Org Prep Daily

September 19, 2006

Evans asymmetric glyoxylate ene reaction

Filed under: procedures — milkshake @ 5:24 am

newev1.gif 

50% ethyl glyoxylate oligomer in toluene (Fluka, 88.6g) was distilled at atmospheric pressure using a short (2in) Vigreaux column and oil bath temperature 130-185C (gradually increased over 30 min period) untill only a small residue remained. First few mL were discarded, and then the entire volume collected. The obtained yellowish distillate containing toluene-ethyl glyoxylate mixture was immediately re-distilled at 30Torr. After toluene freaction, pure ethyl glyoxylate distilled at 48-50C/30Torr. Y=25.88g of a pale yellow mobile liquid (58.5%th). 1H-NMR indicated only a trace of toluene (<3%) in this product. The density of pure Et-glyoxylate is 1.051g/mL at 23C. 1H-NMR(CDCl3): 9.31(s, 1H), 4.23(q, 7Hz, 2H), 1.31(t, 7Hz, 3H)

The glyoxylate oligomerizes readily on contact with metal impurities, activated 4A mol sieves, teflon surfaces. It reacts with moisture to form hydrate. It can be handled briefly (20 min) at room temperature and stored on dry ice bath under Ar for few hours without oligomerization. Unused material can be kept in freezer and depolymerized by distillation at atmospheric pressure just before use.  

The vacuum re-distillation was done in order to break the glyoxylate azeotrope with toluene. (Neat glyoxylate was needed for solvent and reaction stoechiometry studies.) It was later found that the presence of toluene was not detrimental to yield or ee. For preparative experiments, the vacuum re-distillation of glyoxylate was unnecessary – the mix of glyoxylate with toluene (55-75% glyoxylate) obtained from the commercial oligomer solution by simple distillation at atmospheric pressure could be used directly. Since ethyl glyoxylate is used in excess (3.5 to 5 eq.) and the glyoxylate excess improves the yield and shortens the reaction time, using approximate quantity of toluene solution is acceptable for preparative purposes.

Alpha methyl styrene 0.330mL (2.50 mmol) and neat ethyl glyoxylate 1.07mL (12.5mmol) was added to a stirred slurry of [Cu(S-tBuBox)(H2O)2](SbF6)2 4.3mg (0.2mol%) in a 2:1 mixture TBME/chlorobenzene (3 mL) at -20C. After a complete catalyst dissolution, the reaction mixture was kept in a sealed flask in a freezer (-20C) for 36 hours. The reaction mixture was poured onto a column of silica in 1:3 mix ether-hexane and eluted with the same mixture. Y=494mg (90%) of a colorless oil 98.6% ee (chiral GC, cyclodexB column) [alpha]D23 +1.77(benzene, c=6.215), 1H(CDCl3, 400MHz): 7.43(d, 7Hz, 2H), 7.31(m, 4H), 5.40(s, 1H), 5.22(s, 1H), 4.28(dd, 8Hz, 5Hz, 1H), 4.06(m, 2H), 3.07(dd, 14Hz, 5Hz, 1H), 3.01(br s, 1H), 2.86(dd, 14Hz, 8Hz, 1H), 1.22(t, 7Hz, 3H) 13C(CDCl3, 100MHz):174.34, 143.49, 140.22, 128.15, 127.62, 126.29, 116.02, 69.05, 61.39, 40.35, 13.96

With 1 mol% of the catalyst and 3.5 eq. of ethyl glyoxylate, 1 mmol of alpha methyl styrene in 3mL of TBME/chlorobenzene (2:1) at -20C/24h gave 90%Y, 99.0% ee.

newev3.gif

A mixture of 75% ethyl glyoxylate solution in toluene (prepared by atmospheric-pressure distillation of the commercial solution) 1.25mL (9 mmol) and methylene cyclohexane 0.303mL (2.50 mmol) was cooled on ice bath. [Cu(S-tBuBox)(H2O)2](SbF6)2 4.3mg (0.2mol%) solid was added and the mixture was stirred at 0C for 25 hours. The reaction mix was poured onto a column of silica in 1:3 mix ether-hexane and eluted with the same mixture. Y=428mg of a colorless oil (87% th), 97.9% ee (chiral GC, cyclodexB) [alpha]D23 -5.67 (benzene, c=5.15) 1H(CDCl3, 400MHz): 5.48(br s, 1H), 4.23(dd, 8Hz, 5Hz, 1H), 4.19(q, 6Hz, 2H), 2.85(br s, 1H), 2.39(dd, 14Hz, 5Hz, 1H), 2.24(dd, 14Hz, 8Hz, 1H0, 1.98-1.88(br m, 4H), 1.51-1.48(br m, 4H), 1.25(t, 6Hz, 3H), 13C(CDCl3, 100MHz): 174.86, 132.86, 125.19, 69.12, 61.32, 43.13, 28.26, 25.15, 22.05, 14.08

With 1mol% of the catalyst and 5 eq. of ethyl glyoxylate, 0.5 mmol of methylenecyclohexane in 1.5mL of 2:1 mix TBME/chlorobenzene at -20C/24h gave 99% Y in 98.9% ee

  

3 Comments »

  1. Great prep,

    Congratulations and many thanks for the blog, milkshake.

    I just wanted to add that personally y used the ethyl glyoxylate for a tricky aldol/E1cB, and just distilling the stuff under reduced pressure bulb to bulb (kugelhror) and then by NMR integration I could figure out the ratio PhCH3/ethyl glyoxylate. I used and excess of that aldehyde and the reaction went perfect (94% very unusual in the kind of substrates I work for)

    Good luck with

    Comment by HOMO-LUMO — September 20, 2006 @ 6:17 pm

  2. I just performed this distillation, and based on the HNMR of my distillate, my ethyl glyoxalate was still about 45% pure, however it was completely depolymerized and there was no trace of moisture or other impurities. Perhaps next time I perform this, I might be able to obtain a better percentage of the compound.

    I would like to pose a question, though I realize this blog post is relatively old. Why not just distill off the toluene at ~120C? Then whatever is remaining in the flask should be your product, no? This is actually what I observed. After giving up on the last bit of what I was distilling, I noticed that the leftovers was quite viscous and of pale yellow color. This was probably almost-pure product, though I did not actually NMR it before I nah’d it and washed out the flask…

    Comment by wisemanleo — August 23, 2007 @ 2:43 pm

  3. Ethyl glyoxylate forms an azeotrophe with toluene at atmospheric pressure so you get only a modest enrichment at normal pressure. You can break the azeotrophe by vacuum distillation. When I was doing solvent studies on this reaction I needed reasonably pure Et-glyoxylate for the study so I took the freshly cracked distillate with toluene and immediately I re-distilled it through a short (2 in) Vigreaux column at house vacuum (30 Torr, I think) and I got 95% Et-glyoxylate.

    The toluene does not interfere in the ene reaction. If you care about economy (the Fluka glyoxylate is somewhat expensive on scale) I would take Et glyoxylate from the can, crack the hell out of it (oil bath up to 185C) at atmospheric pressure and collect everything – except for the first few mL – and distill almost to dryness, then take the collected yellow distilates (that should contain about 50%+ of glyoxylate) into the reaction. Evans glyoxylate ene uses excess of glyoxylate anyway (the reaction does not complete below 3 equivs of glyoxylate) and running it with 5 equivs instead the usual 3.5 equivs of glyoxylate makes it markedly faster – with more glyoxylate you can lower the catalyst loading etc.

    For toluene-free glyoxylate the vacuum distillation is very easyto do – but you will lose some glyoxylate in mixed fractions and since glyoxylate does not store well you will need to re-crack your toluene-free distillate feshly before every use just the same.

    Freshly cracked glyoxylate is yellowish. The distillation residue is probably a hydrated stuff, it does not dehydrate on heating. (Keep the moisture out because glyoxylate hydrate is dead for the reaction – and it probably inhibits the catalyst so watch out not to get it wet when you store your distilled glyoxylate in the fridge).

    Also, some Evans folks claimed they can use uncracked Fluka stuff but I have not tried this – and the cracking distillation only takes about 30-40 min which is not bad for a piece of mind.

    I know this sounds strange but I have noticed that glyoxylate oligomerization at room temp seems to be accelerated by contact with teflon surfaces – so dont leave a stirbar in your freshly-cracked glyoxylate and don’t keep it too long in a Hamilton syringe with a teflon plunger

    Comment by milkshake — August 23, 2007 @ 3:55 pm


RSS feed for comments on this post. TrackBack URI

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Blog at WordPress.com.

%d bloggers like this: