Carbonyldiimidazole (CDI)

Mechanism + Description

Activation of the alcohol as a mixed carbamate followed by displacement with liberated imidazole

General comments

For a limited range of alcohols and its thio-analogue, has been shown to convert alcohols directly to N-alkylated imidazoles. If certain structural requirements are met, chiral integrity is maintained. Triazole versions of CDI also undergo this transformation.  For amino alcohols where cyclization is possible, CDI has been reported as a greener alternative to Mitsunobu or Appel reagents for ring formation.

Key references

J. Org. Chem. 1997, 62, 7319-7323 Imidazole Transfer from 1,1-Carbonyldimidazole and 1,1¢-(Thiocarbonyl)diimidazole to Alcohols. A New Protocol for the Conversion of Alcohols to Alkylheterocycles

J. Org. Chem. 2004, 69, 5124-5127 Regio- and Stereospecific Syntheses of from the Reaction of 1,1¢-Carbonyldiimidazole with syn– and anti-1,2-Amino Alcohols

J. Org. Chem. 2006, 71, 4147-4154 N,N-Carbonyldiimidazole-Mediated Cyclization of Amino Alcohols to Substituted Azetidines and Other N-Heterocycles

Relevant scale up example

Experimental
100g scale- heat in EtOAc
Org. Process Res. Dev. 2001, 5, 467-471

Green Review

1. Atom efficiency (by-products Mwt)
   Reaction generates one mole of CO (28) and 1 mole imidazole (68) as by-products, so medium atom efficiency.
2. Safety Concerns
   No major concerns. Reactions will generate carbon dioxide off gas.
3. Toxicity and environmental/aquatic impact
   Reagent decomposes to innocuous products. Imidazole is emerging as a material with ECHA review to categorize due to emerging reproductive toxicity issues.
4. Cost, availability & sustainable feedstocks
   CDI is readily available and a cheap reagent – most often used for amide formation.
5. Sustainable implications
   More sustainable than the Mitsunobu reaction, but currently limited in scope. Possibly a good choice for ring formation.