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Double metal catalyst constructs 5-carbon rings

Side-by-side nickel atoms spur on a 4+1 cycloaddition, providing a possible 5-carbon analog to the classic Diels-Alder reaction

by Bethany Halford
February 21, 2019 | A version of this story appeared in Volume 97, Issue 8


Reaction scheme shows a red diene and a 1.1-dichloroalkene reacting in the presence of zinc and a dinickel catalyst to form a cyclopentene.
An example of a 4+1 cycloaddition that generates five-membered rings.

Creating rings, or carbocycles, with a six-carbon skeleton is an elementary exercise for synthetic organic chemists. Ask one how it’s done, and the chemist will inevitably point to the stalwart Diels-Alder reaction, which weds a 1,3-diene with a dienophile in an elegant 4+2 cycloaddition. But there’s been no analogous method for making five-carbon rings—until now. Purdue University chemists Christopher Uyeda and You-Yun Zhou report a new 4+1 cycloaddition that constructs cyclopentenes from a 1,3-diene and a highly reactive vinylidene.

A catalyst with two side-by-side nickel atoms.

“This reaction allows you to access five-membered rings in a very expedient way. That’s been challenging for a long time in cycloaddition chemistry,” Uyeda says.

The key component of the reaction is a dinickel catalyst in which the two metal atoms sit side-by-side. This catalyst helps form a reactive vinylidene from a 1,1-dichloroalkene and then guides the vinylidene to react with a 1,3-diene (Science 2019, DOI: 10.1126/science.aau0364).

Uyeda’s group has spent years designing ligands that can support two metal atoms in close proximity. They had first used dinickel catalysts to make three-carbon rings via a 2+1 cycloaddition between an alkene and a vinylidene to form a methylenecyclopropane. When Uyeda and Zhou tried using a 1,3-diene instead of an alkene, they formed a five-carbon ring. Surprisingly, they’ve never observed three-carbon ring products when working with 1,3-dienes, probably because it’s easier to make the cyclopentenes than the more strained methylenecyclopropanes.

There’s strong evidence that the 4+1 cycloaddition occurs via a stepwise mechanism, in which the two new C-C bonds form in separate steps. In contrast, the Diels-Alder reaction forms both new C-C bonds at the same time. These distinct mechanisms give the reactions different pros and cons. It’s tougher to control stereochemistry in the 4+1 cycloaddition as compared with the Diels-Alder reaction, Uyeda says. But the new reaction works well with some dienes that perform poorly in the Diels-Alder reaction.

Developing the specific catalyst for the 4+1 cycloaddition was the most challenging part of the research, Uyeda says. Yields with the first catalyst were never greater than 50%, despite Uyeda and Zhou’s efforts to optimize the reaction conditions. The breakthrough, Uyeda says, was recognizing that adding just a little bulk to the metals’ ligand—changing an isopropyl group to a cyclopentyl group—led to a remarkable improvement in the reaction. Uyeda thinks that the additional bulk protects the reactive vinylidene and keeps it from decomposing.

This reaction allows you to access five-membered rings in a very expedient way. That’s been challenging for a long time in cycloaddition chemistry.
Christopher Uyeda, organic chemistry professor, Purdue University

Kay M. Brummond, a chemist at the University of Pittsburgh who develops organic reactions, says the new 4+ 1 cycloaddition “offers an exciting and novel way to synthesize polysubstituted cyclopentenes.” She says that because the precursors for the reaction are readily available and the reaction tolerates many functional groups, including epoxides, esters, and nitriles, it will be useful for synthesizing complex molecules.

“Five- and six-membered carbocycles form the backbone of a great many biologically and therapeutically relevant molecules,” adds the University of Sherbrooke’s Claude Spino, who specializes in organic synthesis. “Such additions to the arsenal of 4+1 cycloaddition methods makes me believe that there will soon be a day when we have a way to make five-membered carbocycles that’s as powerful and popular as the Diels-Alder reaction is for making six-membered carbocycles.”



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