cis-Bicyclo[3.3.0]octane-3,7-dione

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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 (2x20mL) 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 (3x250mL), 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).

Foaming!

Evaporating aqueous reaction mixture is a lamentable job –  by weight water has one of the highest evaporation enthalpy values – but with a good rotovap and enough persistence one can even take care of several liters of aqueous mix (if there is no better alternative). The one thing that can turn this into the most frustrating experience is foaming.

I was struggling today; a published homotropanone prep calls for freezing + lyophilizing the entire reaction mix. I scaled that thing by a factor of four and since I did not want to lyophilize a half-liter of the reaction mix, I just put it on the rotavap and suddenly the reasons for the recommended lyophilization became painfully clear…

Desperate people would add n-octanol or even couple of drops of silicone oil to their mix but I did not want to introduce non-volatile impurities into the product. I was dreaming about silanizing the flask glass surface instead (a rinse with Me2SiCl2 and tributylamine in dichloroethane does it) but in the end I just poured 1mL of of hexamethyl disilazane (TMS)2NH straight into my aqueous mixture  – and the foaming ceased like a miracle. It must have been the silicone film on the glass that produced this remarkable effect because when I later transferred the solution into another flask it started foaming crazy anew; and a little more (TMS)2NH and it was calm like a lamb again.

10-hydroxy-cis-perhydroisoquinoline

1-(2′-amino-1′-ethyl)-cyclohexene 17.53g (140 mmol, Alfa) was combined with water 60 mL and conc. 37% aq. HCl 11.5mL (140 mmol) was added, followed by additional water 40mL. The acidity of the mixture was adjusted approximately to pH=2 (on strip indicator paper) by adding few drops of 6M HCl. The mixture was placed on a 40C heating bath. A solution prepared by diluting 11.50g of 37% aqueous formaldehyde (140 mmol, Aldrich, stabilized with MeOH) with water 20mL was slowly added from the addition funnel with vigorous stirring, over a two-hour period. The addition funnel was washed with additional water (2x10mL) and the washings were also added to the mix. After the complete addition, the stirring at 40C was continued for additional 6 hours. Two small spoons of charcoal were then added, the reaction mixture was filtered into a 1L round flask (the charcoal was washed with additional water) and the combined filtrates were evaporated from a 40C bath at 15-20 Torr to dryness. The obtained solid residue was re-dissolved in methanol 80mL at reflux. Boiling acetone 450mL was added into the flask at once and the resulting slurry was allowed to rest at ambient temperature for 6 hours (overnight). The precipitated product was collected by filtration, washed with acetone and dried in vacuo. Y=23.722g (88.5%) of a white crystalline solid.

1H(D2O, 400MHz): 3.357(dd, 12.9Hz, 3.6Hz, 1H), 2.244(td, t:14.2Hz, d:4.0Hz, 1H), 3.159(m, 1H), 3.019(dd, 13.)Hz, 4.7Hz, 1H), 2.115(br m, 1H), 1.763(m, 2H), 1.672-1.258(m, 8H); 13C(D2O, 100MHz): 68.32, 44.75, 40.41(br s), 39.08, 25.96(br s, 2C), 23.45(br s, 2C), 22.26(br s)

Note: The reaction mix turns into emulsion with the formaldehyde addition but becomes homogeneous further on. It is important to add exact amount of formaldehyde (weighed out in a syringe) and use a solution of known concentration; old bottle of poorly-stabilized formaldehyde solution with paraformaldehyde deposits should be left for the biologists.