Deoxygenation without Tin

ORGANIC SYNTHESIS

Synthetic chemists looking to replace hydroxyl groups with hydrogen atoms can now do so without using toxic organotin hydride reagents, thanks to a new deoxygenation procedure for alcohols. The reaction, discovered in chemistry professor John L. Wood's lab at Yale University, uses trialkylborane-water complexes as an alternative to the traditional tin reagents (J. Am. Chem. Soc. 2005, 127, 12513).

Although it's been around for 30 years, the Barton-McCombie deoxygenation--in which an alcohol is converted to a xanthate ester, enabling replacement of the hydroxyl with a hydrogen atom via a radical process--remains one of the most useful reactions in an organic chemist's arsenal. But the organotin hydride reagents that serve as the reaction's hydrogen source are both inconvenient and unpleasant to use. They are toxic, expensive, smelly, and difficult to separate from the reaction products, Wood explains.

Even so, Wood wasn't trying to develop a new deoxygenation process when he made his discovery. Rather, he and graduate student David A. Spiegel were having trouble getting a critical fragmentation reaction to work in their efforts to synthesize a series of phomoidride natural products. After trying a number of reagents, they turned to the conditions of the Barton-McCombie reaction. These, too, failed, quickly reducing the xanthate ester before any fragmentation could occur.

Looking for a way to tweak the reaction conditions, the researchers came across a lone report of a triethylborane-air deoxygenation of a xanthate ester that seemed to proceed via the slow reduction of an alkyl radical. Wood and Spiegel reasoned that they could slow the reaction further by substituting trimethylborane for triethylborane.

To their surprise, not only did the fragmentation not occur, but deoxygenation occurred again. This time, however, the reaction proceeded quickly, quantitatively, and under mild conditions. "It's important to be curious about reactions that don't necessarily do what you want them to do," Wood points out. Realizing that they may have discovered a new procedure for deoxygenation, Wood's team tried the reaction with a series of xanthate esters and found that the reaction was indeed a general deoxygenation procedure.

One question continued to puzzle Wood. Without the tin hydride, what was the source of the hydrogen atom? By the process of elimination, his team traced the source to a small amount of water contaminating the starting material.

"The use of water as a radical hydrogen-transfer agent? Nothing could be more counterintuitive," says Dennis P. Curran, a chemistry professor and radical chemistry expert at the University of Pittsburgh.

Wood enlisted Yale chemistry professor emeritus Kenneth B. Wiberg to do some calculations. They found that the O-H bond dissociation energy dramatically decreases when water complexes to the trialkylborane. "This is a superb example of investigative work that produces both novel mechanistic insights and a method of value for synthesis," says Stanford University chemistry professor Paul A. Wender of the report.

"It's a real stunner that Wood provides both experimental and theoretical evidence that the trimethylborane-water complex can act as a hydrogen-atom donor to carbon radicals," Curran adds. "This is one of those thought-provoking papers that raises more questions than it answers. I have a feeling that there must be more here than meets the eye, and that's intriguing because what meets the eye is already very interesting."