Org Prep Daily

November 28, 2006


Filed under: procedures — milkshake @ 2:40 am


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.


  1. That’s really interesting…I can’t recall seeing many anhydrous Suzuki reactions. I guess water can kick out the morpholine group under the reaction conditions?

    Comment by Canuck Chemist — November 30, 2006 @ 2:24 am

  2. I guess the pyrone ring destruction happens because of hydrolysis – but I have not figured out the exact decomposition product. I noticed that it was something with lower MW than the desired product. It was much less polar on TLC but very close on HPLC to the product.

    This was more like a one-time job for me – I was asked to make some literature compounds for comparison but the published procedure had horrible yield. As soon as I got some decent yield I was finnished with doing it – I did not try to go back and elucidate the structure of sideproducts.

    Comment by milkshake — November 30, 2006 @ 1:42 pm

  3. So is the active coupling partner then the boronic anhydride?

    Comment by Chemist of Sorts — November 30, 2006 @ 3:12 pm

  4. That’s a good point – I don’t know. ArB(OH)3(-) anion usually participates in Suzuki because it is far more reactive than the parent boronic acid. Perhaps the potassium salt forms before the free acid gets a chance to produce the anhydride. Or something involving KHCO3 happens. I don’t know

    Comment by milkshake — November 30, 2006 @ 5:47 pm

  5. The original title is much better.

    Comment by Eric — December 2, 2006 @ 2:42 am

  6. One of my colleagues has seen similar cleavage of cyclic amines from a related dihydro-pyridine scaffold. He was getting some dihydropyridone, but there were other tautomeric issues going on as well.

    Maybe the anhydrous Suzuki-Miyaura (KF or other F source) or the more recent Molander R-BF3- K+ would be more amenable?

    Comment by Atompusher — December 21, 2006 @ 3:09 am

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