Flow chemistry has been often described as a method of generating and handling small quantities of highly reactive species, and that is precisely what Professor Thomas Wirth and his team, from Cardiff University, have taken advantage of with some quite challenging diazo organolithium intermediates.
Using a Vapourtec E-series, Wirth and his team have been able to expand the use of ethyl diazoacetate, a commonly used diazo containing nucleophile but that is usually limited to reaction with aldehyde electrophiles, to access ketone and lactone electrophiles as well. Reaction of ethyl diazoacetate with lithium diisopropylamide generates the ethyl lithiodiazoacetate, sufficiently nucleophilic to attack ketone and lactone groups. In the text, Wirth explains “Diazo compounds are energetic compounds that can react highly exothermically. This prevents their large-scale use under standard batch conditions. Similar to other hazardous reagents, continuous flow technology can provide a solution to this problem”.
A highly unstable intermediate, ethyl lithiodiazoacete decomposes very rapidly above – 50 °C, so Wirth and his team used a dry ice/acetone cooling bath to ensure their reactors were maintained at – 78 °C, generated the intermediate in situ as it was needed, and passed directly to a substituted acetophenone substrate. The yields obtained were consistently higher than those found in the often difficult to replicate batch reaction, and the use of a Vapourtec E-series, capable of pumping the butylithium starting materials, and flow chemistry method greatly reduced the risk of producing and handling such an energetic intermediate.
Research Scientist at Vapourtec, Dr Ryan Skilton comments “diazo compounds are very useful to the synthetic chemist, but they are hazardous to handle in large quantities. Using flow chemistry, Professor Wirth and his team have not only been able to use these highly reactive materials to great effect, but has also demonstrated that the flow protocol makes it possible to work with the diazo organolithium intermediate in a very efficient, and most importantly, much safer way”.
