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July 9, 2008
Also appeared in print Jul. 14, 2008, p. 7


Hydrochlorination Reformation

Transition-metal catalysis lets more substrates take part in a textbook reaction

Carmen Drahl

With the help of an unexpected reagent, chemists Boris Gaspar and Erick M. Carreira at the Swiss Federal Institute of Technology, Zurich, have developed an alternative way to carry out a fundamental transformation in organic synthesis: the addition of hydrogen chloride to alkenes (Angew. Chem. Int. Ed., DOI:10.1002/anie.200801760).

One of the cobalt catalysts used by Gaspar and Carreira.
One of the cobalt catalysts used by Gaspar and Carreira.

The cobalt-catalyzed process, which uses p-toluenesulfonyl chloride (TsCl) to deliver a chlorine atom, could streamline production of alkyl chlorides, which are versatile building blocks for making materials and pharmaceuticals.

The textbook reaction for directly adding HCl to alkenes generally requires strong acid as a catalyst. This makes the reaction difficult to use in the presence of acid-sensitive groups, which are abundant in many important intermediates. In reality, Carreira says, researchers therefore rarely use that reaction to convert alkenes to alkyl chlorides and instead tend to use a three-step process in which the alkene is first hydroxylated and the hydroxyl group is ultimately displaced to make the chloride. The new procedure moves beyond the "tried and tested rut of doing things," Carreira says.

To develop sound hydrochlorination conditions that would work around acid-sensitive groups, Gaspar and Carreira turned to cobalt catalysts. This strategy had already proven successful in Carreira???s group for preparing species such as azides and nitriles from olefins. Their search for an alternative source of Cl for such addition reactions turned up a surprising reagent—TsCl.

Normally, this reagent transfers its toluenesulfonyl moiety in reactions, Carreira explains. But because the team had used a related reagent in their olefin azidation and cyanation work, they decided to give TsCl a shot as a Cl-transfer reagent. The gamble paid off, despite there being little precedent for the reactivity they observed.

In praising the researchers' "exceptionally creative" approach, transition-metal catalysis expert John F. Hartwig at the University of Illinois, Urbana-Champaign, notes that few people would have imagined using TsCl in this way.

The new procedure has the same selectivity as a traditional HCl addition, consistently placing the chlorine atom on the more substituted alkene carbon. Furthermore, the new conditions convert monosubstituted olefins, which typically fail to undergo conventional HCl addition, to the corresponding chlorides. The reaction also works in the presence of acid-sensitive moieties such as silicon-based protecting groups.

The current incarnation of the reaction is not enantioselective, but the catalyst system could be modified to make that possible, says chemist Matthew S. Sigman of the University of Utah. Sigman recently developed a palladium-catalyzed hydrochlorination reaction for styrenes, which do not react under Carreira's conditions (Organometallics 2007, 26, 5680).

The Zurich team is still working out the details of the reaction mechanism, particularly regarding the role of TsCl. But researchers are likely to try the method long before those results are announced, Hartwig says. "Given the recent interest in halogenated natural products and the wide utility of alkyl halides as synthetic intermediates, I expect this method to be used immediately," he says.

DONATION Transition-metal-catalyzed route to alkyl chlorides from alkenes makes use of p-toluenesulfonyl chloride.
DONATION Transition-metal-catalyzed route to alkyl chlorides from alkenes makes use of p-toluenesulfonyl chloride.

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Chemical & Engineering News
ISSN 0009-2347
Copyright © 2009 American Chemical Society


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