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Test your metal: How many of these transition metal-catalyzed couplings have you used?

Oct. 23, 2018

Transition metal-catalyzed coupling reactions are an important family of chemical transformations that are commonly used to create new carbon-carbon and carbon-heteroatom bonds from structurally useful building blocks. These convenient reactions offer chemists a synthetic short-cut to a broad range of pharmaceutical, agrochemical and industrial compounds.

Without transition metal-catalyzed coupling reactions, many of the chemicals used in everyday life couldn’t be produced anywhere near as quickly or cost-effectively (or even at all). They’re so valuable, in fact, that the 2010 Nobel Prize in Chemistry was awarded to Richard F. Heck, Ei-ichi Negishi and Akira Suzuki in recognition of their remarkable contributions to the development of palladium-catalyzed cross-coupling reactions (more on these award-winning transformations below!).

Transition metal-catalyzed coupling reactions fall into two broad categories: homocouplings and heterocouplings (also known as cross-coupling reactions). Homocoupling reactions bring two identical structures together to form a new product, while cross-couplings react two different reagents. Palladium is the most widely-used transition metal catalyst for coupling reactions, although the use of nickel is increasing. Some coupling reactions also employ copper, platinum, iron or cobalt catalysts.

In this blog, we take a closer look at five of the most important transition metal-catalyzed reactions. How many have you used?

1. Ullmann reaction

No list of transition metal-catalyzed couplings would be complete without the Ullmann reaction. First discovered in 1901 by German chemist Fritz Ullmann (making it one of the earliest reported transition metal-catalyzed coupling reactions), this method of generating biaryl products from aryl halides originally used copper powder as a catalyst. Today, greater reaction efficiency can be achieved by activating the metal catalyst prior to use. This is typically achieved by reducing copper iodide with lithium naphthalenide or reducing copper sulfate with zinc. These improvements also mean that the reaction can be performed at lower temperatures.

2. Heck reaction

Since its discovery in the 1970s by Tsutomu Mizoroki and Richard F. Heck, the palladium-catalyzed coupling of aryl, benzyl and styryl halides with alkenes in the presence of a hindered base has become one of the most important carbon-carbon bond-forming transformations in organic chemistry. Now commonly known as the Heck reaction, this flexible method tolerates a wide range of functional groups, including esters, ethers, carboxylic acids, nitriles and phenols, amongst others (that’s one heck of a versatile reagent list!). Over the decades, method optimizations and water soluble catalysts have been developed that allow the reaction to be performed in water – helping to reduce the use of less environmentally-friendly solvents.

3. Negishi cross-coupling reaction

The discovery of the reaction we know today as the Negishi cross-coupling reaction was driven by a need to improve the functional group tolerance of earlier nickel-catalyzed cross-coupling of alkenyl and aryl halides with Grignard reagents (known as Kumada cross-coupling reactions). In the mid-1970s Japanese chemist Ei-ichi Negishi and others studied the impact of using less electropositive organometallic reagents. They found that improved reactivity, yield and stereoselectivity of alkenyl and aryl halides coupling reactions could be achieved when organozinc reagents were used in combination with palladium catalysts. Organozinc reagents offer much greater functional group tolerance than Kumada reactions, as well as fewer side reactions and lower toxicity.

4. Stille cross-coupling reaction

First reported in 1978 by American chemist John Stille, the Stille cross-coupling reaction has proven to be a very useful method of synthesizing ketones from organotin compounds and aryl halides. While it wasn’t the first transition metal-catalyzed coupling reaction of organotins (fellow chemists Colin Eaborn, Toshihiko Migita, and Masanori Kosugi had all reported their own palladium-catalyzed cross-coupling reactions of these compounds a few years earlier), the Stille reaction is notable for its mild reaction conditions and broad functional group tolerance. Although the tin precursors used in this reaction typically have high toxicities, their tolerance to air and moisture offers significant advantages over other organometallics.

5. Suzuki cross-coupling reaction

The Suzuki cross-coupling reaction is one of the best-known transformations of its kind. First reported in 1979 by Japanese chemist Akira Suzuki, this palladium-catalyzed cross-coupling reaction between organoboron compounds and organic halides or triflates is a highly useful method of generating carbon-carbon bonds. The Suzuki reaction offers a number of advantages over other carbon-carbon bond forming transformations. For example, while the Suzuki cross-coupling method employs mild conditions much like the Stille reaction, the boronic acids that are used in the Suzuki reaction are much less toxic and environmentally damaging than the Stille’s organostannane reagents.

Other transition metal-catalyzed coupling reactions

The transformations named here are by no means the only transition-metal catalyzed coupling reactions. There are a whole host of others, including the Buchwald-Hartwig coupling, Castro-Stevens coupling, Glaser coupling, Larock indole synthesis, Miyaura boration and Sonagashira cross-coupling. All of these coupling reactions are important additions to the synthetic chemist’s toolbox – and all rely on transition metal catalysts. To find out more, visit our transition metal-catalyzed coupling reactions page.


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