Org Prep Daily

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

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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.

October 25, 2010

diaminotriazoles from anilines

Filed under: procedures — milkshake @ 3:04 pm

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Dimethylamide of p-aminobenzoic acid 6.00g (36.54 mmol) and (PhO)2C=N-CN 10.14g (Aldrich; 42.56 mmol) in anhydrous THF 60mL was refluxed under nitrogen on a 80C oil bath for 2 days. [Note 1] The cooled reaction mixture was concentrated on rotovap. The obtained oily residue was diluted with anh. THF 20mL and cooled to 0C. Anhydrous hydrazine 1M solution in THF 60mL (Aldrich) was added, the mixture was stirred on ice for 15 min and at ambient temperature for 20 min, then placed on a 70C oil bath and refluxed under nitrogen for 30 min. The reaction mixture was cooled to room temperature, the precipitated product was collected by filtration and washed with MTBE  (tBuOMe), then dried by suction and on highvac. Y= 10.48g of a white fluffy powder (90% th; as a 1:1 solvate with THF)

1H(d6-DMSO, 400MHz): 11.22 (br s, 1H), 8.94 (br s, 1H), 7.52(app d, 8.6Hz, 2H); 7.27(app d, 8.6Hz, 2H), 5.92(br s, 2H); 3.60(m, 4H, THF); 2.95(s, 6H), 1.76(m, 4H, THF); 13C(d6-DMSO, 100MHz): 170.47, 128.29, 114.44, 67.00(THF), 25.11(THF)

Note 1: 1 day reflux would have been enough.

Note 2: The starting aniline was prepared by hydrogenation of dimethylamide of p-nitrobenzoic acid (5% Pt-C, H2 baloon, EtOAc), which was obtained from p-nitrobenzoyl chloride and 40% aq. dimethylamine in THF, at -15 C. The yield was 90% over two steps.

October 6, 2010

5-mercaptooxindole

Filed under: procedures — milkshake @ 2:51 pm

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Chlorosulfonic acid 115 mL (1.73 mol) in a 1L wide-mouth round flask (with a 45/50 joint, equipped with a gas outlet tube) was cooled on ice bath and solid oxindole 25.60g (192.2 mmol) was gradually spooned in with vigorous stirring and cooling on ice, over a 20 min period. (A corrosive fog evolution!). After the complete addition, the flask was removed from the cooling bath and the mixture was stirred for additional 15 min. The flask was then placed on a 70C oil bath and the mixture was stirred at 70C for 2 hours. The resulting dark reaction mix was cooled on ice, then very cautiously poured in a thin stream onto crushed ice 1.4kg that was pre-chilled in a freezer, in a 3L beaker, with stirring. [Note 1] The quenched mixture was stirred until all ice melted, the precipitated solid was collected by filtration on a very large glass Buchner funnel, washed with 0.05 M HCl, semi-dried by filtration and then carefully dried on highvac. [Note 2] Y=42.23g (95% th) of a tan solid.

The sulfonylchloride from the previous step, 42.23g (182.3 mmol) was suspended in anhydrous dichloromethane (100mL) in a 1L round flask. The mixture was cooled on ice slush bath and a solution of triphenylphosphine 167.5g (638 mmol, 3.5 eq.) in anhydrous dichloromethane (300mL) was dropwise added from an addition funnel under nitrogen with cooling over a 45 min period. After complete addition the flask was removed from the cooling bath and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by water addition, 200mL. The flask with the biphasic mixture was placed on a 50C water bath and the mixture was refluxed under nitrogen for 1 hour, then cooled on ice. The precipitated product was collected by filtration, washed thoroughly with ice-chilled dichloromethane and ice water, then dried by suction and on highvac, to provide 19.58g of a pure product.  The biphasic filtrates were de-oxygenated by argon/vacuum purge (3 times). The mixture was made strongly alkaline by addition of 50% aq. NaOH solution, shaken under Ar and then rapidly separated, the organic phase was re-extrated with water. [Note 3] The aqueous phases were promptly washed with fresh dichloromethane (200mL). The combined aqueous extracts were made acidic by addition of 6M HCl, the mixture was cooled on ice, the precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on higvac, to provide a second crop of the product, 7.15g. The combined yield was 26.73g (88.5% th) of a light tan solid.

1H(d6-DMSO, 400MHz): 10.339(s, 1H), 7.151(s, 1H), 7.108(m, 1H), 6.707(d, 8.0Hz, 1H), 5.109(s, 1H), 3.436(s, 2H)

Note 1: Chlorosulfonic acid is viciously corrosive and has a huge quench exotherm – the quench has to be done in a fume hood with the sash pulled down and a full protection as there is a good chance of the reaction mixture splashing out. Plain latex gloves  are no match for ClSO3H – use thick long-sleeved ones.

Note 2: Wet chlorosulfonyl oxindole has thixotropic properties – a wet solid that suddenly starts flowing as a sludge when shocked (this is not a sign of decomposition). The wet sulfonyl chloride after filtration was transferred into a glass dish and thoroughly dried on highvac. Drying this quantity of material took 2 days (over weekend). A thoroughly dry sulfonyl chloride is required for the success of the next step – incomplete drying or substituting anhydrous DCM for a non-anhydrous DCM grade (stabilized with ethanol 1%) resulted in a product containing a large quantity of the corresponding symmetric disulfide.

Note 3: The product is soluble in aqueous NaOH as a thiolate, the alkaline solutions will gradually oxidize on air to the disufide but the extraction can be actually done without a protective atmosphere if one works without delay.

September 29, 2010

Oxindole-5-carboxylic acid

Filed under: procedures — milkshake @ 12:42 pm

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Indole-5-carboxylic acid 5.00g [Combiblocks] (31.0 mmol) solution in ethanol 99% 120mL and tert-butanol 180mL in a 1L RB flask was cooled on ice bath to +5 C. Meanwhile, a solution of lithium bromide 9.0g (103.6 mmol) in neat acetic acid 60mL was placed into an addition funnel. Neat bromine 5.0mL (16.0g; 100.1 mmol) was then charged to this LiBr solution and the addition funnel was briefly swirled by hand to mix the reagents. The resulting bromine+LiBr solution was dropwise added into the vigorously stirred indolecarboxylic acid solution at +5 C over a 90 min period. (After a complete addition the addition funnel was then washed with EtOH 2 x 5 mL and the washings were added to the reaction mix). At the end of the bromine addition the cooling bath was let to expire and the reaction mix was stirred at +5 to +15 C bath for 1 hour and at 15 C for additional 15 min. The reaction mixture was then diluted with additional acetic acid 100mL. Zn dust 20g [Aldrich; <10 micron] (306 mmol) was added in one portion (gas evolution!) and the mixture was stirred in an open flask on ambient water bath overnight (16 hours).

The next day, the precipitated solids were collected by filtration, washed with ethanol and dried by suction. The solid (containing a mix of the product, unreacted Zn metal and Zn salts) was transferred into a large beaker on a hotplate, suspended in boiling methanol (300mL) and filtered. The extraction with boiling methanol was repeated  twice more, to separate the unreacted Zn metal from the product. The combined methanolic filtrates were evaporated to dryness. Separately, the acetic acid+LiBr – containing filtrates from the reaction mix were concentrated to a small volume on rotovap and the produced salt-rich residue was diluted with water 0.6L and acidified with 6M HCl to about pH= 1.5. This mixture was then combined with the evaporation residue obtained from the methanolic filtrates. The solids in the flask were re-suspended by a brief sonication (5 min) and the slurry was cooled down on ice bath, then placed into a freezer (-20C) for 4 hours. The precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac. Y=5.23g (95%) of a light tan solid.

1H(d6-DMSO, 400MHz): 12.58 (br s, 1H), 10.72(s, 1H), 7.82 (dd, 8.3Hz, 1.6Hz, 1H), 7.75 (s, 1H), 6.88 (d, 8.3Hz, 1H), 3.54 (s, 2H)

Note: Skin contact with bromine produces excruciating burns: Heavy duty protective gloves with extended sleeves are required. Make sure that the used syringe does not leak, work in the hood, do not wash bromine-contaminated glassware with acetone (use water or alcohol).

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