Friday, June 12, 2015

Friday Fun: Greening Chromene Synthesis with a Surprise Solvent

Old adage in organic chemistry: "If nothing's happening, keep heating until something does."

A new paper from OPRD takes that advice to heart. The authors, chemists at Merck's Kenilworth discovery site, are attempting to make a difluorochromene as starting material for a gamma-secretase inhibitor. They identify a [3,3] propargyl Claisen reaction as a logical starting point:

Looks simple, right? Well, the original conditions call for heating the alkynyl precursor in N,N-diethylaniline (yuck!) at 195 degrees Celsius (wow!). And all that for a measly 35% yield at scale. From Kong, Meng, and Su:
"There were two challenges for this reaction on large scale: the poor yield and, in particular, substantial amounts of waste produced post reaction. To produce 1 kg of compound 1, we estimated the use of 25 L of N,N-diethylaniline as solvent, 40 L of 4 N HCl to wash away the basic solvent. Combined with the silica gel needed, such a reaction would create roughly 300 kg of solid and liquid waste."
What to do? The authors reason that decomposition of the solvent at such high temperatures might be inducing the starting material to polymerize. Searching for an inert, high-boiling solvent, they land on a run-of-the-mill lab standby: Silicone Oil.

Again, the authors:
"With excellent thermal stability and good heat transfer characteristics, silicone oil has long been used for oil baths in laboratories as well as refrigerants. It is also highly soluble in hydrocarbon solvents such as toluene and xylene as well as chlorinated hydrocarbons, and therefore, it should be a good solvent for nonpolar compounds such as 6 and 1. With the boiling point of 300 °C for silicone oil vs 220 °C for the desired product 1, it should also be possible to obtain compound 1 by distillation, eliminating the workup step and waste production."
Can't argue with any of that reasoning! Sure enough, heating their starting material under nitrogen in Aldrich high-temp silicone oil (14 mL / 1 g) leads to a 64% recovery of 90-95% pure product by distillation. Notably, the same oil can be pushed through a silica gel plug and immediately re-used, with no notable change in yield or color.

Given the sheer number of high-temp cyclizations - ene reactions, Diels-Alder, Cope rearrangements, alkyne trimers, Bergman cyclization - the authors bullishly predict further use of these relatively inert conditions to open up process-scale variants of these banner reactions.

Get your high-temp silicone's set to fly off the shelves this weekend!

Happy Friday,
See Arr Oh


  1. I have seen silicone oil used as a chaser and dilutant in fractional distillation of high-boiling sticky reactions. But running the reaction it is is pretty gutsy.

  2. I usually use PEG 400 as the chaser and to ensure a minimum stirrable volume

  3. I used silicon oil as an undergrad in a Diels-Alder reaction between diphenylacetylene and tetraphenylcylcopentadienone to make hexaphenylbenzene. We ran it in a test tube with a bunsen burner to boil the oil.