Before the preparation, anhydrous potassium carbonate (granulated, Aldrich) was powdered with a spatula and dried in a beaker in glassware-drying oven at 130C overnight. In a microwave-ready pressure vial equipped with a stirbar, 2-chloro-6-(N-morpholinyl)-4-pyranone 216mg (1.00mmol) mixture with thiantrene-1-boronic acid 390mg (1.5mmol, 90% pure, Aldrich), dry potassium carbonate 1.4g and activated 4A molecular sieves 1.1g (powder <5um, Aldrich) was suspended in anhydrous dioxane 16mL and the slurry was sparged with Ar gas for 10 min. Pd(PPh3)4 90mg (7.5mol%) was added and sparging was continued for additional 10 min. The vial was then capped under Ar and heated in a Biotage “Initiator” microwave at 130C for 2 hours. The cooled reaction mixture was poured onto a pad of silica 20g and the solids on the silica pad were washed with ethyl acetate 100mL - these first filtrates were discarded. The silica pad was then washed with a 2:1 chloroform + methanol mix 300mL; the methanolic filtrates were evaporated. Purification of the crude product on a silica column (40 g) in a methanol gradient in chloroform, 0 to 5% MeOH provided the pure product as a sticky glass. This purified product was dissolved in benzene (10mL) and the solution was freeze-dried on highvac. Y=345mg (87%) of a fluffy light-tan amorphous solid.
1H(d6-DMSO, 400MHz): 7.763(app d, 7.6Hz, 1H), 7.601(app t, 7.3Hz, 3H), 7.470(app t, 7.8Hz, 1H), 7.357(m, 2H), 6.254(d, 1.6Hz, 1H), 5.532(d, 1.6Hz, 1H), 3.690(br m, 4H), 3.383(br m, 4H); 13C(d6-DMSO, 100MHz): 177.77, 162.93, 157.95, 135.38, 135.04, 134.59, 133.58, 132.65, 131.26, 129.36, 129.10, 128.82, 128.78, 128.43, 128.24, 114.00, 89.41, 65.24(2C), 44.44(2C)
The procedure for making the 2-chloro-6-(N-morpholinyl)-4-pyranone was posted on Oct 3. The Suzuki procedure works equaly well with 5mol% of Pd-tetrakis (the 7.5mol% loading was due to weighing error).
The above procedure is an improvement over the patent procedure (published Y= 4% th). From reading the patent experimentals, I suspected that all Suzuki procedures reported there (with yields ranging from 2 to 13%) suffered from some kind of execution error - perhaps due to a lack of care when experiments were set and run in parallel. Also, experiment done under typical aqueous Suzuki reaction conditions (Na2CO3, Pd-tetrakis, DME+water) returned no desired product at all. Next, I tried adding water to the anhydrous dioxane experiment - into a reaction mixture that contained the desired product - and this resulted in a rapid destruction of the product under the reaction conditions. So it became clear that the actual problem was the moisture sensitivity of the product in the presence of carbonate. Using a large excess of dry K2CO3 together with 4A molecular thieves supressed this decomposition problem.