Phase-transfer-catalyzed alkylation reaction

Early mechanistic suggestions on the origin of enantioselectivity suggested involvement of n-n stacking or the interaction of the cinchoni-dinium cation with the anion of a reagent.  

In neither of 12 located ion pair structures, a n-n stacking interaction was found. The transition states for the enantioselective alkylations were characterized only for the four most stable ion pairs. Only two of these transition states, TS13 and TS14, belonged to the reactions with activation barriers lower than 30 kcal/mol. 

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The phase transfer catalyzed alkylation reaction of dodecyl phenyl glycidyl ether (DPGE) with hydroxyethyl cellulose (HEC) was studied as a mechanistic model for the general PTC reaction with cellulose ethers. In this way, the most effective phase transfer catalysts and optimum reaction concentrations could be identified. As a model cellulose ether, CELLOSIZE HEC11 was chosen, and the phase transfer catalysts chosen for evaluation were aqueous solutions of choline hydroxide, tetramethyl-, tetrabutyl-, tetrahexyl-, and benzyltrimethylammonium hydroxides. The molar A/HEC ratio (molar ratio of alkali to HEC) used was 0.50, the diluent to HEC (D/HEC) weight ratio was 7.4, and the reaction diluent was aqueous /-butyl alcohol. Because some of the quaternary ammonium hydroxide charges would be accompanied by large additions of water, the initial water content of the diluent was adjusted so that the final diluent composition would be about 14.4% water in /-butyl alcohol. The results of these experiments are summarized in Table 2. 

Martins, E. R Pliego, R. Jr. Unraveling the Mechanism of the Cinchoninium Ion Asymmetric Phase-Transfer-Catalyzed Alkylation Reaction. ACS Catalysis 2013,3,613-616. 

A slow non-competing liquid/liquid reaction with no catalyst present gave only 78 % O-alkylation. Thus the active site of the lipophilic phosphonium ion catalysts appears to be aprotic, just as in analogous phase transfer catalyzed alkylations with soluble quaternary ammonium salts 60), Regen 78) argued that the onium ion sites of both the 17% and the 52% RS tri-n-butylphosphonium ion catalysts 1 are hydrated, on the basis of measurements of water contents of the resins in chloride form. Mon-tanari has reported measurements that showed only 3.0-3.8 mols of water per chloride ion in similar 25 % RS catalysts 74). He argued that such small hydration levels do not constitute an aqueous environment for the displacement reactions. No measurements of the water content of catalysts containing phenoxide or 2-naphthoxide ions have been reported. 

Scheme 17 illustrates enantioselective synthesis of a-amino acids by phase-transfer-catalyzed alkylation (46). Reaction of a protected glycine derivative and between 1.2 and 5 equiv of a reactive organic halide in a 50% aqueous sodium hydroxide-dichloromethane mixture containing 1-benzylcinchoninium chloride (BCNC) as catalyst gives the optically active alkylation product. Only monoalkylated products are obtained. Allylic, benzylic, methyl, and primary halides can be used as alkylating agents. Similarly, optically active a-methyl amino acid derivatives can be prepared by this method in up to 50% ee. 

The efficient phase-transfer-catalyzed alkylation strategy with le was successfully applied by Jew and Park to the asymmetric synthesis of a-alkyl serines, using phenyl oxazoline derivative 53 as a requisite substrate [28]. The reaction is general, however, and provides a practical access to a variety of optically active a-alkyl serines through acidic hydrolysis of 54 (Scheme 5.26). 

Further great advances in the field of asymmetric alkylation reactions have been made by several groups working on chiral phase-transfer-catalyzed alkylation of glycinates (see also Section 3.1). A pioneer in this field is the O Donnell group [53, 54] who developed the first a-amino acid ester synthesis using this methodol-... 

To date, this type of phase-transfer-catalyzed Michael reaction of 28 has been investigated with either acrylates or alkyl vinyl ketones as an acceptor, under the influence of different catalysts and bases. Typical results are listed in Table 4.6 in order to determine the characteristics of each system. 

Early examples of intramolecular aryl radical addition reactions to heteroatom containing multiple bonds included cyclizations on N=N and C=S moieties [52, 53]. Recently, cyclizations to imines have been used as part of a new enantio-selective approach to indolines (Scheme 8). In the first step of the sequence, the required ketimines 19 were obtained by phase-transfer catalyzed alkylation of 2-bromobenzyl bromides 20 with glycinyl imines 21 in the presence of a cincho-nidinium salt [54], Due to the favorable substitution pattern on the imine moiety of 19, the tributyltin hydride mediated radical cyclization to 22 occurred exclusively in the 5-exo mode. The indoline synthesis can therefore also be classified as a radical amination. 

Having determined the most appropriate extraction from plasma we investigated the simultaneous derivati-zation of A9-THC and ll-hydroxy-A9-THC. We have claimed that ethylation of 11-hydroxy-A9-THC proceeded by phase transfer catalysis (7). However, it is known that quaternary ammonium hydroxides are capable of catalyzing alkylations with alkyl iodides in aproptic solvents (8). Furthermore, we had not demonstrated that A9-THC could be derivatized under the same conditions as ll-hydroxy-A9-THC. We found that the minimum requirement for the reaction to proceed is the presence of water, which probably increases the degree of ionization of the quaternary ammonium hydroxide. However, in order for the reaction to go to completion, at least 0.1N NaOH is necessary. This supports the contention that this derivatization is, to some extent, a phase transfer catalyzed alkylation. 

Phase-transfer-catalyzed alkylation provides an excellent analytical approach for many polar active hydrogen compounds. The perceived advantages of the method for the trace analysis of polar CYA are the relative simplicity, the low detection limits, and the absence of interferences. Furthermore, the reaction conditions, although harsh, leave the molecule intact during the analysis, providing convenient identification by gas chromatography/mass spectrometry (GC/MS). It was seen that the detection limits for CYA between MS-SIM and FTD differed by 2 orders of... 

Similar results have been reported using a phase transfer catalyzed alkylation where dimethyl sulfate functioned as electrophile [4]. In this case, the reaction rate was sensitive to changes in the stirring rate suggesting that the reaction may be non-catal-ytic and occurring in the polar solvent (dimethyl sulfate). 

Recently, Lamaty and coworkers [70] demonstrated asymmetric phase-transfer catalyzed alkylation of fert-butyl glycinate-benzophenone Schiff base under solvent-free ball milling conditions (Scheme 21.33). The reaction proceeds with different alkylating agents in the presence of the cinchonidine-derived ammonium salt (10mol%) with very high yields (91-97%). This protocol reduces the reaction time however, the enantioselectivity (36-75% ee) is lower compared to conventional method with solvents (>90% ee) [71]. 

With respect to the application of tartaric acid-derived PTCs [22,23] for natural product synthesis, the work of Shibasaki s group should be highlighted herein. Using his powerful bidentate TaDiAS PTCs, asymmetric phase-transfer-catalyzed alkylations, Michael addition reactions, and Mannich-type reactions have been systematically carried out. 

The phase-transfer-catalyzed alkylation strategy was successfully appHed to the asymmetric cyanomethylation of oxindole 92 by the use of catalyst Hi [123]. This reaction allowed a simple and stereoselective synthesis of (—)-esermethole, a precursor to the clinically useful anticholinesterase agent (—)-physostigmine... 

A carboxylic acid (not the salt) can be the nucleophile if F is present. Mesylates are readily displaced, for example, by benzoic acid/CsF. Dihalides have been converted to diesters by this method. A COOH group can be conveniently protected by reaction of its ion with a phenacyl bromide (ArCOCH2Br). The resulting ester is easily cleaved when desired with zinc and acetic acid. Dialkyl carbonates can be prepared without phosgene (see 10-21) by phase-transfer catalyzed treatment of primary alkyl halides with dry KHCO3 and K2C03- ... 

Preparation of di-n-butyl N,N-diethylcarbamoylmethylphosphonate — Phase transfer-catalyzed reaction of a dialkyl phosphite with an alkyl chloride... 

S. Arai, M. Oku, T. Ishida, T. Shioiri, Asymmetric Alkylation Reaction of a-Eluorotetralone under Phase-Transfer Catalyzed Conditions , Tetrahedron Lett. 1999, 40, 6785-6789. 

The phase-transfer-catalyzed asymmetric alkylation of 1 has usually been performed with achiral alkyl halides, and hence the stereochemistry of the reaction with chiral electrophiles has scarcely been addressed. Nevertheless, several groups have tackled this problem. Zhu and coworkers examined the alkylation of 1 with stereo-chemically defined (5S)-N-benzyloxycarbonyl-5-iodomethyl oxazolidine using 4d to prepare (2S,4R)-4-hydroxyornithine for the total synthesis of Biphenomycin. Unexpectedly, however, product 7 with a 2 R absolute configuration was formed as a major isomer, and the diastereomeric ratio was not affected by switching the catalyst to pseudoenantiomeric 2d and even to achiral tetrabutylammonium bromide (TBAB), indicating that the asymmetric induction was dictated by the substrate (Scheme 2.3) [21]. 

Whilst the use of Taddol as an asymmetric phase-transfer catalyst for asymmetric Michael reactions was only moderately successful, it was much more enantioselec-tive in catalyzing alkylation reactions. For this study, Belokon and Kagan employed alanine derivatives lib and 16a-c as substrates, and investigated their alkylation with benzyl bromide under solid-liquid phase-transfer conditions in the presence of 10 mol % of Taddol to form a-methyl phenylalanine, as shown in Scheme 8.8. The best results were obtained using the isopropyl ester of N-benzylidene alanine 16b as substrate and sodium hydroxide as the base. Under these conditions, (R)-a-methyl phenylalanine 17 could be obtained in 81% yield and with 82% ee [19]. Under the same reaction conditions, substrate 16b reacted with allyl bromide to give (R)-Dimethyl allylglycine in 89% yield and with 69% ee, and with (l-naphthyl)methyl chloride to give (R)-a-methyl (l-naphthyl)alanine in 86% yield and with 71% ee [20]. 

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