Org Prep Daily

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.

13 Comments »

  1. Med Chem at its best. A couple of seemingly trivial steps from a dirt cheap and deceivingly simple aromatic starting material, and, bingo! Generated several cool-looking structural analogues.

    Comment by HPCC — November 4, 2010 @ 11:59 am

  2. Interesting scaffold… do you think that you can alkylate on the pyrimidinone nitrogen atom (at “6 o’clock” in the product as drawn), either after or more likely before the ketoester condensation? Or do you need the primary amine to make the condensation work?

    Comment by partial agonist — November 5, 2010 @ 2:42 pm

    • I suppose a small alkyl on the amino would not upset the reaction – this cyclization starts with enamine formation from the keto group, then the carboxyester closes the ring. (I presume the keto reacts first because this condensation works also with acetylacetone but it does not work diethyl malonate. And it fails with ketoesters that have less reactive keto group, such as pivaloyl- and benzoylacetate ethyl ester).

      But I think direct alkylation of the pyridone NH in the product solution in aq. NaOH would be worth trying

      Comment by milkshake — November 5, 2010 @ 2:57 pm

  3. Hi Milkshake,
    what would be the best method for the methylation of the nitrogen atom of an allylamide derived from N-Boc protected Proline? I don’t know which base could suppress the alpha alkylation?
    Thanks

    Comment by madForIt — November 6, 2010 @ 2:00 pm

    • I would try cesium carbonate, in acetonitrile, with dimethyl sulfate or methyl iodide as a methylating agent. (Be careful, Me2SO4 is very nasty). I would start at 40C, and if this does not work I would go up to reflux. You could also try DMF as a solvent.

      I remember a long time ago (20 years ago) I was trying to alkylate a sidechain of some Fmoc- alpha-protected aminoacid in mildly basic aqueous solution with excess of dimethyl sulfate and I accidentally alkylated the Fmoc-protected alpha amino NH also (without the Fmoc falling off)

      Comment by milkshake — November 6, 2010 @ 4:13 pm

  4. Thank you so much, i will try it on monday.
    What about using a base like DIPEA in CH3CN and MeI?

    Comment by madForIt — November 7, 2010 @ 9:26 am

  5. Maybe you could consider a Mitsunobu alkylation?

    Comment by Al — November 7, 2010 @ 9:43 am

  6. I have “just” to put on a methyl group on a nitrogen amidic atom, avoiding alpha alkylation on carbon..

    Comment by madForIt — November 7, 2010 @ 10:06 am

  7. Hello MS,

    I have a N-protected substituted imidazole ethyl ester and the compound also contains unprotected tetrazole moiety . Is it possible to effect a transesterification using allylic alcohol? What are the conditions worth trying ? please suggest if you have some experience

    Thanks

    Marto

    Comment by marto — January 24, 2012 @ 1:48 pm

  8. Yes I think so but I would avoid using acidic catalysts for transesterification (because of ease of forming allyl cation under acidic conditions). For base-catalyzed transesterification I would use sodium alkoxide of allyl alcohol. I would use 1.1 equivs of NaH in excess of anhydrous allyl alcohol (used as a solvent). The reason why you probably are not succesfull with using a catalytic quantity of base is that tetrazole NH is quite acidic so you end up with generating Na salt of tetrazole. Hence you need to go over 1 equiv. If your transesterification is too slow at room temp (because of the negative charge on tetrazolate salt) you can heat it gradually. What is the protecting group on imidazole – is it tolerant to strong base/nucleophiles?

    Comment by milkshake — January 24, 2012 @ 3:04 pm

  9. Thanks very much for the suggestions. Imidazole is protected with benzyl group so it should not be a problem
    under basic conditions

    Comment by marto — January 24, 2012 @ 11:12 pm

  10. Hi, do you know if there are ways of forming the other regioisomers?

    Comment by RobD — October 31, 2012 @ 4:00 pm

    • I don’t know – I found this cyclization in the literature, it gave a single regioisomer and I presumed it was the correct one but I have not run ROESY to confirm it. I suppose this particular regioisomer arises from enamine formation (from the keto group and the primary amino), followed by cyclization with the ester. If you try to use malonic acid dimethylester, the reaction does not work.

      I suppose one could try to couple for example 2-butynoic acid with some peptide coupling agent or even use an activated ester of acetoacetic acid and cyclize the coupling product, to get the opposite regioisomer

      Comment by milkshake — October 31, 2012 @ 5:06 pm


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