Sodium borohydride discovery

The search for solvents led to the discovery that sodium borohydride is an excellent reducing agent for aldehydes and ketones. The search for catalysts to enhance the reducing power of sodium borohydride led to an anomalous result in the reduction of ethyl oleate. Investigation of this anomalous result led to the discovery of hydroboration. 

Fifty years after the introduction of catalytic hydrogenation into the methodology of organic chemistry another discovery of comparable importance was published synthesis [82] and applications [55] of lithium aluminum hydride and lithium and sodium borohydride. 

The discovery that benzyne (Scheme 30) adds to acridizinium ion to produce an azoniatrip-tycene (34) which, on reduction with sodium borohydride followed by hydrolysis, affords anthracene, offers a new route to the synthesis of related hydrocarbons (71JOC3002). This, the Fields anthracene synthesis, has already found application in the preparation of 1,4,5,8,9-pentamethylanthracene (75TL4639). 

The discovery of tp o-displacement of silicon from the thiazole 2-position under mild conditions led to the development of this reaction as an essential component of a route to complex aldehydes. Subsequent qua-temisation, saturation of the heterocyclic ring using sodium borohydride, and then mercury(II)- or copper(II)-catalysed treatment leads to the destruction of the thiazolidine and the formation of a new, homologous aldehyde an example is shown below." " ... 

The only synthesis published to date by the medicinal chemists Cai et al. was not amenable to scale-up. The discovery route started with the 0-alkylation of 5-iodovanillin (230) with 2-iodoethanol in the presence of K2CO3 and 18-crown-6 ether in DMF to give compound 231 (Scheme 30.41). The Stetter reaction of 3,4,5-trimethoxyphenyl vinyl ketone (232) with aldehyde 231 in the presence of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride catalyst (233) and triethylamine in DMF gave the 1,4-dione (234). Reduction of 234 with sodium borohydride in a MeOH-THF mixture gave the corresponding 1,4-diol (235). Diol 235 was cyclized with 5% trifluoroacetic acid in CHCI3 to furnish a mixture of cis and trans isomers of 2,5-diaryl tetrahydrofurans. 

To complete the synthesis, the aldehyde is required to achieve good alkylation selectivity. The discovery group reported alkylation using K2CO3 to provide a 97 3 ratio of iV-selective alkylation. Sodium borohydride reduction then provides the 5-hydroxy methyl compound in 90% overall yield. This intermediate was then reacted further to form losartan, an... 

Sodium borohydride hydrolysis in aqueous solution can be represented in terms of the overall stoichiometric equation (Eq. 11.1) where NaBFLj reacts with 4 molecules of water to produce 4 molecules of H2 [33]. Although the reaction of NaBH4 hydrolysis has been studied since the discovery of sodium borohydride by Stock in 1933 [34], the theoretical, calculated energy of the reaction is often cited in an incompatible manner to the application, and real experimental data are very scarce [35-38]. The thermodynamic features of the catalyzed hydrolysis in fact are not yet well understood, as the evolved energy depends on the physical state and the hydration degrees of borohydride and metaborate and on-side reactions. 

An example of Ellman s methodology as applied to a chiral reduction has been described in a drug discovery programme undertaken by Merck to develop selective non-steroidal glucocorticoid receptor agonists such as 243. Ketone 238 was converted to ketimine 239 by reaction with (i )-(-l-)-tert-butanesulfinamide and titanium tetraethoxide. Asymmetric reduction was effected by treatment with sodium borohydride followed by deprotection under acidic conditions to afford amine 242. The chiral product was subsequently converted to glucocorticoid receptor agonist 243 (Scheme 14.80). 

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