Org Prep Daily

June 11, 2009

10-hydroxy-cis-perhydroisoquinoline

Filed under: procedures — milkshake @ 5:01 pm

1-(2′-amino-1′-ethyl)-cyclohexene 17.53g (140 mmol, Alfa) was combined with water 60 mL and conc. 37% aq. HCl 11.5mL (140 mmol) was added, followed by additional water 40mL. The acidity of the mixture was adjusted approximately to pH=2 (on strip indicator paper) by adding few drops of 6M HCl. The mixture was placed on a 40C heating bath. A solution prepared by diluting 11.50g of 37% aqueous formaldehyde (140 mmol, Aldrich, stabilized with MeOH) with water 20mL was slowly added from the addition funnel with vigorous stirring, over a two-hour period. The addition funnel was washed with additional water (2x10mL) and the washings were also added to the mix. After the complete addition, the stirring at 40C was continued for additional 6 hours. Two small spoons of charcoal were then added, the reaction mixture was filtered into a 1L round flask (the charcoal was washed with additional water) and the combined filtrates were evaporated from a 40C bath at 15-20 Torr to dryness. The obtained solid residue was re-dissolved in methanol 80mL at reflux. Boiling acetone 450mL was added into the flask at once and the resulting slurry was allowed to rest at ambient temperature for 6 hours (overnight). The precipitated product was collected by filtration, washed with acetone and dried in vacuo. Y=23.722g (88.5%) of a white crystalline solid.

1H(D2O, 400MHz): 3.357(dd, 12.9Hz, 3.6Hz, 1H), 2.244(td, t:14.2Hz, d:4.0Hz, 1H), 3.159(m, 1H), 3.019(dd, 13.)Hz, 4.7Hz, 1H), 2.115(br m, 1H), 1.763(m, 2H), 1.672-1.258(m, 8H); 13C(D2O, 100MHz): 68.32, 44.75, 40.41(br s), 39.08, 25.96(br s, 2C), 23.45(br s, 2C), 22.26(br s)

Note: The reaction mix turns into emulsion with the formaldehyde addition but becomes homogeneous further on. It is important to add exact amount of formaldehyde (weighed out in a syringe) and use a solution of known concentration; old bottle of poorly-stabilized formaldehyde solution with paraformaldehyde deposits should be left for the biologists.

4 Comments »

  1. I had this problem once on 2L scale. Finally I saturated H2O with NaCl and extracted the product with acetone – sounds crazy, but it works. and it was disodium salt!

    Comment by krest17 — June 12, 2009 @ 12:13 am

  2. But for this example I guess it will not work – look’s like product is not soluble in acetone

    Comment by krest17 — June 12, 2009 @ 12:16 am

  3. I have performed similar chemistry but used paraformaldhyde (good bottle) instead and less relative water (forget if had a co-solvent). Also used to add a dye (again forget what it was) into the mix so could visually monitor and add more acid if required. Dye either washed out or removed by plug of charcoal.

    Comment by CMCguy — June 12, 2009 @ 3:47 pm

  4. a very handy prep by Schlosser allows you to make a nice solution of monomeric formaldehyde that is highly reactive and reliably gives good results in quenching enolates if used fresh (same day). It’s a simple distillation. Saved my butt a few times when I was getting poor yields and starting material protonation.

    the ref:

    Schlosser, Manfred; Jenny, Titus; Guggisberg, Yves. Monomeric formaldehyde in ethereal solution. Synlett (1990), (11), 704.

    Comment by chem dude — June 16, 2009 @ 1:34 pm


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