Tributyltin azide production

The presence of the propionamide fragment in the stmcture of the anti-inflammatory agent broperamole (125-1) is reminiscent of the heterocycle-based NSAID propionic acids. The activity of this agent may trace back to the acid that would result on hydrolysis of the amide. Tetrazoles are virtually always prepared by reaction of a nitrile with hydrazoic acid or, more commonly, sodium azide in the presence of acid in a reaction very analogous to a 1,3-dipolar cycloaddition. A more recent (and safer) version of the reaction noted later (see losartan, 77-4) uses tributyltin azide. In the case at hand, reaction of the anion of mefa-bromobenzonitrile (125-1) with sodium azide and an acid affords the tetrazole (125-2). Condensation of the anion from that intermediate with ethyl acrylate leads to the product from Michael addition saponiflcation gives the corresponding carboxylic acid (125-3). This is then converted to the acid chloride reaction with piperidine affords broperamole (125-4) [136]. 

S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2 -(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine. The product can be prepared starting from 1.40 g of N-valeryl-N-[(2 -cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester and 2.25 g of tributyltin azide with subsequent flash chromatography melting interval 105°-115°C (from ethyl acetate). 

Two new preparations of 1,8-cineole (553) [the biogenesis of which from geraniol (25) in Rosmarinus officinalis has been elucidated ] have been recorded. A Diels-Alder adduct 625 (R = Me) of methyl vinyl ketone and isopropenyl methyl ketone was converted to the diazoketone (R = CH = N2) with diethyl oxalate/base, then toluenesulfonyl azide, and treatment of the latter with [Rh(OAc)2]2 in methylene chloride at room temperature for five minutes converted it in very high yield to the tricyclic compound 626. Lithium dimethylcuprate then yielded the ketone 627, conversion of which to 1,8-cineole (553) was known.The other 1,8-cineole synthesis was a by-product of an observation which enabled the two stereoisomers of limonene 1,2-epoxide to be separated. The cjs-epoxide 549 was brominated to stereoisomers of a dibromocineole 628, under conditions when the rran.s-epoxide did not react, and could be distilled pure afterward. The dibromo compound 628 yielded 1,8-cineole (553) with tributyltin hydride. 

Radical chlorination (SOjClj, AIBN) of tetra-O-acetyl-p-D-glucopyranosyl azide produced the S-chloro compound 15, whereas use of NBS in place of SOjClj gave a product via bromination at C-l. The reaction of a 1-bromo-l-chloroglucopyranosyl derivative with tributyltin hydride in the presence of acrylonitrile is discussed in Chapter 2, and use of the 6-bromo compound, that results from photobromination of tri-O-acetyl-1,6-anhydro-(3-D-glucopyranose, in substitution and oxidation reactions is mentioned in Chapters 5,7, and 16. 

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