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Taming Diazomethane

Organic Synthesis: Hazardous reagent generated without distillation

by Bethany Halford
March 26, 2012 | A version of this story appeared in Volume 90, Issue 13

This scheme shows how a cyclopropyl product forms from a Diazald derivative.

With the help of an inexpensive iron porphyrin catalyst, chemists in Switzerland have developed a safe way to generate diazomethane, an important reagent for cyclopropanation reactions (Science, DOI: 10.1126/science.1218781). The new user-friendly protocol provides chemists with easy access to cyclopropyl groups for pharmaceuticals and materials.

As tools of the chemical trade go, diazomethane (CH2N2) demands special care. Not only is it explosive, but it’s also highly toxic. Even less explosive analogs of the compound, such as trimethylsilyldiazomethane, have proven deadly, with two chemists succumbing to the effects of that compound in separate events in 2008 (C&EN, May 9, 2011, page 15).

Chemists usually generate diazomethane by treating the N-nitroso compound Diazald with base and then distilling the resulting diazomethane with a specialized apparatus to lessen the chance of explosion. Now, Erick M. Carreira and Bill Morandi of the Swiss Federal Institute of Technology, Zurich, have developed a way of generating diazomethane in situ and then trapping its reactive carbene with a metal catalyst, circumventing the need for distillation.

The team slowly adds a Diazald derivative to 6 M potassium hydroxide. An iron porphyrin catalyst then consumes the resulting diazomethane by forming a metal-carbene complex. Next, this complex reacts with a double bond in another reagent to form a cyclopropyl group. The researchers found the reaction works well to cyclopropanate styrene derivatives, dienes, and enynes.

“The lack of practical, scalable methods for the construction of cyclopropanes is a long-standing problem in industrial chemistry,” notes Matthew M. Bio, director of process development at Amgen. He says the reaction “will certainly find application in pharmaceutical and fine chemicals manufacturing. This development has the potential to significantly reduce the cost of bringing new cyclopropane-bearing therapeutics and materials to market.”


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