Benzyl chloride, alkylation with hydrolysis

Finally, as shown in Scheme 12.65, it is valuable to remember that simple amino acids can often easily be converted (by simply heating them) into the corresponding diketopiperazines, which can be further manipulated. Thus, L-alanine dimerizes on heating and when the dimer is treated with trimethyloxyonium tetrafluoroborate, methylation on oxygen ensues. Treatment of the dimethoxy bis-enol ether generates a monoanion that can be benzylated on carbon. Alkylation with benzyl chloride followed by hydrolysis regenerates L-alanine and the methyl substituted phenylalanine. Such a pattern of reactivity can be widely employed. 

Benzyl chloride undergoes all the transformations of the alkyl halides. Hydrolysis with hot aqueous alkalis yields the corresponding alcohol, benzyl alcohol C6H5.CH2OH, a colourless liquid which boils at 206°. (Chap. V. 4, p. 220.)... 

The synthesis of the basic skeleton of 1-benzylisoquinoline alkaloids has been reported by Uff et al. 15) starting from isoquinoline and benzyl chloride (Scheme 5). The preparation of Reissert compound iV-benzyl-l-cyano-l,2-di-hydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply 1-benzylisoquinoline (25) in an overall yield of 75-84%. 

Aldehyde synthesis 2,4-Dimethylthiazole (1) when treated with n-butyllithium in dry THF and then with benzyl chloride yields 2-(2-phenylethyl)-4-methylthiazole (2) in 94% yield. This product is then alkylated with trimethyloxonium fluoroborate and reduced with sodium borohydride to give 2-(2-phenylethyl)-3,4-dimcthylthiazolidine (3) in high yield. The final step is hydrolysis using mercuric chloride as catalyst 3-phenyl-propanal (4) is obtained in 60% yield. 

Alkylation of metallated a-(dialkylamino)nitriles with alkyl halides, epichlorohydrin, allyl halides or ethyl bromoacetate followed by hydrolysis furnishes an array of ketones in good yield. - For example, reaction of (42) with benzyl chloride leads to the formation of deoxybenzoins. Alkylation of a-(dialkyl-amino)nitriles is also possible if the latter are derived from aliphatic aldehydes. - ... 

Reaction of the imine 75, from 3,4-dimethoxybenzaldehyde and amino-acetal, with benzoyl chloride and potassium cyanide leads to the open-chain Reissert analog 76. This analog can be alkylated with benzyl chloride in the presence of dimethylformamide, but acid hydrolysis of the alkylation product leads to 77. ... 

The anion of the isoquinoline Reissert compound (26) has also been alkylated with a wide variety of other alkyl halides.519-35 38 48-62-66,90 93 The alkylation product from 26 and allyl chloride undergoes isomerization to 38 on base-catalyzed hydrolysis.90 The phthalazine Reissert compound (3) has also been alkylated, in the presence of sodium hydride, with methyl iodide39 and with benzyl halides40 to give, after hydrolysis, 1-substituted phthalazines. A phthalazine analog of 34 (n = 3) has been prepared.1511 An additional example of the alkylation of the quinoline Reissert compound in the 4-position has appeared.943... 

Alkylation of phosphorus by alkyl halides has also been carried out in the presence of free iodine (19). Thus, red phosphorus reacted exothermically with three equivalents of benzyl iodide and two equivalents of iodide at 110° to give (after hydrolysis) tribenzylphosphine oxide and dibenzylphosphmic acid in 81% and 7% yields, respectively. Similar results were obtained from benzyl chloride under these conditions. 

Scheme 9.173. A representation of a comparison between base-catalyzed hydrolysis and decarboxylation (accompanied by a retroaldol-type process), and acid-catalyzed hydrolysis and decarboxylation. Both are shown following alkylation of ethyl 2-carboxycyclopentanone with benzyl chloride.

The balance between the S l and 8 2 reactions can be altered by changes in the solvent or by suitable substituents. Thus we have already seen (Table 5.2) that polar solvents accelerate reactions of neutral alkyl derivatives RX but retard their S 2 reactions with anionic nucleophiles. In such cases, an increase in solvent polarity favors the S l reaction, and a decrease favors the S 2. This is seen nicely in the case of borderline reactions such as that of benzyl chloride. In aqueous alcohol, hydrolysis is of an intermediate character, hydroxide ion accelerating the reaction, which, however, is not of first order in HO. In the more ionizing solvent, formic acid, for-molyis is of zeroth order in formate ion, the reaction being S l. In acetone, on the other hand, a poor ionizing solvent, benzyl chloride readily undergoes normal 5 2 reactions. Thus ... 

Among the various carboxylic acid derivatives, acyl chlorides are especially useful because they are readily converted to acid anhydrides, esters, and amides by nucleophilic acyl substitution (Table 19.1). Yields are high and the reaction rates are much greater than the corresponding rates of alkyl halides with the same nucleophiles. Benzoyl chloride, for example, is about 1,000 times more reactive than benzyl chloride toward hydrolysis at 25°C. 

Entries 3 and 4 are acylahon and alkylation, respectively, of hydroxyl groups. Entry 3 shows the formation of a pentaacetate on reaction of a-D-glucopyranose with acetic anhydride, and entry 4 shows the formation of a tetrabenzyl ether on reachon of methyl a-D-glucopyranoside with benzyl chloride. Benzyl ethers are stable to acid and base hydrolysis, organometallic reagents, and numerous other reaction conditions and are often used to protect... 

Reaction of ethyl acetoacetate with sodium ethoxide followed by addition of benzyl chloride gives an alkylated acetoacetate ester. Subsequent acid-catalyzed hydrolysis with heat leads to decarboxylation of the P keto acid. 

The respective amide was prepared from 7-substituted 5-oxo-2,3-dihydro-5//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acids via acid chlorides with different benzylamines (00M1P3). 6-Carboxamides were N-benzylated, and a side-chain phenolic hydroxy group was O-alkylated. 7-Aryl-5-oxo-2,3-dihydro-5//-pyrido[l, 2,3-r/e]-1,4-benzoxazine-6-carboxylic acid was obtained from the ethyl ester by alkalic hydrolysis. 

A very similar reagent is benzyl t-butyl imidodicarboxy late 27, which is prepared from benzyl alcohol and benzoyl isocyanate, followed by exhaustive acylation with t-butoxycarbonyl chloride. Aminolysis of the resulting triacylamine yields 27. Treatment of the sodium salt of compound 27 with alkyl halides, followed by hydrolysis, gives primary amines53. 

Johnson and McCants (161) were the first to show that the alkaline hydrolysis of alkoxysulfonium salts, obtained by 0-alkylation of sulfoxides, proceeds with inversion of configuration at sulfur. This method was employed to interconvert (/ )- and (5)-benzyl p-tolyl sulfoxides 37 as shown in Scheme 21. In contrast to the hydroxide anion, the chloride, bromide, and iodide anions as well as the nitrogen atom of pyridine react with chiral ethoxydiarylsulfonium salts, not at sulfur but at the a-carbon atom of the ethoxy group, yielding the starting sulfoxide with retained configuration (284). On the other hand, the nucleophilic attack of the fluoride anion is directed at sulfur as in the case of the hydroxide anion (285). 

Alkylation of 7V-benzyl-p-toluenesulfonamide (12a) with a threefold excess of fra j-l,4-dichloro-2-butene (ila) gives the allylic chloride 11b. which is treated with sodium acetate in DMF followed by hydrolysis to afford the allylic alcohol 10a in an overall 68% yield. 

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