Hydrazoic acid, additions 1,3-dipolar

P25 Each of these [previous methods] involves one or more of the following drawbacks uses expensive and toxic metals, demonstrates severe water sensitivity, or produces hydrazoic acid, which is highly toxic and explosive as well as volatile. The few methods that seek to avoid hydrazoic acid liberation during the reaction, by avoiding acidic conditions, require a very large excess of sodium azide. In addition, ah of the known methods use organic solvents, in particular, dipolar aprotic solvents such as DMF. This is one of the solvent classes that process chemists would rather not use. (Adapted from Demko and Sharpless, 2001)... 

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]. 

Alkynes undergo 1,3-dipolar addition reactions with organic azides to form triazolesCommonly, hydrazoic acid additions to alkynes also give triazoles and this aspect of their chemistry has been... 

High enantioselectivites in the aza-Michael reaction have been achieved using alternate organocatalysts, and the addition of benzotriazole to nitroolefins occurs with up to 94% ee using bifimctional catalysts such as (11.64). Guerin and Miller have developed an alternate approach to the enantioselective introduction of triazoles based on the asymmetric conjugate addition of azide followed by a 1,3-dipolar cycloaddition of the product with an alkyne. In this approach, the addition of hydrazoic acid to Michael acceptors such as (11.133) proceeds with good ee in the presence of the dipeptide (11.134). ... 

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