Org Prep Daily

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).

September 17, 2010

4-carboxy-3,5-dimethylpyrrole-2-carboxaldehyde

Filed under: procedures — milkshake @ 7:27 pm

4-carbethoxy-3,5-dimethylpyrrole-2-carboxylic acid tert-Bu-ester 16.35g was dissolved in neat trifluoroacetic acid 85 mL and the solution was stirred at room temperature for 30 min (the mix turned Burgundy red with gas evolution [Note 1]), then cooled to +5 C on ice/water bath. Neat triethyl orthoformate 16.5 mL (1.6 eq.) was added and the mix was stirred at +5 C for 35 min, then concentrated on rotovap from ambient water bath to a small volume. The residue was diluted gradually with water addition, 300mL, the resulting slurry was shaken for 5 min and the precipitated ethyl ester intermediate was collected by filtration, washed thoroughly with water and dried by suction.

This intermediate ethyl ester was suspended in ethanol 150 mL, placed on a 120 C oil bath and stirred to complete dissolution. A solution of KOH 20g (pellets, 85%) in water 200mL was then added to the mix, the flask was equipped with a short-path distillation adaptor and the reaction mixture was distilled under a stream of nitrogen gas on a 120C oil bath for 90 min. (Only water distilled at this point and the ethyl ester hydrolysis was complete by HPLC, [Note 2] ) The reaction mixture was cooled, charcoal (5 spoons) was added and the reaction mix was then stirred on ambient water bath for 30 min, and filtered (the charcoal was thoroughly washed on Buchner funnel with water). The combined filtrates were acidified with addition of 6M HCl, the precipitated product was collected by filtration on a large Buchner funnel, washed thoroughly with water and semi-dried by suction. [Note 3]

The crude product was dissolved in EtOH (900mL) at reflux, the solution was allowed to crystallize at ambient temperature overnight (14 hours). The product was collected by filtration, washed with EtOH, dried by suction and on highvac. Concentrating the supernatants to a small volume (but not to dryness), diluting the slurry with ethanol 100mL and refluxing the mix for 30 min, then letting the mix to crystallize at RT overnight provided a second crop of a pure product. The combined yield was 8.32g (81% th, overall Y) of a light-tan crystalline solid.

1H (d6-DMSO, 400MHz): 12.12(s, 1H), 12.10(very br s, 1H), 9.61(s, 1H), 2.46(s, 3H), 2.42(s, 3H)

Note 1: The original procedure calls for the tBu ester deprotection/acid-promoted decarboxylation to be performed  at 45C/15 min. In my hands, running this step at ambient temperature (23 C) for 30 min provided a cleaner reaction mixture and a less colorful final product.
Note 2:  Performing the hydrolysis under a nitrogen blanket seems to improve the final product purity. Also, 3,5-dimethylpyrrole-4-carboxylic acids esters are rather sluggish to hydrolyze, probably because of the steric hinderance and pyrrole NH deprotonation. Distilling ethanol from the reaction mixture  accelerates the hydrolysis by increasing the mixture boiling point.
Note 3: The crude material is static and rather hard to crush when completely dry – it is best handled moist.

September 15, 2010

Knorr pyrrole synthesis

Filed under: procedures — milkshake @ 1:31 pm

A solution of tert-butyl acetoacetate 31.65g (200mmol) in acetic acid 40 mL was cooled on ice bath to 5C and a solution of NaNO2 14.00g (1 eq.) in water 20mL was injected slowly under the level of the reaction mix with cooling and vigorous stirring, over a 20 min period, so that the internal temperature did not exceed +15C. The syringe was washed with water (2 x 3 mL) and the washings also added to the mix. The reaction mix was stirred on melting ice bath to RT in an open flask overnight (16 hours).

Separately, in a 3-necked 1L round bottom flask with a large egg-shaped stirbar and internal thermometer and an addition funnel, anhydrous sodium acetate 20g and ethyl acetoacetate 29.0g (1.1 eq.) were dissolved in acetic acid 100mL on a 60C oil bath. With vigorous stirring, Zn dust 10g (Aldrich, < 10micrometer) was then added followed by dropwise addition of the nitrosated mixture (from tBu acetoacetate and sodium nitrite). This addition was carried out over a 45 min period, while an additional Zn dust 40g was simultaneously added to the mix in approx 5 g portions few minutes apart. Each Zn addition was accompanied by a temperature spike, the internal temperature in the flask was kept below +85C. (The bath temperature was 60C and the the internal temperature in the flask was controlled by the rate of addition of Zn dust and the nitrosation mix. The total quantity of used Zn dust was 50g). At the end, the addition funnel was washed with additional acetic acid (3 x 10 mL) and this was added to the mix and continued for 1 more hour at 60C. The resulting foamy reaction mixture was finally diluted by addition of water, 100mL, and the mixture was stirred for one more hour at 60C. The reaction mix was then poured into a large beaker, diluted with water 0.5L, some crushed ice was added (total mix volume was 1.5L) and the slurry was placed on ice bath and stirred for 1 hour. The precipitate was collected by filtration, washed thoroughly with water and dried by suction.

The obtained crude product was dissolved in a 1:1 mix of ethanol+ethyl acetate (0.5L) with gentle heating, the solution was filtered from the leftover Zn dust (Zn washed with EtOAc on Buchner) and the filtrates were evaporated to dryness. The solid residue was suspended in acetonitrile 60mL and the slurry was placed into a freezer (-20C) overnight. The precipitate was collected by filtration, washed with cold acetonitrile, dried by suction and on highvac. Y=35.55g (66.5%) of a white sugar-like crystalline solid.

1H(CDCl3, 400MHz): 8.93 (br s, 1H), 4.29 (q, 7.1Hz, 2H), 2.53(s, 3H), 2.50(s, 3H), 1.57(s, 9H), 1.36(t, 7.1Hz, 3H)

Note: There were couple more grams of the product left in the supernatants that could be likely isolated on a column, or doing a fractional crystallization from MeCN, but it was not worth the trouble.

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