Org Prep Daily

May 26, 2007

TPAP oxidation, 1-Alloc-4-piperidinecarboxaldehyde

Filed under: procedures — milkshake @ 11:20 pm

tpap.gif

Piperidine-4-methanol 10.0g (86.8 mmol) was dissolved in mixture of THF 160mL and water 160mL and K2CO3 18.0g (130mmol) was added. The mixture was stirred until complete dissolution of the solids (10 min), the resulting bi-phasic mixture was cooled to 0C. After 20 min at 0C, neat allyl chloroformate 11.0mL (103.5 mmol, 1.2 eq,) was added dropwise with vigorous stirring over a 5 min period. The mixture was stirred on ice bath for 1 hour, then the bath was allowed to melt and reach ambient temperature over 3 hour period. The reaction mixture was extracted with ether (2x200mL). The organic extracts were washed with sat. aqueous NaHCO3 200mL, combined, dried with MgSO4 and evaporated. The residue was dried on highvac (0.5 Torr, 60C).
Y=16.85g (97.5%) of the Alloc-protected piperidinemethanol intermediate as a pale yellow oil 1H(d6-DMSO, 400MHz): 5.920(m, 1H), 5.280(dq, d:17.2Hz, q:1.7Hz, 1H), 5.174(dq, d:10.5Hz, q:1.6Hz, 1H), 4.503(dt, d:5.2Hz, t:1.6Hz, 2H), 4.477(t, 5.3Hz, 1H), 3.985(br m, 2H), 3.239(t, 5.8Hz, 2H), 2.752(very br s, 1H), 1.643(m, 2H), 1.532(m, 1H), 0.994(m, 2H)

16.85g (84.56mmol) of 1-Alloc-4-piperidinemethanol from the previous step was combined with anhydrous N-methylmorpholine-N-oxide 23.8g (203mmol, 2.4 eq.) and activated powdered 4A sieves 38g. The mixture was suspended in anh. dichloromethane 210mL with added anh. MeCN 40mL (40 min stirring). The slurry was cooled to 0C, TPAP 306mg (0.87mmol, 1mol%) solid was added in one portion and the mixture was vigorously stirred at 0-5 C for 90 min under Ar. The cooling bath was allowed to melt and reach the ambient temperature over 2 hour period. The stirring was then continued at RT for additional 9 hours (overnight). The reaction mixture was diluted with EtOAc (250mL), filtered through a pad of silica (100g), the silica was washed with EtOAc 0.5L. The combined filtrates were evaporated and the residue dried on highvac to remove N-methyl morpholine. The obtained crude aldehyde (14.0g) was purified on a column of silica (250g) in hexane-EtOAc 1:1 mixture (3L).
Y=9.18g of a pure aldehyde as a colorless oil, with a faint mowed-grass odor (55% th, 53.5% overall Y).
LC/MS (+ESI): 198 (M+1); the 1H-NMR spectra of the purified product was quite awfull because the product was a mixture of aldehyde hydrate with the parent aldehyde

TPAP review: Synthesis 1994, 639-666.
[The typical catalyst loading in TPAP oxidations is 5 mol%. In this large-scale experiment I used less catalyst and stopped the reaction before complete conversion of the alcohol because some sideproducts started appearing on the baseline.]

10 Comments »

  1. I wonder how DMP would work on this one.

    Comment by kinasepro — May 27, 2007 @ 11:41 am

  2. It is a scale-up. I think DMP would give a better yield in this case- but DMP reagent has a huge molecular weight and is expensive so unless you make your own…

    Comment by milkshake — May 27, 2007 @ 5:47 pm

  3. Do you also find that TPAP oxidations are somewhat moody with respect to yield? In my experience, sometimes I simply cannot get >50% in my flask although the TLC indicated a spot-to-spot reaction. This happened to me on more than one occasion on different substrates using a similar workup protocol to yours above.

    Comment by Grubbs the cat — May 29, 2007 @ 4:24 am

  4. Frankly I don’t know what went wrong. One possiblility was an old soggy catalyst(definitely not a dark-green free-flowing crystal as stipulated). The other one is that the aldehyde overoxidized. There was some baseline stuff happening. Next time I do oxidation on 1 mol scale I will do Swern, to show everybody in the lab that I can be fierce.

    Comment by milkshake — May 29, 2007 @ 5:07 am

  5. MnO2 is pretty cheap too, and I recently heard some academic jumping up and down about how he could do his red-am’s in one pot with it… On #3, maybe try washing and sonicating the sieves?

    Comment by kinasepro — May 30, 2007 @ 12:10 am

  6. i was going to suggest swern too – its a good reaction. been somewhat supplanted as a first choice by ibx oxidation in my bag of tricks, but still good for sensitive stuff

    PS #5. that would be richard taylor(york), you can do wittigs in one pot too, plus some other stuff. neat fun on paper at least

    Comment by kiwi — May 30, 2007 @ 4:02 am

  7. @kinasepro

    I hda never thought of sonicating sieves…. Washing (more sort of rinsing) I do regularly.
    Is there evidence that organic molecules can stick to sieves? (I suppose that makes sense given they are weakly acidic – any basic cpd could bind similar to a SCX resin)

    Comment by Grubbs the cat — May 30, 2007 @ 6:59 am

  8. What about tempo oxidation (cheap!)? Could you Boc protect your starting materail? Boc-Pro-ol to Boc-Pro-al in this 1992 Tet Lett

    doi:10.1016/S0040-4039(00)61180-2

    Comment by VTChris — May 30, 2007 @ 2:59 pm

  9. The Boc aldehyde is commercial. Unfortunately the next step to a spirocyclic piece is the interrupted Fisher indole cyclization with an aryllhydrazine, promoted by acid (it is best done by heating in TFA). I cannot hydrogenate so the Cbz protection is also out and I would very much like to avoid Fmoc because the media in some other steps are quite alkaline. I guess I could use Troc or trifluoroacetamide or some arylsulfonyl protection group. But I need N-allyl-subtituted piperazine ring in the final product; N-allyl is very pleasant to make from Alloc in one step.
    I agree, the TEMPO oxidation could be a good alternative, maybe with Ph-I(OAc)2, to be gentle to C=C.
    I am just finishing the final step as we speak. By the next week I should see if the compound has any activity – if yes I would have to optimize both the oxidation and the subsequent cyclization.

    Comment by milkshake — May 30, 2007 @ 9:55 pm

  10. Privet communication from S. Ley: he recommends to use up to 20 eq. NMO for fast reoxidation of Ru. Not reoxidised Ru-species can cause a lot of side reactions. With 20 eq. NMO rxn is often finished after 2-5 min.
    NB: NMO is sold hydrated, and water retards the Ley oxidation. Also you use MS, sometimes it’s not enough. NMO may be dehydrated by treating a solution in CH2Cl2 with MgSO4 or by heating under vacuum during ca. 4 hours at 90 ºC. NMO must be dehydrated shortly before use to avoid decomposition. (this is a private comm. of prof. G. Tojo)

    Comment by Alexey — June 3, 2007 @ 12:51 pm


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