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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. 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 |
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