.
A 500mL three-necked round flask equipped with a reflux condenser, internal thermometer, pressure-equalised addition funnel and a large egg-shaped magnetic stirbar was charged with 25% sodium methoxide in methanol 31.55g (Aldrich; 146mmol) and methanol 100mL. The flask was placed on ice slush bath and after 15 min a solution of 1,3-acetonedicarboxylic acid dimethyl ester 25.00g (Acros; 143.55 mmol) in methanol 10mL was added within 15 min, the addition funnel was washed with methanol (2×20mL) and the washings were also added into the mix. The cooling bath was then removed and the flask was placed on a 65C oil bath and stirred for approximately 30 min. (The mixture gradually became homogeneous as the precipitated Na-enolate salt of the di-Me-acetonedicarboxylate re-dissolved with heating). When the internal temperature in the flask has stabilized, a mixture of 40% aqueous glyoxal 12.00g (Alfa; 82.7 mmol, 115% of the theoretic amount) with methanol 30mL was introduced dropwise from the addition funnel – very slowly – over a period of 1h45min, with a vigorous stirring on the 65C oil bath. After the complete addition the funnel was washed with methanol (10mL) and the washings were also added to the mix. The resulting cloudy reaction mixture was stirred for extra 15 min at 65C, then diluted with THF 200mL and the flask was removed from the heating bath. The mixture was stirred at RT overnight (12 hours). The precipitated intermediate (as a disodium salt hydrate) was collected by filtration using a large sintered-glass Buchner funnel. The collected solids were washed thoroughly with THF and then dried by suction for about 2 hours.
This intermediate salt (a cream-colored heavy powder, 27.92g; 90%Y) was dissolved in water 400mL in a 1L flask. 37% concentrated HCl 46 mL was added dropwise with a vigorous stirring (as to limit the formation of dumplings) and the resulting heterogeneous mixture was placed on a 100C oil bath. The mixture was stirred at reflux at 100-120C for 1 hour and at 120C for additional 2 hours – during this time the mixture became homogeneous as the gummy deposits gradually dissolved. The flask was then removed from the heating bath, a large spoon of activated charcoal was added into the stirred mix, the charcoal was removed by filtration while warm (the charcoal was washed with additional water) and sodium chloride 100g was added to the combined filtrates. The mixture was stirred on ambient bath until the complete salt dissolution (5 min). This mixture was then extracted three times with dichloromethane (3×250mL), the organic extracts were washed with saturated aq. NaHCO3 200mL. The combined extracts were dried with magnesium sulfate and evaporated to dryness from ambient water bath. The obtained crystalline residue was dried on highvac for about 30 min.
Y=7.790g of a white crystalline solid, pure by NMR (78.5% overall from di-Me acetonedicarboxylate) .
1H(CDCl3, 400MHz): 3.048(m, 2H), 2.585(ddd, 19.5Hz, 8.7Hz, 1.8Hz, 4H), 2.156(dd, 19.5Hz, 5.2Hz, 4H)
Note 1: The product is also available commercially [Aldrich 5g/$400]
Note 2: A very slow addition of the glyoxal solution and a careful control of the reaction temperature (65C) by the oil bath during the first step is required for a good yield. The reaction is not very sensitive to moisture so a common-grade MeOH was used from a freshly-opened bottle. (The reflux in the first step was done under Ar but this may be unnecessary). The final product can be re-crystallized from MeOH; in this preparation NMR-uniform material was obtained directly by evaporating the DCM extracts and drying the residue briefly in vacuo.
Note 3: This preparation was based on a large-scale (1.5 mol) procedure from OrgSyn (Vol 64, p.27, 1986). The medium-scale (140mmol) experiment described here was run in higher dilution, on a stirplate and with the oil bath inplace of a heating mantle. Also the hydrolysis step was simplified at this medium scale, etc – these modifications probably helped to improve the product yield and purity.
Note 4: This preparation provided 80% overall yield when run on twice as large scale (1L flask, 50.1g of di-Me-acetondicarboxylate, 300mL MeOH, 63.2g of 25% NaOMe, 24.25g of 40% glyoxal in 50mL of MeOH, 94mL of conc. HCl). Few minor changes: acetondicarboxylate was added neat by syringe, quite fast (over 10 min at 0C) as there is not much exotherm during the additon. In the second step, the intermediate salt (57.5g) was dissolved first in hot water (800mL) and the solution was placed on oil bath (120C) and conc. HCl (94mL) was added at approx 80C internal temperature with intense stirring, and the resulting emulsion was then stirred at reflux on 115-120C oil bath for additional 150 min. In this way the mix is easier to stir magnetically (as the formation of sticky dumplings is completely prevented).
