Curtius Rearrangement - Wikipedia

Chemical reaction

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]

Reaction mechanism

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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,[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. 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

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Research has shown that the Curtius rearrangement is catalyzed by both Brønsted[9] 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.[10]

Photochemical rearrangement

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Photochemical decomposition of the acyl azide is also possible.[11] 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.[12] 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

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Darapsky degradation

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In one variation called the Darapsky degradation,[13] 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.[14]

Harger reaction

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The photochemical Curtius-like migration and rearrangement of a phosphinic azide forms a metaphosphonimidate[15] in what is also known as the Harger reaction (named after Dr Martin Harger from University of Leicester).[16] 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.[16]

Synthetic applications

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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.[17][18] Likewise, when the Curtius reaction is performed in the presence of benzyl alcohol, Cbz-protected amines are formed.[19]

Triquinacene

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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).[20]

Oseltamivir

[edit]

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.[21]

Dievodiamine

[edit]

Dievodiamine is a natural product from the plant Euodia ruticarpa, 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.[22]

See also

[edit]

• Beckmann rearrangement
• Bergmann degradation
• Hofmann rearrangement
• Lossen rearrangement
• Schmidt reaction
• Tiemann rearrangement
• Neber rearrangement
• Wolff rearrangement

References

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1. ^ Curtius, Th. (1890). "Ueber Stickstoffwasserstoffsäure (Azoimid) N3H" [On hydrazoic acid (azoimide) N3H]. Berichte der Deutschen Chemischen Gesellschaft zu Berlin. 23 (2): 3023–3033. doi:10.1002/cber.189002302232.
2. ^ Curtius, T. (1894). "20. Hydrazide und Azide organischer Säuren I. Abhandlung" [Hydrazides and azides of organic acids I. paper]. Journal für Praktische Chemie. 50: 275–294. doi:10.1002/prac.18940500125.
3. ^ Kaiser, C.; Weinstock, J. (1988). "Amines from mixed carboxylic-carbonic anhydrides: 1-phenylcyclopentylamine". Organic Syntheses; Collected Volumes, vol. 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.
6. ^ Carey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. p. 948. ISBN 978-0387683546.
7. ^ 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.
8. ^ L'Abbe, G. (1969). "Decomposition and addition reactions of organic azides". Chem. Rev. 69 (3): 345–363. doi:10.1021/cr60259a004.
9. ^ 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.
10. ^ Fahr, E.; Neumann, L. (1965). "Curtius-Reaktion mit Bortrihalogeniden". Angew. Chem. 77 (13): 591. Bibcode:1965AngCh..77..591F. doi:10.1002/ange.19650771308.
11. ^ 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.
12. ^ 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.
13. ^ 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.
14. ^ 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.
15. ^ 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.
16. ^ a b 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.
17. ^ 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.
18. ^ 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. PMID 16146363.
19. ^ 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.
20. ^ Woodward, R. B.; Fukunaga, T.; Kelly, R. C. (1964). "Triquinacene". J. Am. Chem. Soc. 86 (15): 3162–3164. doi:10.1021/ja01069a046.
21. ^ 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. PMID 19123206.
22. ^ 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. PMID 23786450.

External links

[edit] Wikimedia Commons has media related to Curtius rearrangement.

• "Mechanism In Motion: Curtius rearrangement". YouTube. 24 August 2010.

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coupling Carbonyl allylation Carbonyl olefin metathesis Castro–Stephens coupling Chan rearrangement Chan–Lam coupling Claisen condensation Claisen rearrangement Claisen-Schmidt condensation Combes quinoline synthesis Corey–Fuchs reaction Corey–House synthesis Coupling reaction Cross-coupling reaction Cross dehydrogenative coupling Cross-coupling partner Dakin–West reaction Darzens reaction Diels–Alder reaction Doebner reaction Wulff–Dötz reaction Ene reaction Enyne metathesis Ethenolysis Favorskii reaction Ferrier carbocyclization Friedel–Crafts reaction Fujimoto–Belleau reaction Fujiwara–Moritani reaction Fukuyama coupling Gabriel–Colman rearrangement Gattermann reaction Glaser coupling Grignard reaction Grignard reagent Hammick reaction Heck reaction Henry reaction Heterogeneous metal catalyzed cross-coupling High dilution principle Hiyama coupling Homologation reaction Horner–Wadsworth–Emmons reaction Hydrocyanation Hydrovinylation Hydroxymethylation Ivanov reaction Johnson–Corey–Chaykovsky reaction Julia olefination Julia–Kocienski olefination Kauffmann olefination Knoevenagel condensation Knorr pyrrole synthesis Kolbe–Schmitt reaction Kowalski ester homologation Kulinkovich reaction Kumada coupling Liebeskind–Srogl coupling Malonic ester synthesis Mannich reaction McMurry reaction Meerwein arylation Methylenation Michael reaction Minisci reaction Mizoroki-Heck vs. Reductive Heck Nef isocyanide reaction Nef synthesis Negishi coupling Nierenstein reaction Nitro-Mannich reaction Nozaki–Hiyama–Kishi reaction Olefin conversion technology Olefin metathesis Palladium–NHC complex Passerini reaction Peterson olefination Pfitzinger reaction Piancatelli rearrangement Pinacol coupling reaction Prins reaction Quelet reaction Ramberg–Bäcklund reaction Rauhut–Currier reaction Reformatsky reaction Reimer–Tiemann reaction Rieche formylation Ring-closing metathesis Robinson annulation Sakurai reaction Seyferth–Gilbert homologation Shapiro reaction Sonogashira coupling Stetter reaction Stille reaction Stollé synthesis Stork enamine alkylation Suzuki reaction Takai olefination Thermal rearrangement of aromatic hydrocarbons Thorpe reaction Ugi reaction Ullmann reaction Wagner-Jauregg reaction Weinreb ketone synthesis Wittig reaction Wurtz reaction Wurtz–Fittig reaction Zincke–Suhl reaction Homologation reactions Arndt–Eistert reaction Hooker reaction Kiliani–Fischer synthesis Kowalski ester homologation Methoxymethylenetriphenylphosphorane Seyferth–Gilbert homologation Wittig reaction Olefination reactions Bamford–Stevens reaction Barton–Kellogg reaction Boord olefin synthesis Chugaev elimination Cope reaction Corey–Winter olefin synthesis Dehydrohalogenation Elimination reaction Grieco elimination Hofmann elimination Horner–Wadsworth–Emmons reaction Hydrazone iodination Julia olefination Julia–Kocienski olefination Kauffmann olefination McMurry reaction Peterson olefination Ramberg–Bäcklund reaction Shapiro reaction Takai olefination Wittig reaction Carbon-heteroatom bond forming reactions Azo coupling Bartoli indole synthesis Boudouard reaction Cadogan–Sundberg indole synthesis Diazonium compound Esterification Grignard reagent Haloform reaction Hegedus indole synthesis Hurd–Mori 1,2,3-thiadiazole synthesis Kharasch–Sosnovsky reaction Knorr pyrrole synthesis Leimgruber–Batcho indole synthesis Mukaiyama hydration Nenitzescu indole synthesis Oxymercuration reaction Reed reaction Schotten–Baumann reaction Ullmann condensation Williamson ether synthesis Yamaguchi esterification Degradation reactions Barbier–Wieland degradation Bergmann degradation Edman degradation Emde degradation Gallagher–Hollander degradation Hofmann rearrangement Hooker reaction Isosaccharinic acid Marker degradation Ruff degradation Strecker degradation Von Braun amide degradation Weerman degradation Wohl degradation Organic redox reactions Acyloin condensation Adkins–Peterson reaction Akabori amino-acid reaction Alcohol oxidation Algar–Flynn–Oyamada reaction Amide reduction Andrussow process Angeli–Rimini reaction Aromatization Autoxidation Baeyer–Villiger oxidation Barton–McCombie deoxygenation Bechamp reduction Benkeser reaction Bergmann degradation Birch reduction Bohn–Schmidt reaction Bosch reaction Bouveault–Blanc reduction Boyland–Sims oxidation Cannizzaro reaction Carbonyl reduction Clemmensen reduction Collins oxidation Corey–Itsuno reduction Corey–Kim oxidation Corey–Winter olefin synthesis Criegee oxidation Dakin oxidation Davis oxidation Deoxygenation Dess–Martin oxidation DNA oxidation Elbs persulfate oxidation Emde degradation Eschweiler–Clarke reaction Étard reaction Fischer–Tropsch process Fleming–Tamao oxidation Fukuyama reduction Ganem oxidation Glycol cleavage Griesbaum coozonolysis Grundmann aldehyde synthesis Haloform reaction Hydrogenation Hydrogenolysis Hydroxylation Jones oxidation Kiliani–Fischer synthesis Kolbe electrolysis Kornblum oxidation Kornblum–DeLaMare rearrangement Leuckart reaction Ley oxidation Lindgren oxidation Lipid peroxidation Lombardo methylenation Luche reduction Markó–Lam deoxygenation McFadyen–Stevens reaction Meerwein–Ponndorf–Verley reduction Methionine sulfoxide Miyaura borylation Mozingo reduction Noyori asymmetric hydrogenation Omega oxidation Oppenauer oxidation Oxygen rebound mechanism Ozonolysis Parikh–Doering oxidation Pinnick oxidation Prévost reaction Reduction of nitro compounds Reductive amination Riley oxidation Rosenmund reduction Rubottom oxidation Sabatier reaction Sarett oxidation Selenoxide elimination Shapiro reaction Sharpless asymmetric dihydroxylation Epoxidation of allylic alcohols Sharpless epoxidation Sharpless oxyamination Stahl oxidation Staudinger reaction Stephen aldehyde synthesis Swern oxidation Transfer hydrogenation Wacker process Wharton reaction Whiting reaction Wohl–Aue reaction Wolff–Kishner reduction Wolffenstein–Böters reaction Zinin reaction Rearrangement reactions 1,2-rearrangement 1,2-Wittig rearrangement 2,3-sigmatropic rearrangement 2,3-Wittig rearrangement Achmatowicz reaction Alkyne zipper reaction Allen–Millar–Trippett rearrangement Allylic rearrangement Alpha-ketol rearrangement Amadori rearrangement Arndt–Eistert reaction Aza-Cope rearrangement Baker–Venkataraman rearrangement Bamberger rearrangement Banert cascade Beckmann rearrangement Benzilic acid rearrangement Bergman cyclization Bergmann degradation Boekelheide reaction Brook rearrangement Buchner ring expansion Carroll rearrangement Chan rearrangement Claisen rearrangement Cope rearrangement Corey–Fuchs reaction Cornforth rearrangement Criegee rearrangement Curtius rearrangement Demjanov rearrangement Di-π-methane rearrangement Dimroth rearrangement Divinylcyclopropane-cycloheptadiene rearrangement Dowd–Beckwith ring-expansion reaction Electrocyclic reaction Ene reaction Enyne metathesis Favorskii reaction Favorskii rearrangement Ferrier carbocyclization Ferrier rearrangement Fischer–Hepp rearrangement Fries rearrangement Fritsch–Buttenberg–Wiechell rearrangement Gabriel–Colman rearrangement Group transfer reaction Halogen dance rearrangement Hayashi rearrangement Hofmann rearrangement Hofmann–Martius rearrangement Ireland–Claisen rearrangement Jacobsen rearrangement Kornblum–DeLaMare rearrangement Kowalski ester homologation Lobry de Bruyn–Van Ekenstein transformation Lossen rearrangement McFadyen–Stevens reaction McLafferty rearrangement Meyer–Schuster rearrangement Mislow–Evans rearrangement Mumm rearrangement Myers allene synthesis Nazarov cyclization reaction Neber rearrangement Newman–Kwart rearrangement Overman rearrangement Oxy-Cope rearrangement Pericyclic reaction Piancatelli rearrangement Pinacol rearrangement Pummerer rearrangement Ramberg–Bäcklund reaction Ring expansion and contraction Ring-closing metathesis Rupe reaction Schmidt reaction Semipinacol rearrangement Seyferth–Gilbert homologation Sigmatropic reaction Skattebøl rearrangement Smiles rearrangement Sommelet–Hauser rearrangement Stevens rearrangement Stieglitz rearrangement Thermal rearrangement of aromatic hydrocarbons Tiffeneau–Demjanov rearrangement Vinylcyclopropane rearrangement Wagner–Meerwein rearrangement Wallach rearrangement Weerman degradation Westphalen–Lettré rearrangement Willgerodt rearrangement Wolff rearrangement Ring forming reactions 1,3-Dipolar cycloaddition Annulation Azide-alkyne Huisgen cycloaddition Baeyer–Emmerling indole synthesis Bartoli indole synthesis Bergman cyclization Biginelli reaction Bischler–Möhlau indole synthesis Bischler–Napieralski reaction Blum–Ittah aziridine synthesis Bobbitt reaction Bohlmann–Rahtz pyridine synthesis Borsche–Drechsel cyclization Bucherer carbazole synthesis Bucherer–Bergs reaction Cadogan–Sundberg indole synthesis Camps quinoline synthesis Chichibabin pyridine synthesis Cook–Heilbron thiazole synthesis Cycloaddition Darzens reaction Davis–Beirut reaction De Kimpe aziridine synthesis Debus–Radziszewski imidazole synthesis Dieckmann condensation Diels–Alder reaction Feist–Benary synthesis Ferrario–Ackermann reaction Fiesselmann thiophene synthesis Fischer indole synthesis Fischer oxazole synthesis Friedländer synthesis Gewald reaction Graham reaction Hantzsch pyridine synthesis Hegedus indole synthesis Hemetsberger indole synthesis Hofmann–Löffler reaction Hurd–Mori 1,2,3-thiadiazole synthesis Iodolactonization Isay reaction Jacobsen epoxidation Johnson–Corey–Chaykovsky reaction Knorr pyrrole synthesis Knorr quinoline synthesis Kröhnke pyridine synthesis Kulinkovich reaction Larock indole synthesis Madelung synthesis Nazarov cyclization reaction Nenitzescu indole synthesis Niementowski quinazoline synthesis Niementowski quinoline synthesis Paal–Knorr synthesis Paternò–Büchi reaction Pechmann condensation Petrenko-Kritschenko piperidone synthesis Pictet–Spengler reaction Pomeranz–Fritsch reaction Prilezhaev reaction Pschorr cyclization Reissert indole synthesis Ring-closing metathesis Robinson annulation Sharpless epoxidation Simmons–Smith reaction Skraup reaction Urech hydantoin synthesis Van Leusen reaction Wenker synthesis Cycloaddition 1,3-Dipolar cycloaddition 4+4 Photocycloaddition (4+3) cycloaddition 6+4 Cycloaddition Alkyne trimerisation Aza-Diels–Alder reaction Azide-alkyne Huisgen cycloaddition Bradsher cycloaddition Cheletropic reaction Conia-ene reaction Cyclopropanation Diazoalkane 1,3-dipolar cycloaddition Diels–Alder reaction Enone–alkene cycloadditions Hexadehydro Diels–Alder reaction Intramolecular Diels–Alder cycloaddition Inverse electron-demand Diels–Alder reaction Ketene cycloaddition McCormack reaction Metal-centered cycloaddition reactions Nitrone-olefin (3+2) cycloaddition Oxo-Diels–Alder reaction Ozonolysis Pauson–Khand reaction Povarov reaction Prato reaction Retro-Diels–Alder reaction Staudinger synthesis Trimethylenemethane cycloaddition Vinylcyclopropane (5+2) cycloaddition Wagner-Jauregg reaction Heterocycle forming reactions Algar–Flynn–Oyamada reaction Allan–Robinson reaction Auwers synthesis Bamberger triazine synthesis Banert cascade Barton–Zard reaction Bernthsen acridine synthesis Bischler–Napieralski reaction Bobbitt reaction Boger pyridine synthesis Borsche–Drechsel cyclization Bucherer carbazole synthesis Bucherer–Bergs reaction Chichibabin pyridine synthesis Cook–Heilbron thiazole synthesis Diazoalkane 1,3-dipolar cycloaddition Einhorn–Brunner reaction Erlenmeyer–Plöchl azlactone and amino-acid synthesis Feist–Benary synthesis Fischer oxazole synthesis Gabriel–Colman rearrangement Gewald reaction Hantzsch ester Hantzsch pyridine synthesis Herz reaction Knorr pyrrole synthesis Kröhnke pyridine synthesis Lectka enantioselective beta-lactam synthesis Lehmstedt–Tanasescu reaction Niementowski quinazoline synthesis Nitrone-olefin (3+2) cycloaddition Paal–Knorr synthesis Pellizzari reaction Pictet–Spengler reaction Pomeranz–Fritsch reaction Prilezhaev reaction Robinson–Gabriel synthesis Stollé synthesis Urech hydantoin synthesis Wenker synthesis Wohl–Aue reaction

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