Org Prep Daily

October 23, 2006

Noyori asymmetric transfer hydrogenation

Filed under: procedures — milkshake @ 11:41 am

noyori.gif

RuCl2(cymene) 24mg (Aldrich, 0.04mmol Ru) and (S,S)-TsDPEN 40mg (0.096mmol, Aldrich) in a 250mL (14/20 joint) round flask equipped with a stopcock was flushed with Ar using a long needle.  Dichloromethane (4mL, from Aldrich SureSeal) was added and the mixture was stirred under Ar (without reflux condenser) on 40C oil bath for 1 hour. The Ru-salt and the ligand dissolved. After 1 h, the solvent was removed by blowing a stream of Ar into the flask on the 40C bath. De-ionised water 16mL was added into the dry flask (with a film of active catalyst on the wall) and was de-gassed by vac/Ar purge (3-times). A mixture of solid HCO2Na 2.72g (40mmol), CTAB 15mg (0.04mmol) and the starting F-spiroketone 1.110g (4.0 mmol) was added and the flask was flushed with a stream of Ar. Ethyl acetate 2 mL (a good grade, not deoxygenated)  was added and the mixture was stirred vigorously under Ar at 40C for 16 hours (the crystals of the starting material gradualy dissolved, the progres was monitored by TLC). The cooled reaction mixture was extracted twice with EtOAc (2x100mL). The combined extracts were dried (with 4A powdered molecular sieves), filtered and evaporated. The residue was purified on a column of silica (80g) in a gradient of methanol in chloroform, 0 to 2.7% of MeOH, then 2.7% isocratic. Y=1.123g (100%) of a light-yellow sticky glass.  

The optical purity was assayed using a reverse-phase chiral HPLC column, Chiralpak AD-RH, in water-acetonitrile (no TFA) at 50 or 55C, at 0.8mL/min. The e.r. was 0.5:99.5 by integration. The opposite ligand enantiomer provided 100%Y of the product with e.r. = 99.4:0.6 (with the minor enantiomer peak eluting on the tail of the main one).

The 1H-NMR spectra in DMSO show a 1:1 mixture of rotamers about the amide bond. 1H(d6-DMSO, 400MHz): 7.168(dd, 9.4Hz, 3.1Hz, 1H), 6.977(td, t:8.6Hz, d:3.1Hz, 1H), 6.802(dd, 9.0HZ, 4.8Hz, 1H), 5.509(dd, 6.0Hz, 2.7Hz, 1H), 4.672(m, 1H), 4.039(m, 1H), 3.595(m, 1H), 3.411(m, 0.5H), 3.282(m, 0.5H), 3.049(m, 0.5H), 2.919(m, 0.5H), 2.086(m, 1H), 2.008(s, 1.5H), 1.993(s, 1.5H), 1.805-1.469(m, 5H)

8 Comments »

  1. That’s a departure from the usual preps published here. It looks tough with the catalysts, which to me seems very prohibitively expensive considering the scale that these reactions are done in. I’m still trying to figure out the role of the oily salt.

    Comment by Richard — October 23, 2006 @ 12:02 pm

  2. This is not a process prep but it is convenient enough for a multigram quantity and it would be tolerably cost-effective if agreement was reached with Noyori or if his patents were by-passed (by using altered ligand or Ru-salt). When you buy TsDPEN from Aldrich, you pay for intel property – but a 5g bottle of the ligand (which is more expensive than Ru source) would be enough to make > 120g of the product.

    I know that the process group at Merck used Noyori asym transfer hydrogenation but with the older protocol that has iPrOH + tBuOK as the hydrogen source. The obvious problem with iPrOK / iPrOH is basicity, moisture sensitivity and potential reversibility (which can erode ee if you push the conversion). I did not have a choice – my substrate was base-sensitive. There is a similar protocol also using NEt3+formic acid in dichloromethane but the aqueous formate is IMHO easier to degass and work up. CTAB is just a phase transfer catalyst. I cut the CTAB amount from published 10mol% to 1mol% for more facile workup and added a smal amount of EtOAc because my substrate was solid (the published method is without a co-solvent).

    Comment by milkshake — October 23, 2006 @ 12:41 pm

  3. For transfer-hydrogenation, what are the usual H sources and catalysts used on process scales? For that matter, can anyone recommend a good book on process chemistry? (I’m trying to learn.)

    Comment by Jordan — October 23, 2006 @ 3:04 pm

  4. Why the C16 for the phase transfer catalyst? That seems like an awful lot of carbons…

    Comment by milo — October 23, 2006 @ 6:38 pm

  5. good book on process chemistry…Practical Process Research & Development (Neal G. Anderson)

    Comment by Henry Jackson — October 23, 2006 @ 11:06 pm

  6. You can use Bu4N+ X- (C16 in place of C19). The original procedure called for water (without organic co-solvent) and 10mol% of CTAB. This cationic detergent forms micelles at very low concentrations. The authors tried to advertise this procedure as some kind of liposome – accelerated green chemistry when it was pretty obvious that it served just as a phase-transfer catalyst, bringing the formate into organic phase. Formate reduction of the Ru catalyst probably isn’t theslowest step – aqueous Na-formate works even without the phase-transfer catalyst – but PTC helps to speed it up. After struggling to isolate my product from a “micellar” 10%CTAB reaction, I cut the CTAB loading to 1 mol%. The asym reduction worked just as before but the workup was much nicer (except that the org extract is easier to dry with sieves than with MgSO4). I did not modify the phase-transfer ammonium salt since then. 

    Comment by milkshake — October 24, 2006 @ 1:21 pm

  7. Ah yes… green chemistry. If only I was smart enough to come up with a way to combine “green” chemistry with “nano” chemistry…

    Thanks for the note that Bu4N+X- works as well, I was really perplexed by the CTAB…

    Comment by milo — October 24, 2006 @ 9:07 pm

  8. I really enjoy reading your preps. Better than Org Syn! Please comment as much as possible on all reactions you list. You are very insightful, thank you!
    J

    Comment by J — October 25, 2006 @ 3:28 am


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