Azides safely used to synthesize diamines

Academic researchers often develop organic synthesis methods that offer efficient new routes to industrially important chemicals. But many of these methods are considered untouchable in an industry setting because they involve hazardous reagents that can’t be safely handled on a larger scale or because they are cost-prohibitive to implement. Sometimes, though, a success story does come along.

An industry-academic collaboration led by Hao Xu of Georgia State University and Marino Nebuloni of Italian specialty chemical company Redox Laboratory has developed a gram-scale procedure for directly adding azides to olefins to make vicinal primary diamines (Org. Process Res. Dev. 2017, DOI: 10.1021/acs.oprd.7b00312).

Xu’s group first reported the mild-mannered method in late 2015, converting unfunctionalized linear and cyclic olefins to diamines at room temperature using trimethylsilyl azide, a benziodoxole oxidizing reagent, and an iron catalyst with a tridentate ligand (Angew. Chem. Int. Ed. 2015, DOI: 10.1002/anie.201507550). The reaction drew the attention of industrial chemists as a general approach for producing diamines, Xu tells C&EN. This interest led to the trans-Atlantic partnership to explore the possibility of large-scale applications.

The collaboration with Redox Laboratory involved a safety assessment of the reagents, diazide intermediates, and product diaminium salts. The assessment revealed that the most problematic compounds, the diazide intermediates, are thermally stable but moderately shock-sensitive, and that the diaminium salts made from them are more stable. Guided by that knowledge, the team optimized the procedure to develop a gram-scale reaction to produce diaminium salts directly without having to purify the diazides.

“1,2-Vicinal diamines represent a common scaffold found in many small molecules and a useful building block to synthetic organic chemists,” says Angela Puchlopek-Dermenci, principal scientist in chemical research and development at Pfizer and an associate editor of Organic Process Research & Development,which published the new study. But azidation of olefins commonly used to prepare them is often avoided in industry because of the hazards of handling azides and diazides, she explains.

“The new approach is consistent with industry best practices for safely using energetic compounds,” Puchlopek-Dermenci adds. “In this case, the researchers demonstrate through process safety testing the utility of this iron-catalyzed olefin diazidation method as a rapid, yet safe and scalable, way to access this useful class of compounds.”

Xu says the new chemical process for pharmaceutical production is being patented by Georgia State, and the collaborative team plans to report a second-generation method that is more environmentally friendly and tailored for deactivated substrates as well as functionalized olefins and N-heterocycles.