Amines, hydride displacement

Reactions of Esters Esters are much more stable than acid chlorides and anhydrides. For example, most esters do not react with water under neutral conditions. They hydrolyze under acidic or basic conditions, however, and an amine can displace the alkoxyl group to form an amide. Lithium aluminum hydride reduces esters to primary alcohols, and Grignard and organolithium reagents add twice to give alcohols (after hydrolysis). 

A number of less hindered monoalkylboranes is available by indirect methods, eg, by treatment of a thexylborane—amine complex with an olefin (69), the reduction of monohalogenoboranes or esters of boronic acids with metal hydrides (70—72), the redistribution of dialkylboranes with borane (64) or the displacement of an alkene from a dialkylborane by the addition of a tertiary amine (73). To avoid redistribution, monoalkylboranes are best used /V situ or freshly prepared. However, they can be stored as monoalkylborohydrides or complexes with tertiary amines. The free monoalkylboranes can be hberated from these derivatives when required (69,74—76). Methylborane, a remarkably unhindered monoalkylborane, exhibits extraordinary hydroboration characteristics. It hydroborates hindered and even unhindered olefins to give sequentially alkylmethyl- and dialkylmethylboranes (77—80). 

The nucleophilic displacement reactions with azide, primary amines, thiols and carboxylatc salts arc reported to be highly efficient giving high (>95%) yields of the displacement product (Table 9.25). The latter two reactions are carried out in the presence of a base (DBU, DABCO). Radical-induced reduction with tin hydrides is quantitative. The displacement reaction with phenolates,61j phosphines,6M and potassium phthalimide608 gives elimination of HBr as a side reaction. 

The nature of the aromatic substituents is apparently not critical for SSRI activity, as indicated by the structure of duloxetine (23-5), where one ring is replaced by thiophene and the other by naphthalene. The synthesis starts as above by the formation of the Mannich base (23-1) from 1-acetyl thiophene with formaldehyde and dimethyl-amine. Treatment of that intermediate with the complex from lithium aluminum hydride and the 2R,3S entantiomer of dimethylamino-l,2-diphenyl-3-methyl-butane-2-ol gives the S isomer (23-2) in high enantiomeric excess. Treatment of the aUcoxide from (23-2) and sodium hydride with 1-fluoronaphthalene leads to the displacement of halogen and thus the formation of ether (23-2). The surplus methyl group is then removed by yet another variant of the von Braun reaction that avoids the use of a base for saponifying the intermediate urethane. Thus, reaction of (23-3) with trichloroethyl formate leads to the A -demethylated chlorinated urethane (23-4). Treatment of that intermediate with zinc leads to a loss of the carbamate and the formation of the free secondary amine duloxetine (23-5) [23]. 

Whereas the Ti linker involves an immobilization of a diazonium salt on an amine resin, the T2 linker represents the reversal of this concept. As outlined in Scheme 10, m-aminophenol (54) was attached to Merrifield resin 53 by displacing the chloride group via the phenolic group with the aid of sodium hydride in dimethylformamide (DMF) (see Experimental... 

The radiolabel was introduced by displacement of a quaternary amine with potassium 14C-cyanide to give a nitrile. The nitrile was readily converted to indole-3-acetic acid by hydrolysis with 20% aqueous potassium hydroxide. Reduction of the indole-3-acetic acid derivative with lithium aluminum hydride in tetrahydrofuran gave a typtophol with 95% yield. 

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