Often times I hear frustration from the pharma community on the types of examples that are used to show applicability of instrumentation in continuous flow synthesis. Perhaps it is simply too time consuming to sieve through the literature to find a match to the project at hand….and flow examples are still in their infancy compared with examples of microwave examples — we need a great book of examples broken down by transformation (ala, Larock or by formation of privileged structures). Believe me, I am in front of this everyday and it is a job to find something that sparks the interest of many, but upsetting that traction has not taken root in our synthetic communities as well as it should for this technology.
Ha — now that’s better… a recent article had me thinking where many would fold up shop, this group dissected some of the usual development it takes to improve a reaction in flow: solubility, treatment of dangerous reagents, flow of more than one component in a reaction and the applicability of the research. A recent publication on the synthesis of hydantoins provided an excellent look at some of the issues, but also a concise plan for developing methods using flow designs:
Julia Monteiro, Bartholomäus Piebera Arlene Corrêa, Oliver Kappe Synlett 2015
Below I have indicated the scheme followed by a table of yields under optimized conditions:
What you don’t see is how they get there and what issues are present at the starting point (makes for great problem solving): The first that becomes apparent is the use of KCN as a dangerous reagent and how things can play out on scaling, the second is how to mix organic and aqueous based reagents together without precipitation or clogging at high temp (certainly sounds at first that this would not be something to start with), and lastly would the proper flow of the reactants provide addition of the CN and ammonia groups followed by CO reaction and rearrangement in enough time to provide a useful set of transformations. Of course the answer to all if these is yes — each works well, but how about the perspective in thinking……KCN at high temp and some pressure –well the get thing about continuous flow is that there is no head-space and at high temp no room for the generation of dangerous gas reactants [it is a huge benefit that is not talked about enough]. Secondly, mixing of a biphasic solution — this is a bit challenging and an interesting read — you have to time the pumping of reagents and the mixing isn’t intuitive but something that can be achieved by telescoping with several solvents to maintain a laminar (as close to as needed) flow for the reaction and once proper mixing is achieved, the adequate Tres can be achieved with 2 separate pumps.
The group went on to show a match comparison with a microwave batch version resulting in lower conversion to the product for many of the initial reasons talked about. With that in hand, they went on to show that a number of changes in the starting aldehydes and ketones provided excellent yields of a variety of hydantoins….so you can see this should be a great concept generator of similar scaffolds that can be constructed in a similar manner.