Curtius rearrangement
Curtius rearrangement | |
---|---|
Named after | Theodor Curtius |
Reaction type | Rearrangement reaction |
Identifiers | |
Organic Chemistry Portal | curtius-rearrangement |
RSC ontology ID | RXNO:0000054 |
The Curtius rearrangement (or Curtius reaction or Curtius degradation), first defined by Theodor Curtius in 1885, is the thermal decomposition of an acyl azide to an isocyanate with loss of nitrogen gas.[1][2] The isocyanate then undergoes attack by a variety of nucleophiles such as water, alcohols and amines, to yield a primary amine, carbamate or urea derivative respectively.[3] Several reviews have been published.[4][5]
Preparation of acyl azide
The acyl azide is usually made from the reaction of
Reaction mechanism
It was believed that the Curtius rearrangement was a two-step processes, with the loss of nitrogen gas forming an
The migration occurs with full retention of configuration at the R-group. The migratory aptitude of the R-group is roughly tertiary > secondary ~ aryl > primary. The isocyanate formed can then be hydrolyzed to give a primary amine, or undergo nucleophilic attack with alcohols and amines to form carbamates and urea derivatives respectively.
Modifications
Research has shown that the Curtius rearrangement is
Photochemical rearrangement
Photochemical decomposition of the acyl azide is also possible.[17] However, photochemical rearrangement is not concerted and instead occurs by a nitrene intermediate, formed by the cleavage of the weak N–N bond and the loss of nitrogen gas. The highly reactive nitrene can undergo a variety of nitrene reactions, such as nitrene insertion and addition, giving unwanted side products.[18] In the example below, the nitrene intermediate inserts into one of the C–H bonds of the cyclohexane solvent to form N-cyclohexylbenzamide as a side product.
Variations
Darapsky degradation
In one variation called the Darapsky degradation,
Harger reaction
The photochemical Curtius-like migration and rearrangement of a phosphinic azide forms a metaphosphonimidate[21] in what is also known as the Harger reaction (named after Dr Martin Harger from University of Leicester).[22] This is followed by hydrolysis, in the example below with methanol, to give a phosphonamidate.
Unlike the Curtius rearrangement, there is a choice of R-groups on the phosphinic azide which can migrate. Harger has found that the alkyl groups migrate preferentially to aryl groups, and this preference increases in the order methyl < primary < secondary < tertiary. This is probably due to steric and conformational factors, as the bulkier the R-group, the less favorable the conformation for phenyl migration.[23]
Synthetic applications
The Curtius rearrangement is tolerant of a large variety of functional groups, and has significant synthetic utility, as many different groups can be incorporated depending on the choice of nucleophile used to attack the isocyanate.
For example, when carried out in the presence of
Likewise, when the Curtius reaction is performed in the presence ofTriquinacene
Oseltamivir
In their synthesis of the
Dievodiamine
Dievodiamine is a
See also
- Beckmann rearrangement
- Bergmann degradation
- Hofmann rearrangement
- Lossen rearrangement
- Schmidt reaction
- Tiemann rearrangement
- Neber rearrangement
- Wolff rearrangement
References
- .
- .
- ^ Kaiser, C.; Weinstock, J. (1988). "Amines from mixed carboxylic-carbonic anhydrides: 1-phenylcyclopentylamine". Organic Syntheses; Collected Volumes, vol. 6, p. 910.
- ^ Smith, P. A. S. (1946). "The Curtius reaction". Organic Reactions. 3: 337–449.
- .
- .
- ISBN 978-0387683546.
- .
- .
- PMID 5054412.
- ISBN 978-0387683546.
- ISBN 978-0387683546.
- doi:10.1139/v77-209.
- .
- .
- .
- .
- .
- ^ August Darapsky (1936) "Darstellung von α-Aminosäuren aus Alkyl-cyanessigsäuren" (Preparation of α-amino acids from alkyl cyanoacetic acids), Journal für Praktische Chemie, 146 : 250-267.
- .
- .
- .
- .
- .
- PMID 16146363.
- ^ Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. (1988). "1-N-Acylamino-1,3-dienes from 2,4-pentadienoic acids by the Curtius rearrangement: benzyl trans-1,3-butadiene-1-carbamate". Organic Syntheses; Collected Volumes, vol. 6, p. 95.
- .
- PMID 19123206.
- PMID 23786450.