Schmidt rearrangements

The Schmidt reactions refer to the acid-catalyzed reactions of hydrazoic acid with electrophiles, such as carbonyl compounds, tertiary alcohols and alkenes. These substrates undergo rearrangement and extrusion of nitrogen to furnish amines, nitriles, amides or imines. 

The Schmidt reaction of carboxylic acids with hydrazoic acid has the advantage over Curtius rearrangement that it is only one step from the acid to the amine, but the conditions are more drastic (usually sulphuric acid plus sodium azide). Under these harsh conditions, the isocyanate intermediate is rarely isolated. For these reasons, the Curtius rearrangement is frequently employed to convert acids to amines. The Schmidt reaction of ketones with hydrazoic acid is a powerful method for the synthesis of amides and lactams. TTiis process is somewhat related to the Beckmann rearrangement of oximes however, the Schmidt reaction is more succinct, allowing the conversion of ketones to amides in a single operation. Considering its widespread 

The Schmidt reaction was discovered in 1924 by Karl Friedrich Schmidt (1887-1971) who successfully converted benzophenone to benzanilide using hydrazoic acid. Schmidt collaborated with Curtius at the University of Heidelberg, where Schmidt became a Professor of Chemistry in 1923. 

The Schmidt reaction of carboxylic acids proceeds via acylium ion, which undergoes addition with hydrazoic acid to generate acyl azide. This azide rearranges with loss of nitrogen to give isocyanate, which leads to an amine upon hydrolysis.  

Reaction of ketones with hydrazoic acid gives azidohydrin intermediates, which undergo rearrangement to form amides.  

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 244, Springer International Publishing Switzerland 2014 

Schmidt Reactions. In Name Reactions for Homologations-Part 11, Li, J. J., Ed. Wiley Hoboken, NJ, 2009, pp 353-372. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 229, Springer-Verlag Berlin Heidelberg 2009 

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Conversion of pregnanes to androstanes via the Schmidt Rearrangement 17/3-aminoandrost-5-en-3/3-ol, 145 Cyclobutanol formation by ketone irradiations... 

Schmidt rearrangement, 144 2,3-Seco-cholestane-2,3-dioic acid, 356... 

Thus, acetylation of aniline affords acetanilide (20), an analgesic widely used in proprietary headache remedies. A similar transformation on p-aminophenol gives the analgesic, acetaminophen (21). It is of interest that the latter is also formed in vivo on administration of 21. An interesting preparation of this drug involves Schmidt rearrangement of the hydrazone (24) from p-liydroxyacetophenone. ... 

In addition to the Beckmann reaction, the Schmidt rearrangement is used to generate M-alkylated lactams, too. Alkyl azides 231 react with the cyclic ketones (and aldehydes) in the presence of proton or Lewis acids. On running the inter-molecular reactions, in most cases symmetric ketals 230 have been converted... 

Another way to obtain a carbamate via an isocyanate intermediate is the conversion of an imidazolide RCOIm into the azide RCON3, followed by the Curtius-Schmidt rearrangement and treatment with an alcohol [2241... 

The obtained spiro keto esters 2-181 could be converted into 2-183, employing among other transformations an intramolecular Schmidt rearrangement [101] of the azido ketones 2-182. 

Further confirmation was gained by the successful Schmidt rearrangement. This was done in the variation described by Schroeter ( 5). 

Benzodiazocines 429 were prepared to be tested as calcium-sensitizing agents (equation 181). A mixture of isomeric lactams was obtained when the Schmidt rearrangement was applied to 427, but only one product 428 was produced using the Beckmann reaction. 

The synthesis of lactams has attracted considerable attention in recent years. This is presumably because they represent versatile synthetic intermediates that are present h many biologically important molecules. Despite the wide range of methodologies that have been examined for the synthesis of lactams, the Beckmann and Schmidt rearrangements still remain by far the most convenient and general methods. The strongly acidic conditions required for the Schmidt rearrangement often lead to undesired byproducts. This is a major limitation particularly with acid-labile substrates. 

Sandmeyer reaction, 306 Sandwich compoimds, 275 Sawhorse projections, 7 Saytzev elimination, 249, 256 Schiff bases, 221 Schmidt rearrangement, 122 Selectivity, 156, 169, 326 a, 362 a, 370 372 aj,385 a bonds, 6 o complexes, 41,131 Sigmatropic rearrangements, 352-357 antarafacial, 353 carbon shifts, 354 hydrogen shifts, 352 orbital symmetry in, 352 photochemical, 354 suprafadal, 353 thermal, 353... 

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