Phase Transfer Alkylating Agents

Sulfones are weakly acidic substances, but owing primarily to their inability to undergo side reactions under mild conditions, they alkylate cleanly. Likewise, hydrocarbons (Table 10.4) and amines (Table 10.5) alkylate under phase transfer conditions to give the anticipated products. In fact, the principal advantage of the phase transfer method is in the convenience and economy of the method and not in the unique nature of the chemistry. 

Diactivated substrates such as diesters, dinitriles, ketosulfones, etc. (see Table 10.3) also alkylate as anticipated, but these systems often show a dependence on the position of alkylation (C vs. 0) due to differences in solvent polarity. In addition to the expected chemistry of these diactivated substrates, several observations have been reported on differences in alkylation depending on solvent and the presence or absence of crown ether (see Eqs. 10.10 and 10.11) [22]. 

Phenylacetonitrile (benzyl cyanide) was the first compound reported to undergo phase transfer alkylation and is probably the most abundantly studied example of this procedure [ 1 ]. It is a good substrate for study because it is reasonably acidic, but not readily alkylated by aqueous sodium hydroxide in the absence of catalyst at any synthetically useful rate. It has the further advantage that it can be mono-or dialkylated depending on conditions and it, like most nitriles, is not prone to rapid hydrolysis. It is a versatile synthetic intermediate, however, in the sense that the nitrile function can be hydrolyzed, reduced, or added to by organometallics after an alkylation has been carried out. 

Phenylacetonitrile reacts with alkyl, allyl, and benzyl halides as one would expect (see Eq. 10.1). In the presence of excess alkylating agent and base, dialkylation is usually observed. The yield of alkylation product is usually high with normal alkyl halides (Cl, Br, I) and somewhat lower for secondary halides. There is no report of the successful alkylation of phenylacetonitrile by a tertiary alkyl halide under phase transfer conditions. This is undoubtedly due to the facile dehydrohalogenation reaction of such haloalkanes. It is probably the elimination problem which keeps 2-phenylethyl chloride from alkylating phenylacetonitrile in high yield [23], despite the fact that it is a primary halide. It is not clear why 1-phenylethyl chloride should alkylate the same substrate almost quantitatively under the same conditions [23], although the fact that the latter is a benzyl halide no doubt is part of the reason. 

As noted above, the mono- or dialkylation of phenylacetonitrile can be controlled by the amounts of alkylating agent and base present and the reaction time. 

---

Asymmetric induction has also been evaluated in the reaction of a-aryl substituted ketones, esters, and lactones (43). The potential of the method is demonstrated by the synthesis of some naturally occurring or nonnaturally occuring chiral compounds (Scheme 15). Similarly, asymmetric synthesis of ( — )-physostigmine, a clinically useful anticholinesterase agent, is accomplished by using phase-transfer alkylation of... 

Dichloro monomers can also be polymerized with bisphenols in the presence of fluorides as promoting agents.78 The fluoride ions promote the displacement of the chloride sites to form more reactive fluoride sites, which react with phenolate anion to form high-molecular-weight polymers. Adding 5-10 mol % phase transfer catalysts such as A-alkyl-4-(dialkylamino)pyridium chlorides significantly increased the nucleophilicity and solubility of phenoxide anion and thus shortened the reaction time to one fifth of the uncatalyzed reaction to achieve the same molecular weight.79... 

Quaternary ammonium compounds (quats) are prepared - by moderate heating of the amine and the alkyl halide in a suitable solvent - as the chlorides or the bromides. Subsequently conversion to the hydroxides may be carried out. Major applications of the quat chlorides are as fabric softeners and as starch cationizing agent. Several bio-active compounds (agrochemicals, pharmaceuticals) possess the quat-structure. Important applications of quat bromides are in phase transfer catalysis and in zeolite synthesis. 

This chapter compares the reaction of gas-phase methylation of phenol with methanol in basic and in acid catalysis, with the aim of investigating how the transformations occurring on methanol affect the catalytic performance and the reaction mechanism. It is proposed that with the basic catalyst, Mg/Fe/0, the tme alkylating agent is formaldehyde, obtained by dehydrogenation of methanol. Formaldehyde reacts with phenol to yield salicyl alcohol, which rapidly dehydrogenates to salicyladehyde. The latter was isolated in tests made by feeding directly a formalin/phenol aqueous solution. Salicylaldehyde then transforms to o-cresol, the main product of the basic-catalyzed methylation of phenol, likely by means of an intramolecular H-transfer with formaldehyde. With an acid catalyst, H-mordenite, the main products were anisole and cresols moreover, methanol was transformed to alkylaromatics. 

A similar reaction is the methylenation of 3,4-dihydroxybenzaldehyde in the presence of a phase-transfer catalyst on a benign calcium carbonate surface [26]. Presumably, bonding of the vicinal hydroxyl groups is low thereby enhancing the reaction with the alkylating agent under the action of solvent-free microwave irradiation (Eq. 15). 

Several solvent-free N-alkylation reactions have been reported which involve the use of phase transfer agent, tetrabutylammonium bromide (TBAB), under microwave irradiation conditions, an approach that is described in Chapt. 5 [34],... 

W. Nerinckx, M. Vandewalle, Asymmetric Alkylation of a-Aryl Substituted Carbonyl Compounds by Means of Chiral Phase Transfer Catalysts. Applications for the Synthesis of (+)-Podocarp-8(14)-en-13-one and of (-)-Wy-16,225, A Potent Analgesic Agent , Tetrahedron Asymmetry 1990,1, 265-276. 

Belokon et al. (261) subsequently found that salen-Cu(II) complexes are effective catalysts for the asymmetric alkylation of amino acid derivatives. Excellent se-lectivities are observed with 1 mol% of 88b-Cu in toluene at ambient temperature, Eq. 225. Although no stereochemical model is advanced to account for the selec-tivities, these workers suggest the catalyst may be acting as a chiral phase-transfer agent. 

The choice of the catalyst is an important factor in PTC. Very hydrophilic onium salts such as tetramethylammonium chloride are not particularly active phase transfer agents for nonpolar solvents, as they do not effectively partition themselves into the organic phase. Table 5.2 shows relative reaction rates for anion displacement reactions for a number of common phase transfer agents. From the table it is clear that the activities of phase transfer catalysts are reaction dependent. It is important to pick the best catalyst for the job in hand. The use of onium salts containing both long and very short alkyl chains, such as hexade-cyltrimethylammonium bromide, will promote stable emulsions in some reaction systems, and thus these are poor catalysts. 

The 0,5-dialkyl dithiocarbonates (Table 4.8) are readily prepared under phase-transfer catalytic conditions by the reaction of an alkylating agent with potassium O-alkyl dithiocarbonate [35, 39], which can be obtained from carbon disulphide and the appropriate potassium alkoxide [cf. 40]. Monosaccharides are converted into 5-glycosyl dithiocarbonates via the in situ formation of the tosylate, followed by reaction with potassium O-alkyl dithiocarbonate (Scheme 4.6) [41], In a similar manner, 5-glycosyl 7V,7V-diethyldithiocarbamates are obtained from the monosaccharide and A.A-diethyldithiocarbamate (see 4.3.2) [42]. 

Reaction of 2-aminopyrroles with equimolar amounts of dimethyl sulphate under phase-transfer catalysed basic conditions produces the 2-amino-1-methylpyrrole in good yield [17]. When two equivalents of the alkylating agent are used, a mixture of the mono- and dimethylamino-l-methylpyrroles and 2-amino-1-methylpyrroles is obtained. 

It has been reported that alkylation of 2-pyridone and 2-quinolone and other related potentially tautomeric azinones under solid-liquid phase-transfer catalytic conditions generally produces the A-alkylated derivatives exclusively in 65-90% yield [58], although it has been suggested that the yield of the O-alkylated derivative can be increased by the use of long-chain quaternary ammonium salts and when bulky alkylating agents are used [69]. 

Whereas alkylation of activated methylene systems by classical methods produces a mixture of mono- and dialkylated products, with the latter frequently predominating, phase-transfer catalytic procedures permit better control and it is possible to obtain only the monoalkylated derivatives. Extended reaction times or more vigorous conditions with an excess of the alkylating agent lead to dialkylated products or, with dihaloalkanes, carbocyclic compounds as the technique mimics dilute concentration conditions, e.g. the resonance stabilized cyclopentadienyl anion, generated under solidiliquid two-phase conditions, or under liquiddiquid conditions, reacts with 1,2-dihaloethanes to form spiro[2,4]hepta-4,6-diene (70-85%) [1-3]. Reaction with dichloromethane produces bis(cyclopenta-2,4-dien-l-yl)methane (60%) [4],... 

Spurred by our desire to avoid use of expensive dipolau aprotic solvents in nucleophilic aromatic substitution reactions, we have developed two alternative phase transfer systems, which operate in non-polar solvents such as toluene, chlorobenzene, or dichlorobenzene. Poleu polymers such as PEG are Inexpensive and stable, albeit somewhat inefficient PTC agents for these reactions. N-Alkyl-N, N -Dialkylaminopyridinium salts have been identified as very efficient PTC agents, which are about 100 times more stable to nucleophiles than Bu NBr. The bis-pyridinium salts of this family of catalysts are extremely effective for phase transfer of dianions such as bis-phenolates. 

---