Curtius rearrangement

The Curtius rearrangement (or Curtius reaction or Curtius degradation), first defined by Theodor Curtius rearrangement
Curtius in 1885, is the thermal decomposition of an acyl azide to an isocyanate with loss of nitrogen
Named after Theodor Curtius
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 Reaction type Rearrangement
been published.[4][5] reaction
Identifiers
Organic curtius-
Chemistry rearrangement
Portal
RSC ontology RXNO:0000054
ID

Contents
Preparation of acyl azide
Reaction mechanism
Modifications
Photochemical rearrangement
Variations
Darapsky degradation
Harger reaction
Synthetic applications
Triquinacene
Oseltamivir
Dievodiamine
See also
References
External links

Preparation of acyl azide

The acyl azide is usually made from the reaction of acid chlorides or anydrides[6] with sodium azide or
trimethylsilyl azide.[7] Acyl azides are also obtained from treating acylhydrazines with nitrous acid.[8]
Alternatively, the acyl azide can be formed by the direct reaction of a carboxylic acid with diphenylphosphoryl
azide (DPPA).[9]

Diphenylphosphoryl azide
Reaction mechanism
It was believed that the Curtius rearrangement was a two-step processes, with the loss of nitrogen gas forming an acyl nitrene, followed by
migration of the R-group to give the isocyanate. However, recent research has indicated that the thermal decomposition is a concerted process,
with both steps happening together, due to the absence of any nitrene insertion or addition byproducts observed or isolated in the reaction.[10]
Thermodynamic calculations also support a concerted mechanism.[11]

Mechanism of the Curtius rearrangement

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 catalyzed by both Brønsted[12] and Lewis acids, via the protonation of, or coordination to
the acyl oxygen atom respectively. For example, Fahr and Neumann have shown that the use of boron trifluoride or boron trichloride catalyst
reduces the decomposition temperature needed for rearrangement by about 100 °C, and increases the yield of the isocyanate significantly.[13]

Photochemical rearrangement

Mechanism of the photochemical Curtius rearrangement

Photochemical decomposition of the acyl azide is also possible.[14] 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.[15] 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,[16] or Darapsky synthesis, a Curtius rearrangement takes place as one of the steps in the
conversion of an α-cyanoester to an amino acid. Hydrazine is used to convert the ester to an acylhydrazine, which is reacted with nitrous acid to
give the acyl azide. Heating the azide in ethanol yields the ethyl 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.[17]
Harger reaction

The photochemical Curtius-like migration and rearrangement of a phosphinic azide forms a metaphosphonimidate[18] in what is also known as
the Harger reaction (named after Dr Martin Harger from Leicester City).[19] 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.[20]

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 tert-butanol, the reaction generates Boc-protected amines, useful intermediates in organic
synthesis.[21][22] Likewise, when the Curtius reaction is performed in the presence of benzyl alcohol, Cbz-protected amines are formed.[23]

The Curtius rearrangement is used in the syntheses of the drugs tranylcypromine, candesartan, bromadol, terguride, benzydamine, gabapentin,
igmesine and tecadenoson.

Triquinacene

R. B. Woodward et al. used the Curtius rearrangement as one of the steps in the total synthesis of the polyquinane 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 the
methyl carbamate groups (3) with 84% yield. Further steps then gave triquinacene (4).[24]

Oseltamivir
In their synthesis of the antiviral drug oseltamivir, also known as Tamiflu, Ishikawa et al. used the Curtius rearrangement in one of the key steps
in converting the acyl azide to the amide 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 of avian influenza.[25]

Dievodiamine
Dievodiamine is a natural product from the plant Evodia rutaecarpa, which is widely used in traditional Chinese medicine. Unsworth et al.’s
protecting group-free total synthesis of dievodiamine utilizes the Curtius rearrangement in the first step of the synthesis, catalyzed by boron
trifluoride. The activated isocyanate then quickly reacts with the indole ring in an electrophilic aromatic substitution reaction to give the amide in
94% yield, and subsequent steps give dievodamine.[26]

See also
Beckmann rearrangement
Bergmann degradation
Hofmann rearrangement
Lossen rearrangement
Schmidt reaction
Tiemann rearrangement
Neber rearrangement
Wolff rearrangement

References
1. Curtius, Th. (1890). "Ueber Stickstoffwasserstoffsäure (Azoimid) N3H" (http://gallica.bnf.fr/ark:/12148/bpt6k90721q/f915.imag
e.langEN) [On hydrazoic acid (azoimide) N3H]. Berichte der Deutschen Chemischen Gesellschaft zu Berlin. 23: 3023–3033.
doi:10.1002/cber.189002302232 (https://doi.org/10.1002%2Fcber.189002302232).
2. Curtius, T. (1894). "20. Hydrazide und Azide organischer Säuren I. Abhandlung" (https://zenodo.org/record/1427976)
[Hydrazides and azides of organic acids I. paper]. Journal für Praktische Chemie. 50: 275–294.
doi:10.1002/prac.18940500125 (https://doi.org/10.1002%2Fprac.18940500125).
3. Kaiser, C.; Weinstock, J. (1988). "Amines from mixed carboxylic-carbonic anhydrides: 1-phenylcyclopentylamine" (http://www.
orgsyn.org/demo.aspx?prep=cv6p0910). Organic Syntheses.; Collective Volume, 6, p. 910
4. Smith, P. A. S. (1946). "The Curtius reaction". Organic Reactions. 3: 337–449.
5. Scriven, Eric F. V.; Turnbull, Kenneth (1988). "Azides: their preparation and synthetic uses". Chemical Reviews. 88 (2): 297–
368. doi:10.1021/cr00084a001 (https://doi.org/10.1021%2Fcr00084a001).
6. Weinstock, J (1961). "Modified Curtius reaction". J. Org. Chem. 26: 3511. doi:10.1021/jo01067a604 (https://doi.org/10.1021%
2Fjo01067a604).
7. Warren, J. D.; Press, J. B. (1980). "Formation and Curtius rearrangement of acyl azides from unreactive acid chlorides".
Synth. Commun. 10: 107–110. doi:10.1080/00397918008061812 (https://doi.org/10.1080%2F00397918008061812).
8. Pozsgay, V.; Jennings, H. J. (1987). "Azide synthesis with stable nitrosyl salts". Tetrahedron Lett. 28 (43): 5091–5092.
doi:10.1016/s0040-4039(00)95598-9 (https://doi.org/10.1016%2Fs0040-4039%2800%2995598-9).
9. Shioiri, T.; Ninomiya, K.; Yamada, S. (1972). "New convenient reagent for a modified Curtius reaction and for peptide
synthesis". J. Am. Chem. Soc. 94: 6203–6205. doi:10.1021/ja00772a052 (https://doi.org/10.1021%2Fja00772a052).
10. Rauk, A.; Alewood, P. F. (1977). "A theoretical study of the Curtius rearrangement. The electronic structures and
interconversion of the CHNO species". Can. J. Chem. 55 (9): 1498–1510. doi:10.1139/v77-209 (https://doi.org/10.1139%2Fv7
7-209).
11. L'Abbe, G. (1969). "Decomposition and addition reactions of organic azides". Chem. Rev. 69 (3): 345–363.
doi:10.1021/cr60259a004 (https://doi.org/10.1021%2Fcr60259a004).
12. Yukawa, Y.; Tsuno, Y. (1959). "The decomposition of substituted benzazides in acidic solvents, the acid catalysis". J. Am.
Chem. Soc. 81: 2007–2012. doi:10.1021/ja01517a055 (https://doi.org/10.1021%2Fja01517a055).
13. Fahr, E.; Neumann, L. (1965). "Curtius-Reaktion mit Bortrihalogeniden". Angew. Chem. 77 (13): 591.
doi:10.1002/ange.19650771308 (https://doi.org/10.1002%2Fange.19650771308).
14. Wentrup, C.; Bornemann, H. (2005). "Curtius rearrangment of acyl azides revisited - formation of cyanate". Eur. J. Org. Chem.:
4521–4524. doi:10.1002/ejoc.200500545 (https://doi.org/10.1002%2Fejoc.200500545).
15. Eibler, E.; Sauer, J. (1974). "Ein Betrag zur Isocyanatbildung bei der Photolyse von Acylaziden". Tetrahedron Lett. 15 (30):
2569–2572. doi:10.1016/s0040-4039(01)92295-6 (https://doi.org/10.1016%2Fs0040-4039%2801%2992295-6).
16. 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.
17. Gagnon, P. E.; Bovin, P. A.; Craig, H. M. (1951). "Synthesis of amino acids from substituted cyanoacetic esters". Can. J.
Chem. 29: 70–75. doi:10.1139/cjc-29-1-70 (https://doi.org/10.1139%2Fcjc-29-1-70).
18. Bertrand, G.; Majoral, J.; Baceiredo, A. (1980). "Photolytic rearrangement of phosphorus azide: evidence for a transient
metaphosphonimidate". Tetrahedron Lett. 21 (52): 5015–5018. doi:10.1016/s0040-4039(00)71119-1 (https://doi.org/10.1016%
2Fs0040-4039%2800%2971119-1).
19. Harger, M. J. P.; Westlake, S. (1982). "Photolysis of some unsymmetrical phosphinic azides in methanol". Tetrahedron. 38
(20): 3073–3078. doi:10.1016/0040-4020(82)80195-6 (https://doi.org/10.1016%2F0040-4020%2882%2980195-6).
20. Harger, M. J. P.; Westlake, S. (1982). "Photolysis of some unsymmetrical phosphinic azides in methanol". Tetrahedron. 38
(20): 3073–3078. doi:10.1016/0040-4020(82)80195-6 (https://doi.org/10.1016%2F0040-4020%2882%2980195-6).
21. Am Ende, David J.; Devries, Keith M.; Clifford, Pamela J.; Brenek, Steven J. (1998). "A Calorimetric Investigation to Safely
Scale-Up a Curtius Rearrangement of Acryloyl Azide". Organic Process Research & Development. 2 (6): 382–392.
doi:10.1021/op970115w (https://doi.org/10.1021%2Fop970115w).
22. Lebel, H.; Leogane, O. (2005). "Boc-protected amines via a mild and efficient one-pot Curtius rearrangement". Organic
Letters. 7 (19): 4107–4110. doi:10.1021/ol051428b (https://doi.org/10.1021%2Fol051428b). PMID 16146363 (https://pubmed.
ncbi.nlm.nih.gov/16146363).
23. 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" (http://www.orgsyn.org/demo.aspx?prep=cv6p0095).
Organic Syntheses.; Collective Volume, 6, p. 95
24. Woodward, R. B.; Fukunaga, T.; Kelly, R. C. (1964). "Triquinacene". J. Am. Chem. Soc. 86 (15): 3162–3164.
doi:10.1021/ja01069a046 (https://doi.org/10.1021%2Fja01069a046).
25. Ishikawa, H.; Suzuki, T.; Hayashi, Y. (2009). "High-yielding synthesis of the anti-influenza neuramidase inhibitor (-)-oseltamivir
by three "one-pot" operations". Angew. Chem. Int. Ed. 48 (7): 1304–1307. doi:10.1002/anie.200804883 (https://doi.org/10.100
2%2Fanie.200804883). PMID 19123206 (https://pubmed.ncbi.nlm.nih.gov/19123206).
26. Unsworth, William P.; Kitsiou, Christiana; Taylor, Richard J. K. (5 July 2013). "An Expedient Protecting-Group-Free Total
Synthesis of (±)-Dievodiamine". Organic Letters. 15 (13): 3302–3305. doi:10.1021/ol4013469 (https://doi.org/10.1021%2Fol4
013469). PMID 23786450 (https://pubmed.ncbi.nlm.nih.gov/23786450).

External links
"Mechanism In Motion: Curtius rearrangement" (https://www.youtube.com/watch?v=L9o2eFc0T9Q).

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