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Metalated nitriles: electrophile-dependent alkylations
Fraser F Fleming1, Zhiyu Zhang, Guoqing Wei
1Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282-1530, USA. flemingf@duq.edu
Organic Letters
|January 28, 2005
Summary
Researchers developed a new method for synthesizing chiral nitriles using organometallic chemistry. This approach controls stereochemistry during alkylation, offering access to valuable diastereomeric compounds.
Area of Science:
- Organic Chemistry
- Stereoselective Synthesis
- Organometallic Chemistry
Background:
- Chiral nitriles are important building blocks in pharmaceuticals and agrochemicals.
- Controlling stereochemistry in nitrile synthesis remains a challenge.
Purpose of the Study:
- To develop a novel method for stereoselective synthesis of chiral nitriles.
- To investigate electrophile-dependent stereochemical outcomes in nitrile alkylation.
Main Methods:
- Sequential carbonyl addition-conjugate addition to oxonitriles to form C-magnesiated nitriles.
- Alkylation of C-magnesiated nitriles with various electrophiles (alkyl halides, sulfonates, ketones, aldehydes, acyl cyanides).
- Conversion of C-magnesiated nitriles to N-lithiated nitriles using butyllithium (BuLi) to alter stereoselectivity.
Main Results:
- C-magnesiated nitriles undergo stereoselective alkylation.
- Retention of stereochemistry observed with alkyl halides, sulfonates, and ketones.
- Inversion of stereochemistry observed with aldehydes and acyl cyanides.
- Conversion to N-lithiated nitriles reverses alkylation stereoselectivity.
Conclusions:
- A versatile method for synthesizing chiral nitriles with controlled stereochemistry has been established.
- Electrophile choice dictates the stereochemical outcome of alkylation.
- The N-lithiated nitrile intermediate provides access to diastereomeric products with a quaternary stereocenter.