Phase transfer alkylation chemistry

Summary. Asymmetric catalytic phase transfer alkylations are effective within a limited pool of substrates. No generalized catalyst is effective with a wide range of substrates instead, catalyst and conditions must be tuned for each reaction. The rationale for enantioselectivity has been probed by theory and experiment, but much work remains to unravel the details of the chemistry. 

Heteropoly acids can be synergistically combined with phase-transfer catalysis in the so-called Ishii-Venturello chemistry for oxidation reactions such as oxidation of alcohols, allyl alcohols, alkenes, alkynes, P-unsaturated acids, vic-diols, phenol, and amines with hydrogen peroxide (Mizuno et al., 1994). Recent examples include the epoxidations of alkyl undecylenates (Yadav and Satoskar, 1997) and. styrene (Yadav and Pujari, 2000). 

Finally, one example of trityl salt analogues in the phase-transfer catalysis is presented. The highly stable triazatriangulenium cations 62 [161, 162] were jnst recently introduced to the phase-transfer chemistry [163], Persistent to strongly basic and nncleophilic conditions, these salts revealed efficient catalytic activity in addition reactions (Scheme 64). Modification of the alkyl side chains on nitrogen allowed matching the fair hydro/lipophilicity with the optimised conditions in the alkylation, epoxidation, aziridination and cyclopropanation reactions. The results are comparable to those of tetrabutylammonium salts and in some cases showed even a better outcome. 

The alkylation reaction of various alkali and alkaline-earth metal carbonates with alkyl halides R(CH2)nX (X = Cl, Br, I) is a primary synthetic procedure in organic chemistry for obtaining various symmetrical and unsymmetrical dialkyl carbonates under phase-transfer conditions in polar aprotic solvents [45]. Excellent yields may be obtained by running the reaction at 383 K in ionic liquids such as... 

Esters 16b,c are used in reactions catalyzed by cinchona alkaloid-based phase-transfer catalysts, since the size of the ester is important for efficient asymmetric induction in these reactions [35], However, the syntheses of esters 16b,c adds considerable cost to any attempt to exploit this chemistry on a commercial basis. Fortunately, it was possible to develop reaction conditions which allowed the readily available and inexpensive substrate 16a to be alkylated with high enantios-electivity using catalyst 33 and sodium hydroxide, as shown in Scheme 8.18 [36]. The key feature of this modified process is the introduction of a re-esterification step following alkylation of the enolate of compound 16a. It appears that under... 

Hedayatullah M (1981) Alkylation of pyrimidines in phase-transfer catalysis. Journal of Heterocyclic Chemistry 18 339-342. 

The chemistry of sulfones is dominated by the reactions of sulfonyl carbanions. The sulfone group has a unique ability to facilitate deprotonation of attached alkyl, alkenyl and aryl groups and will permit multiple deprotonation to yield polyanions. These properties, combined with the relative intertness of the sulfone (S02) group to nucleophilic attack, have made the S02 group the first choice for stabilisation of carbanions and account for the extensive application of sulfones in synthesis. Sulfonyl carbanions can be generated and reacted under a wide variety of conditions extending from aqueous phase transfer reactions using sodium hydroxide as base to the use of alkyllithiums in polar aprotic solvents. The reactivity of sulfonyl carbanions depends on the nature of the metal counterion (Li+, Na+, K+ and Mg2+ are the most important ones) and the presence of additives, e.g. TMEDA, HMPA and Lewis acids. 

Next, process chemistry for the practical synthesis of 7b (MGS0028) is discussed (Schemes 3.5-3.7) [42-45]. First, the synthesis of key intermediate (+)-29 from racemic acetoxycyclopentene (34) is shown in Scheme 3.5 [43]. The key reaction in this approach was Trost s asymmetric ally lie alkylation reaction of ethyl 2-fluoroacetoacetate with 34, which afforded 35 in high yield and high enantioselectivity, especially when a bulky tetra-n-hexyl ammonium bromide was used as a phase-transfer reagent (89% yield, 94-96%... 

The synthesis of the chiral copper catalyst is very easy to reproduce. The complex catalyses the asymmetric alkylation of enolates of a range of amino acids, thus allowing the synthesis of enantiomeric ally enriched a,a disubstituted amino acids with up to 92% ee. The procedure combines the synthetic simplicity of the Phase Transfer Catalyst (PTC) approach, with the advantages of catalysis by metal complexes. The chemistry is compatible with the use of methyl ester substrates, thus avoiding the use of iso-propyl or ferf-butyl esters which are needed for cinchona-alkaloid catalyzed reactions[4], where the steric bulk of the ester is important for efficient asymmetric induction. Another advantage compared with cinchona-alkaloid systems is that copper(II)(chsalen) catalyses the alkylation of substrates derived from a range of amino acids, not just glycine and alanine (Table 2.4). 

Dolling, U. H., D. L. Hughes, A. Bhattacharya, K. M. Ryan, S. Karady, L. M. Weinstock, V. J. Grenda, and E. J. J. Grabowski, Efficient Asymmetric Alkylations via Chiral Phase-Transfer Catalysis Applications and Mechanism, Phase-Transfer Cctalysis New Chemistry, Catalysts, and AppUcatwns, C. M. Starks, ed., ACS... 

There are two obvious limitations to the use of surfactants in preparative chemistry. The first is that the high molecular weight of surfactants makes it impracticable to use them in large excess over reactants, and second, surfactants complicate product isolation. The isolation problem can often be solved by precipitating the surfactant, e.g., alkyl sulfates can often be precipitated from water as their potassium salts, or alkylammonium ions as their perchlorates, but both limitations are neatly solved using the two-phase system of phase-transfer catalysis. 

PEG itself is useful as a phase-transfer catalyst because it is an acyclic analog of a crown ether [86]. This property of PEG and its potential as a support for a substrate were combined in a recent synthesis of monoethers of hydro-quinone and resorcinol [87]. In this chemistry (Eq. 17), a dihydroxyl PEG 4,000 (n=ca. 90) 33 was first allowed to react with an excess of oxalyl chloride. The resulting diacid chloride was then allowed to react with the hydroquinone or resorcinol to form a diester, which was easily isolated by solvent precipitation with diethyl ether. Subsequent treatment of this phenolic ester with an alkyl iodide in the presence of K2CO3 in DMF led to the PEG-bound monoether ester. In this reaction, the PEG acted both as a support and as a phase-transfer catalyst. Subsequent hydrolysis generated the monoether of the hydroquinone or resorcinol. 

While PEGS can themselves serve as phase-transfer catalysts [86], onium salts are generally more effective as catalysts. Using the chemistry shown in Eq. 18, a methoxy-PEG5ooo derivative 47 was first treated with the Cs salt of 4-hydroxybenzyl alcohol to form the alcohol 48. Conversion of the alcohol to the bromide followed by reaction with tributylamine produced a quaternary ammonium salt 49. This salt was as active as low molecular weight salts in typical phase-transfer catalyzed reactions like those of alkyl halides with KI, KCN, phenol, and pyrrole [88]. Yields were often in the >90% range. Reactions were typically carried out at <40 °C and could be performed either with water or without solvent. Control experiments showed that the ammonium group of 49 was necessary as the simple alcoholic PEG derivative 48 was much less effec-... 

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