Carboxylic acids Curtius rearrangement

By application of the Schmidt reaction, the conversion of a carboxylic acid into an amine that has one carbon atom less than the carboxylic acid, can be achieved in one step. This may be of advantage when compared to the Curtius reaction or the Hofmann rearrangement, however the reaction conditions are more drastic. With long-chain, aliphatic carboxylic acids yields are generally good, while with aryl derivatives yields are often low. 

The ketocarbene 4 that is generated by loss of Na from the a-diazo ketone, and that has an electron-sextet, rearranges to the more stable ketene 2 by a nucleophilic 1,2-shift of substituent R. The ketene thus formed corresponds to the isocyanate product of the related Curtius reaction. The ketene can further react with nucleophilic agents, that add to the C=0-double bond. For example by reaction with water a carboxylic acid 3 is formed, while from reaction with an alcohol R -OH an ester 5 is obtained directly. The reaction with ammonia or an amine R -NHa leads to formation of a carboxylic amide 6 or 7 ... 

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and tire Curtius rearrangement. Although the Hofmann rearrangement involves a primary-amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms. 

How would you prepare o-methvlbenzylamine from a carboxylic acid, using both Hofmann and Curtius rearrangements ... 

This version of the Curtius rearrangement has been applied to the synthesis of amino acid analogs and structures containing amino acids. Several m-2-aminocyclopropane carboxylate esters were prepared by selective hydrolysis of cyclopropane-1,2-dicarboxylates, followed by reaction with DPPA.267... 

Another reaction that can be used for conversion of carboxylic acids to the corresponding amines with loss of carbon dioxide is the Hofmann rearrangement. The classic reagent is hypobromite ion, which reacts to form an A-bromoamide intermediate. Like the Curtius reaction, this rearrangement is believed to be a concerted process and proceeds through an isocyanate intermediate. 

The carboxylic acid group is converted by CDI and sodium azide into an acid azide, which via a Curtius rearrangement gives the corresponding amine.[135a3... 

A total synthesis of O-methylarnottianamide (223) was performed by Falck et al. (177) (Scheme 34). The regio- and stereospecific cycloaddition of the 2,4-dinitrophenyl (DNP) salt of 6,7-methylenedioxyisoquinoline (218) with a-methoxystyrene 219 resulted in 220. Compound 220 was hydrolyzed, then aromatized, and the resultant aldehyde was oxidized to carboxylic acid 221. Curtius rearrangement of the appropriate azide yielded urethane 222, which... 

An attempted synthesis of biotin using thiocarbonyl ylide cycloaddition was carried out (131,133,134). The crucial step involves the formation of the tetrahydrothiophene ring by [3 + 2] cycloaddition of a properly substituted thiocarbonyl ylide with a maleic or fumaric acid derivative (Scheme 5.27). As precursors of the thiocarbonyl ylides, compounds 25a, 72, and 73 were used. Further conversion of cycloadducts 74 into biotin (75) required several additional steps including a Curtius rearrangement to replace the carboxylic groups at C(3) and C(4) by amino moieties. 

Curtius rearrangement of the heteroaroyl azides, obtained from the reaction of the carboxylic acid chlorides with sodium azide, provides a route to the amino-pyrroles and -indoles (e.g. B-70MI30504, B-77MI30506, 78CPB1054), which, because of the ease of synthesis of the carboxylic acids, is frequently preferable to reduction of the nitro compounds. 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

Preparation from Nitrene Intermediates. A convenient, small-scale method for the conversion of carboxylic acid derivatives into isocyanates involves electron sextet rearrangements, such as the ones described by Hofmann and Curtius (12). For example, treatment of benzamide [55-21 -0] with halogens leads to an AJ-haloamide (2) which, in the presence of base, forms a nitrene intermediate (3). The nitrene intermediate undeigoes rapid rearrangement to yield an isocyanate. Ureas can also be formed in the process if water is present (18,19). 

A Curtius rearrangement was reported as the key step in the synthesis of protected anilines and aromatic ureas.84 The reaction is a single step from the corresponding carboxylic acid and produces urea or aniline, depending on the conditions. 

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