US researchers have cracked a long standing problem in chemical synthesis - the catalytic alpha-alkylation of aldehydes - by combining two catalysts in one pot. The reaction is the first to combine a transition metal catalyst with an organocatalyst, and offers a simple route to compounds that have previously been out of reach, the researchers say.
The reaction relies on the interplay between both catalysts to generate two reactive compounds - an activated aldehyde and alkyl radical - that combine to form the product. Coupling aldehydes to a range of reaction partners, while controlling the product stereochemistry to give a single enantiomer, is a long standing aim of synthetic chemists - but had proven elusive, says David MacMillan, who led the research at Princeton. The new reaction gives good conversion rates, but most importantly, gives complete stereochemical control of product.
The organocatalyst had been used previously by the Princeton group to activate aldehydes. But, despite activation, the aldehyde would only react with a narrow range of highly reactive partners. Adding the inorganic catalyst - a photoactive ruthenium complex - solved this problem, generating a highly reactive alkyl radical in situ that readily attacked the activated aldehyde.

The dual catalytic cycles © Science

The photoactive inorganic ruthenium catalyst that the researchers chose is commonly used to mimic the processes of photosynthesis and operates through a single electron transfer process. However, whereas the light-activated catalysts typically used in synthesis require a powerful UV lamp, a standard light bulb was enough to activate the ruthenium catalyst, which could both pull apart the carbon-halogen bond to form the radical species and reduce the reaction intermediate to generate the desired product.  
'To my knowledge, no-one has taken photoredox catalysis and applied it to organic syntheses' says MacMillan. 'What is amazing is that the light from a standard fume hood is enough to get the reaction to go.'
'Photochemistry usually requires specialist equipment, including a high energy radiation source.' says Matthew Gaunt of the University of Cambridge, UK. 'This system, requiring only the energy from a standard light bulb, makes the process instantly accessible to any synthetic chemist.'
The general chemistry represented could be applied to other organic transformations, say the researchers. Equally, with it requiring such a low energy light source, it has the potential to be scaled-up far beyond the two gram scale that has so far been achieved.
'This is a transformation I consider a "dream reaction",' says Benjamin List, a leader in the field of organocatalysis at the Max Planck Institute in Germany. 'This is clearly a reaction of great promise for natural product synthesis and the production of pharmaceuticals.'
Fred Campbell
Interesting? Spread the word using the 'tools' menu on the left.

ReferencesD A Nicewicz and D W C MacMillan, Science   DOI:10.1126/science.1161976


Sept 4, 2008
Chemistry World

Marriage of photoredox catalysis and organocatalysis creates new enantioselective reaction
Bethany Halford
BY COMBINING two well-established ways of activating molecules—photoredox catalysis and organocatalysis—chemists at Princeton University have achieved the first enantioselective α-alkylation of aldehydes (Science, DOI: 10.1126/science.1161976).
Thanks to the new combined-catalysis concept, this once-elusive asymmetric reaction has become "operationally trivial," according to the researchers, chemistry professor David W. C. MacMillan and postdoc David A. Nicewicz. Furthermore, they say, the combined-catalyst strategy could provide routes to a number of other enantioselective transformations.
MacMillan and Nicewicz selected a ruthenium(II) bipyridine complex, Ru(bpy)32+, as their photoredox catalyst. Although this single-electron-transfer agent has been used in a number of areas, such as energy storage, it hasn't been popular in organic synthesis. The Princeton chemists reasoned they could use the complex to harvest energy from ambient light, such as the overhead lamp in a fume hood, and thereby introduce a single electron into the catalytic cycle. Single-electron mechanisms are common in nature, MacMillan points out, but "as synthetic chemists we don't typically consider one-electron pathways."
In the mechanism proposed by MacMillan and Nicewicz, the ruthenium complex generates an electron-deficient alkyl radical from an alkyl bromide. This radical combines with an enamine formed from the condensation of an aldehyde and a chiral amine catalyst. Subsequent hydrolysis generates an α-alkylated aldehyde. Because it only takes weak light, rather than high-energy ultraviolet light, to initiate the catalytic cycle, MacMillan thinks the process could be useful for manufacturing-scale syntheses.
"MacMillan has managed to effect a challenging transformation with an efficient, versatile, mild, and environmentally benign process," comments John M. Schwab, an organic chemist at the National Institute of General Medical Sciences, in Bethesda, Md.
"I believe this will provide a new paradigm for asymmetric catalysis and at the same time open up the doorway to many new reactions that are currently unknown," MacMillan says. To that end, his group has already applied the "photoredox organocatalysis concept" to a number of other transformations, including benzylation, trifluoromethylation, amination, and alkylcyanation of aldehydes.