Org Prep Daily

July 26, 2011

Expanding liquids break closed vessels

Filed under: lab destruction — milkshake @ 2:05 pm

I had a dumb mishap today: A 100mL Schlenk storage flask with 1,5-cyclooctadiene shattered. When I distilled my COD by vacuum transfer this morning I filled the storage flask all the way to the top and then turned the teflon stopcock shut. There was no head space left in the flask; as the liquid warmed from about 10C up to room temperature it expanded enough to burst the glass.

Coincidentally, my colleague finished off a 20L jacketed glass reactor in a similar manner just yesterday – he was cleaning it after the experiment and the heating jacket was shut off, both the inlet and outlet valves were closed while the jacket was still filled with polysiloxane heat transfer fluid. When the reactor was rinsed with ambient water it suddenly shattered: a small temperature difference was apparently enough to cause the silicone fluid expansion in the jacket and there was no air bubble space nor a tubing attachment whereto the silicone liquid could expand. Looking back, this jacket over-pressurizing would not have happened if one of the valves was left open.

I suppose we proved that liquids are incompressible and expand with heat.

Link: The Great Boston Molasses Disaster

June 23, 2011

Last post

Filed under: industry life, Uncategorized — milkshake @ 12:57 am

Today is my first day with a small privately held biotech company that is developing self-assembling polymers for targeted drug delivery. The group and the projects are awesome – and as much as I am excited about the research and the company, for obvious reasons I shouldn’t be writing about it. So there will be nothing new to add here. This is it – thank you for visiting!

April 29, 2011

Neglected lab solvents

Filed under: procedures — milkshake @ 9:34 am

Trifluoroethanol as a solvent dramatically accelerates epoxide opening with amines and also conjugate addition of amines to enones and acrylates. Thermal Diels-Alder is another good reaction to try in TFE.

1-methoxy-2-propanol behaves as a higher-boiling version of iPrOH. It has a reasonable volatility and it is miscible with water (so it could be pulled off on a rotovap – but also drowned if needed). It has no apparent toxicity issues (unlike methoxyethanol) . This obscure solvent was introduced as an eco-friendly paint thinner but it turns out to be quite useful for direct non-catalyzed SNAr of halogenated heteroaromatics with amines, a reaction that benefits from protic media but where the solvolysis poses a problem. I also used this solvent for high-temp cyclizations done in a microwave reactor.

tert-BuOMe: I suppose the minty reek turns people off but MTBE is a great ether replacement in column chromatography, salt precipitation and recrystallizations. Ortho-litiations have sometimes improved regioselectivity in MTBE,  and since this solvent is more resistant to cleavage by organolithiums, it is recommended for room-temperature lithiations with BuLi. MTBE typically does not have radical scavenger stabilizers and  the formation of peroxides is negligible – so when you are running a high dilution experiment or evaporating a large volume of fractions from column that contain only miligram quantities of your desired material, MTBE is a good solvent choice.

Acetonitrile: Some people use MeCN only for reverse phase HPLC and it is a pity – MeCN is a wonderful solvent for silylations, acylations, alkylations. Straight acetonitrile is also a pretty good solvent for re-crystallizing very lipophilic compounds.

Benzene is rather useful for recrystallizing stuff, especially with cyclohexane as an anti-solvent. (Benzene+cyclohexane mixtures have a nearly constant boiling point and do not freeze in the fridge). I have seen many examples where a compound could be successfully re-crystallized only from benzene – maybe this has to do with an empiric fact that benzene frequently co-crystallizes with compounds (so in such cases the solvate formation  changes the properties of the crystal structure).

Methanesulfonic acid: Old-fashioned cyclizations (Skraup, Isatin, Fisher Indole etc) are typically performed in neat concentrated sulfuric acid. Replacing sulfuric acid with MeSO3H frequently improves the purity and yield. The quench is also less exothermic with methanesulfonic acid.

December 7, 2010

Diastereoselective cinnamate reduction, Oppolzer auxiliary

Filed under: procedures — milkshake @ 2:48 pm

6-Methoxy-2H-chromene-3-carboxylic acid 12.56g (60.9 mmol) suspension in anhydrous dichloromethane 100mL was combined with 7.0 mL of neat oxalyl chloride, followed by 4 drops of DMF. The mixture was stirred under gas outlet tube filled with Drierite for 1 day; by this time the gas evolution ceased. The homogenous reaction mixture was evaporated to dryness, the residue was briefly dried on highvac, the resulting solid was crushed with a spatula and re-dried on highvac for 1 day. Y=13.66g (100%) of a yellow solid. [This acyl chloride readily decomposes on storage – it is best kept under high vacuum while protected from a direct sunlight, and used on the same day.]

Oppolzer (+)sultam auxiliary 5.785g (26.87 mmol) solid in a 0.5L flask was flushed with dry Ar, 60% NaH in mineral oil 1.505g (37.6 mmol) was added followed by anhydrous toluene 250mL (gas evolution). The slurry was briefly sonicated for 5 min on a sonicator bath, then stirred at ambient temperature under Ar for 2h45 min. The mix was then cooled to 0 C, a solid acyl chloride 5.983g (26.87 mmol) was added in one portion, the mixture was placed placed on ambient water bath and stirred vigorously for 2 hours under Ar. (There was a delayed gas evolution accompanied by foaming). At the completion of the acylation, the reaction was quenched by addition of silica (50g) followed by hexanes (100mL). After additional 10 minutes, the entire reaction mix was applied onto a column of silica (500g) in hexanes-ethyl acetate 10:1, then rapidly eluted with the 10:1 mix and then with hexanes-ethyl acetate 7:3 mix (3L). (There is a risk of the product crystallizing on the column if the elution is too slow.) A yellow band was collected.  Combined fractions provided upon evaporation and drying on highvac 9.965g (92% th) of the chromene-acylated auxiliary as a yellow fluorescent solid. 1H(CDCl3, 400MHz): 7.31(br s, 1H), 6.80(m, 2H), 6.73(d, 2.4Hz, 1H), 5.03(dd, 13.6Hz, 1.2Hz, 1H), 4.81(dd, 14.0Hz, 1.2Hz, 1H), 4.12(dd, 7.6Hz, 4.8Hz, 1H), 3.77(s, 3H), 3.54(d, 13.6Hz, 1H), 3.43(d, 13.6Hz, 1H), 2.05(m, 1H), 1.93(m, 4H), 1.43(m, 2H), 1.30(s, 3H), 1.02(s, 3H) [Note 1]

The intermediate from the previous step 2.020g (5.00 mmol) in a 300mL RB flask was dissolved in anh THF 50mL under Ar and the solution was cooled to -50 C. L-Selectride 1M solution in THF 6.5 mL was added dropwise with vigorous stirring over 5 min period and the reaction was then maintained at -50C for additional 45 min. The reaction was quenched at -55 C by dropwise addition of 2M sulfuric acid 25 mL, the cooling bath was removed and the reaction mixture was stirred at ambient temperature in an open flask for 2 hours. The reaction mix was then partitioned between ether 120 mL and water 80 mL. The organic phase was separated, washed with water 100mL and saturated sodium bicarbonate 100mL. The aqueous phases were re-extracted with ether 130 mL. The combined organic extracts were dried (MgSO4) and evaporated. The evaporation residue was kept under Ar [Note 2] until it could be purified on a column of silica (120g) in ethyl acetate gradient in hexanes (0 to 30% EtOAc). The obtained column-purified material (1.57g; 98:2 dr by 1H-NMR) was suspended in cyclohexane 60mL, the slurry was refluxed for 10 min and then allowed to sit at ambient temperature overnight. The solid product was collected by flitration, washed with hexanes, dried by suction and on highvac. Y=1.410g (69.5% th) of a diastereomerically pure material. 1H(CDCl3, 400MHz): 6.77(d, 8.9Hz, 1H), 6.69(dd, 8.9Hz, 3.0Hz, 1H), 6.59(d, 2.9Hz, 1H), 4.44(ddd, 10.7Hz, 3.3Hz, 2.0Hz, 1H), 4.04(t, 10.3Hz, 1H), 3.92(t, 6.3Hz, 1H), 3.74(s, 3H), 3.58(m, 1H), 3.54(d, 13.9Hz, 1H), 3.47(d, 13.9Hz, 1H), 3.03(m, 2H), 2.08(m, 2H), 1.90(m, 2H), 1.41(m, 2H0, 1.20(s, 3H), 0.99(s, 3H) [Note 2]

This reduced chromane-auxiliary intermediate 1.410g (3.477 mmol) was dissolved in THF 140 mL and the solution was cooled to 0 C. Water 36mL and 50% H2O2 15mL was added, followed by 1M aqueous LiOH 5.0mL (prepared freshly from Aldrich LiOH monohydrate). The reaction mixture was stirred at 0 C for for 20 min, then quenched with 2M H2SO4 1.5mL and warmed to ambient temperature. The reaction mix was partitioned between ether 300 mL and water 150 mL. The organic phase was washed with additional water 200mL, then shaken for 5 min with 1M Na2SO3 200mL (to convert the peroxyacid into a carboxylic acid) . The aqueous phases were sequentially re-extracted with additional ether 300mL.
The combined organic phases containing a mixture of the product and the liberated auxiliary were extracted twice with 3:1 mix of water with conc. aqueous ammonia (2x100mL) and then with water. These combined ammonia extracts were then acidified with 6M HCl (140mL) with cooling on ice bath, the acidified mixture was then extracted 3-times with dichloromethane (3x150mL). The dichloromethane extracts were washed with water (100mL), combined, dried (MgSO4) and evaporated. The residue was re-crystallized from cyclohexane 60mL at reflux (then kept at ambient temperature overnight), the precipitated product was collected by filtration, washed with hexanes (2x10mL) and dried on highvac. Y=682mg of white cotton-like fluffy needles (94% th, (S)-enantiomer, >99% ee) [note 3] 1H(CDCl3, 400MHz): 6.77(d, 8.8Hz, 1H), 6.69(dd, 8.8Hz, 2.8Hz, 1H), 6.63(d, 2.8Hz, 1H), 4.39(m, 1H), 4.16(m, 1H), 3.75(s, 3H), 3.06(m, 3H); 13C(CDCl3, 100MHz): 177.9, 153.7, 148.0, 120.5, 117.4, 114.0, 113.8, 66.2, 55.7, 38.4, 27.3; [alpha]D27= +2.04(c=0.981) Chiral HPLC assay: Chiralpak  AD-RH, 17 to 20% MeCN in water with 0.1% TFA, at 75C @ 0.8 mL/min

Note 1: Using the same procedure, Oppolzer (-) sultam auxiliary 6.238g (29 mmol) with 60% NaH 1.625g (40.6 mmol) and acylchloride 6.967g (31 mmol) provided 11.06g of the opposite enantiomer (94.5% th)

Note 2: The L-Selectride reduction procedure can be difficult to manage on a large scale. Air oxidation of borane species that carried over into the crude product inspite the workup seems to be responsible for variable yields (40-50%) on a larger scale. [A careful workup with perborate would probably solve this problem.]

Note 3:  Using the above procedure, L-Selectride reduction of the acylated intermediate prepared from the (-) auxiliary provided 1.210g (59.5%th) of the reduced intermediate, which was then hydrolyzed as above in 93% yield to provide 580mg of pure (R)-enantiomer (>99% ee)

Note 4: A more direct approach to the optically pure chromane acid, by asymmetric hydrogenation with a Ru catalyst, is described here

November 20, 2010

2-acetyl-3-ethoxyacrylic acid ethyl ester (E/Z)

Filed under: procedures — milkshake @ 7:13 pm

A mixture of ethyl acetoacetate 52.0g (399 mmol), ethyl orthoformate 59.2g (399 mmol) and acetic anhydride 81.6g (800 mmol) in a 0.5L round flask was refluxed under nitrogen on a 150 C oil bath for 90 min. The reflux condenser was replaced with a shortpath distillation apparatus and the formed ethyl acetate was distilled out from the reaction mixture at atmospheric pressure under nitrogen from a 150C oil bath. (This took additional one hour). The cooled reaction mixture was then distilled at 6 Torr from an oil bath (30 C to 90 C) to remove the formed acetic acid. The distillation residue was then fractionally distilled on highvac. After a small fruity-smelling front fraction (few mL) the desired product distilled at 75-82 C/0.25 Torr.

The obtained main fraction of the product was re-distilled on highvac, b.p. 80 C/0.15 Torr. Y = 48.2g of a colorless slightly oily liquid. The pure product has only a faint (non-fruity) odor.

1H-NMR (CDCl3, 400MHz) shows two sets of closely-spaced signals of the E and Z isomers, approximately of equal height:  7.671(s, 0.5H), 7.639(s, 0.5H), 4.251(m, 4H), 2.407(s, 1.5H), 2.346(s, 1.5H), 1.402(m, 3H), 1.339(m, 6H)

Note: A condensation of this material (2.5 mmol) with the diaminotriazole (2.0 mmol) from the preceding experimental in AcOH 5 mL at RT (10 min) and then at 110 C (for one hour) followed by evaporation and precipitation of the residue with MeCN provided the following cyclization product in 76% Y.
1H(d6-DMSO, 400MHz): 10.353 (s, 1H), 9.010(s, 1H), 7.774(app d, 8.8Hz, 2H), 7.423(app d, 8.8 Hz, 2H), 4.370(q, 7.1Hz, 2H), 3.084(s, 3H), 2.976(s, 6H), 1.368(t, 7.1Hz, 3H)

November 4, 2010

beta ketoester cyclization with aminotriazoles

Filed under: procedures — milkshake @ 11:02 am

.

The diaminotriazole.THF from the previous step, 637mg (2.0 mmol) was dissolved in acetic acid 5 mL. Cyclohexanone-2-carboxylic acid ethyl ester 0.48mL (3 mmol) was added and the mixture was stirred at reflux on a 130C oil bath for 90 min. The cooled reaction mixture was evaporated to dryness and the oily residue was suspended in acetonitrile 5mL with sonication. The crystalline precipitate was collected by filtration, washed with acetonitrile, then dried by suction and on highvac. Y=664.5mg of a white crystalline solid (94%Y)

1H(dDMSO, 400MHz): 12.70(br s, 1H), 9.80(s, 1H), 7.69(dt, d: 8.6Hz, t:1.8Hz; 2H), 7.38(dt, d:8.8Hz, t:2.0Hz, 2H), 2.97(s, 6H), 2.61(br t, 5.7Hz, 2H), 2.40(br t, 5.9Hz, 2H), 1.72(m, 4H)

Note: Using the same reaction conditions, ethyl acetoacetate provided 92% Y of a cyclization product. Cyclopentanone-2-carboxylic acid ethyl ester gave 55.5 %Y (the product in this case crystallized directly from the reaction mixture – and it was washed with AcOH and then MeCN). The products were isomerically pure, by 1H-NMR and HPLC.

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