If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.


Reaction Mechanisms

Reaction expands nitrogen-containing rings and options for medicinal chemists

Reimagined 19th-century method could potentially take advantage of more than 1,600 commercially available reagents

by XiaoZhi Lim, special to C&EN
August 9, 2021


Reaction scheme showing an indole reacting with a chlorodiazirine to get a quinoline substituted with a phenyl group.
Credit: Adapted from J. Am. Chem. Soc.
Reacting an indole (left) with a chlorodiazirine expands the molecule into a quinoline with an added phenyl group (right).

A two-step process inserts a carbon atom into the aromatic nitrogen-containing rings of pyrroles and indoles to expand them into pyridines and quinolines, respectively. The technique expands the tool kit for adding functional groups to pyridine or quinoline scaffolds, which are found in countless drugs and drug candidates (J. Am. Chem. Soc. 2021, DOI: 10.1021/jacs.1c06287).

Researchers led by Mark D. Levin of the University of Chicago updated a reaction first described in 1881 called the Ciamician-Dennstedt rearrangement that produces six-membered pyridine rings by inserting a carbene into a five-membered pyrrole ring. “It looks like it should be really useful, but in practice it doesn’t work as well as it should,” Levin says. Chemists typically generate the carbene by adding chloroform or similar trihalogenated compounds to the reaction, which limits the substituents on the resulting pyridine ring to halogens.

Instead, Levin’s team replaced the chloroform reactants with chlorodiazirines, which break down to a carbynyl cation and nitrogen gas. Like a carbene, the carbynyl cation can add to pyrroles or indoles, expanding them into pyridines or quinolines.

The chlorodiazirine reactants can be prepared in one step by oxidizing commercially available amidines with bleach, and there are more than 1,600 such amidines bearing different substituents to choose from. Levin hopes this reaction will make it easier for medicinal chemists to synthesize challenging pyridine or quinoline drug leads without having to build them all from scratch.


This story was updated on Aug. 19, 2021, to correct a misspelling. The reaction expands indoles into quinolines, not quinolones.


This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.