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Cyanation Optimization

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Maham Haider

on 28 April 2017

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Transcript of Cyanation Optimization

Natural Product Derivatives
Mild Palladium-Catalyzed Cyanation of (Hetero)aryl Halides and Triflates in Aqueous Media
Daniel T. Cohen and Stephen L. Buchwald
Optimization
Finding the Optimum for Each Variable
Scope
Thank You!
Mild, efficient, and low-temperature palladium-catalyzed cyanation is reported.
Previous attempts required higher temperatures to achieve good catalytic activity.
Method was applied to the synthesis of lersivirine (reverse transcriptase inhibitor)

Problems with Existing Reaction
The Constants and the Variables
Catalyst Poisoning
The Hassle
High Temperatures
CN as a great Ligand
Inactive off-cycle species
Cyanide Source that is Sparingly Soluble
Grinding the Cyanide Source
50-80 degree Centigrade
Less Efficient
Lowers substrate scope
The Palladium Source
Nucleophile: Zn(CN)2
Solvent: THF
Third Generation Palladacycle Precatalyst
Commercially Available
Inexpensive
Less Toxic
Preliminary solvent screen
Ligand
Activating the Catalyst
Solvent
Aryl Bromides with Electron Withdrawing Groups
Aryl Bromides with Electron Donating Groups
Heteroaryl Bromides
Larger Scale
The molecules that the reaction works with
Advantages
Mild
Hassle Free
Broad Range
Late Stage Cyanation
As the pKa of the base increased, the yield decreased
* Maximum yield with no base >> CN ideal base for activation

H2O : THF ratio
5 : 1 ratio lead to full conversion of aryl chloride
and 89% isolated yield of nitrile
Testing direct applications in pharmaceutical research
10 mmol without significant modification to reaction conditions
88% yield at 40 degree Centigrade
Efficient
No grinding of cyanide source
No vigorous drying of glassware
Wide range of five and six membered heterocycles
Full transcript