OK it was an extended time away from posting — I totally blame the Turkey, Ham, Beer, Stuffing, Pie — at least I have tapered off over the years.
So what’s sitting on my desk — after several pontifications, I have gotten back to thinking about how chemists think about their chemistry and where it can go in flow processes — so, OK, retrosynthesis — but I often think in classes of fragments and what they can do (think of it as a review on enaminone transformations so to speak). In this case, Ian Baxendale got me thinking about ynones or alpha, beta-acteylenic ketones — used quite a bit right? furans, flavones, pyrazoles, pyrimidines and heck back at Bayer I used them in a number of dipolarcycloadditions and intramolecular cyclizations to isoxazoles and pyrroles……you get the point……if interested in a nice article on using a flow approach to ynones and their divergent reaction with different nucleophiles then (Chem Eur Journal 2010) is the ticket.
In the three schemes below we see the utility of using several clean-up and scavenging steps to develop an outnumbering process to libraries of heterocycles with a single ynone. By starting with a simple acid chloride under Sonogashira coupling conditions (Pd(OAc)2, Hunig’s Base) with an acetylene at 100C over a 30 min period, the ynone is formed and used with several reagents (hydrazines, guanidines, etc) to form libraries. To take this to the crux, 4 columns were used to clean up the ynone or post nucleophilic reaction: polyol for the acid chloride, CaCO3 for the HCl and knock the ammonium salts, sulfonic acid for the tertiary amines and finally an immobilized thiourea for the Pd catalyst prior to diverting the product to additional steps. On a personal level, this really shows the power of combining purification techniques (many which have fallen through the educational cracks of developing a thought process around what’s going on in a reaction — I was lucky enough to learn most of this because I had too many nitrogens around my compounds of interest) with the power of flow methodology.
Happy Reading! Good to be back!