Org Prep Daily

January 7, 2008

3′-(2-amino-1,3,4-thiadiazol-5yl)-benzoic acid ethyl ester

Filed under: procedures — milkshake @ 2:08 am


3-Iodobenzoic acid ethyl ester 13.18g (47.7mmol) solution in anh THF (220mL) was cooled to -78C under Ar. After 20 min a 2M solution of isopropylmagnesium chloride in ether 38mL (76mmol) was slowly added along the flask wall over 15 min at -78C. The flask was placed on a -55C bath and stirred at -55C to -40C for 50 min and then at -40C to -34C for 90 min. The reaction mixture was then cooled back to -78C, anhydrous DMF 20mL was slowly added along the flask wall with intense stirring (a slurry formed), the flask was then placed on a -30C bath and the bath was allowed to expire and reach ambient temperature over 2 hours. The reaction was quenched with saturated aq. NH4Cl (250mL), stirred for 45 min, diluted with water 50mL and ether 100mL, shaken, separated. The organic phase was washed with additional sat. NH4Cl  (250mL) and sat. NaCl (200mL). The aqueous phases were re-extracted with ether (250mL). The combined organic extracts were dried with MgSO4 and evaporated (down to 1.5 Torr, at 40C). The residue was dried on highvac overnight. Y=8.84g (104%) of the crude aldehyde as a pale yellow oil, 94% pure by HPLC, 1H-NMR.

1H(d6-DMSO, 400MHz): 10.103(s, 1H), 8.447(dd, 1.7Hz, 1.4Hz, 1H), 8.254(dt, d: 7.8Hz, t: 1.5Hz, 1H), 8.170(dt, d: 7.7Hz, t: 1.5Hz, 1H), 7.764(t, 7.7Hz, 1H), 4.367(q, 7.1Hz, 2H), 1.350(t, 7.1Hz, 3H)

4.110g (approx 22.18mmol) of the crude aldehyde from the previous step was dissolved in a mixture of acetic acid 20mL and water 10mL. Thiosemicarbazide 2.50g was dissolved in a mixture of acetic acid 20mL and water 20mL with heating, the hot solution was added into the stirred solution of aldehyde. A white precipitate formed. The stirred mixture was allowed to cool to RT. After 1 hour, the precipitated thiosemicarbazone was collected by filtration, washed with some additional AcOH+water 1:1 mixture (2x10mL), then with copious quantity of water, dried by suction and on highvac. The obtained crude thiosemicarbazone (white solid, 4.73g) was suspended in anhydrous ethanol 250mL, iron(III)chloride hexahydrate 21.6g (80mmol) was added and the mixture was refluxed on an 85C oil bath for 2 hours. Charcoal 1g was then added, the mixture was cooled to RT, filtered and the filtrates were concentrated to a small volume (about 30mL). Meanwhile, EDTA disodium salt 35g (94mmol) was dissolved in a mixture of water 200mL and 28% ammonia 20mL. The concentrated reaction mixture was poured in a thin stream into the vigorously-stirred solution of EDTA. The flask was washed with additional ethanol (2x10mL) then with water (2x25mL); the washings were also added to the mix. After 15 min stirring, the precipitated crude product was collected by filtration, washed with water until nearly-white, then dried by suction and on highvac. The crude product (4.36g) was dissolved in refluxing acetonitrile 250mL, the solution was quickly filtered while hot, the Buchner funnel was washed with some additional hot acetonitrile (50mL) and the filtrates were evaporated. The residue was suspended in acetonitrile 40mL, the solids were collected by filtration, washed with acetonitrile (2x20mL), dried by suction and on highvac. Y= 3.780g (80.5% from semicarbazone, 68.5% overall) of a cream-colored solid, about 96% pure by HPLC.

1H(d6-DMSO, 400MHz): 8.304(t, 1.6Hz, 1H), 7.986(m, 2H), 7.623(t, 7.8Hz, 1H), 7.513(br s, 2H), 4.355(q, 7.1Hz, 2H), 1.348(t, 7.1Hz, 3H); LC/MS(+ESI): 250 (M+1)


  1. Is remaining iodide responsible for 104% yield?

    It’s like first time I see MeCN as a purification aid (not counting chromatography).

    Comment by liquidcarbon — January 7, 2008 @ 10:25 am

  2. maybe it is is some residual inorganics – I could not see much on HPLC, not even DMF signals on NMR. One vacuum distillation would probably make it perfectly pure but why bother when in the next step, the thiosemicarbazone crystallizes out.

    MeCN is pretty good for re-crystallizing very polar or very greasy compounds. The added advantage is that MeCN is UV transparent so a sample from the mix can be injected directly into HPLC. Also it has just one sharp characteristic signal in 1H-NMR

    Comment by milkshake — January 7, 2008 @ 12:36 pm

  3. Inorganics might account for yield boost but perhaps isolated as an adol hydrate form even though 1H NMR suggests otherwise. If is Mg salts wonder if would complex with the thiosemicarbazide although with 25% excess probably no interference?

    Are temperatures indicated Bath or Internal? In doing similiar chemistry observed the significant transmetalation did not really occur till about -25 to -20C (internal) which then was rapid to complete conversion(10-15 minutes) so had been taking inconsistent yield hits as unreacted SMs before began monitored more closely. Esters appeared OK till around 0C before possible side reactions evidenced.

    Comment by CMC guy — January 7, 2008 @ 3:27 pm

  4. It was the external bath temperature reading. I don’t think there was much difference between internal and external temperature at this scale – and the react mixture was not that concentrated, it was done in a large flask with efficient stirring and deep bath and the bath temperature was raised gradually so if there was any exotherm it did not get much chance at self-accelerating.

    I did not know at what temperature the ester would interfere (I have done similar iodobenzoic acid tertiary amides before, they can be transmetallated at -20 to -15 without problem). To stay on the safe side (conditions described by Knochel) my initial plan was to keep the reaction on a -40C bath for about an hour. Somebody came and talked to me and distracted me so I forgot to keep feeding the bath with dry ice, hence it got 90 min at -40 to -34C, but luckily no spoilage.

    Also you are right I added too much semicarbazide, 25% excess is unecessary and since semicarbazide is not that soluble on its own, it can crash out and contaminate the semicarbazone. Not that it would matter too much – but in the oxidation reaction mix I have seen few blobby chunks of material floating in the end, a material that looked a lot like elementar sulfur. Hence I added some charcoal and filtered, to get it out

    Comment by milkshake — January 7, 2008 @ 3:36 pm

  5. What’s the name of the reaction? Milkshake special? 🙂

    Just curious,


    Comment by Javaslinger — January 9, 2008 @ 3:15 pm

  6. The first trasmetallation with isopropyl Grignard is from Knochel work, this is pretty general (the only question there was whether DMF was a good enough electrophile that would formylate before the ester got hurt).

    The oxidation of semicarbazone to aminothiadiazole is old stuff, there are many precedents and related oxidative cyclizations like this – the imino group typically gets oxidized to nitrilium salt and the nitrilium grabs onto some nucleophile nearby.These oxidative cyclizations are milder than if you simply started with a derivative of carboxylic acid and tried to dehydrate it – you woud need to use something like polyphosphoric acid to do that. The only procedural modification that I used in this case was the EDTA workup (the old procedures isolated the products by precipitation of the HCl salt by concentrated HCl but I was bit worried about the ester stability in 12M HCl). I think ferricyanide or periodic acid oxidation should work also but I did not bother to try.

    Comment by milkshake — January 9, 2008 @ 6:12 pm

  7. I recently discovered a tidbit of information for doing corey-fuchs reactions.

    CBr4… a nasty toxic reagent… often has water(1-2%) when I buy it from acros/aldrich. This is a pain in the butt when trying to run the corey0fuchs because it kills your ylide dead in the water. The purification books says to sublime your cbr4 to purify it.. which is not much fun to say the least. An easier method is to simply dissolve your cbr4 in some dcm (say like 20-30g per 150mL) which should give a nasty looking cloudly solution with water droplets on top. Now just chuck in your mag sulfate, flter to give a nice clear solution into a tared flask. Rotovap, flush with ar and store in the desiccator taking some when you need it.

    This is awfully simple, and I am surprised I never thought of it before the several sublimations I did with it.

    Comment by tom — January 10, 2008 @ 2:00 pm

  8. In the similar vein I needed about 300g of anhydrous tBuOOH but the anhydrous 6M tBu hydroperoxide is appalingly expensive. People have been drying smaller amounts of tBuhydroperoxide with sieves but sometimes the mix with sieves can explode because of overheating. I found out that diluting the commercial 70% aqueous solution with three volumes of DCM, saturating the mix with MgSO4, decanting and re-drying with fresh MgSO4 followed by evaporation produced 95%+ anhydrous stuff (with tBuOOtBu as the only identifiable impurity)

    Comment by milkshake — January 10, 2008 @ 3:05 pm

  9. one thing i forgot to mention is you should certainly clean out the rotovap when your done by evaporating fresh dcm through the system… as the cbr4 will sometimes sublime and get into the bumptrap. When you remove trace solvent on high vac always set up a little trap in between the flask and the manifold.. otherwise you will see a nice white solid forming in your manifold. MgSO4 is impressively useful to say the least though!

    Comment by tom — January 10, 2008 @ 4:15 pm

  10. I will admit not not having seen any of this ‘old stuff’ oxidative cyclization before.

    Imine —> Nitrilium capturing the sulfur…

    Comment by TWYI — January 11, 2008 @ 11:48 pm

  11. there is a similar one with 2-pyridylhydrazine and aldehyde. Oxidation of the hydrazone produces pyrrazolopyridine quite cleanly. Another one uses 2-pyridylmethylamine and aldehyde. Pyridine can be replaced with pyridazine, 1,2,4-triazine and so on.

    This kind of cyclization is sometimes useful in medicinal chemistry: you start with a lead that has some civilised heterocycle – like thiazole or imidazole – then adding/removing heteroatoms and moving them around eventually gets you to monsters like thiadiazole. It turns out some of them are actually quite easy to make, if you need them.

    Comment by milkshake — January 13, 2008 @ 9:08 pm

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