Org Prep Daily

June 19, 2009

cis-Bicyclo[3.3.0]octane-3,7-dione

Filed under: procedures — milkshake @ 1:35 am

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A 500mL three-necked round flask equipped with a reflux condenser, internal thermometer, pressure-equalised addition funnel and a large egg-shaped magnetic stirbar was charged with 25% sodium methoxide in methanol 31.55g (Aldrich; 146mmol) and methanol 100mL. The flask was placed on ice slush bath and after 15 min a solution of 1,3-acetonedicarboxylic acid dimethyl ester 25.00g (Acros; 143.55 mmol) in methanol 10mL was added within 15 min, the addition funnel was washed with methanol (2x20mL) and the washings were also added into the mix. The cooling bath was then removed and the flask was placed on a 65C oil bath and stirred for approximately 30 min. (The mixture gradually became homogeneous as the precipitated Na-enolate salt of the di-Me-acetonedicarboxylate re-dissolved with heating). When the internal temperature in the flask has stabilized, a mixture of 40% aqueous glyoxal 12.00g (Alfa; 82.7 mmol, 115% of the theoretic amount) with methanol 30mL was introduced dropwise from the addition funnel – very slowly – over a period of 1h45min, with a vigorous stirring on the 65C oil bath. After the complete addition the funnel was washed with methanol (10mL) and the washings were also added to the mix. The resulting cloudy reaction mixture was stirred for extra 15 min at 65C, then diluted with THF 200mL and the flask was removed from the heating bath. The mixture was stirred at RT overnight (12 hours). The precipitated intermediate (as a disodium salt hydrate) was collected by filtration using a large sintered-glass Buchner funnel. The collected solids were washed thoroughly with THF and then dried by suction for about 2 hours.

This intermediate salt (a cream-colored heavy powder, 27.92g; 90%Y) was dissolved in water 400mL in a 1L flask. 37% concentrated HCl 46 mL was added dropwise with a vigorous stirring (as to limit the formation of dumplings) and the resulting heterogeneous mixture was placed on a 100C oil bath. The mixture was stirred at reflux at 100-120C for 1 hour and at 120C for additional 2 hours – during this time the mixture became homogeneous as the gummy deposits gradually dissolved. The flask was then removed from the heating bath, a large spoon of activated charcoal was added into the stirred mix, the charcoal was removed by filtration while warm (the charcoal was washed with additional water) and sodium chloride 100g was added to the combined filtrates. The mixture was stirred on ambient bath until the complete salt dissolution  (5 min). This mixture was then extracted three times with dichloromethane (3x250mL), the organic extracts were washed with saturated aq. NaHCO3 200mL. The combined extracts were dried with magnesium sulfate and evaporated to dryness from ambient water bath. The obtained crystalline residue was dried on highvac for about 30 min.

Y=7.790g of a white crystalline solid, pure by NMR (78.5% overall from di-Me acetonedicarboxylate) .

1H(CDCl3, 400MHz): 3.048(m, 2H), 2.585(ddd, 19.5Hz, 8.7Hz, 1.8Hz, 4H), 2.156(dd, 19.5Hz, 5.2Hz, 4H)

Note 1: The product is also available commercially [Aldrich 5g/$400]

Note 2: A very slow addition of the glyoxal solution and a careful control of the reaction temperature (65C) by the oil bath during the first step is required for a good yield. The reaction is not very sensitive to moisture so a common-grade MeOH was used from a freshly-opened bottle. (The reflux in the first step was done under Ar but this may be unnecessary). The final product can be re-crystallized from MeOH;  in this preparation NMR-uniform material was obtained directly by evaporating the DCM extracts and drying the residue briefly in vacuo.

Note 3: This preparation was based on a large-scale (1.5 mol) procedure from OrgSyn (Vol 64, p.27, 1986). The medium-scale (140mmol) experiment described here was run in higher dilution, on a stirplate and with the oil bath inplace of a heating mantle. Also the hydrolysis step was simplified at this medium scale, etc – these modifications probably helped to improve the product yield and purity.

Note 4: This preparation provided 80% overall yield when run on twice as large scale (1L flask, 50.1g of di-Me-acetondicarboxylate, 300mL MeOH, 63.2g of 25% NaOMe, 24.25g of 40% glyoxal in 50mL of MeOH, 94mL of conc. HCl). Few minor changes: acetondicarboxylate was added neat by syringe, quite fast (over 10 min at 0C) as there is not much exotherm during the additon. In the second step, the intermediate salt (57.5g) was dissolved first in hot water (800mL) and the solution was placed on oil bath (120C) and conc. HCl (94mL) was added at approx 80C internal temperature with intense stirring, and the resulting emulsion was then stirred at reflux on 115-120C oil bath for additional 150 min. In this way the mix is easier to stir magnetically (as the formation of sticky dumplings is completely prevented).

36 Comments »

  1. Great post. I have a question off-topic though. How can you get hydroxylation in an aromatic ring ortho to a CF3 group?

    Comment by PPM — June 21, 2009 @ 5:26 pm

  2. I don’t know. CF3 is not exactly an ortho-directing group for any aromatic substitution reaction that I know of. I have done lithiations of 5-CF3-2-Cl-pyridine into the 4-position with LDA+ iPr2NCO2Li Schlosser combo but it works only because pyridine naturally likes to get lithiated with LDA into the 4-position (if there is el-withdrawing group in 5-position) and its still somewhat tricky in the case of CF3 group. So I am not sure what you have in mind, and I don’t know what your substrate looks like. What gave you the idea that this is a possible transformation?

    Comment by milkshake — June 21, 2009 @ 11:20 pm

  3. Thank you for your reply. Can we put a bromine ortho to CF3 by bromination? Perhaps no since CF3 is a meta-directing group.

    Comment by PPM — June 22, 2009 @ 1:22 pm

  4. Why not do it the other way round – electrophilic trifluoromethylation of a phenol? Is that not possible?

    Comment by Ed — June 23, 2009 @ 2:26 am

  5. Thank you. We have resorcinol. Can we put CF3 group in between the two OH groups?

    Comment by PPM — June 23, 2009 @ 1:09 pm

  6. A directed metallation might be possible on a protected resorcinol dependent on what other functionality you are working around – should metallate between the two oxygens. I suspect that on the unprotected system a standard Friedel Crafts type reaction would go on the 4 position.

    Should it work I’ll take a 90% royalty of your 15000 bucks thank you very much.

    http://gw.innocentive.com/ar/challenge/8454111

    Comment by Ed — June 23, 2009 @ 2:23 pm

  7. You are cruel. Thank you.

    Comment by PPM — June 23, 2009 @ 2:30 pm

  8. Ed, I just deleted a detailed proposal that I wrote few minutes before, and I decided to send it to Innocentive instead. Our research group could use some extra cash for buying chemicals. Thank you for the tip!

    (Btw the final Innocentive compound is commercially available, from a small company in China. Maybe we should ask them how they are making it)

    Comment by milkshake — June 23, 2009 @ 3:15 pm

  9. All the best.

    Comment by PPM — June 23, 2009 @ 5:44 pm

  10. Dear PPM, you are mostly welcome. I think it is wonderful that your company is employing multi-faceted experts like yourself – and when you have yet another chemistry problem please don’t hesitate to ask for help here.

    Comment by milkshake — June 23, 2009 @ 7:16 pm

  11. I think the innocentive challenges are something that you will be very good at!

    Comment by Ed — June 24, 2009 @ 2:24 am

  12. Hello
    What is the best procedure to prepare sodium tert-butoxide readily in the lab?
    Thanks

    Comment by gurung — June 24, 2009 @ 3:04 am

  13. I have never done it myself, but I suppose its K metal and reflux with tBuOH, preferably with some higher-boiling co-solvent so that K metal melts and reacts faster. There is Paquette compendium and also the old Fieser-Fieser, they will have a reference. The only thing, KOtBu is quite cheap, why would anyone need to make it, especially since K metal is so nasty (and expensive to buy)

    Comment by milkshake — June 24, 2009 @ 5:53 am

  14. Ed: Flattery gets you everywhere. Now seriously, there is some money to be made at innocentive, and our finances are quite tight at the moment so any extra funds we could get for our research would be very helpful. I think I will try.

    To your previous question: CF3 radical behaves much like electrophile, with el rich aromatics in the presence of an oxidant. The difficulty is that the ring trifluoromethylation goes all over, there is very little regioselectivity. You could expect at least 3 main products with resorscinol derivates.

    Comment by milkshake — June 24, 2009 @ 5:55 am

  15. NaOtBu also used to readily available and generally was good quality although if need precise equivalents believe using NaH works well (tare flask, wash out oil with hexane or heptane, dry vac, get weight add tBuOH, don’t recall if heated). Know I followed prep and may even have been Vogel or other text.

    Comment by CMCguy — June 24, 2009 @ 9:59 pm

  16. I love it – to get 15K using others ideas. BTW, Milkshake – do you know anybody good and personally enough who won innocentive. I have hard time to believe in fare play there, but I like challenges they have.

    Comment by krest17 — June 24, 2009 @ 11:57 pm

  17. I knew about Innocentive – they have been around for years but I never heard of anyone who won. Then again, I haven’t really followed it that closely. Until now that is, with money tight – I thought about supplementing our research budget: if nothing comes out of it I only wasted two evenings. I have just completed the second submission. The deadlines are in few weeks so we will see.

    Regarding PPM – I think he demonstrates that integrity, like all virtues, works best in moderation

    Comment by milkshake — June 25, 2009 @ 12:24 am

  18. MS, hope you win. You have helped others a lot here already, it’s your turn. Besides, you are not doing it for your personal gain in this case. In fact, come to think of it, why not take advantage of your experience and get something in return. Pls let us know how it goes eventually.

    Comment by pc — June 25, 2009 @ 11:04 am

  19. I wish you win – you deserve it.

    Comment by krest17 — June 25, 2009 @ 12:47 pm

  20. thank you for the well wishes – but I unabashedly submitted even a proposal for a non-ablative material for rocket nose cone, a subject about which I know absolutely nothing…

    Comment by milkshake — June 25, 2009 @ 2:09 pm

    • I am how fair they’d play either. I have never submitted one, but I work on some the challenges just for kicks – to keep my sanity. Hope you win and do let us know.

      MB

      Comment by Moody Blue — June 26, 2009 @ 12:32 pm

      • Its hard to verify but I suppose when some company promises to pay 10 or 15k for the best proposal Innocentive might want to insist that someone actually gets paid (so that their business does not get bad reputation within the research community).

        The sneaky aspect is that for each problem they typically get 100-300 submissions from people with all kinds of backgrounds – and most likely there are going to be several pretty good proposals which are not completely identical. After discarding chaff and collating useful ideas, the company that posted a challenge gets the whole solution space of their problem covered rather thoroughly by pooled imagination of several hundreds people – but they have to pay only one guy.

        Comment by milkshake — June 26, 2009 @ 1:45 pm

  21. I meant I am not sure how fair they’d play!! My fingers are getting slower as I age!!

    Comment by Moody Blue — June 26, 2009 @ 1:10 pm

  22. I was fortunate enough to win an award through Innocentive a couple of years back. I have a very high opinion of the firm and the business concept. Good luck with your submissions Milkshake!

    Comment by Cat Herder — June 29, 2009 @ 1:11 am

    • how long did it take from the submission deadline till you got notified about the outcome?

      Comment by milkshake — June 29, 2009 @ 2:06 am

  23. Good question. I’ll have to check my files, but my recollection was that it took 2-3 months. If it was appreciably different than that estimate, I’ll let you know.

    Comment by Cat Herder — June 29, 2009 @ 8:00 pm

  24. WRT to the first comment. We had good luck transforming a ortho bromo methoxy aromatic to the ortho trifluro methyl methoxy via the Cu(I) Iodide mediated decomposition of sodium trifluro acetate. The original ref is Chem Lett, 1981 pg 1719. We made some modification to lower the amount of reagents. That can be found at syn comm pg 965, 1988. It is radical mediated as we made the penta fluroethyl using the same methdology (and potassium pentafluroproprionate.

    Comment by John — July 9, 2009 @ 11:21 am

  25. Hello users, what is the method/name reaction used to couple aryl N-H to aryl halides? Thanks!

    Comment by DC — July 12, 2009 @ 8:55 pm

  26. #25 without looking (see Larock) would suggest you may be searching Ulman(sp) a Cu catalyzed variant. Believe can do coupling of this type with Pd also but can’t recall what names are.

    Comment by CMCguy — July 12, 2009 @ 10:57 pm

  27. When it is done with copper salt its called Ullmann. If it is catalyzed with Pd its called Buchwald or Buchwald-Hartwig arylation

    Comment by milkshake — July 13, 2009 @ 12:23 pm

  28. #25 me also doing the same job,
    go and collect the good review at Account of Chemical Research from ACS
    GOOD LUCK

    Comment by GUURNG — July 19, 2009 @ 12:58 am

    • What is the reference?

      Comment by DC — July 19, 2009 @ 8:53 pm

  29. Thanks for the replies everyone!

    Comment by DC — July 19, 2009 @ 8:53 pm

  30. Organic Syntheses, Coll. Vol. 7, p.50 (1990); Vol. 64, p.27 (1986).

    Comment by anonymous — September 10, 2009 @ 9:28 pm


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