Carboxylic acids, reaction with hydrazoic

Carboxylic acids and esters can also be converted to amines with loss of the carbonyl group by reaction with hydrazoic acid, HN3, which is known as the Schmidt reaction,278 The mechanism is related to that of the Curtius reaction. An azido intermediate is generated by addition of hydrazoic acid to the carbonyl group. The migrating group retains its stereochemical configuration. 

Schmidt reaction (see review ). This reaction provides a method for the conversion of a carboxylic acid into an amine in one step. On reaction with hydrazoic acid in benzene in the presence of sulfuric acid, an acid is converted beyond the stage of the acyl azide (a) into the conjugate acid (b), which loses nitrogen more easily than the azide itself, with rearrangement to the isocyanate (d). The one-step... 

Carboxylic acids and esters can also be converted to amines with loss of the carbonyl group by reaction with hydrazoic acid, HN3. This is known as the Schmidt... 

When the Schmidt reaction is applied to a,j8-unsaturated carboxylic acids, the product of the rearrangement is an enamine, which hydrolyzes to the corresponding ketone. Entry 3 in Scheme 8.9 is an example of this type of reaction. Reaction with hydrazoic acid converts ketones to amides, and is thus an alternative method for effecting the same transformation as the Beckmann rearrangement. A drawback of... 

The conversion of a carboxylic acid into an amine by treatment with hydrazoic acid in concentrated sulphuric acid is known as the Schmidt reaction or rearrangement ... 

Reaction of carboxylic acids, aldehydes or ketones with hydrazoic acid... 

The reaction of carboxylic acids, aldehydes or ketones with hydrazoic acid in the presence of a strong acid is known as the Schmidt reaction A common application is the conversion of a carboxylic acid 1 into an amine 2 with concomitant chain degradation by one carbon atom. The reaction of hydrazoic acid with a ketone 3 does not lead to chain degradation, but rather to formation of an amide 4 by formal insertion of an NH-group. 

There are actually three reactions called by the name Schmidt reaction, involving the addition of hydrazoic acid to carboxylic acids, aldehydes and ketones, and alcohols and alkenes. The most common is the reaction with carboxylic acids, illustrated above.Sulfuric acid is the most common catalyst, but Lewis acids have also been used. Good results are obtained for aliphatic R, especially for long chains. When R is aryl, the yields are variable, being best for sterically hindered compounds like mesi-toic acid. This method has the advantage over 18-13 and 18-14 that it is just one laboratory step from the acid to the amine, but conditions are more drastic. Under the acid conditions employed, the isocyanate is virtually never isolated. 

The reaction of carboxylic acids with hydrazoic acid in concentrated sulfuric acid to give amines is faster with acids whose t-factor equals 4. 

In the reaction of hydrazoic acid with carboxylic acids the amine is probably formed by way of an intermediate identical with that... 

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]. 

Benzoic acids substituted with alkyl, halo, hydroxyl, alkoxyl, cyano, or nitro groups react to give the corresponding substituted anilines in 41-80% yields. The carboxyl group in an a-amino acid does not react with hydrazoic acid the reaction proceeds, however, if the amino group is further removed. This difference in reactivity is shown by the conversion of a-aminoadipic acid to i(-ornithlne (75%). ... 

The thietane ring of the carboxylate derivative 352 is apparently opened by loss of carbon dioxide. possibly via a thiete intermediate. Isonitriles and ynamines effect ring-expansions of 2,4-bis(imino)thietanes, and similar reactions of enamines and ynamines with tris(imino)thietane, 353 have been reported. The nucleophiles — methanol, ethanethiol, and diethylamine — attack the a-carbon atom of 353, which bears the iminosulfonyl group, to give ring-opened products, for example, 353a. The reactions with sodium azide or hydrazoic acid take a different course. ... 

This method is unusually mild, using neutral conditions and low temperatures (20 °C and less). It tolerates a number of functional groups in the components (e.g. acetals, esters, alkenes, etc.)- The alcohol, the carboxylic acid and triphenylphosphine are treated dropwise in an inert solvent (dichloromethane, THF, ether) with diethyl azodicarboxylate (DEAD). The ester is formed rapidly. However, tedious chromatography is frequently required to remove the by-products, triphenylphosphane oxide and hydrazo ester. The main value of the reaction lies in the clean inversion of configuration at a secondary carbinol center and in its selectivity towards primary hydroxy groups (vide infra). Inversions are usually performed with benzoic or p-nitrobenzoic acid. The benzoates are purified and saponified with aqueous base to furnish the inverted alcohols in overall yields of ca. 50%. Elimination is the main side reaction. Thus, from (44) 75% of the desired Sn2 product (45) is formed, along with 25% of the elimination product (46) (equation 19). The mechanism of the reaction has been clarified to the point that betaine (47) is the pri-... 

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