Benzylic halides, alkylation

Compounds, eg, phenacyl halides, benzyl halides, alkyl iodides, or alkyl esters of sulfonic acids, react with DMSO at 100—120°C to give aldehydes (qv) and ketones (qv) in 50—85% yields (eq. 8) (41) ... 

Salts of sulfinic acids ace converted to sulfones by the action of pri-lary/ secondary, and benzyl halides, alkyl sulfates, and aryl halides in which the halogen atoms are activated by nitro groups in the ortbo or para positions. The reaction fails with t-amyl halide. The yields vary widely, depending upon the nature of the reactants. From salts of benzenesulfinic acid and simple alkylating agents, sulfones are produced in 50-90% yields. Satisfactory results have been obtained when the aryl sulfinic acid contains nitro, cyano, and acetamido groups. Keto sulfones are made in 48-62% yields by alkylation with a-halo ketones. ... 

Tosylates and other sulfonates and sulfates couple with Grignard reagents, most often those prepared from aryl or benzylic halides.Alkyl sulfates and sulfonates generally make better substrates in reactions with Grignard reagents than the corresponding halides (10-57). The method is useful for primary and secondary R. 

Oxidative addition [1, 38] of 1-alkenyl, i-alkynyl, allyl, benzyl, and aiyl halides to a palladium(O) complex affords a stable rra .s-<7-palladium(II) complex (11). The reaction proceeds with complete retention of configuration for alkenyl halides and with inversion for allylic and benzylic halides. Alkyl halides having /3-hydrogens are rarely useful because the oxidative addition step is very slow and may compete with /3-hydride elimination from the a-organopalladium(II) species. However, it has been recently shown that iodoalkanes undergo the cross-coupling reaction with organoboron compounds (Section 2.4.5). 

Disulphides have been obtained by the solid state reaction of benzyl halides, alkyl halides and acyl halides at room temperature in the presence of benzyltriethylammonium tetrathiomolybdate. For example, butyl iodide, benzyl bromide and benzoyl chloride give the corresponding disulphides in 70-74%... 

The reaction of benzyl chloride with ethyl oxalyl chloride proceeded at room temperature or at 60°C, and the yields of l,3-diphenylpropan-2-one were 11% and 45%, respectively. Thus, the carbonylation was carried out at 85°C, and the results are summarized in Table 7.7. The stoichiometric ratio of benzylic halide/alkyl oxalyl chloride was 2 1, and the most satisfactory results were obtained with a ratio of 1 1. 

Benzylic halides that are secondary resemble secondary alkyl halides in that they undergo substitution only when the nucleophile is weakly basic If the nucleophile is a strong base such as sodium ethoxide elimination by the E2 mechanism is faster than substitution... 

Rearrangement is especially prevalent with primary alkyl halides of the type RCH2CH2X and R2CHCH2X Aluminum chloride induces ionization with rearrangement to give a more stable carbocation Benzylic halides and acyl halides do not rearrange... 

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. 

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. 

Pyrroles do not react with alkyl halides in a simple fashion polyalkylated products are obtained from reaction with methyl iodide at elevated temperatures and also from the more reactive allyl and benzyl halides under milder conditions in the presence of weak bases. Alkylation of pyrrole Grignard reagents gives mainly 2-alkylated pyrroles whereas N-alkylated pyrroles are obtained by alkylation of pyrrole alkali-metal salts in ionizing solvents. 

A study of alkylations with a group of substituted benzyl halides and a range of Friedel-Crafts catalysts has provided insight into the trends in selectivity and orientation that accompany changes in both the alkyl group and the catalysts. There is a marked increase in substrate selectivity on going from / -nitrobenzyl chloride to /i-methoxybenzyl chloride. For example, with titanium tetrachloride as the catalyst, Aitoi Abenz increases from 2.5 to 97. This increase in substrate selectivity is accompanied by an increasing preference for para substitution. With /i-nitrobenzyl chloride, the ortho para ratio is 2 1 (the... 

A mechanism of this type permits substitution of certain aromatic and ahphatic nitro compounds by a variety of nucleophiles. These reactions were discovered as the result of efforts to explain the mechanistic basis for high-yield carbon alkylation of the 2-nitropropane anion by p-nitrobenzyl chloride. p-Nitrobenzyl bromide and iodide and benzyl halides that do not contain a nitro substituent give mainly the unstable oxygen alkylation product with this ambident anion ... 

However, it has recently been shown (42) that monomeric enamines such as 42 react normally to give the benzothiazoline salt (43) on alkylation with alkyl and benzyl halides. 

A fundamental problem in the alkylation of enamines, which is inherent in the bidentate system, is the competition between the desired carbon alkylation and attack at the nitrogen. With unactivated alkyl halides (3,267), this becomes especially serious with the enamines derived fromcycloheptan-one, cyclooctanone, cyclononanone, and enamines derived from aldehydes. Increasing amounts of carbon alkylation are found with the more reactive allyl and benzyl halides (268-273). However, with allyl halides one also observes increasing amounts of dialkylation of enamines. 

Differences in solubility of the reactants may for example be utilized as follows. Sodium iodide is much more soluble in acetone than are sodium chloride or sodium bromide. Upon treatment of an alkyl chloride or bromide with sodium iodide in acetone, the newly formed sodium chloride or bromide precipitates from the solution and is thus removed from equilibrium. Alkyl iodides can be conveniently prepared in good yields by this route. Alkyl bromides are more reactive as the corresponding chlorides. Of high reactivity are a-halogen ketones, a-halogen carboxylic acids and their derivatives, as well as allyl and benzyl halides. 

The reaction works well with primary alkyl halides, especially with allylic and benzylic halides, as well as other alkyl derivatives with good leaving groups. Secondary alkyl halides give poor yields. Tertiary alkyl halides react under the usual reaction conditions by elimination of HX only. Nitriles from tertiary alkyl halides can however be obtained by reaction with trimethylsilyl cyanide 4 ... 

In an alternate synthesis of the intermediate ketone, the benzylic halide, 69, is used to alkylate sodium phenoxide. Cyclization of the acid (70) obtained on hydrolysis of the ester by means of trifluoroacetic anhydride again gives 67... 

In contrast, A, JV-diethyl-3-(methylsulfanyl)-5-phenyl-3//-azepin-2-amine (22) on treatment with methyl or benzyl halides and potassium amide in liquid ammonia undergoes alkylation solely at the masked benzylic 5-position to yield 4,4-disubstituted 4//-azepines, e.g. 23.224... 

Notes, (a) The alkylating agent must be reactive, i.e. a methyl, ethyl, ally] or benzyl halide. 

In the reaction of 88 with /(-phenethyl bromide, l-phenethyl-3-phenylpropyl methyl sulfoxide and bis-3-phenylpropyl sulfoxide, besides 3-phenylpropyl methyl sulfoxide are obtained118. Sulfoxides, bearing a /1-hydrogen to the sulfmyl function, give olefins upon thermolysis. Utilizing this reaction, Trost and Bridges120 alkylated benzyl phenyl sulfoxide, 3,4-methylenedioxybenzyl phenyl sulfoxide, phenylthiomethyl phenyl sulfoxide, phenylsulfinylmethyl phenyl sulfoxide and cyanomethyl phenyl sulfoxide with alkyl, allyl and benzyl halides and subjected these sulfoxides to thermolysis, obtaining olefins in one-pot processes. 

Phenylsulfonyl)nitromethane is preferentially C-alkylated by benzylic halides and primary alkyl iodides, affording secondary a-nitrosulfones338. 

Primary amines can be prepared from alkyl halides by the use of hexamethylenetetramine followed by cleavage of the resulting salt with ethanolic HCl. The method, called the Delepine reaction, is most successful for active halides such as allylic and benzylic halides and a-halo ketones, and for primary... 

Lewis acids are also used in conjunction with acyl halides. The reagent Nal—BF3 etherate selectively cleaves ethers in the order benzylic ethers > alkyl methyl ethers > aryl methyl ethers. 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0")2 ] by treatment with a strong base such as LDA. The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCH2COOH and RR"CHCOOH. This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 458),... 

Yet another approach uses electrolysis conditions with the alkyl chloride, Pe(CO)s and a nickel catalyst, and gives the ketone directly, in one step. In the first stage of methods 1, 2, and 3, primary bromides, iodides, and tosylates and secondary tosylates can be used. The second stage of the first four methods requires more active substrates, such as primary iodides or tosylates or benzylic halides. Method 5 has been applied to primary and secondary substrates. 

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