Diketene (Aldrich, stabilised with CuSO4) was distilled at reduced pressure (b.p. 70C/100Torr) to remove the stabilizer. Oven-dried glassware under stream of Ar was used because diketene and the intermediate tetrachloro beta lactone are moisture-sensitive. BocOOBoc was obtained from Boc2O (prep posted on Sept 7).
29.8g (354mmol) of freshly-distilled diketene was dissolved in carbon tetrachloride 250mL and BocO-OBoc (diBoc peroxide) 2.50g (10.67mmol, 3mol%) was added. This solution was transferred via canula into an addition funnel. Over the next 7 hours, this solution was added dropwise into vigorously-stirred carbon tetrachloride 80mL in a 0.5L flask that was kept on oil bath at 70C. (Under Ar-blanketed gas outlet. No condenser was necessary). After complete addition, the mixture was stirred at 70C for extra 90min. The mixture was cooled to R.T., additional BocOOBoc 0.835g (1 mol%) was added , the mixture was brought back to 70C and stirred for 90min at this temperature. (1H NMR indicated nearly complete conversion of diketene). The reaction mixture was then concentrated on rotavap and carefully dried on highvac. Y =77.85g (92%) of a pale-yellow oily liquid with a characteristic hydrocinnamaldehyde/rotten willow leaves-like odor. The purity of this crude product was approx 80% by 1H-NMR.
1H(CDCl3, 400MHz): 4.487(d, 17.3Hz, 1H), 3.977(d, 17.4Hz, 1H), 3.810(dAB, 15.9 Hz, 1H), 3.742(dAB, 15.9Hz, 1H) [impurity: 1.478 s + lots of baseline grass]
6.250g (26 mmol) of the crude tetrachlorobetalactone was dissolved in anh. dichloromethane (150mL) and the solution was cooled to 0C. Neat morpholine 2.40mL (27.5mmol) was added dropwise over 10 min. After additional 5 min, solid NaHCO3 powder 4.40g (52.3 mmol, 2 eq.) was added in a single portion, the cooling bath was removed and the mixture was stirred at RT for 22 hours. (one day). The reaction mixture was filtered through a 1.5 x 2 inch plug of silica, the silica was washed with ethyl acetate 300mL. The filtrates were evaporated and the obtained solid residue was re-crystallized from a mix of ethyl acetate 20mL and cyclohexane 80mL (RT, overnight). The precipitated product was collected by filtration, washed with hexane and dried on higvac. Y=3.507g (53.5%) of a white crystalline solid. (There was some more product left in the supernatants but I was lazy that night).
1H(d6-DMSO, 400Mhz): 14.981(s, 1H), 6.696(s, 1H), 5.820(s, 1H), 3.598(br m, 4H), 3.507(br m, 4H)
The signals of the keto tautomer are barely detectable in the d6-DMSO solution of morpholide. With the corresponding piperide analog, the keto/enol ratio is much higher, about 15:85. These enol compounds fail to give good proton spectra in CDCl3 (= broad blobs). The signals in DMSO are nice and sharp, except for the methylene protons next to the amide nitrogen .
The tetra-Cl-beta lactone could be distilled on Kugelrohr at or below 70C/0.05 Torr but the distillation is risky. Acidic impurities (for example from hydrolysis) catalyse a self-accelerated decomposition of the lactone. Since the crude intermediate works quite well and the enolamides produced in the following step are stable and crystalline, it is best to avoid distilling this unstable lactone. The lactone did not store well – within 2 month at RT it turned into a black foamy slush with HCl gas evolution.