Org Prep Daily

March 12, 2009

Combined SN arylation and Suzuki

Filed under: procedures — milkshake @ 8:30 pm

A solution of 4-bromo-2-fluoronitrobenzene 1.300 g (5.909 mmol) and 1,3-propanediol 5.0mL (69mmol) in anhydrous dioxane 20mL in a 100mL 14/20 joint flask was placed on ambient water bath and a solution of sodium tert-butoxide 1.00 g (10.8 mmol) in anh dioxane 40mL was added dropwise from an addition funnel over 15 min with vigorous stirring. The resulting deep-orange reaction mix was stirred under Ar for additional 2 hours. A solution of potassium carbonate 2.80 g (20mmol) in water 30 mL was added into the flask and the mixture was deoxygenated by argon sparge (long needle through the septa) on ultrasonic bath for 15 min. A solid mix of pinacolate ester of 4-pyrazolylboronic acid 1.50 g (7.73mmol) and Pd(PPh3)4 600mg (0.519mmol; 8.8mol%) was added in one portion and the mixture was sparge-deoxygentaed with Ar for additional 10 min on ultrasonic bath, then vigorously stirred under Ar on a 95C oil bath for 150 minutes. The reaction mix was cooled and portioned between saturated aqueous ammonium chloride 200mL and ethyl acetate 200mL. The aqueos phase was re-extracted with EtOAc (200mL). The organic extracts were washed with additional sat ammonium chloride (200mL) and then combined, dried (MgSO4) and evaporated. The obtained solid yellow residue was suspended in benzene 20mL, heated briefly to reflux and then allowed to sit at RT for 1 hour. The precipitated product (1.248g) was collected by filtration, washed with additional benzene (2x10mL) and dried on highvac. Concentrating the supernatants and re-crystallizing the oily residue from benzene (5mL) overnight provided additional small fraction of the product (47mg, 95% pure). The combined yield was 1.295g (83% th) of a pale yellow solid, >98% by HPLC.

1H(d6-DMSO, 400MHz): 13.165(br s, 1H), 8.455(s, 1H), 8.124(s, 1H), 7.891(d, 8.5Hz, 1H), 7.529(d, 1.5Hz, 1H), 7.344(dd, 8.5Hz, 1.5Hz, 1H), 4.577(t, 5.1Hz, 1H), 4.301(t, 6.1Hz, 2H), 3.594(q, 5.4Hz, 2H), 1.899(quint, 6.2Hz, 2H); LC/MS(+ESI): 264(M+1)

92 Comments »

  1. LOL. So you work in industry, yet use benzene for recrystallization and mentioned using CCl4 in a recent comment! :D Seriously, I love products that serendipitously crystallize. You should have cooled your sample overnight in the freezer to isolate some low-melting solid benzene as well!!!

    More seriously… Have you developed any tricks for inducing diols to crystallize? Most of mine which are long-alkyl chain terminal 1,2-diols will solidify upon standing once you turn your back. Also, they are commonly flashable using 50% EtOAc:hexanes. I try adding 10:1 hexanes to the residual few mLs of EtOAc post-column upon rotovapping and rotovapping again, but all I get is an immiscible mixture of hexanes on top and EtOAc and diol at the bottom…

    Not hoping for any miracles, but, ya know, there’s nothing worse than a liquid which starts solidifying when you start weighing it out in a pipette or syringe-needle assembly!…

    Cheers, community! ;)

    Comment by HPCC — March 13, 2009 @ 5:17 am

  2. I used benzene because it is a very good solvent for crystallizations. (Is is not too dangerous in small volumes if you don’t pour it in on yourself. Dioxane is probably more carcinogenic than benzene). But in this case a number of solvents would have worked because the final product turns out to be a real brick.

    I don’t have much experience with crystallizing diols but I made many aminohydroxypropyl morpholines intended as solubilizing side-chains, and sometimes they crystallized after purification and careful drying. I suppose the moisture is a real problem. I would try to crude-distill them on highvac on Aldrich Kugelrohr apparatus if possible – that should make them very dry and remove the other volatiles and salts. Then I would try something like cyclohexane+benzene mix for the re-crystallization.

    Comment by milkshake — March 13, 2009 @ 5:37 am

  3. HPCC milkshake’s suggestion about KR distillation is an excellent one IMO (C-treatment and/or running through plug of SiO2 or Al2O3 easy cleans to try too) as is the use of cyclohexane and benzene (although might not use together as first option). I have found a number of times that cyclohexane (100% or co-solvent) worked well (magic) when “normal” options unsatisfactory (although not in analogous situations to what you face). Benzene can also be good for certain cases (at least for small scale) and can usually substitute Toluene or p-Xylene, either alone or in combos (Benzene so much easier to remove if have to start over).

    Being in Process most my career crystallization was bread & butter in all projects. I did have experience working with long chains molecules of many functional varieties (OH, NHR, OCOR etc) and some multifunctional molecules (do recall 1,3 diols but do not remember if had to crystallize any 1,2s). Might wish to try Heptane rather than hexanes (or use n-hexane flavor rather than mix), especially if you use very little EtOAc, Et2O or THF (just enough to dissolve then leave “loosely capped” to slow evap).

    Another “trick” is to do the crystallization at “ambient temp” on your bench (assume AC working in lab) or better in back of hood (usually slightly cooler). Sometimes once XTLs started you can then put in ice/frig to boost recovery but if you try to do this too early material “gums”. Although I would begin with everything dry it could be a hydrate might form/XTL so might to a couple “wet ones”. Unfortunately there is an endless variety of options and although can approach systematically does seem more Art than Science and odd “luck” (in Pasteur’s sense) a factor (leaving over long weekends and holidays can give best results).

    Comment by CMC Guy — March 13, 2009 @ 1:08 pm

  4. One question on subject RXN, was the Suzuki Pd catalyst stuff you made or purchased? I have had wide experiences, mostly bad, when using this catalyst from “major suppliers”.

    Comment by CMC Guy — March 13, 2009 @ 1:43 pm

  5. it was Strem tetrakis, bright lemony yellow shiny flakes packaged under Ar into a narrow-mouth bottle and sealed with a tape and plenty of paraffin all over the cap. The opened bottle keeps well in the freezer (the material has a healthy light color for couple of months, even a whole year) if one doesn’t forget to flush the bottle with Ar after each use and then parafilm it. Strem products can be now purchased through Fisher also

    Comment by milkshake — March 13, 2009 @ 2:09 pm

  6. i wonder how much of the dimer coming from substitution on both sides of diol you have in your final product (and in crude material as well). thx.

    Comment by petr — March 13, 2009 @ 4:15 pm

  7. There is no detectable dimer on HPLC when done in this way because a huge excess (>20 equivs based on OH count) of propane diol stays around the product throughout the arylation. But I was less lucky on the first attempt, when I pre-formed the propanediol monoalkoxide by mixing t-butoxide (10 equivs) with propane diol (11 equivs) in THF and then added a solution of the fluoronitrobromobenzene to the slurry – there was lot of dimeric material (>30% by HPLC) because the diol monoalkoxide is poorly soluble and most of it fell out of solution.

    Dimer would complicate things great deal because it has even worse solubility than the desired product and it co-precipitates.

    Comment by milkshake — March 13, 2009 @ 4:39 pm

  8. i am just curious because i play around with the similar reaction riht now (ethylene glycol and chloroheteroarene) and despite any effort (dilution, rate of addition, order of addition, etc…) i am not able to avoid formation of dimer :( statistics is simply against me

    Comment by petr — March 14, 2009 @ 8:17 am

  9. Can you have a large excess of glycol – for example using glycol is as a co-solvent?

    Comment by milkshake — March 15, 2009 @ 12:11 am

  10. Milkshake,
    Compeltely off topic.
    Did you purchase satisfactory HPLC grade ACN from any of the vendors advertising in the pipeline. any comments. thanks.

    Comment by sks — March 17, 2009 @ 4:05 pm

  11. No, I didn’t – we got recently loads of acetonitrile delivered both from Fisher and VWR – all this stuff came from the old orders that were back-ordered since January and early February (some of it even from December) and finally it all arrived at once. So right now we have enough to last us for few months of current usage but we still have acetonitrile-saving measure in effect (all prep HPLC purifications are run in methanol+acetonittrile 1:1 mix even though this adds a slight burden since one cannot apply a methanolic solution directly onto the lyo).

    The acetonitrile we got was mostly billed at the January prices – it was much higher than the 2008 prices but still modest in comparison to what the going acetonitrile prices are these days. As we don’t get those January prices from anyone anymore (and we really cannot afford to pay >300 USD per case in the long run) we are trying to live on what we have in house as long as possible, praying that the prices come down eventually.

    Comment by milkshake — March 17, 2009 @ 4:36 pm

  12. thanks. i will have to do some shopping around then.

    Comment by sks — March 18, 2009 @ 12:05 pm

  13. I love your work and would like to make it structure searchable via ChemSPider. I had a conversation on my blog recently about community contributions to synthesis procedures (here: http://www.chemspider.com/blog/supporting-synthetic-procedures-from-the-synaptic-leap.html) and what you are doing on this blog is a great contribution and I would like your permission to post synthesis details to ChemSPider. I have put an example here: http://www.chemspider.com/Chemical-Structure.21432088.html. We’re willing to do the work on our side to migrate the information and will put appropriate linkages back to the originating source as you request. I welcome your feedback. Thanks

    Comment by ChemSpiderMan — March 23, 2009 @ 10:58 pm

  14. Of course I would be completely delighted, as long as the reproduced procedure references this site and all the experimental details are provided (I don’t object to changing/re-formating the drawings, etc) . Please let me know what can I do to make it easier for you to port the stuff to ChemSpider. The schemes and structures in my past procedures are unfortunately all in the gif format already but in the future I can try to provide the Chemdraw source file also – if that helps you.

    Also I wish you the best luck with what you are building – Google used to be a rather small operation at one time also. Crummy self-serving companies like Symyx deserve to fall into the dustbin.

    Comment by milkshake — March 24, 2009 @ 1:25 am

  15. If you can send me the ChemDraw file I’ll take it from there…just send me your structure and the URL for the post. if you happen to have spectra too send them too and I’ll add them to the structure record… see http://www.chemspider.com/spectra.aspx …they will then feed the spectral game here… http://www.spectralgame.com

    Thanks!!

    Comment by ChemSpiderMan — March 25, 2009 @ 12:17 am

  16. Looks good to me. I noticed that Google Chrome, my favorite browser, cuts out for some reason the bottom-most line in ChemSpider window but that is just a detail. Thank you for doing this work – I never got down to indexing Orgprepdaily or making it searchable.

    Comment by milkshake — March 25, 2009 @ 12:22 am

  17. Spectra: unfortunately I don’t have them readily available in electronic formate – I mean I can hunt the files down and pull them out from the server if absolutely necessary (for example when asked by a journal referee) but I like to work with printouts.

    ChemDraw files in Orgprepdaily: for the old posts I lost them already but I can try to include ChemDraw file attachment with the new posts.

    Also I apologize that your two previous comments did not show up – I have Spam filter Akismet set up that anything that contains more than one link gets automatically held for approval. Sorry about it.

    Comment by milkshake — March 25, 2009 @ 12:33 am

  18. It’s not absolutely necessary to provide spectra at all…just if you want to share them. You do enough for the the community already!

    Comment by ChemSpiderMan — March 25, 2009 @ 1:48 am

  19. Some questions if I may:

    - Can one use disposable plastic syringes for nBuLi?

    - Silly discussion today: In an aldol product, which oxygen atom is more basic – the carbonyl or alcohol oxygen, and why?

    - Can one use molecular sieves together with nBuLi, DIBAL-H and similar organometallic reagents?

    - I plan to reduce a cyclic a,ß-unsaturated ketone with Selectride and react the resulting enolate with the triflating agent phenyl triflimide. Should I use the lithium, sodium or potassium variant of Selectride for optimal results?

    Comment by Rennip — March 27, 2009 @ 2:29 pm

  20. one trick that worked for me with the crystallisations (for X-ray) not for teh purification is leaving the coloumn fractions to evaporate on their own, especially the middle ones. Right concentration of the mix. of solvents I guess…but I should mention that it was mostly hexane:EA or DCM/MeOH or Acetone:hexane mixtures.

    Now, my question:

    Which microwave reactor would you prefer of the two i.e Biotage initiator or CEM hybrid, and why?

    Comment by xyz — March 27, 2009 @ 8:14 pm

  21. xyz: I have used Biotage microwave small-scale reactors, we have 3 of them, two manual and one with autosampler. Great machine for high-temperature medium-pressure reactions up to 20 mL.

    I only saw the CEM instrument five years ago and I was not impressed. We had a demo loaner in our lab at our previous company and we did not buy it, we got the “Smith Creator” – which is what then became Biotage. I have no idea what CEM is like nowadays, I can only say that the quality of Biotage MW reactors is very good, we had only few major repairs over the years. The pressure septa vials are very useful for conventional chemistry also.

    Rennip: I have only a limited experience with Li-Selectride reduction of enones, I cannot advise you on that. Activated sieves will have some Si-OH surface groups and some residual water no matter how hard you dry them, so you will lose a portion of your organometallics. But I see no reason why you couldn’t, I just don’t understand why would you want to that. (The liquid Na-K alloy can be immobilized on dry silica for the safety purposes, and it works fine). Carbonyl is more basic than OH but less than alkoxide anion. It very much depends on the carbonyl also – if i remember correctly the basicity goes something like this: lactams > amides and ureas> urethans> ketones> esters> carbonates. NMP is so basic already that you can use it instead of tertiary amine in some reactions.
    Disposable plastic syringes 20mL and below work perfectly fine for BuLi, but please do not use the 50mL big plastic syringes or any syringes with a rubber-tipped plunger

    Comment by milkshake — March 28, 2009 @ 2:02 am

  22. - Can one use molecular sieves together with nBuLi, DIBAL-H and similar organometallic reagents?

    It’s unusual to see a experimental that describes the use of MS and that species because they react readily with water, drying the reaction mixture. They are usually used in slight excess to destroy any trace of water that “dry” solvents could have.

    Comment by Vasili — March 28, 2009 @ 3:55 am

  23. milkshake:
    “Activated sieves will have some Si-OH surface groups and some residual water no matter how hard you dry them, so you will lose a portion of your organometallics. But I see no reason why you couldn’t, I just don’t understand why would you want to that.”

    The idea was to remove any small amounts of water from my “dry” solvent when doing the reaction, but if the mol-sievs are more likely to cause problems than solve the water problem, I will not use them.

    “Carbonyl is more basic than OH but less than alkoxide anion.”

    OK. I argued that OH would be more basic as the free electron pair is in the higher energy sp3 orbital, further away from the nucleus, compared to the electrons in an sp2 orbital on the carbonyl oxygen. My labmate argued that a protonated carbonyl oxygen has two resonance forms, and therefore should be more basic. To that, I replyed that in one of these resonance forms, carbon has only a sextett, and thus this form would give only a very minor contribution to the resonance hybrid.

    “Disposable plastic syringes 20mL and below work perfectly fine for BuLi, but please do not use the 50mL big plastic syringes or any syringes with a rubber-tipped plunger”

    Great. I like disposable stuff. It is good for the economy, too.

    Vasili:
    “They are usually used in slight excess to destroy any trace of water that “dry” solvents could have.”

    Got it. Thanks. I usually do this.

    Comment by Rennip — March 28, 2009 @ 7:12 am

  24. Being kind and answering questions only leads to more:

    - I usually use a saturated solution of CuSO4 to remove pyridine, and this works fine, but is this a general method for amines, and is it really any better than the more traditional 5 % HCl?

    - If my crude product is contaminated with small amounts of an alcohol, can it be removed by using anhydrous CaCl2 to dry the organic phase? I seem to remember that CaCl2 forms “alcohols of crystallization”. Is this a viable strategy?

    Comment by Rennip — March 28, 2009 @ 11:32 am

  25. Milkshake:

    Thank you for the info that you shared.

    Comment by xyz — March 28, 2009 @ 2:10 pm

  26. Rennip: I don’t know of any good method for removing amines apart from the acidic wash. Saturated NH4Cl is useful for removing strongly basic amines, 1M citric acid takes care of most tertiary amines but typically requires a re-wash with water followed with sat bicarbonate because citric acid is quite soluble in things like EtOAc. CaCl2 will not help you and I suggest that you don’t use it for drying organic compounds.

    Comment by milkshake — March 29, 2009 @ 3:39 am

  27. Milkshake…this is to let you know that I have copied all of your procedures, all the way back to September 2006 (!) over to ChemSPider now. It was a few hours of work to get that done but they look great. I am now looking at ways to set it up as an “Org Prep Daily” subset so that people can go to http://www.chemspider.com/orgprepdaily to find that subset only. Will keep you informed.

    Comment by ChemSpiderMan — March 29, 2009 @ 10:21 am

  28. Thank you for doing this, your work is much appreciated.

    Comment by milkshake — March 30, 2009 @ 12:09 am

  29. Milkshake, and others: Is there any equivalent for Chemsitry preprints as that of arxive.org for Maths and physics? That seems to be very useful for those institutes which do not subscribe for all the journals.

    Comment by xyz — March 31, 2009 @ 11:45 am

  30. unfortunately there is none. I am not expert but from what I heard there were few attempts but so far nothing much came out of it. I think now would be a good time to try again because MIT and Harvard accepted policies that force their groups to publish in open journals. But you have to appreciate the force of inertia, and the power of self-serving organizations like ACS, Wiley, Thieme and Elsviever – so this would probably need rather high profile-groups to endorse it from the beginning, to get it going

    Comment by milkshake — March 31, 2009 @ 1:07 pm

  31. Speaking of alkali metals on silica, has anyone used these products? http://signachem.com/
    Sounds pretty cool to me.

    Comment by LiqC — April 2, 2009 @ 2:44 am

  32. Hello,

    Great blog! Does anyone have experience on preparing KC8? It is used a lot lately but I can’t find a reference…

    Cheers!

    Comment by Chris — April 2, 2009 @ 12:04 pm

  33. I have never made KC8 myself but the procedure if remember correctly called for dry-stirring the components while heating on oil bath above the K melting point, under Ar, and the end product should be a bronze-colored powder that has to be handled under strictly oxygen-free conditions (preferably in a glovebox). If you are close to a decent university library, check whether you can get hold of the Leo Paquette’s compendium of organic reagents. It is a most helpful reference – far superior to Fieser. We have it here at the institute somewhere but first try to look it up yourself.

    Comment by milkshake — April 2, 2009 @ 3:45 pm

  34. Thanks for the info milkshake, I got the references and I will try to make it soon. I have a glovebox with Ar, and I’m thinking to heat it up with a heating mantle inside, instead of using oil bath what do you think?

    Comment by Chris — April 4, 2009 @ 7:44 pm

  35. I would not make this in a glovebox. It is too much hassle to run large scale experiments in a glovebox – every piece of equipment that goes there has to be thoroughly pumped, the clean up after the experiment is difficult, etc. I would make KC8 in in the hood, just with the usual dual bank highvac/Ar manifold and good air-free-grade stopcock adapter using a reaction flask that fits through the glovebox antechamber and I would only take the flask with the product into the glovebox for the transfer and storage in some bottle there.

    Comment by milkshake — April 4, 2009 @ 8:08 pm

  36. Maybe that’s the better way. I was also thinking KC8 might react with Ar at 160C.

    Comment by Chris — April 4, 2009 @ 8:30 pm

  37. If you can make anything react with argon gas, at 160C, you will have an instant JACS/Angew Chem paper…

    My point was that K metal can be cleaned and weighted out in air (you have to work fast on a humid day), and graphite obviously has no problem, then you do few vacuum/Ar purges and you should have no problem with doing the KC8 preparation in the hood. The only trouble with air is when you open it, so the bottling/storing/weighing out the product should be best done in the glovebox

    Comment by milkshake — April 4, 2009 @ 11:20 pm

  38. Milkshake,

    In all of your Suzuki coupling experience – have you gotten a chance to use any of the Molander trifluoroborates? They seem to be really catching on.

    Comment by T — April 6, 2009 @ 9:54 am

  39. unfortunately I did not – but they look nice and can solve some of the purification and analysis problems with free boronic acids or cyclic boronate esters. I would be happy to try fluoroboronates, I just did not have the chance yet

    Comment by milkshake — April 6, 2009 @ 3:57 pm

  40. USE A GLASS STIR BAR IN THE KC8 PREP!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

    I would hope that everyone would know that but just in case. . . .scary thoughts about K + teflon = BANG.

    Same goes for Na(K) = bang. Hell, I use glass-coated stir bars for anything harder than Cp2Co-ish range (-1.3V) (Connelly and Geiger, Chem Rev, 1996, 96, 877-910).

    Weird that KC8 got brought up here; lit says I should use it for my next step but I’m balking because I would want to use it on a 15g+ scale. ugh. I think that falls in to the “do it twice” realm of nasty reagents. I’m going to screen some other reductants for safety and ease (who wants to make KC8 all the time?). Besides, KC8 for this reaction is like trying to sculpt David with a sledgehammer. . . .

    Comment by cookingwithsolvents — April 8, 2009 @ 8:43 am

  41. I never did high-temp dry stirring of Teflon with molten K, its probably not a good idea… But when I did Birch reductions the stirbars got black soon yet no bang. I also did reduction of PPh3 to KPPh2 with K in refluxing dioxane on large scale and I stirred it with large teflon stirbar.

    Comment by milkshake — April 8, 2009 @ 8:53 am

  42. I read 3-4 procedures about KC8 prep and didn’t see any mention on teflon stirbar incompatibility. Thanks for the useful information. Did you have any explosion?
    Otherwise, if handled in a glovebox after the preparation, why would it be a nasty reagent?

    Comment by Chris — April 8, 2009 @ 1:25 pm

  43. Unless I am misinformed, the only observed compounds with argon are HArF and CUOAr, which were published in Nature and Science, respectively (Nature 2000 406, 74 & Science 2002 295, 2242). These compounds were characterized by FTIR spectroscopy in low-temp. noble gas matrices. Pretty interesting stuff. Does anyone know if a Ne or He compound has been observed?

    Comment by G1 — April 8, 2009 @ 7:20 pm

  44. Na(K) + teflon = bang (or can)
    e.g. JACS 1992, 114, 4611

    I don’t have a reference for KC8 preps w/ teflon stir bars blowing up handy. There may not be one but I wouldn’t go throwing molten reducing agents @ teflon (or anything else w/ highly reducible groups). You don’t want to be that letter to C&E News, right? Glass-coated stir bars are cheap. If you don’t drop ‘em most people only need one or two.

    KC8 is nasty because it is very “staticky” (graphite, right?) and is messy. Traces on kimwipes, flasks, etc go up when they hit air. Of course, if your glove box isn’t quite up to par then the little bits on kimwipes, etc don’t do anything when they hit air. . .

    People like KC8 ’cause you just filter off the graphite/KCl when you are done = super-easy workup. No Hg pool to deal with and no real surface-area/initiation effects or whatever. Mg can be tough to “initiate” for transition metal reactions. Zn isn’t always reducing enough and zincates are a b*tch if you have ‘em. Li reacts with N2 and who has an Ar glove box these days (or even an Ar line…)? Molecular reductants like Cp2Cr, Cp2Co, and Cp*2Co and the like are expensive or you have to make them plus possible workup problems. My personal feeling is that if you can have naphthalene around your reaction, one should try Na(nap) before jumping to KC8. It’s not really any more dangerous than any other Na or Mg reaction and Na(nap) is bringing a pretty big hammer to the party (-3V ish depending on the solvent).

    In my experience (mostly TM’s), though, you are better off starting simple and going more complex. A typical list of conditions tried, in rough order: Na mirror (smear it on the reaction vessel or vial walls to expose surface area. Mg turnings + heavy stir bar (Grignard trick) or + I2 initiation (may cause huge problems w/ TM chemistry or work great, YMMV). “activated” mg (dil. HCl wash followed by rapid H2O then Et2O wash then dry. Needs a GOOD box atmosphere to be stored, better off making fresh most times). Maybe Na sand if you all ready have it(also staticky, though). Na(Hg). Na(napth). KC8.

    Comment by cookingwithsolvents — April 9, 2009 @ 10:09 am

    • Hi cookingwithsolvents, since you have the experience in preparing KC8, could you tell me how to dispose the excess KC8 if I don’t need anymore, will that be similar to K? Thank you!

      Comment by het — July 18, 2012 @ 4:19 pm

      • I am not sure if the person you are asking for advice still comes here – this web site got pretty dormant lately.

        I have not worked with C8K. I presume that covering it with light mineral oil under Ar and then adding iPrOH slowly until the bronze color goes away and bubbling stops should be a reasonable method to quench it. By the way, I worked with K-naphthalenide (up to 0.5M solution in THF) and that reagent quench is very tame (if all K metal had dissolved)

        Comment by milkshake — July 18, 2012 @ 8:09 pm

  45. Thanks for the valuable info! I was asking just to find out more about the chemical’s safety from your experience, not because it just sounds safe to me.

    Comment by Chris — April 9, 2009 @ 2:55 pm

  46. Could you suggest a list of the dedicated suppliers of things that we routinely use in the labs?

    For example, for deuterated solvents it is Cambridge isotopes

    TLC, and column supplies=?
    Bulk inorganic supplies like (Nacl, NaHCO3, Na2SO4 etc)=?
    Goggles, lab coats, Plastic syringes and needles=?
    Stir bars, and spatulas=?
    Test tubes=?
    Glass ware =?
    Bulk solvents=?
    Bulk organic chemicals=?
    Dry solvents=?
    Gas(N2, Ar, H2 etc) suppliers=?
    Manifolds=?
    NMR tube cleaners=(Not Aldrich; Breaks too easily)?
    NMR tubes=?
    Stands (racks) for NMR tubes=?
    Ph & Filter papers=?
    Anything that you can think of that I missed above=?
    Thanks
    .

    Comment by xyz — April 17, 2009 @ 9:13 am

  47. The choice of suppliers may depend on where you are. We are located in South Florida, on East coast. Here is what I like:
    TLC plates and bulk column silica: EMD-Merck brand plates and bulk silica (we buy it through VWR at a discount; they have a partnership with EMD) . I hear that Silicycle silica is also excellent.
    Combiflash columns: Silicycle
    Glassware: Chemglass
    Bulk solvents, mostly 4L bottles of HPLC and ACS grade: Fisher brand, EMD and Baker and Burdick and Jackson brand through VWR – depends on who provides a better discount and more reliable delivery. I have had mixed impression with solvent quality from Mallinckrodt.
    Anhydrous solvents: Aldrich/Fluka Sureseal
    Chemicals: Mostly Aldrich and Acros (through Fisher, because of their discount) but I like also Matrix, Lancaster, Oakwood. (TCI has sometimes very good prices but not as reliable isomeric purity).
    Strem for ligands and organometallics. (Alfa ought to be avoided, except for air-stable metal salts, their packing techniques can be atrocious. Aldrich air-sensitive solid organometallics are also a mixed bag)
    NMR solvents: Cambridge Isotopes, although sometimes it is worth to buy Sigma-Aldrich when they advertise their price specials
    NMR tubes: Wilmad Glass has excellent quality and prices for high-end NMR tubes, the cheap Wilmad disposable NMR tubes (bought in bulk) are also OK. Wilmad NMR tube cleaner is very fragile though and I clean my tubes without it.
    Glassware: Chemglass. Their air-free adapters are excellent for inert/highvac work.
    Manifolds: Chemglass, but Aldrich manifolds are also decent if overpriced
    Gas supliers – we had decent experience with Airgas and Praxair but it depends on your location and the local company representative
    Test tubes, gloves, plastic syringes etc – mostly from Fisher but one has to pick up the correct brand. (some very cheap test tubes were coming consistently shattered but changing the brand fixed the problem. The same thing with latex gloves.) I found the VWR has often a complementary selection of brands so I use them for buying some natural rubber tubing, polyethylene chemical resistant tapes, notebooks etc. so I suggest you check VWR also.
    Vacuum pumps: I used to like Welsh direct drive pumps but their quality went down drastically in the last two years, and we have had too many pumps leaking oil because of the faulty shaft seal, apparently a recurring problem with their direct drive pumps. And our local Welsh rep is a complete flake. We bought our pumps already so we are stuck but Leybold vacuum pumps would be my top choice.

    Comment by milkshake — April 17, 2009 @ 12:03 pm

  48. Thank you very much.

    Comment by xyz — April 18, 2009 @ 9:07 am

  49. 1. I need to introduce 4- fluro benzyl in pyridine systems using suzuki reaction (Bromo substrate also contains free NH2 group)..Please give me any related refs..

    2. I would like to substiute amino (NH2) group in 2-Chloro pyridine..conditions are reported with very harsh conditions..heating with ammonia in pressure container at 220 0C..I need milder way of doing this transformation..

    Any organometallic reactions are also OK..

    Thanks

    Marto

    Comment by marto — April 18, 2009 @ 11:24 am

  50. benzyl by Suzuki: if i remember there are reports of using benzylboronic acids (check publications from Gossen group) but it is non-trivial so I think you would have a better luck with Negishi coupling using F-benzyl grignard (available from Aldrich) in which case you would likely need to protect your amino, for example with a trityl group. One can also do a traditional Suzuki with arylboronic acid under a baloon of carbon monoxide, this produces diaryl ketone, you would then have to reduce your keto to CH2, with things like TsNHNH2 plus cyanoborohydride.

    For 2- amination of halopyridines I have seen a procedure from Merck process group with NH3 solution in ethylene glycol catalyzed with Cu2O. The guy’s name is Daniel Zewge (I spoke with him at a conference) and I think he published it in Tet Let. The procedure still requires a pressure flask but the pressures and temperatures are quite reasonable (80 C, 3.5 atm internal pressure, for a 2-bromopyridine) and one could probably do it also in Biotage microwave 20mL vial – that one holds up 21 atm. There is also an amination procedure either from Buchwald or Hartwig group, that uses LiN(TMS)2 as the aminating agent with a Pd-phosphine complex.
    Alternatively you can use azide followed by reduction, something analogous to a procedure for 4-aminopyridine, posted here in Org Prep Daily on August 27, 2008. But you may need to do it at reflux in acetonitrile or at 100C in DMF because your substrate is far less reactive. Good luck!

    Comment by milkshake — April 18, 2009 @ 5:57 pm

  51. Hi MS,

    Thanks very much for your suggestions..cheers Marto

    Comment by marto — April 21, 2009 @ 11:12 am

  52. Hello again,

    Thanks for the useful info for KC8. Now I have another question. I used a medium frit funnel to filter it off and it clogged…Any suggestions? Also apart from THF, do you think I can use any other solvents? Do you know if C6H5F reacts with it? I know C6H6 should not.

    Thanks

    Comment by Chris — April 21, 2009 @ 1:05 pm

  53. I would filter off the spent reagent through a pad of Celite (“Kieselguhr”), this should prevent the clogging

    Comment by milkshake — April 21, 2009 @ 1:38 pm

  54. Good suggestion. Thanks.

    Comment by Chris — April 21, 2009 @ 1:50 pm

  55. Glad you are having success. KC8 works in most common solvents (Et2O, C6H6, etc…it’s not dissolved so if you aren’t retaining the K solvent doesn’t matter much) but stay away from halogenated ones just in case. . .

    Comment by cookingwithsolvents — April 22, 2009 @ 1:09 pm

  56. I need to do a reduction with lithium aluminum deuteride, and am wondering if the reagent is worth purifying before use. Since the reagent is kind of expensive and also a kind of a black box reagent, I have no idea how much I should use if I don’t purify it first. The purification seems easy enough – extract with anhydrous ether and evaporate solvent. Do you have an opinion on this? Thanks!

    Comment by Ron — April 25, 2009 @ 2:56 am

  57. I never worked with LiAlD4 before. You can do the purification if you really want to – but be aware that homogennous solutions of LAH are fairly sensitive to oxygen, and once purified, solid LAH is much more likely to catch on fire. (The other reason for LAH catching on fire are traces of uncomplexed AlH3). What I would do instead is to use the reagent as it is and run some small pilot experiment, like 20mg – just enough for NMR, to see how the commercial stuff behaves. It will not be too much extra work and it will decrease chances that you will blow all your expensive reagent on one unsuccessful experiment.

    Comment by milkshake — April 25, 2009 @ 1:53 pm

    • Thanks for your input, I appreciate it!

      Comment by Ron — April 25, 2009 @ 2:38 pm

  58. Greetings milkshake, thanks for posting this procedure which sparked off some ideas for me. One question, is protection of the pyrazole hydrogen for the pinacolate ester necesary ? You did not do so in your reaction, but a related paper in Angew. Chemie Int Ed (2006 v45 p1282) by Fu and co-workers at MIT commented on the need for protecting the pyrazole hydrogen for decent yields. Do you or others have any comments ? Thanks.

    Comment by Maw — April 25, 2009 @ 8:15 pm

  59. it probably depends on the Pd catalyst (it has been my experience that some of the most active Pd Buchwald catalysts with bulky phosphines are deactivated by coordinating species quite easily). We did not have trouble with unprotected pyrazole pinacolatoboronate when using old-fashioned Pd tetrakis.

    Boc group tends to fall off pyrazole during conventional Suzuki at 95C and carbonate as a base. But if you use milder conditions (THF-water, Cs2CO3, SPhos as a ligand + Pd2(dba)3 at 50C, 30min) with the commercial but expensive Boc-protected pyrazole-4-pinacolatoboronate, you can keep Boc on your pyrazole product.

    Comment by milkshake — April 25, 2009 @ 10:31 pm

  60. No alkoxide displacement of the Br? Strictly electronic affect governing the chemoselectivity? Interesting…

    Comment by synthon — May 5, 2009 @ 8:26 pm

  61. I played with polyhalogenated nitrobenzenes a little in a previous project, it turns out that unlike halopyridines, with halo-nitrobenzenes the ortho position is far more activated for direct SN-Ar than para. Combine it with the F>Cl>Br order of reactivity of halogens in SN-Ar, I think the result is not too surprising.

    Comment by milkshake — May 5, 2009 @ 10:56 pm

  62. Greetings, do you by any chance know if they sell stir bars that would fit and stir contents inside an NMR tube? I guess they would be of spherical shape.

    Comment by Chris — May 7, 2009 @ 9:01 pm

  63. Hello guys,

    Do you know if K reacts with SO2?

    Comment by Nick — May 23, 2009 @ 6:48 pm

  64. I never had the opportunity to find out – but given that Mg and Na burn happily in gaseous CO2…

    If I remember correctly dithionites are made by reduction of SO2 with stuff like Zn metal

    Comment by milkshake — May 24, 2009 @ 5:01 am

  65. Hello, I was wondering if tert-BuLi will deprotonate benzene and toluene (I know it deprotonates THF and ether)

    Comment by Chris — June 5, 2009 @ 10:14 pm

  66. I think tert-BuLi might deprotonate toluene methyl under harsh conditions but probably not at -78C. Also, there are very potent “superbase” systems obtained from a slurry of tBuOK with BuLi (or sec-BuLi or tBuLi) in hexane. These system contain “butyl potassium” soluble species and can metallate unactivated aromatics like naphtalene; they also metallate allylic positions of alkenes and methyls on benzene ring.

    Comment by milkshake — June 6, 2009 @ 9:00 am

  67. Milkshake, thank you so much. I’ll try to look up for references as I want to find out more about this.

    Comment by Chris — June 6, 2009 @ 10:49 pm

  68. Look up the old publications from Manfred Schlosser, from about 25-30 years ago, I think he is the guy who introduced the tBuOK+BuLi superbase system. the list of his publication is for example here:
    http://isic.epfl.ch/schlosser_e.htm

    Comment by milkshake — June 6, 2009 @ 11:34 pm

  69. milkshake

    can we make 35-40% peracetic acid from 30%H2O2 and acetic acid catalyzed by sulfuric acid. OR higher concentration of h2o2 is necesarry. Do you have any ref to make 40% peracetic acid from the percentage mentioned above

    your comments are appreciated.

    Comment by pasupathy — July 29, 2009 @ 11:47 pm

  70. I never used peracetic acid. There must be huge amount of work on this – I would direct you to Fieser and Fieser, or better yet, Leo Paquette’s Compendium of Organic Reagents and Beilsten/Crossfire. By the way, peracetic acid is an intermediate in acetic acid manufacturing, by autooxidation of acetaldehyde with air. It is commercially available and very cheap because it is produced on a big scale. If I am not mistaken hydrogen peroxide is also manufactured from peracetic acid.

    The reason why it is used in lower concentration is that concentrated AcOOH is rather explosive.

    if you are looking into cheap peroxidation agents, you may want to check monoperoxophtalic acid (I think its used as a magnesium salt) and Oxone-acetone mix where the DMDO is generated and consumed in situ. Then there is peroxoformic acid, but the product is typically the ring-opened trans diol monoformate ester

    Comment by milkshake — July 30, 2009 @ 12:24 am

    • thx for the suggestion and reply

      Comment by pashu — August 3, 2009 @ 1:02 am

  71. I have seen your reply in the pipeline regarding the runaway associated with bromination of acetophenone. You have said catalytic acid is needed when you do the reaction. Currently involved in the bromination aryl-alkyl ketone. Is it wise if we do the reaction in acetic acid as solvent. Or DCM/cat acetic acid combination. Are there more precaution to be taken to do this transformation. Do throw more insights.

    regards
    pshu

    Comment by pashu — August 4, 2009 @ 5:02 am

    • Yea, I would definitely use acetic acid or water+acetic acid as a solvent and add the bromine solution at slow rate initially – you want to make sure that the reaction proceeds at a reasonable rate and bromine is actually being consumed and the brown color is disappearing, before you add the whole quantity of bromine and then suddenly the mix takes off like a rocket.

      If you need to initiate the bromination after the initial Br2 addition (of a small portion of Br2) you can either heat it up until the color disappears, or you can add a small quantity of aqueous concentrated HBr to the mix.

      Comment by milkshake — August 4, 2009 @ 7:19 pm

      • Added cat amt of aq con HBr and acetic acid before adding bromine. Running the reaction in DCM. I saw HBr liberation only after 1 h of adding initial portion of bromine inspite of warming it to 40 deg for few min. Then how does adding acid speeds up the initiation. Is it worth running without any solvent

        Comment by pashu — August 5, 2009 @ 3:41 am

  72. Suzuki reaction of less reactive 4-pyridyl boronic acid with moderately reactive hetererocyclic bromo compound gave poor yield. We tried few conditions for this reaction (Pd-[PPh3]2Cl2, Na2CO3, and similar conditions) but always got very low yield (10-15 % only). Would be very helpful if you have any experience with such boronic acids?

    Comment by marto — August 18, 2009 @ 12:42 am

  73. Unfortunately I have very limited experience. My understanding is that apart from the chelating properties, one of the difficulties with pyridylboronic acids is that they de-borylate hydrolytically, to pyridine.

    I think you have two ways to fix this problem:
    A) use pyridyl-BF3(-)K Molander-type of salt instead of boronic acid. You can make this salt easily from the boronic acid and KHF2, or even form it in situ, by employing excess of KF or CsF as a base.
    B) Use more active Pd catalyst and work at lower temperature/less basic media. For example KHCO3 is a suitable base for Suzuki, and a very active catalyst can be obtained in situ from tBu3P.HBF4 or S-Phos and Pd(dba)2 etc.

    Comment by milkshake — August 18, 2009 @ 10:17 am

    • Maybe you can use the mild Suzuki conditions described in a Org Process R&D (ASAP web publication) article from Fray, Gillmore et al from Pfizer Sandwich, DOI: 10.1021/op900092h, web publication July 24, 2009

      Comment by milkshake — August 18, 2009 @ 11:05 am

  74. Thanks very much for the help

    Comment by marto — August 18, 2009 @ 10:54 pm

  75. Greetings MS, I need your help..I am trying to prepare 3-Fluoro-4-methyl pyridine from 3-amino-4-methyl pyridine using diazotization in HBF4 addition of NaNO2 portionwise ..addition at -10 0C stirred at that temp for 30 min ..followed by rt stirring..no product was obtained..I saw a literture procedure for similar substrates which mentioned to heat the obtained solid at higher temp..Dont know why the mixture need to be heated at higher temp..very low yield also reported..would be grateful if you have any experince with such reactions..Suggestions of similar reactions would be very much helpful..

    One more help

    I would like to use carbanions generated from 5-methyl pyrimidine with electrophiles..such reactions are not reported in the literature..What kind of base just sufficient for deprotonation?..do you think bases such as Potassium-t-butoxide/DBU/similar basic could be used..I am bit hesitant to use BuLI/LDA bases..I fear those conditions will affect other functional groups..

    Thanks
    Marto

    Comment by marto — November 11, 2009 @ 2:57 am

  76. Marto, I have only a limited experience on this but you are asking the right kind of questions. Methyl on pyrimidine should have acidic C-H but perhaps methyl in positions 2 and 4 would be acivated more. I have been running Dieckmann condensation reactions with 2,3-dimethylnitrobenzene and ethyl oxalate last week, and the ortho methyl deprotonates easily with bases like ethoxide or tert-butoxide whereas the meta methyl is inert (the main probalem was rather to prevent the anion from crapping up – it is not stable and reacts with the nitro) . I would first recommend to check the literature, then do few simple experiments like you have suggested, and if this fails I would recommend looking into brominating or chlorinating that methyl and do benzyl zinc or Grignard from it. I know, direct metallation of methyl group would be much nicer.

    Diazotation: first you need to actually make the diazonium, and in case of aminopyridines this requires very strongly acidic media, people used things like undiluted HBF4.Et2O or conc sulfuric acid. Aminopyridines do not diazotate easily. Then if you go by the tetrafluoroborate route you need to isolate the diazonium tetrafluoroborate, dry it (!!) and do a careful pyrolysis of the dry salt because tetrafluoroborates are fairly stable. This pyrolysis is rather exothermic, produces gases and can go runaway easily, people were doing tricks like diluting the solid tetrafluoroborate with solid anhydrous KHF2, packing this solid mix into a glass tube and then carefully heating the tube from one end to another. I have no experience with this.
    I would instead propose an alternative, which worked well for my colleagues with 2-aminoquinazolines, and gave 2-fluoroquinazolines in 40-50% isolated yield, but it is even more dangerous. You will need to buy lots of Olah’s reagent – anhydrous HF-pyridine complex which has a composition about 9HF.pyridine, it is a high-boiling alternative of anhydrous HF and it is just as nasty as anhydrous HF. (Look for other vendors than Aldrich – Aldrich stuff is very expensive, we bought liter quantities of it from some custom synthesis company much cheaper). In a plastic (polyethylene or teflon) wide-mouth bottle you dissolve your substrate in excess of neat Olah’s reagent, cool on ice/salt bath, add tBuONO neat, dropwise (Aldrich 90% tBuONO is suitable) about 1.3 equivs, stirr at -20 to -10 for awhile, then pour on crushed ice excess very carefully, let it melt and extract with dichloromethane. Thats it.

    Except that working with large quantities of anhydrous HF can cause horrific injuries, you need very good gloves, facial shield (not just goggles), calcium gluconate ointment at hand etc. When our safety guy learned what we were about to work with (anhydrous HF) he informed the poison control and burn unit at nearby hospital, made an accident emergency plan and so on. And your sep funnel gets etched if you don’t wash it right away, and the washings contain lots of aqueous HF so they are still dangerous on contact.

    Comment by milkshake — November 11, 2009 @ 9:52 am

  77. Thanks very much for help.

    Marto

    Comment by marto — November 12, 2009 @ 6:28 am

  78. Hi MS,

    I am struggling to deprotect SEM group (SEM group is attached to ring nitrogen of substiuted amino pyrazole). I tried few conditions TBAF , rt stirring as well as reflux, SM recovered. I tried strong acidic conditions ( 6N HCl, rt/ heat) that resulted in decomposition of SM.

    Please advise me any other conditions if you have some experience.

    Is any other PG worth trying for amino pyrazole (Ring nitrogen protection – BOC was not useful)..

    Thanks

    Marto

    Comment by marto — April 7, 2010 @ 3:18 am

  79. I don’t have much experience with deprotecting SEM, but you can also try some concentrated aqueous (48%) HF diluted with acetonitrile before you throw away your material.

    Boc does not hold on pyrazole too well – it falls off under common Suzuki conditions (100C, aqueous K2CO3). Maybe you can try p-Methoxytrytyl (from the trytyl chloride) or 1-ethoxyethyl (from ethyl vinyl ether and py.TsOH), those are acid-cleavable groups that should be stable under basic conditions.

    Comment by milkshake — April 7, 2010 @ 1:29 pm

  80. Thanks very much for the suggestions.

    Comment by marto — April 8, 2010 @ 12:47 am

  81. Did any one prepare KC8 . Is it easy or hard to make it ..any suggestions who made KC8 please.

    Comment by Mario — January 15, 2013 @ 10:28 pm

    • I did not make it. It is reportedly easy but the product is very air sensitive and pyrophoric so your Schlenk techniques need to be good and you better generate it directly in the reaction flask…It is made by fusing freshly cleaned K metal with graphite flakes (the graphite grade is important) at 130-150C under Ar, without any stirbar (or with a glass coated one) , at the end all K metal is absorbed and the lakes attain bronze color

      Comment by milkshake — January 16, 2013 @ 6:35 pm

      • milkshake i have tried to do tht way and at the end i dont end up with bronze color complelty (some bronze and some blackish ). any ideas how to overcome this.

        thanks milkshake again.

        Comment by Mario — January 16, 2013 @ 6:44 pm

        • I dont know – however if you have some additional unreacted graphite it probably does not matter because in the next step you will be probably using C8K for reductions and graphite will be the byproduct, so having there a bit more should not change things

          Comment by milkshake — January 17, 2013 @ 12:36 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

The Shocking Blue Green Theme. Blog at WordPress.com.

Follow

Get every new post delivered to your Inbox.

Join 136 other followers

%d bloggers like this: