Org Prep Daily

December 4, 2007


Filed under: procedures — milkshake @ 3:51 am


A solution of 25% wt sodium methoxide in methanol 3.0mL (12.8 mmol) was added dropwise to a solution of diethoxyacetonitrile 6.2g (48 mmol) in anh methanol 15mL with cooling on ambient water bath over 5 min period. The mixture was stirred at RT under Ar for 26 hours. [Note 1] To this solution containing (EtO)2CHC(OMe)=NH, solid p-bromobenzylamine hydrochloride 5.04g (22.65 mmol) was added followed by additional 25% NaOMe 3.0mL (12.8mmol). The mixture was refluxed under Ar at 70C on oil bath for 17 hours (overnight). The reaction mixture was evaporated, the residue was diluted with tert-BuOMe 50mL, the salts were removed by filtration (washed with additional TBME) and the filtrates were evaporated. The residue was dried on highvac (50C, 0.5Torr, 1 hour) to yield the crude amidine 7.64g as a dark brown honey.

The crude amidine was slowly added in a thin stream into vigorously stirred conc. sulfuric acid 50 mL with cooling on ice bath. The flask after amidine was rinsed with additional conc. sulfuric acid (2x10mL, then 4 mL) and these washings were also added to the reaction mixture. The cooling bath was removed and the dark mixture was stirred at RT under Ar for 1 day. The reaction mixture was poured onto ice (250 g) in a 1L beaker, the flask was washed with water and washings were added to the mixture. The mixture was made alkaline by careful addition of conc. aqueous ammonia (approx 220mL, exothermic!) with external cooling on water bath. When the mixture has cooled to RT the precipitated product was collected by filtration, washed with water and dried by suction. The obtained crude product was suspended in a mixture of ethanol 400mL and water 100mL. 6M HCl 4mL was added and the mixture was heated and sonicated until complete dissolution took place. Charcoal (3 spoons) was added, the mixture was heated to a brief reflux (2 min) then cooled to RT and filtered. The charcoal was washed with ethanol+water mixture (1:1, 1oomL). The filtrates were made basic by addition of conc. ammonia 3mL and gradually concentrated down to approx 125mL volume to remove ethanol. The precipitated product was collected by filtration, washed with water and dried by suction, then on highvac. Y=3.943g (78% overall) of a pure product as a light tan solid.

1H(d6-DMSO, 400MHz): 8.809(s, 1H), 7.793(app d, 1.8Hz, 1H), 7.730(d, 8.7Hz, 1H), 7.215(dd, 8.7Hz, 1.9Hz, 1H), 6.553(s, 1H), 6.112(br s, 2H); 13C(d6-DMSO, 100MHz): 157.12, 151.74, 139.61, 130.03, 125.90, 124.44, 124.17, 120.63, 95.85; LC/MS(+ESI): 223, 225 (M+1)

Note 1: The progress of  methyl imidate formation from nitrile can be readily followed on NMR – by diluting samples of react mixture with CD3OD + TMS standard: (EtO)2CHC(OMe)=NH : 4.836(s, 1H), 3.760(s, 3H), 3.590(m, 4H), 1.213(t, 7.1Hz, 6H); (EtO)2CHCN: 5.490(s, 1H), 3.699(m, 4H), 1.239(t, 7.1Hz, 6H)

Note 2: A slightly more optimised version follows: 12 mL of 25% wt NaOMe in MeOH was added to a water-cooled solution of (EtO)2CHCN 11.81g in anh. MeOH 30mL over 10 min. After 12 hours at RT, solid p-bromobenzylamine hydrochloride 10.17g was added and the mix was refluxed under Ar at 70C for 14 hours, then evaporated. The residue was re-dissolved in TBME 50mL, filtered (salts washed with additional TBME) the filtrates were evaporated and the residue dried on highvac at 50C. The obtained crude amidine (15.19g) was slowly poured into ice-cooled conc. sulfuric acid 100mL, the flask was washed with additional H2SO4 (2×20 then 5mL) and the washings were combined with the reaction mixture. The mix was stired at RT for 11 hours, then poured on ice (0.5kg) and carefully alkalised with conc aq. ammonia 450mL (with cooling: exothermic). Upon cooling to RT, the precipitated crude product was collected by filtration, washed with water and dried by suction. The crude product was refluxed with EtOH 0.5L and water 0.25L mixture acidified with 6M HCl 8mL until complete dissolution took place (30min). The solution was cooled, charcoal 2.5g was added, the mix was brought to brief reflux again (5 min), cooled to RT and filtered, the charcoal washed with additional EtOH. The filtrates were concentrated to about half volume, made basic with conc. ammonia 8mL, concentrated slowly down to approx 220mL. The precipitated product was collected by filtration, washed with water, dried by suction and on highvac.
Y = 8.455g (83%) of a light tan solid (96% pure by HPLC, NMR)


  1. I can’t imagine what you were doing with this stuff…

    Comment by kinasepro — December 4, 2007 @ 11:17 pm

  2. a completely puzzling coincidence

    Comment by milkshake — December 4, 2007 @ 11:29 pm

  3. on a side note… How difficult is it to get into the Ph.D program at scripps florida?

    Comment by Tom — December 5, 2007 @ 12:03 pm

  4. I don’t know. In medicinal chemistry we are separate from the graduate groups (we take postdocs though). I believe the admission goes through LaJolla first – I can find out. It would probably help if you could send a polite e-mail to the professors here: the worst thing that can happen is that they refer you to Scripps grad program office. If you are interested in organic chemistry program we have here only two organic chemistry-related groups, the Roush and the Periana group.

    Comment by milkshake — December 5, 2007 @ 12:50 pm

  5. While I am at it I got another question.. [(PPh3)2Pd]Cl2 been sitting in a crappy desiccator for over a year…The desiccant has an indicator which has turned from blue to pink(meaning it is no good). It looks like the bottle was never opened…. Should I trash it or is there a snowballs chance in hell of it working for a few sonogashira couplings? I am undergrad working at UNCA over the break and there aren’t many people around who are knowledgeable about this kind of stuff..

    Comment by Tom — December 5, 2007 @ 6:28 pm

  6. Unopened bottle should be fine: PdCl2.2PPh3 catalyst is not air/moisture sensitive (unlike tetrakis). It could be somewhat light sensitive – so open the bottle and check if there are still nice light bright yellow crystals. You can even take 1-H NMR spectra of it, if you want – Pd(II) is not paramagnetic so it should not upset proton signals. But I think you should be fine. I would not bother to put the bottle into desicator, even here in Florida – just a dark drawer should be fine.

    By the way, if you have PdCl2(Dppf).CH2Cl2 you can use it as a catalyst instead – it is very similar in Sonogashira but slightly more stable. Are you doing aryl-I or aryl-Br Sonogashira?

    Comment by milkshake — December 5, 2007 @ 6:52 pm

  7. Well I am making a series of analogues of a potent anti-tumor agent… Many of the coupling partners are commercially aval. but 3-4 aren’t. They will have to be made, and a few of them are ArI and a few ArBr so I will be doing both. I have found a few refs. were they treat the ArBr with BuLi then I2 to afford the ArI in decent yields… So I may try that if the ArBr are slow to react. I only need to make a small amount of each final compound.. as I will be assaying them myself(get to go down to the slaughterhouse.. get some cow brains.. blend them up and extract tubulin).

    I have Pd(OAc)2 on order, I also have some of the tetrakis which I just got in… I quickly loaded up a small brown bottle full of desiccant.. placed the unopened tetrakis in it and sealed it.. then put it in the fridge. The CuI i ordered 99.999% and I also have some that I purified via a technique I saw on Org. Synth. where they use soxhlet with THF to remove some nasty yellow shit from the CuI. I get my THF from a sodium still that I built, and the amines I will distill fresh from CaH2… I plan to degas by bubbling Ar gas through the THF/amine for like 10-20 mins.

    I pretty much plan on trying each of the catalysts till I get one that works.

    Comment by Tom — December 5, 2007 @ 10:11 pm

  8. the most important thing is to flush tetrakis with Ar or N2 after each use and keep it in freezer. Any color darker than lemony yellow can be bad news. Strem has good tetrakis , Fisher represents Strem so you can place the order through them.

    For aryl bromide sonogashira I have a favorite protocol, it is very fast and easy, the procedure was posted on November 16 2006. But for some mysterious reasons the procedure works well only for aryl bromides – aryl iodides need a different system… Also, don’t overload your reaction with copper – you need ony a trace of copper to get it going because the acetylide formation is not rate limiting step – and too much copper can cause your alkyne to dimerize to a great extent.

    Comment by milkshake — December 6, 2007 @ 9:14 am

  9. Strem tetrakis is gorgeous; Aldrich’s is total garbage (green, brown, dark yellow).

    For the Ar-I vs. Ar-Br differences, I suspect it is a relative rate issue, and the competition between transmetallation and simple reduction of the Ar-X. I saw some similar trends in lots of Suzukis.

    Comment by Jose — December 6, 2007 @ 2:42 pm

  10. I think complexation of I(-) to Pd can be also a factor. I had a problem with strongly-coordinating 2,4-diamino-5-bromopyrimidines, the Sonogashira was rather slow but I got it going, with the PdCl2.Dppf 3 mol% + NEt3 1.5 eq in THF, with 0.5 mol% of CuBr or CuI added as the last component. When I switched to the corresponding iodo compounds, the reactions would not complete – the initial rate was much faster but it stopped very early on. I also did not see any salt precipitation whereas the bromide reaction can be followed easily by watching the level of NEt3.HBr precipitate (this works very nice with a set of 10+ reactions all in the same-size vials). My guess is that NEt3.HI is much more soluble, it does not precipitate and by coordination it shuts down the catalyst. The easy way to find out would be to add some HgO to the reaction, to eat I(-).

    Comment by milkshake — December 6, 2007 @ 4:01 pm

  11. I think that I just found some bad tetrakis…. I looked in the freezer and found a bottle of dark orange tetrakis that looks pretty old. I am guessing it is the bad shit.

    PdCl2.Dppf [(PPh3)2Pd]Cl2 interchangable in the procedure you wrote up? I think I will try that for the bromides. I found one Cu free procedure using the acetate with pyyrolodine and PPh3 at reflux temp. I might give that a shot for the iodides. I would be happy to write up a procedure for it later on…. after I figure out the molecule is active/inactive.

    I do have a write up for a homologation reaction I did on an indole-2-carboxaldhyde -> alkyne using a one pot corey-fuchs variant. It involves the synthesis of the reagent and the prep along with all the 1H 13C spectras. I haven’t been able to find an instance where this reaction was done in the literature either.

    Comment by Tom — December 7, 2007 @ 2:08 pm

  12. this Corey-Fuchs would be nice, especially if you have the NMR spectra. Please send me what you have – if it is a reliable procedure – to: tomasv@[ institute name here].edu, I can put it up for you the same day. Thank you!

    If you are doing a medchem work, it is not a good idea to post structures of final compounds – active or not – before either the project got cancelled already or patent application was published – because disclosing a structure can hurt patentability of the whole series of your compounds. You don’t want to hurt the IP position of your group/employer. Intermediates are much less problematic – but then again, you should maybe check with your boss. Disclosing an improved re-synthesis of literature compound would probably be the safest alternative.

    The PdCl2.Dppf in the procedure is pretty interchangeable, for PdCl2.2PPh3 as a catalyst if you add one extra PPh3 to it. The orig paper (that I cannot find now) called for for PdCl2.2PPh3 + extra 1 PPh3 per Pd. They claimed it was particularly good for the poorly-reactive aryl bromides. They said they did not even need to degass the reaction mix when they used freshly-distilled THF and a tight vial filled near to the top, without much head space. The important thing was to add the CuI or CuBr last before capping the vial and use only very small amount of Cu as to not to overload it with Cu. I tried that procedure side-by-side with PdCl2.Dppf and the result with the PdCl2.Dppf catalyst was only marginally better (and it needed no extra PPh3) so I kept using it ever since.

    Comment by milkshake — December 7, 2007 @ 4:29 pm

  13. Well my boss doesn’t have a lot to do with the project as I came up with just about the whole thing myself. I will probably keep the procedure on the fully elaborated molecule to myself. However, I have done it on an unfunctionalized indole-2-carboxaldhyde to give good results. The procedure is a variant of the corey-fuchs using Michel, P.; Gennet, D.; Rassat, A. Tetrahedron Lett., 1999, 40, 8575-8578. The procedure I used is very similar and works pretty well… much to my surprise, as the typical corey-fuchs fails to give the alkyne. I found a good prep of the reagent needed… and it is indeed as stable as the authors claim it to be(kept under argon in the freezer) for months.

    Comment by Tom — December 7, 2007 @ 9:26 pm

  14. Tom…this is what good tetrakis looks like. Anything much darker is not so good. 🙂

    Comment by Ψ*Ψ — December 9, 2007 @ 7:54 pm

  15. Ah very nice. the orange shit in my freezer is crap. I love the thread about the alfa people being like our tetrakis comes in 3 colors…

    Comment by Tom — December 9, 2007 @ 10:34 pm

  16. While we are on colors… why the hell does acros ship yellow buli while aldrich ships clear buli?

    Comment by Tom — December 9, 2007 @ 10:38 pm

  17. oak barrel-aged to full maturity

    Comment by milkshake — December 9, 2007 @ 10:45 pm

  18. I always thought that BuLi itself is yellow and that the clear stuff is hydrolyzed…? Was I wrong?

    Comment by Dan — December 10, 2007 @ 2:16 pm

  19. Usually the BuLi solutions I had were little yellowish. (The old poorly sealed stuff had white ppt in it.)

    I discourage people from using Acros septa bottle because I had a bad experience; I don’t trust their “airtightness”.

    Comment by milkshake — December 10, 2007 @ 3:30 pm

  20. I greatly prefer the Acros bottles, actually. The only trouble is making sure you don’t accidentally twist off the bottom metal cap while unscrewing the black plastic top piece. Some black electrical tape around the metal cap upon arrival is usually enough to prevent accidents and to remind me what I should be doing while opening a bottle.

    In my experience, color is a poor indicator of BuLi quality. Good bottles can be yellow or colorless, and “no change”/”change” in color is not a good predictor of “still good”/”gone bad”. Just titrate the stuff.

    Comment by Metalate — December 10, 2007 @ 4:16 pm

  21. Check out the new Acros sureseals. I just got a bottle of ether the other day and I must say that they are quite good. Gone are shitty metal screw-caps which come off easily. It is now quite easy to remove the top cap without affecting the seal.

    I think that the white ppt is a good indicator of quality.

    Comment by Tom — December 10, 2007 @ 4:33 pm

  22. i used your procedure for dess martin except I used oxone to make the IBX. That worked like a charm. DMP is prety badass… I can’t believe I never used it before.. beats the hell out of mno2

    Comment by Tom — December 14, 2007 @ 11:03 pm

  23. The DMP procedure is just a reproduction of the protocol from the Ireland group. I think the original procedure published by Martin – for acetylating IBX – did not have TsOH so the mix had to be heated quite dangerously high and the outcome was not as reproducible.

    Comment by milkshake — December 15, 2007 @ 2:34 am

  24. Hi MS,

    I would like to do a nucleophilic substiution of benzylic (not exactly – chloride attached to pyridone methylene group) chloride. Please tell me any reagents for the reaction of this chlorides with aryl grignard reagents..I dont have any litearture support for this reaction.
    In essence, I would like to introduce 4- fluoroaryl in place of chlorides..

    =-CH2 Cl to =-CH2Ar (Ar – 4-fluorophenyl)

    If there are not any reactions you may be are aware of then please suggest me conditions wherein convesrion of =-CH2 Cl to CHO or COOEt

    Would be great any lit for SP3-SP2 coupling (milder conditions are preferred as the system is not really stable towards basic conditions)..

    Please help me as my timeline is fast appraoching..

    Thanks a lot for your advice about cyclopropyl acetic acid..We could complete the target within the timeline



    Comment by marto — June 28, 2009 @ 10:14 am

  25. Marto, sorry but I don’t want to do lit searchers for you. Its called Kumada coupling and there is huge amount of literature on the subject, and I don’t have much experience with it.

    For coupling of Grignards with halides, people used Cu(I), Fe, Ni and Pd catalysts. I would suggest to start with CuCN (or CuI or CuBr.Me2S) in catalytic amount, for example 10 mol%, and a slight excess of Grignard. If this does not work then some NiCl2.bidentate phosphine complex, or Pd(PPh3)4, or some iron complex. Furstner had lots of articles recently – with Fe catalysts like Fe(acac)3 (few mol%), and excess of Grignard but I didn’t follow it much because I never needed it for anything.

    Comment by milkshake — June 28, 2009 @ 10:27 am

  26. Hi Ms,

    I apoligies for the trouble..thanks very much for the help..



    Comment by marto — June 29, 2009 @ 8:04 am

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