Efficient Asymmetric Alkylations via Chiral Phase-Transfer Catalysis: Applications and Mechanism

Abstract

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-1-indanone with methyl chloride in 50% sodium hydroxide/toluene using N-(p-trifluoromethylbenzyl)cinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2-phenyl-1-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation employing 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7-dichloro-5-methoxy-2-propyl-1-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3-dihydroxy-5-methoxy-2-propyl-1-inden-1-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an interme diate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. Efficient asymmetric alkylations have been a long-sought goal in organic synthesis.In the recent literature three different approaches have been used for asymmetric alkylations of ketones: 1) chiral alkylating reagents (2, 3); 2) chiral auxiliaries (4-9); and 3) chiral catalysts (10-12). Two examples of the first approach are shown in Figure 1. Murphy observed an asymmetric induction of 8% during the alkylation of 2,4,6-trimethylphenol with allyl (+)-camphor-10-sulphonate. Duhamel methylated the Schiff base of methyl glycinate with l,2,4,6~bis-(0-isopropylidene)~3-methoxy-sulfonyl-α-D-glucose (A*) and produced S-alanine in 65% yield, 40% enantio meric excess (ee).The use of chiral auxiliaries has been developed into elegant three-step sequences to achieve high ee's ( Figure 2). In the general scheme a ketone is derivatized with a chiral amine. Low temperature lithiation and alkylation followed by hydrolysis pro duces the alkylated ketone in moderate to excellent ee's. The auxiliaries most often used are (S)-valine tert-butyl ester (Koga), l-amino-2-methoxymethylpyrrolidine (Enders) and (S)-2-amino-l-

Environmentally Friendly Solvent-Free Processes: Novel Dual Catalyst System in Henry Reaction

“…Initial attempts to condense nitroalkanes with aldehydes under standard solvent-free conditions in the presence of catalytic amounts of mineral bases (KOH or NaOH) were unsuccessful, leading to decomposition of products presumably due to base-catalyzed eliminations of water to form nitroolefins and their tendency to polymerize readily . Further investigations revealed that the addition of catalytic amounts of a surfactant, for example, poly(ethylene glycol) (PEG) or Triton-X, dramatically improved the nitroaldol reaction rate, leading to faster and cleaner conversions . Thus, our solvent-free nitroaldol protocol involves condensation of an appropriate aldehyde with a 1-nitroalkane utilizing a novel dual catalytic system consisting of an inexpensive mineral base, KOH, and an appropriate surfactant (e.g., Triton-X or poly(ethylene glycol)) .…”

“…Further investigations revealed that the addition of catalytic amounts of a surfactant, for example, poly(ethylene glycol) (PEG) or Triton-X, dramatically improved the nitroaldol reaction rate, leading to faster and cleaner conversions . Thus, our solvent-free nitroaldol protocol involves condensation of an appropriate aldehyde with a 1-nitroalkane utilizing a novel dual catalytic system consisting of an inexpensive mineral base, KOH, and an appropriate surfactant (e.g., Triton-X or poly(ethylene glycol)) . The role of surfactant is not totally clear at this point, and further work is needed.…”

“…The PEG (poly(ethylene glycol)) units in Triton-X are also capable of complexing the metal ion (analogous to crown ether complexations), thereby solubilizing the base (KOH) in the organic medium . Since Triton-X is a surfactant, fundamentally it could also catalyze the reaction by increasing the liquid−liquid interfacial area, thereby improving the reaction kinetics 1 Waste-Free Synthesis of Nitroalcohols …”

“…Crown ether type selective complexations of metal ions would allow us to adjust the process to make it substrate/reagent selective. The chiral variant of nitroaldol, if successful, would allow us to directly produce physiologically active enantiomers without a complicated resolution process and is under active investigation. − …”

Reactions of nitrochlorobenzenes with sodium sulfide: change in selectivity with phase-transfer catalysts

“…Reaction 2 indicates that it may be possible to change the course of the reaction from one product to another by using a phase-transfer catalyst and suitably manipulating the experimental conditions. The only information in the literature on the use of phase-transfer catalysts to change the selectivity of a reaction is the asymmetric syntheses via chiral phase-transfer catalysts (Dolling et al, 1987; Soai and Watanabe, 1990).…”