Benzhydryl carbon

The substitution of the lone proton on the benzhydryl carbon by a methyl group again affords compounds with antihistamine activity. Reaction of an appropriate acetophenone (21) with phenyl-magnesium bromide affords the desired tertiary alcohols (22). 

Performance of an imaginary 1,2-shift on the benzhydrol antihistamines, that is, attachment of the side chain directly to the benzhydryl carbon while leaving the hydroxyl group intact, affords a series of molecules with markedly altered biologic activities. 

Benzhydrylamine Derivatives Attachment of piperazine nitrogen directly to a benzhydryl carbon leads to a pair of compounds which show vasodilator activity, and which should be useful in disease states marked by impaired blood circulation. Reaction of piperonyl chloride (18) with a mixture of piperazine and piperazine dihydrochloride leads to the monoalkylation product (19). (It may be supposed that the mixture of free base and salt equilibrates to the monobasic salt, thus making the second amine less nucleophilic.) Alkylation of 19 by means of benzhydryl chloride then... 

Patent applications have been filed covering compounds without the distal nitrogen constrained in a ring directly attached to the benzhydryl carbon. SmithKline Beecham scientists filed a patent application on diaryldi-amines typified by compound 48 [33], and Meiji Seika Kaisha researchers filed a patent application covering diphenylalkylpiperidines as mu opioid agonists—for instance, compound 49 [34]. 

Substitution reactions. Benzylation of phenols by benzyl methyl carbonates with Pd catalysis proceeds via transesterification and decarbonylation. Triarylmethanes are obtained from a reaction of benzhydryl carbonates with arylboronic acids. ... 

The manufacture of a related compound is first described. 28.1 parts of p-chloro-benzhy-dryl bromide are heated to boiling, under reflux and with stirring, with 50 parts of ethylene chlorohydrin and 5.3 parts of calcined sodium carbonate. The reaction product is extracted with ether and the ethereal solution washed with water and dilute hydrochloric acid. The residue from the solution in ether boils at 134° to 137°C under 0.2 mm pressure and is p-chloro-benzhydryl-(/3-chloroethyl) ether. 

If pure benzhydryl bromide is desired the above reaction mixture is dissolved in ether, washed with water, sodium carbonate solution and finally with water. The ether is removed, benzene added and distilled off and the benzhydryl bromide distilled in vacuo. Yield 85%. 

The crude benzhydryl ether was a clear reddish oil. It was dissolved in 75 ml of 20% hydrochloric acid and the aqueous acid solution then washed three times with 50 ml portions each of ethyl ether. The aqueous acid solution was then decolorized with activated carbon and thereafter slowly admixed with 75 ml of 28% aqueous ammonia. The benzhydryl ether separated as an oily material and was removed from the aqueous mixture by extraction with three 50 ml portions of ethyl ether. 

Charge delocalization of benzyl type carbanions is clearly monitored by the ortho and para carbon shifts [506 507]. Delocalizaton includes a second phenyl ring in benzhydryl anions, as indicated by an increased deshielding of the carbanionic carbon [507] (Table 4.77). Additional deshielding introduced by a third phenyl ring, however, is only about 10 ppm (Table 4.77) due to steric hindrance of coplanarity in the triphenylmethyl carbanion. 

Dinitrobenzofuroxan (DNBF) is known as a superelectrophile due to its high reactivity both as an electrophile and in its pericyclic addition reactions. NMR studies show that reaction with 2-aminothiazole and its 4-methyl derivative yield anionic carbon-bonded adducts such as (11) by reaction at the 5-position, whereas the 4,5-dimethyl derivative reacts via the exocyclic amino group. Kinetic studies of the first two compounds, both in acetonitrile and in 70 30 (v/v) water-DMSO, have been used to assess their carbon nucleophilicities and place them on the Mayr nucleophilicity scale.55 In a related study, the nucleophilic reactivity, in acetonitrile, of a series of indoles with both DNBF and with benzhydryl cations have been compared and used to determine nucleophilicity parameters for the indoles.56... 

The reaction of cyanide ion with substituted benzhydryl carbenium ions to form nitriles and isocyanides is controlled by the rates of reaction at carbon and nitrogen.124 In slow reactions, far from the diffusion limit, the attack is completely at the cyanide carbon. Very fast reactions, with little or no reaction barrier reacting at the diffusion-controlled limit, occur at both the N and the C of the cyanide ion. XN2 reactions occur almost exclusively at carbon regardless of the substrate or source of the cyanide ion. The HSAB principle cannot predict the products of these reactions. 

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