Ephedrinium salt

Using a similar protocol, Loupy and coworkers have reported the synthesis of chiral ionic liquids based on (ll ,2S)-(-)-ephedrinium salts under microwave irradiation conditions (Scheme 4.21a) [75]. Importantly, the authors were also able to demonstrate that the desired hexafluorophosphate salts could be prepared in a one-pot protocol by in situ anion-exchange metathesis (Scheme 4.21b). The synthesis and transformation of so-called task-specific ionic liquids is discussed in more detail in Section 7.4. 

The overall steric demands of the catalyst and the substrate are important in the spatial arrangement of the H-bonded complex. Consequently, although the less rigid ephedrinium salts have been used with some success, they are generally less effective than the derivatives of the cinchona alkaloids, the rigidity of which imposes a greater stereochemical restraint on the structure of the H-bonded complexes. 

The catalysed reaction of aryl aldehydes with ammonia and chloroform (7.4.3) in the presence of chiral ephedrinium salts leads to the asymmetrically induced formation of a-amino acids. Yields are variable and with ca. 20-30% ee [49]. 

Direct phase-transfer catalysed epoxidation of electron-deficient alkenes, such as chalcones, cycloalk-2-enones and benzoquinones with hydrogen peroxide or r-butyl peroxide under basic conditions (Section 10.7) has been extended by the use of quininium and quinidinium catalysts to produce optically active oxiranes [1 — 16] the alkaloid bases are less efficient than their salts as catalysts [e.g. 8]. In addition to N-benzylquininium chloride, the binaphthyl ephedrinium salt (16 in Scheme 12.5) and the bis-cinchonidinium system (Scheme 12.12) have been used [12, 17]. Generally, the more rigid quininium systems are more effective than the ephedrinium salts. 

Asymmetric induction using catalytic amounts of quininium or A-methyl-ephedrinium salts for the Darzen s reaction of aldehydes and ketones with phenacyl halides and chloromethylsulphones produces oxiranes of low optical purity [3, 24, 25]. The chiral catalyst appears to have little more effect than non-chiral catalysts (Section 12.1). Similarly, the catalysed reaction of sodium cyanide with a-bromo-ketones produces epoxynitriles of only low optical purity [3]. The claimed 67% ee for the phenyloxirane derived from the reaction of benzaldehyde with trimethylsul-phonium iodide under basic conditions [26] in the presence of A,A-dimethyle-phedrinium chloride was later retracted [27] the product was contaminated with the 2-methyl-3-phenyloxirane from the degradation of the catalyst. 

Phase-transfer catalysed oxidation of ketones with dioxygen under basic conditions in the presence of triethyl phosphite and a cinchonium salt produces a-hydroxy-ketones (Schemes 12.14 and 12.15, Table 12.9) in good overall yield (-95%) and with a high enantiomeric excess [>70% ee using N-(4-trifluoromethyIbenzyl)cincho-nium bromide] [29], Lower asymmetric induction is observed with ephedrinium salts, polymer-supported salts and, surprisingly, by cinchonidinium salts. 

Borohydride reduction of imines in the presence of ephedrinium salts [8] has produced, at the best, ca. 4% ee. 

Compared with boranes, borohydrides are inexpensive and easy to handle. As early as 1978 Colonna and Fornasier reported that aryl alkyl ketones such as acetophenone can be reduced asymmetrically by sodium borohydride by use of an aqueous-organic two-phase system and chiral phase transfer catalysts [20], In this study, the best enantiomeric excess (32%) was achieved when pivalophenone (11) was reduced in the presence of 5 mol% benzylquininium chloride (12) (Scheme 11.4) [20]. Other chiral phase-transfer catalysts, for example ephedrinium salts, proved less effective. 

The first example is an asymmetric reduction of different phenyl alkyl ketones with sodium tetrsdiydroborate in an ephedrine-derived chiral reverse micelle [29]. The combination of R — n-C 2H25 in the ephedrinium salt and R = Ph, R = t-Bu in the ketone gave the best results with 84 % yield and 24 % ee. 

More recently, ephedrinium salts have been synthesized under solvent free and microwave activation (Scheme 9). Their application as sole source of chirality in the Baylis-Hillman reaction has represented the first example of significant asymmetric induction by a chiral ionic solvent (ee 20-44%). 

The 2,2-regioisomer was favoured using the ephedrinium salt instead of TBAB. It is formed from the thermodynamic enolate while the 2,6-regioisomer came from the kinetic enolate. The results obtained show the preference for the thermodynamic enolate using the ephedrinium salt as catalyst, probably as a result of the stabilization of the enolate through a tt-tt interaction between the catalyst and the enolate. 

Solid-liquid phase transfer without solvent was reported for a prochiral acceptor reaction. In the presence of M-(p-methoxyphenylmethyl)ephedrinium salt, aminomalonate underwent addition to 13 giving (S)-39 in 76% ee [33,34,35]. The selectivity was higher in the absence of solvent than in toluene or chloroform. Introduction of the electron-donating group at the M-benzyl arene moiety enhanced the selectivity. A Jt-Jt interaction between 13 and the aromatic ring of the catalyst was suggested, since the enantiomeric excesses correlated with the Hammett s factor. 

It was shown by Buriak and Osborn [80] that non-micelle-forming anions improved the enantioselectivity of an imine hydrogenation catalyzed by rhodium complexes in the same way as reverse micelles. Complexation of the sulfate or sulfonate anion with the catalyst appears to be responsible for the enhancement of the enantioselectivity. The very strong dependence of the product chirality on the structure of the anion is discussed. Finally, a long-chain ephedrinium salt 17 as surfactant, should be mentioned. 

In basic medium, ephedrinium salts decompose to oxiranes 42 which exhibit a very high rotatory power and, even if present in small amounts in the products, are a source of error in evaluations of asymmetric synthesis... 

The closely related addition of diethyl acetamidomalonate to chalcone was examined in the presence of a chiral ephedrinium salt, with the purpose of studying the effect of sonication both on the reactivity and the enantio-selectivity.47 In toluene, the yield and enantioselectivity are dramatically... 

Michael-addition of diethyl(acetylamido) malonate to chalcone using asymmetric phase transfer catalyst (ephedrinium salts) in presence of KOH in the solid state has been carried outJ The yield is 56% with ee of 60% (Scheme 10). 

The low vapor pressure and high thermal stability of CILs render them suitable for enantioseparations in gas chromatography (GC). Recently, CILs have been used as chiral stationary phases (CSPs) in GC [40]. Armstrong and coworkers carried out enantiomeric separation of chiral alcohols and diols, chiral sulfoxides, some chiral epoxides and acetamides using a CIL based on ephedrinium salt. Using an ephedrinium CIL (4) as the CSP, enantiomeric separation of alcohols and diols was achieved (Fig. 1). The presence of both enantiomeric forms of ephedrine makes it possible to produce CSPs of opposite stereochemistry, which could reverse the enantiomeric elution order of the analytes. This offers an additional advantage that may not be easily achieved with common and widely used chiral selectors in GC such as the cyclodextrins. However, there was a decrease in enantiomeric recognition ability of the CSP after a week which the authors attributed to dehydration-induced... 

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