Phase-transfer-catalyzed alkylation

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. 

E. J. Corey, Y. Bo, J. Busch-Peterson, Highly Enantioselective Phase Transfer Catalyzed Alkylation of a 3-Oxygenated Propionic Ester Equivalent Application and Mechanism , J. Am Chem Soc 1998, 120, 13000-13001. 

The utilization of polar polymers and novel N-alkyl-4-(N, N -dialklamino)pyridinium sedts as stable phase transfer catalysts for nucleophilic aromatic substitution are reported. Polar polymers such as poly (ethylene glycol) or polyvinylpyrrolidone are thermally stable, but provide only slow rates. The dialkylaminopyridininium salts are very active catalysts, and are up to 100 times more stable than tetrabutylammonium bromide, allowing recovery and reuse of catalyst. The utilization of b is-dialkylaminopypridinium salts for phase-transfer catalyzed nucleophilic substitution by bisphenoxides leads to enhanced rates, and the requirement of less catalyst. Experimental details are provided. 

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. 

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. 

Figure 4. Phase transfer catalyzed hydrophobe alkylation of hydroxyethyl cellulose...

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. 

Solid-liquid phase-transfer catalyzed alkylation of anions. Aliquat 336 is a particularly effective catalyst for alkylation of carboxylate anions (equation 1). The combination of Bu4NBr and Ti02 is slightly less effective (93% yield).6... 

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]. 

Table 2.1 Cinchona alkaloid-derived monomeric catalysts and their performance in the phase-transfer-catalyzed alkylation of 1. 

With the critical role of 3,3 -diaryl substituents of 1 in mind, Maruoka and coworkers examined the effect of 4,4 - and 6,6 -substituents of one binaphthyl subunit. As shown in (Scheme 5.4), the introduction of simple aromatic groups even at the 4,4 -position leads to a meaningful effect on the stereoselectivity of the phase-transfer-catalyzed alkylation of 2 [9]. 

Despite numerous efforts to develop the asymmetric phase-transfer-catalyzed alkylation of 2 into a powerful method for the synthesis of natural and unnatural a-amino adds, the stereochemistry of the alkylation of 2 with chiral electrophiles has scarcely been addressed. 

The chiral phase-transfer catalysis of le was further applied to the facile synthesis of L-Dopa ester and its analogue, which usually have been prepared by either asymmetric hydrogenation of eneamides or enzymatic processes, and tested as potential drugs for the treatment of Parkinson s disease. Phase-transfer-catalyzed alkylation of 2 with the requisite benzyl bromide 35a in toluene-50% KOH aqueous solution proceeded smoothly at 0 °C under the influence of (R,R)-le to furnish fully protected L-Dopa tert-butyl ester this was subsequently hydrolyzed to afford the corresponding amino ester 36a in 81% yield with 98% ee. Debenzylation of 36a under... 

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). 

Access to enantioenriched carbonyl compounds of high value which possess quaternary a-carbon stereocenters containing hetero-functionalities represents one of the most challenging tasks in phase-transfer-catalyzed asymmetric alkylation. In due course, Maruoka and coworkers devised the asymmetric alkylation of cyclic a-amino-P-keto esters 67 with C2-symmetric phase-transfer catalyst lh as a means of obtaining aza-cyclic amino acids with quaternary stereocenters (Scheme 5.32) [33]. 

The broad substrate range, in particular with regard to the alkyl halide component, led to numerous interesting applications of this asymmetric phase-transfer-catalyzed alkylation using alkaloids as catalyst [6-18], Selected examples are described below. 

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-... 

Ruder, S. M. Kulkami, V. R. Phase transfer catalyzed alkylation of 2-(diethoxyphosphinyl)-cyclohexanone. Synthesis 1993, 945—947. 

N. R. Phase transfer catalyzed N-alkylation of sym-N,N -diarylureas. Organic Preparations and Procedures International 1992, 24, 83-87. 

Table 4.5 Phase-transfer-catalyzed enantioselective benzylation of aldimine Schiff bases derived from a-alkyl-a-amino acids.3) (For experimental details see Chapter 14.15.1).

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. 

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