Org Prep Daily

October 25, 2010

diaminotriazoles from anilines

Filed under: procedures — milkshake @ 3:04 pm


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


Filed under: procedures — milkshake @ 2:51 pm


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.

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