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  Cover Story  
  September 6,  2004
Volume 82, Number 36
pp. 59-61
 

  VARIATIONS ON THE COUPLING THEME
Chemistries similar to Suzuki coupling are multiplying access to synthetic targets
 

  A. MAUREEN ROUHI, C&EN WASHINGTON  
   
 
 

Strictly speaking, suzuki coupling is the palladium-catalyzed reaction of an organic halide and an organoboron compound to form a carbon-carbon bond. It is only one of a family of palladium-catalyzed cross-coupling reactions between an organic halide, acting as an electrophile, and an organometallic reagent, acting as a nucleophile. Others in this family are the Negishi and Stille reactions, which could be viewed as Suzuki variations based on modifying the organometallic reagent: an organozinc for the Negishi and an organotin for the Stille.

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Another variation is to replace the palladium catalyst with a different metal. Still another is to use, instead of the organometallic reagent, a metal-free nucleophile--such as an amine--in order to make a carbon-nitrogen bond. These variations on a theme are yielding new solutions to chemical development problems.

At Clariant, for example, Grignard chemistry is always an option in preparing biaryls. In the Grignard coupling, the organometallic reagent is an arylmagnesium halide. The chemistry complements Suzuki coupling, and whenever it is possible to use the Grignard reaction, the economics often are better, says Ralf Pfirmann, Clariant's global business director for pharmaceuticals.

That's because the Grignard route does not use boronic acids and often produces higher yields than does the Suzuki reaction, Pfirmann says. Moreover, because of Clariant's highly active proprietary palladium catalysts for this coupling, much less palladium is required. Clariant's experience is that up to 70% of the aryl-aryl couplings they get inquiries about can be done through the Grignard route, he says.

Meanwhile, use of organosilicon compounds instead of organoboron reagents is gaining in industry. Several drawbacks of boronic acids in particular have opened opportunities for other chemistries, says Scott E. Denmark, a chemistry professor at the University of Illinois, Urbana-Champaign, and a proponent of couplings with organosilicon compounds. Boronic acids are not easy to handle, he explains. They are difficult to purify, and they do not tolerate manipulations of the molecule that they are a part of.

Philip DeShong, a chemistry professor at the University of Maryland, College Park, and another proponent of couplings with organosilicon compounds, concurs. Although many boronic acids are stable and available commercially, highly functionalized ones are difficult to prepare, and some boronic acids are unstable and lose boron readily, he explains. Furthermore, boronic acids tend to couple with each other rather than with the Suzuki partner, forming significant amounts of homocoupling product, he adds.

Organosilicon compounds overcome many of these drawbacks. As it happens, silicon is easy to incorporate into organic molecules, and Denmark and DeShong have advanced different silicon reagents for coupling.

DeShong has focused on arylsiloxanes of the type C6H5Si(OR)3. He says these are easy to prepare, are not prone to homocoupling, and are reactive with a broad range of coupling partners, including aryl and heteroaryl iodides, bromides, chlorides, and triflates, as well as alkenyl halides.

Furthermore, DeShong has uncovered a unique reactivity: When another group, such as fluorine, is added to arylsiloxanes such as C6H5Si(OR)3, the resulting silicate, C6H5Si(OR)3F, can couple with cyclic allylic esters. "There's a patent pending on this chemistry," DeShong says. "Boronic acids can't do it." In work being written up for publication, the chemistry has been applied to a cyclic allylic carbonate in the synthesis of an analog of 7-deoxypancratistatin, a promising antitumor agent.

ON THE OTHER HAND, Denmark has raised the profile of organosilanols, which are the silicon equivalents of alcohols. From mechanistic work and empirical optimization, his group has determined that in most of the couplings of organosilicon compounds, silanols are really the active components. "The wonderful thing about silanols is that they are just like ordinary alcohols: shelf stable, not air sensitive, and not water sensitive. They can be chromatographed and distilled." Denmark has developed coupling protocols for a variety of organosilanols, notably alkenylsilanols.

Chemists at Johnson & Johnson are raving about Denmark's chemistry. It has just been used to make hundred-gram quantities of an intermediate to a drug candidate, says Neelakandha S. Mani, principal scientist for scale-up synthesis.

The task was to attach a vinyl group to a methoxyquinoline. The Suzuki route would have accomplished that by coupling a bromoquinoline with a vinylation coupling agent. The typical reagent is vinylboronic acid dibutyl ester, which costs $17.08 per g, according to Mani. Its reaction produces significant amounts of the by-product.

"We were looking for not only an inexpensive coupling partner but also an inexpensive overall process--one where you don't have to spend too much time purifying the product," Mani says. "The simplest and fastest way to go" was with Denmark's reaction, which uses polyvinyldimethylsiloxane, a cyclic oligomer of vinyldimethylsilanol that costs 80 cents per g, or 5% of the cost of the boronic acid. And, Mani says, "the product that's coming out is clean. We just love this chemistry."

The most recent development from Denmark's lab is coupling of 2-indolyldimethylsilanols with aryl iodides and bromides. "Indoles are very important pharmacophores, as well as natural product cores," Denmark says. With organosilanes, a cross-coupling can occur at the activated position of indoles. If a boronic acid is in that position, it usually just falls off under coupling conditions, he explains.

Elsewhere, Suzuki couplings using nickel as catalyst are being promoted. At Solvias, for example, researchers resort to nickel systems when palladium catalysis is not effective. The use of nickel is not novel, but only in recent years have catalytic systems become efficient and versatile enough for industrial consideration.

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NICKEL IS PREFERABLE to palladium because it is less expensive and easier to remove from products, says Simon Sellers, president of the fine chemicals division of Sumitomo Chemicals America. Recently, Sumitomo began offering nickel-based systems for Suzuki coupling. "We have seen instances where our chemistry has been preferred for a custom synthesis job because nickel can be cleaned up easily to less than 1 ppm," Sellers says.

Sumitomo has worked out protocols involving either phosphine or nonphosphine ligands. Reactions proceed under mild conditions, which is an advantage when the chirality of substrates must be maintained. One system allows coupling of phenylboronic acid with bromo- or chlorooctane in up to 87% yield. According to Sellers, this nickel-catalyzed sp3-sp2 carbon-carbon bond formation is unprecedented. Sumitomo has not disclosed details.

Qiao-Sheng Hu, an assistant professor of chemistry at the College of Staten Island of the City University of New York, also promotes nickel systems as less expensive alternatives. He has shown that the tricyclohexylphosphine-nickel(0) complex, which costs much less, efficiently catalyzes room-temperature couplings of aryl arenesulfonates with boronic acids. He points out that this catalyst works consistently at room temperature with substrates that may not be activated.

"The mild reaction conditions, the wide availability of aryl arenesulfonates and the catalyst, and the high yields make this catalytic system very useful in organic synthesis," he says. However, the system needs more work. Nickel(0) is air sensitive, and Hu is testing whether air-stable nickel(II) chloride complexes will work.

Perhaps the most exciting variations are reactions in which the nucleophilic organometallic reagent is replaced by a metal-free nucleophile. These typically lead to carbon–X coupling, in which X is nitrogen or some other heteroatom. Thus, coupling of an aryl halide and an amine forms aromatic amines, a reaction made practical by catalytic systems almost simultaneously developed by Stephen L. Buchwald and John F. Hartwig, chemistry professors at Massachusetts Institute of Technology and Yale University, respectively. Buchwald's amination chemistry is being commercialized by Rhodia Pharma Solutions and Lanxess (see page 62).

Before the Buchwald-Hartwig method, no general reaction for the conversion of aryl halides into aromatic amines was available. The reaction "has had a profound effect on the way that drug discovery chemists make aromatic amine derivatives," Buchwald says. "Because so many of the compounds they want to make are aromatic amines, this reaction is one of the most highly used in their repertoire."

Others have joined in making aminations practical. In the past two years, Solvias has been honing its amination capability. With its proprietary ligand SK-CC02-A, the company is advancing the reaction's usefulness. Early this year, Degussa introduced so-called cataCXium P ligands, which are proving to be effective in amination of aryl chlorides. And just recently, Johnson Matthey licensed Q-Phos, a ligand from the Hartwig lab.

If as much R&D is focused on amination as has happened with Suzuki coupling, amination could soon be practiced as widely. Then chemists will likely turn to other coupling reactions that have great potential but are still underdeveloped.

 
MORE ON THIS STORY

FINE CHEMICALS
Suzuki-coupling chemistry takes hold in commercial practice, from small-scale synthesis of screening compounds to industrial production of active ingredients

WHEN COOPERATIVE RIVALRY WORKS
Two fine chemicals companies separately but cooperatively bring key technology to market

OUTSIDE-THE-BOX APPROACH TO BIARYLS
By not using a Suzuki coupling, seasoned process chemist dramatically reduces cost of synthesis

     
  Chemical & Engineering News
ISSN 0009-2347
Copyright © 2004
 


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MORE ON THIS STORY
WHEN COOPERATIVE RIVALRY WORKS
Two fine chemicals companies separately but cooperatively bring key technology to market
OUTSIDE-THE-BOX APPROACH TO BIARYLS
By not using a Suzuki coupling, seasoned process chemist dramatically reduces cost of synthesis


Related Story
FINE CHEMICALS
[C&EN, July 14, 2003]  


 
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