| Curtius rearrangement | |
|---|---|
| Named after | Theodor Curtius |
| Reaction type | Rearrangement reaction |
| Identifiers | |
| Organic Chemistry Portal | curtius-rearrangement |
| RSC ontology ID | RXNO:0000054 |
TheCurtius rearrangement (orCurtius reaction orCurtius degradation), first defined byTheodor Curtius in 1885, is thethermal decomposition of anacyl azide to anisocyanate with loss ofnitrogen gas.[1][2] The isocyanate then undergoes attack by a variety ofnucleophiles such as water,alcohols andamines, to yield a primary amine,carbamate orurea derivative respectively.[3] Several reviews have been published.[4][5]
It was believed that the Curtius rearrangement was a two-step processes, with the loss of nitrogen gas forming anacyl nitrene, followed by migration of the R-group to give theisocyanate. However, recent research has indicated that the thermal decomposition is aconcerted process,[6] with both steps happening together, due to the absence of any nitrene insertion or addition byproducts observed or isolated in the reaction.[7] Thermodynamic calculations also support a concerted mechanism.[8]
The migration occurs with full retention of configuration at the R-group. Themigratory aptitude of the R-group is roughly tertiary > secondary ~ aryl > primary. The isocyanate formed can then behydrolyzed to give a primaryamine, or undergonucleophilic attack withalcohols and amines to formcarbamates andurea derivatives respectively.
Research has shown that the Curtius rearrangement iscatalyzed by bothBrønsted[9] andLewis acids, via the protonation of, or coordination to the acyl oxygen atom respectively. For example, Fahr and Neumann have shown that the use ofboron trifluoride orboron trichloride catalyst reduces the decomposition temperature needed for rearrangement by about 100 °C, and increases the yield of the isocyanate significantly.[10]
Photochemical decomposition of the acyl azide is also possible.[11] However, photochemical rearrangement is not concerted and instead occurs by anitrene 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 asnitrene insertion and addition, giving unwanted side products.[12] In the example below, the nitrene intermediate inserts into one of the C–H bonds of thecyclohexane solvent to form N-cyclohexylbenzamide as a side product.
In one variation called theDarapsky degradation,[13] orDarapsky synthesis, a Curtius rearrangement takes place as one of the steps in the conversion of an α-cyanoester to anamino acid.Hydrazine is used to convert the ester to anacylhydrazine, which is reacted withnitrous acid to give the acyl azide. Heating the azide inethanol yields theethyl carbamate via the Curtius rearrangement. Acid hydrolysis yields the amine from the carbamate and the carboxylic acid from the nitrile simultaneously, giving the product amino acid.[14]
The photochemical Curtius-like migration and rearrangement of a phosphinic azide forms a metaphosphonimidate[15] in what is also known as theHarger reaction (named after Dr Martin Harger fromUniversity of Leicester).[16] This is followed by hydrolysis, in the example below withmethanol, 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.[16]
The Curtius rearrangement is tolerant of a large variety offunctional groups, and has significant synthetic utility, as many different groups can be incorporated depending on the choice ofnucleophile used to attack the isocyanate.
For example, when carried out in the presence oftert-butanol, the reaction generatesBoc-protected amines, useful intermediates inorganic synthesis.[17][18]Likewise, when the Curtius reaction is performed in the presence ofbenzyl alcohol,Cbz-protected amines are formed.[19]
R. B. Woodward et al. used the Curtius rearrangement as one of the steps in thetotal synthesis of thepolyquinane triquinacene in 1964. Following hydrolysis of the ester in the intermediate (1), a Curtius rearrangement was effected to convert the carboxylic acid groups in (2) to themethyl carbamate groups (3) with 84% yield. Further steps then gave triquinacene (4).[20]
In their synthesis of theantiviral drugoseltamivir, also known as Tamiflu, Ishikawa et al. used the Curtius rearrangement in one of the key steps in converting the acyl azide to theamide group in the target molecule. In this case, the isocyanate formed by the rearrangement is attacked by a carboxylic acid to form the amide. Subsequent reactions could all be carried out in the same reaction vessel to give the final product with 57% overall yield. An important benefit of the Curtius reaction highlighted by the authors was that it could be carried out at room temperature, minimizing the hazard from heating. The scheme overall was highly efficient, requiring only three “one-pot” operations to produce this important and valuable drug used for the treatment ofavian influenza.[21]
Dievodiamine is anatural product from the plantEuodia ruticarpa, which is widely used intraditional Chinese medicine. Unsworth et al.’sprotecting group-free total synthesis of dievodiamine utilizes the Curtius rearrangement in the first step of the synthesis, catalyzed byboron trifluoride. The activated isocyanate then quickly reacts with theindole ring in anelectrophilic aromatic substitution reaction to give the amide in 94% yield, and subsequent steps give dievodamine.[22]
