CURTIUS
REARRANGEMENT
PRESENTED TO: Dr. MOHD. AMIR, Dept.
of Pharmaceutical Chemistry
Stanzin Kunzang, [Link]
Pharmaceutical Chemistry 1st Semester,
SPER, Jamia Hamdard
Rearrangement reactions
Curtius Rearrangement
Mechanism
Preparation of Azides
CONTENTS
Variations
Key features
Applications
Examples
Rearrangement Reactions
An atom or group of atoms migrate from one position to another; such reactions are
rearrangement reactions.
After rearrangement, the molecule formed has the atoms arranged differently but has the same
molecular formula as the parent. Therefore, such rearrangements create structural isomers.
The most common migrations are 1,2 rearrangements in which migrating group moves to the
adjacent atom. However, longer rearrangements are also possible.
The rearrangement reactions are of three types, depending on the number of electrons the
migrating group carries along with it.
1. Nucleophilic (migration with electron pair), two methods including carbocation formation e.g
Pinacol, Wagner & nitrene formation e.g Curtius, Lossen, Hoffmann.
2. Electrophilic (migration without electron pair) e.g Wolff
3. Free radicals (migration with one electron)
Curtius Rearrangement
The thermal/photochemical decomposition of acyl azides to produce isocyanates and
nitrogen is known as the Curtius rearrangement.
The isocyanates may be isolated, or subsequent reaction with water leads to amines.
This overall process of converting an azide to a primary amine is commonly referred
to as the Curtius reaction.
Mechanism
Step 1: Thermal/Photochemical decomposition
The thermal/photochemical decomposition leads to the loss of nitrogen from the acyl
azide and formation of an unstable acyl nitrene intermediate where the R group
migrates to the electron deficient nitrogen to give an isocyanate.
Step 2: Transformation of isocyanate
The isocyanate can be either isolated or reacted with water, reaction with water results in the
formation of carbamic acid, which is an unstable compound that gets converted into an amine
after losing a CO2 molecule.
Preparation of Azides
1) By Acyl Chloride
2) By Ester
3) By Carboxylic acid
Variations
Darapasky Degradation Harger Reaction
The Curtius rearrangement produces ethyl The Harger reaction involves Curtius-like
carbamate by heating the azide in ethanol photochemical rearrangement of
and acid hydrolysis of the carbamate gives phosphinic azide which produces
an amino acid is known as Darapasky metaphosphonimidate further hydrolysis
Degradation. with methanol results in the formation of a
phosphoramidite.
The intermediate Isocyanate
Curtius rearrangement is
formed in Curtius reaction can be
Intramolecular in nature.
isolated unlike Hoffmann
rearrangement.
Key
Features
Optically active azides gives Driving force of the reaction is
complete retention in conversion of electron
configuration during the deficient nitrene (highly
reaction, similar to Hoffmann unstable) to isocyanates
rearrangement. (stable).
Applications
• In Curtius rearrangement, further reaction on the
isolated isocyanate with different solvents, water,
alcohol and amine would result in primary amine,
carbamate and urea, respectively.
• The Curtius rearrangement has been utilized in the
synthesis of a wide variety of medicinal agents with
amines and amine‐derived functional groups such as
ureas and urethanes.
• Due to complete retention of stereochemistry of the
molecule, it has been used in synthesis of complex
structured molecules with substituted groups.
• It is applied in synthesize and develop of natural
compounds.
• It has been used in synthesis of various drugs like
Triquinacene, Haemanthidine, Colchicine,
Salicylihalamide A, Belactosin A, Diisocyanodociane
and many more.
Examples of Curtius Rearrangement
Example of reaction in alcohol solvent resulting in carbamate as final
product.
Example of reaction in water as solvent results in primary amine as the final product.
Example of reaction of acyl azide with primary amine as solvent produces urea derivative.
REFERENCES:
• Organic Reactions, Vol 3, The Curtius Reaction, pg no.338-376, Peter [Link], 3rd edition, John Wiley & sons, inc.
• Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Rearrangement Reactions, pg no. 1091-1092, Jerry March, 4th editi
John & Wiley.
• Ghosh AK, Sarkar A, Brindisi M. The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses. Or
Biomol Chem. 2018 Mar 28;16(12):2006-2027. doi: 10.1039/c8ob00138c. Epub 2018 Feb 26. PMID: 29479624; PMCID: PMC5864567
• [Link]
page=343
• [Link]
• [Link]
• Carnaroglio D. et al, One-pot sequential synthesis of isocyanates and urea derivatives via a microwave-assisted Staudinger–aza-Wittig
reaction Beilstein J. Org. Chem. 2013, 9, 2378–2386. doi:10.3762/bjoc.9.274
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