Alkyl halides methylating agents used

Secondary amine 5 was alkylated with A-methyl-carboxyl-2-chloroacetamidrazone (30) (prepared from chloroacetonitrile and methyl hydrazonocarboxylate in 70% yield). Initially, DMF, powdered K2CO3 and 1.1 equivalents of the alkyl halide 30 were used. The time cycle for this reaction was important - the reaction would darken after prolonged reaction times. An even better reaction profile was observed using 1.05 equivalents of the alkylating agent in DMSO. 

The alkyl halide must be one that reacts readily by an 8 2 mechanism Thus methyl and primary alkyl halides are the most effective alkylating agents Elimination competes with substitution when secondary alkyl halides are used and is the only reac tion observed with tertiary alkyl halides... 

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. 

As alkylating agent an alkyl halide, alkyl tosylate or dialkyl sulfate is used in most cases the latter type of reagent is often used in the preparation of methyl and ethyl ethers by employing dimethyl sulfate and diethyl sulfate respectively. Dimethyl sulfate is an excellent methylating agent, but is acutely toxic as well as carcinogenic." ... 

The 1,3,5-benzothiadiazepine system (561) has recently been prepared for the first time via methylation of the sulfimide (560 R = CH2Ph) with trimethyloxonium fluoroborate. The rearrangement did not take place however when R = Me or when alkyl halides were used as alkylating agents. The product (561) rearranged readily in acid to give a benzothiazo-line (79JCR(S)214>. 

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. 

Conversion of phenols into their methyl or ethyl ethers by reaction with the corresponding alkyl sulphates in the presence of aqueous sodium hydroxide affords a method which avoids the use of the more expensive alkyl halides (e.g. the synthesis of methyl 2-naphthyl ether and veratraldehyde, Expt 6.111). Also included in Expt 6.111 is a general procedure for the alkylation of phenols under PTC conditions.38,39 The method is suitable for 2,6-dialkylphenols, naphthols and various functionally substituted phenols. The alkylating agents include dimethyl sulphate, diethyl sulphate, methyl iodide, allyl bromide, epichlorohy-drin, butyl bromide and benzyl chloride. 

When primary alkyl phenyl tellurium or secondary alkyl phenyl tellurium compounds in methanol were treated with an excess of 3-chloroperoxybenzoic acid at 20, the phenyltelluro group was eliminated and replaced by a methoxy group. This reaction, which converts alkyl halides used in the synthesis of alkyl phenyl telluriums to alkyl methyl ethers, produced the ethers in yields as high as 90%3-4 Olefins are by-products in these reactions4 With ethanol as the solvent, ethyl ethers were formed. Other oxidizing agents (hydrogen peroxide, ozone, (ert.-butyl hydroperoxide, sodium periodate) did not produce alkyl methyl ethers. 

Extractive alkylation has a reaction scheme identical with that for the previous procedure. The substrate with a carboxyl group reacts in an aqueous solution with a quaternary base and is extracted in the form of an ion pair into a polar solvent of low solvation capacity (dichloromethane) that contains alkyl halide. Low solvation of the anion of the acid and high solvation of the reaction product lead to increased reactivity of the anion and to a rapid reaction with the alkylation agent in the organic phase. Methyl iodide [27] is used to prepare methyl esters and pentafluorobenzyl bromide [28] is used for the preparation of esters providing a high ECD response. 

Alkyl halides are common alkylating agents in this reaction. Benzene is converted to toluene at atmospheric pressure by methyl chloride in the presence of aluminum chloride. Nitroparaffins have been used as solvents for the aluminum chloride catalyst. An amalgamated aluminum Catalyst is more effective than aluminum chloride in certain alkylations by alkyl chlorides. Boron trifluoride must be accompanied by water, alcohol, or some other polar compound in order to be effective in similar alkylations. Hydrogen chloride, hydrogen fluoride, ferric chloride, and beryllium chloride also have been used as catalysts. 

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