioselective Phase-Transfer Methylation of 6,7-Dichloro-5-methoxy-2-phenyl-l-indanone J. Org. Chem. 1987, 52, 4745. 

By analogy with results obtained from asymmetric alkylations of indanone derivatives under PTC conditions, a tt- tt interaction model between catalyst and electrophilic species is proposed (Scheme 19). 

The first breakthrough in asymmetric alkylation came in 1984 when Dolling and coworkers [14] reported a 94% ee in the phase-transfer alkylation of indanone derivatives using Cinchona alkaloids as catalysts, Eq. (2). 

Fluorine substituents on the aromatic ring in chiral quaternary ammonium salts also play an important role for the improvement of enantioselectivity in asymmetric alkylations of the Schiff base of glycine esters in an aqueous biphase system. Dolling first demonstrated asymmetric methylation of indanone (44) by cinchonidine ammonium salt (43) (Scheme 5.12) [18]. 

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... 

Hughes DL, Dolling UH, Ryan KM, Schoenewaldt EE, Grabowski, EJJ. Efficient catalytic asymmetric alkylations. 3. A kinetic and mechanistic study of the enantioselective phase-transfer methylation of 6, 7-dichloro-5-methoxy-2-phenyl-l-indanone. J. Org. Chem. 1987 52(21) 4745 752. 

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°. 

This asymmetric phase-transfer method has been applied to enantio-selective Robinson annelation as shown in Scheme 14 (41). First, alkylation of a 1-indanone derivative with the Wichtetie reagent as a methyl vinyl ketone equivalent in the presence of p-CF3BCNB gives the S-alkylation product in 92% ee and 99% yield. With 1 -(p-trifluoro-methylbenzyl)cinchonidinium bromide, a pseudo-enantiomeric diaste-reomer of p-CF3BCNB, as catalyst, the -alkylation product is obtained in 78% ee and 99% yield. These products are readily convertible to the... 

Muzart and coworkers have reported a new catalytic enantioselective protonation of prochiral enolic species generated by palladium-induced cleavage of p-ketoesters or enol carbonates of a-alkylated 1-indanones and 1-tetralones [21 ]. Among the various (S)-p-aminocycloalkanols examined, 17 and 18 were effective chiral catalysts for the asymmetric reaction and (J )-enriched a-alkylated 1-indanones and 1-tetralones were obtained with up to 72% ee. In some cases, the reaction temperature affected the ee. 

In the laboratory of D. Ma, the asymmetric synthesis of several metabotropic glutamate receptor antagonists derived from a-alkylated phenylglycines was undertaken. The preparation of (S)-1-aminoindan-1,5-dicarboxylic acid (AIDA) started with the Perkin reaction of 3-bromobenzaldehyde and malonic acid. The resulting ( )-cinnamic acid derivative was hydrogenated and the following intramolecular Friedel-Crafts acylation afforded the corresponding indanone, which was then converted to (S)-AIDA. 

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... 

In middle of the 1980s, efficient asymmetric phase-transfer reactions using catalytic amounts of Al-benzylcinchoninium chlorides were developed by researchers at Merck. This catalyst was able to alkylate 2-substituted-2-phenyl indanones with high ee (up to 94% ee) [20]. 

Some years ago, Huffman et al. [49] reported an efficient synthesis of the estrogen p-modulator 68 using an asymmetric a-alkylation of the indanone derivative 70 (obtained from 2-fluoroanisole 69) with 1,3-dichlorobut-2-ene 71 in the presence of PTC 72. This resulted in the key intermediate 73 and following subsequent reactions then yielded the tricyclic estrogen p-modulator 68 in 34% overall yield (Scheme 12). 

A diaryIprolinol silyl ether induces ee < 99% for aldehyde a-alkylation on 1,4-addition to acridinium salts. Computational chemistry has been used to explain stereoinduction by a family of iodooxazoline catalysts developed for enantioselective a-tosyloxylation of ketones by m-CPBA/TsOH. a-Benzoyloxylation of ketones (cyclohexanones and 1-indanones) by dibenzoyl peroxide occurs enantioselectively in the presence of a mixture of 9-amino-(9-deoxy)epi-dihydroquinidine and salicylic acid. ° The scope and limitations of asymmetric a-oxyacylation of cyclic ketones by chiral Ai-alkyl-O-acyl hydroxylamines have also been reported. ... 

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. 

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