5-mercaptooxindole

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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.

Oxindole-5-carboxylic acid

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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).

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

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.

Knorr pyrrole synthesis

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.

Look ma, no bromine!

After heating up some simple 2-chloro-4-amino-5-bromopyrimidines with an excess of p-MeS-aniline, I got the corresponding 2-anilino-substituted products  - but with the bromine clipped off. The aniline was apparently the reducing agent in this case, producing lots of deep-blue colored oxidized aniline stuff in the process.

I suppose it has to do with the chemical similarity of this aniline with the leuco form of methylene blue, a known reducing agent.

All your structure are belong to us

I downloaded Symyx Draw this morning, it is offered as a free program for academia. It is used for drawing reaction schemes, creating SMILES strings, entering structures into Symyx databases, etc. and I am quite anxious to get rid of it: Symyx Draw automatically assigned Chemdraw files to a default association with itself (all files, not just those accessed by/copied into Symyx Draw).  And now when I try to reset the file association back to Chemdraw with the help of Chemdraw file connection prompt my computer would ignore the change. A newly drawn Chemdraw file then comes out with a cheerful Symyx icon and will reopen with Symyx Draw too (unless I rightclick and select Chemdraw from the list)….  I do not wish to have all my Chemdraw files appropriated by Symyx Draw without myself deciding to do so. And its not like that they would have asked during the installation. And I resent that in this way they try to mess with a functionality of a (better) competing software that we have already purchased.

I have had some experience with this company: after Symyx acquired MDL, Symyx stopped offering standalone ACD access subscription. (Available Chemical Directory – the most complete database of commercially-available chemicals, their pricing and vendor contact info). Symyx wanted the MDL customers to switch to their Symyx Discovery Gate “all inclusive” chemical search package which also bundled ACD access in it. The cost of the Discovery gate is so high that many academic institutions cannot afford it; for example my current employer does not have it. But I had the misfortune of struggling with the  Discovery Gate in my previous job – its  Java-heavy web-based interface provides the ACD search functionality too – but for me the most important difference was that a regular search that used to take one or two click per compound with the standalone ACD database from MDL was now taking about ten clicks per compound  in the Discovery Gate (with the extra download delays in between): now try to browse through few hundred compounds in the ACD database with this dog. A Symyx customer service representative informed me that they were not offering the standalone access anymore but I could put my concerns into writing (I wrote them an e-mail and I never received a reply to it).

Also, several times I spoke with our chem-informatics guy at the previous job, about our compound submission database – we used to have a simple one from MDL that worked perfectly well  - before it got integrated into a spiffy new Symyx database. And he too has been really frustrated with the Symyx chemical inventory and bio data integrated database that we were using thereafter for our compounds and biology data and chemical collections and high-throughput screening – all in one unwieldy mammoth database. He told me that he had to eventually get a third party software and write a new interface for us in chemistry just to help us with viewing and searching our compounds after we had entered them into the Symyx database (for which our employer paid hundreds of thousands USD). He said he felt hamstrung by having to work with this enormous and poorly designed package that someone high above in the management had chosen for us.

I suppose is always the same – a ginormous all-inclusive package that hardly does any of its basic functions well – and the company that does not care about the needs of the users and promotes its “complete solutions” to the management folks who actually decide about purchasing this stuff… I have the impression that when Symyx bought MDL it set out to max up the profits while riding on the popularity of MDL software; I think in the long run Symyx will drive away many MDL customers by these tactics and will not create too many new ones because eventually the word gets around. For example the ACD access is pretty important but in the end one can get a list of vendors and commercial availability/pricing info from alternative sources.

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The individual Chemdraw licence complete with a decent manual costs about $170 for academia and private users (I bought one for myself last year when I needed to prepare my job presentations). I have no special love for CambridgeSoft but at least they never pulled a surprise like this on me and never told me to go and stuff myself with my concerns.