Benzylic halides, as alkylating agents

The methylation of N-methyl derivatives of maleic hydrazide gives in general O-alkylated products. The opposite results are obtained with benzyl halides as alkylating agents. In this case the O-benzyl derivative (71) is formed, which is then further benzylated to the lV,0-dibenzyl derivative (72). When ethyl chloroacetate is used, the direction of alkylation is dependent on pH. At pH above 8, O-alkylation occurs at pH below 8, N-alkylation takes place exclusively in neutral and acidic solutions only IV-alkylated products are formed. 

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. 

Therefore carry out the acetoacetic ester synthesis using a benzyl halide as the alkylating agent. 

The reaction of 75b with benzyl bromide was used to optimise the catalyst. After screening Pt complexes containing several typical chiral diphosphines, the best catalysts were again found to be Pt(DuPhos)(Cl)(Ph)]. A variety of benzylic, naphthylmethyl and anthracenylmethyl halides were screened as alkylating agents. Low to moderate diastereoselectivies (0 0% de to C2-76) were observed and in one case (75b, Ar = o-trifluoromethylbenzyl) both enantiomers of compound C2-I6 were isolated enantiomerically pure on a gram scale. 

The method has been extended to a general synthesis of a-alkylidene- and a-alkyl-ketones. The same group describes the reaction of allylic and benzylic halides with silyl enol ethers in the presence of catalytic quantities of zinc(ii) bromide. Other workers also report the use of secondary benzylic halides, allylic halides, and diethyl thioacetals as alkylating agents in the presence of Lewis acids. t-Alkyl halides also alkylate these systems with titanium(iv) chloride as catalyst. ... 

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. 

Various alkylating agents are used for the preparation of pyridazinyl alkyl sulfides. Methyl and ethyl iodides, dimethyl and diethyl sulfate, a-halo acids and esters, /3-halo acids and their derivatives, a-halo ketones, benzyl halides and substituted benzyl halides and other alkyl and heteroarylmethyl halides are most commonly used for this purpose. Another method is the addition of pyridazinethiones and pyridazinethiols to unsaturated compounds, such as 2,3(4//)-dihydropyran or 2,3(4//)-dihydrothiopyran, and to compounds with activated double bonds, such as acrylonitrile, acrylates and quinones. 

Method B The crushed acid (11 mmol), finely powdered KOH (1 equivalent for each C02H group), and Aliquat or TBA-Br (0.1 mmol) are shaken for 5 min and then stirred with the alkylating agent (11 mmol for RX 5.5 mmol for X(CH2) X, 20 mmol with allylic and benzylic halides) (Table 3.9). The reaction is worked up as described in 3.3.2.A alternatively, the mixture can be heated at 140°C for 10 min and the caked residue finely powdered before the addition of the alkylating agent). 

Compositions and functions of typical commercial products in the 2-alkyl-l-(2-hydroxyethyl)-2-imidazolines series are given in Table 29. 2-Alkyl-l-(2-hydroxyethyl)-2-imidazolines are used in hydrocarbon and aqueous systems as antistatic agents, corrosion inhibitors, detergents, emulsifiers, softeners, and viscosity builders. They are prepared by heating the salt of a carboxylic acid with (2-hydroxyethyl)ethylenediamine at 150—160°C to form a substituted amide 1 mol water is eliminated to form the substituted imidazoline with further heating at 180—200°C. Substituted imidazolines yield three series of cationic surfactants by ethoxylation to form more hydrophilic products quatemization with benzyl chloride, dimethyl sulfate, and other alkyl halides and oxidation with hydrogen peroxide to amine oxides. 

With Friedel-Crafts halides (usually A1C13 and BF3) it is necessary to use equimolar or excess catalyst when alcohols are the alkylating agents. With primary alcohols usually 2 mol of catalyst per mole of alcohol must be used. Complexing the alcohol, as well as binding the water formed in the reaction explains the experimental findings. With secondary and tertiary alcohols, lesser amounts of catalyst are needed. The reactivity of different alcohols follows the order methyl < primary < secondary < tertiary, allyl, benzyl. The ease of carbocation formation according to Eq. (5.51) is most probably responsible for this reactivity order ... 

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