Org Prep Daily

March 16, 2007

Notes on Terrible Reactions

Filed under: procedures — milkshake @ 5:18 pm

black_scorpion_2.jpg

There is a very informative discussion thread In the Pipeline today. It is about reactions that never work or are underwhelming in terms of yield and ease of workup/purification. So, to steal the subject, I would like to add few random notes:

PPA: A less viscous reagent alternative is called Eaton reagent, it is a P2O5 solution in methanesulfonic acid and you can buy it ready-made from Lancaster.

Azide reduction with phosphine: the iminophosphorane adduct is slow to hydrolyze in case of triphenyl phosphine, always use trimethylphosphine solution instead (stinky and expensive, but much faster, the phosphine is volatile and the phosphine oxide extracts into water).

Skraup: We called this kind of drastic conditions “Chemical Inquisition” in Prague. I guess it depends on the substrate. There are some high-yielding Sraups published in Org Process R&D journal, the process people typically use 3-nitrobenzenesulfonic acid as co-oxidant because the crap produced from the spent oxidant is soluble.

MnO2 oxidations: Like with silica or alumina, MnO2 is desactivated by moisture. You can re-activate it in glassware-drying oven, at 110-130C. (Works much faster after oven activation – but can be less selective. You can also add 4A powdered sieves). Non-polar solvents improve the reaction rate, sometimes doing the oxidation in cyclohexane instead of DCM is what is needed. Always use >20 equivalents to get to completion. BaMnO4 is a pretty good alternative to MnO2, and it is very easy to make (permanganate,  Ba salt and KI as a reducing agent)

Grignard: Initiating the reaction is the tricky part, people have used 1,2-dibromomethane, iodine, TMSCl – but for me the best working initiation technique is to place few equivalents of Mg turnings into an oven-dried flask with a large egg-shaped stirbar, flush it thoroughly with dry argon, add few drops of Br2 and dry-stir the Mg turnings in the Br2 vapors overnight. Then add freshly distilled ether solvent via canula (the bromine color disappears) and then carefully your substrate. I got some Grignards like BrMg(CH2)3MgBr by this technique that are hard to make by other methods (unless you want to mess with Rieke Mg).  The Mg turnings are fairly fragile and crushing them in oxygen-free and nitrogen-free environment uncovers a highly-reactive newly-formed surface which is further protected by MgBr2 formation. MgBr2 is soluble in ether. Please note that one has to use Ar because N2 reacts with fresh Mg surfaces, to produce dark Mg nitride.

Also, the Knochel transmetallation with iPrMgCl or iPrMgBr always worked great in my hands, with aryl iodides, at -20C.

Swern-like oxidation with SO3.pyridine in DMSO: the commercial SO3. pyridine often contains pyridine hydrogen sulfate impurity that can upset the reaction, always add few extra drops of pyridine and let the complex with DMSO form, before adding the alcohol.

Mitsunobu: The complex formation is pretty exothermic and overheated complex of DEAD with PPh3 decomposes quickly. Always start the reaction on ice bath. You can add phenol to phosphine before DEAD addition but secondary alcohols should not be premixed with the DEAD/PPh3 complex – a significant amount of eliminated product could form in absence of nucleophile. Use DIAD as a cheap and lazy DEAD alternative (the reactions take >2 times longer). You can use a slight excess of PPhe3 and kill the unreacted phosphine during workup, by adding few drops of 30% H2O2 (the oxidation is instantaneous). PPhe3O crystallizes quite nicely from a benzene-cyclohexane mixture so if your product is reasonably soluble you can dissolve the mix in benzene, dilute with cyclohexane and let it precipitate. The filtrates can be often applied onto a column directly, without evaporation.

DCC couplings: Acetonitrile or carbon tetrachloride are great solvents for DCC coupling, as dicyclohexyl urea is much less soluble there than in DCM or chloroform.  You can dissolve the crude product in a small volume of ethyl acetate and put it in the fridge, to precipitate the last bits of the urea.

Lazy silyl protections: TfOSiR3 + lutidine usually works marvels, but ClSiR3 with DBU as a base plus catalytic DMAP in acetonitrile is in my opinion much more general than imidazole in DMF.

Hydrogenations: Pt on charcoal (5%) is much faster than Pd-C for ArNO2 reduction and unlike Pd-C, with some care one can reduce chloro-nitro compounds without the ring dechlorination (0.05-0.1 wt ratio of 5%Pt-C to substrate, in ethyl acetate or ethanol, H2 baloon, RT, 1 hour). Also, don’t use MeOH as a solvent in hydrogenations – unless you like to play with fire.

Vilsmeyer formylation: Oxalyl chloride in DMF usualy works faster and cleaner than the more traditional POCl3 in DMF. Oxalyl chloride is added first, with cooling on ice (gas evolution!), followed by substrate.

Thioamide preparation: Lawesson reagent is not fun to work up, for many substrates P2S5 is a nicer alternative. 

Strecker aminonitrile hydrolysis to aminoacids: Aminonitriles tend to crap up during acidic hydrolysis to aminoacid, partial retro-Strecker happens. But if you formylate first with excess of formic-acetic mixed anhydride at RT without any base (96% formic acid is first mixed with an equal volume of acetic anhydride and allowed to sit under Ar for 4 hours, then the substrate is added) the acid hydrolysis of the formyl aminonitrile is very clean and N-formyl later falls off during HCl hydrolysis. This trick is was used by Vachal and Jacobsen in their tert-leucine paper. (I told them to try it.)

Initiating  periodnane oxidations: Dess-Martin periodnane sometimes needs initiation, typicialy when a nice, freshly-made reagent is used. People have been adding a drop of tert-butanol or even a trace of water, to get the reaction started. But the addition of a small amount of pyridine works even better and the added advantage is that pyridine protects highly acid-labile groups in the molecule, like TES-O or 1-ethoxyethyl, from being cleaved by the reagent.

SeO2 allylic oxidations: Working up stoechiometric SeO2 reaction is awful, there is a nice Sharpless procedure for using catalytic SeO2 oxidation (5mol%) with salicylic acid as a co-catalyst and anhydrous tBuOOH (2-3 eqivs) as co-oxidant. It works well at 40C in DCM (in 1 day), the only complication is that salicylic acid gets slowly eaten and has to be replenished, I found that tetrazole is a better co-catalyst that does not have this stability problem. (Anhydrous tBuOOH solutions are somewhat expensive on large scale, diluting the 70% aqueous solution of tBuOOH with dichloromethane, saturating the aqueous layer with MgSO4 and extracting with dichloromethane and drying the extract with MgSO4 is easy way to make your own anhydrous solution).
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91 Comments »

  1. Ah! I’ve been looking for an alternative solvent for a DCC coupling, never thought to try acetonitrile. Thanks!

    Comment by Propter Doc — March 16, 2007 @ 5:30 pm

  2. Yes, acetonitrile works quite nicely for active ester formation and HOBt, HOSu is soluble there. For symmetrical anhydride formation I would use CCl4 because acetonitrile is somewhat hygroscopic so the filtration of anhydride solution in acetonitrile would have to be done under positive pressure.

    Comment by milkshake — March 16, 2007 @ 5:35 pm

  3. All hail Milkshake, the god of synthetic education.

    Comment by Paul — March 16, 2007 @ 6:06 pm

  4. I was in doubt just the other day if I can get rid of excess Ph3P with peroxide. Pentane, as in geranyl chloride OrgSyn Prep, works great. I made a mistake though, I should have filtered the oxide first. I poured it onto a siliga plug, elution with pentane didn’t give me much of my compound, and the oxide bleeded through with pentane/ether.

    I was reducing a perbenzylated sugar ester with DIBAL, to alcohol; it was perfect with my 2.1 equiv, but in other person’s case the primary benzyl fell off.

    Comment by liquidcarbon — March 16, 2007 @ 6:35 pm

  5. oh, and I’d like to complain on one ofKnochel’s couplings – ROTs + LiI + LiBr + Zn in DMA or DMPU = RZnX; add LiCl+CuI and your aldehyde. We tried several times. Nothing good, mixture of halides and SM and reduced SM.

    Comment by liquidcarbon — March 16, 2007 @ 7:05 pm

  6. Side question – what’s the best way to dry morpholine?

    Comment by andrew — March 16, 2007 @ 7:09 pm

  7. I would try distillation at atmospheric pressure, maybe with some CaH2, and take the middle cut (discard first few mL and do not distill to completion), this works well for triethylamine. The Aldrich stuff from a fresh bottle is usualy pretty good though

    Comment by milkshake — March 16, 2007 @ 7:36 pm

  8. If I recall those 1980s papers using tritiated water to test drying agents (Burfield and Smithers?), really active 4A sieves are about as good as it gets for anything without active hydrogens.

    Comment by Derek Lowe — March 16, 2007 @ 8:45 pm

  9. I like ADDP for the Mitsunobu, just as effective and quick as DEAD, but much more bench stable. For reduction of ArNO2 in the presence of ArCl or ArBr, I’ve had good success with Raney Ni or, in the case of ArCl, adding 2% TCA. As long as you add Pd/C to MeOH under Ar slowly, it rarely catches fire. Adding too quickly (causing it to finely disperse in the air) significantly increases the likelihood of a fire. I’ve formylated some secondary amines with acetic-formic anhydride and have found that waiting ~10-15 min before adding substrate is sufficient. As for Lawesson’s reagent, I usually adsorb the reaction mixture to celite and throw it on a column, works well if your substrate isn’t too polar.

    Comment by Zinc — March 16, 2007 @ 11:06 pm

  10. This is awesome. These tidbits should be in every Organic Chemistry text. They could be in the margin or something. The text would read: “The Grignard reaction is a reaction between..blah blah blah…” and then in a box it would say: Milkshake says: “Initiating the reaction is the tricky part, people have used 1,2-dibromomethane….” That would be awesome.

    Comment by Chemgeek — March 16, 2007 @ 11:11 pm

  11. ArNO2–>ArNH2: Reflux in abs. ethanol with aqueous hydrazine and graphite powder for about 3 hours. Filtration over Celite and concentration gives the amine in (in my experience) quantitative yield. Use 300 mesh graphite from Alfa. Tet. Lett. 1985, 6233-6234.

    Comment by dan — March 17, 2007 @ 11:29 am

  12. Dan: How well does that work? Hmmmm…

    Comment by Ψ*Ψ — March 17, 2007 @ 3:09 pm

  13. I used Zn in AcOH at reflux, there was an ester in the molecule. Not very clean, but very easy.

    Comment by liquidcarbon — March 17, 2007 @ 5:59 pm

  14. I do a lot of really bulky grignards, and I’ve had a lot of luck with this series of activation steps:
    1) a few drops of 1,2 dibromoethane
    2) Adding some of the alkyl bromide down the side of the flask without stirring.
    3) Heating the side of the flask with a heat gun.

    And if I don’t get initiation, I bust out the big guns.
    4) Praying to Victor Grignard

    Comment by Naffer — March 17, 2007 @ 7:02 pm

  15. Have you ever thought about writing a book? “Milkshake’s guide to practical organic chemistry” It would sell well.

    Comment by propter doc — March 17, 2007 @ 8:23 pm

  16. No book contract yet but I can sell you my autographed picture – and if you tape it inside your hood it will make your reactions run faster and also increase their yield, by 35 to 48%

    Now with the 100% money-back guarantee within the first 30 days(minus S&H). The operators are standing by, call 1-800-GET-MILK.

    Comment by milkshake — March 18, 2007 @ 12:13 am

  17. Few drops of DIBAL-H can initiate Grignard very nicely

    Comment by Activation — March 18, 2007 @ 12:03 pm

  18. But what about the DIBAL then, that’s in your Grignard afterwards – isn’t it going to interfere?

    Comment by milkshake — March 18, 2007 @ 5:11 pm

  19. Don’t forget WATER!! Water is bad, that’s why need initiation. Refer to OPRD, 2002, 906

    Comment by Activation — March 18, 2007 @ 9:17 pm

  20. Any tips/comments for the Delipine synthesis of 1\deg; amines via hexamine? It seems like a decent route compared with the alternatives (Staudinger azide and Gabriel phthalimide), but I don’t hear it mentioned much. Is there something fatally wrong with this?

    Comment by drew — March 19, 2007 @ 9:47 am

  21. Simple and easy Ar-NO2 to Ar-NH2: just use SnCl2 x 2H20 in DMF/EtOH, or EtOH/H20. Room temp, overnight, very clean, unlikely to touch anything else. March says In and Sm also work, if you are busy working on your lifetime elements list….

    Comment by Jose — March 19, 2007 @ 12:10 pm

  22. Mitsunobu – that could be why my attempted acylation of 1,5-cis-cyclooctanediol monobenzyl ether failed so miserably. I wasn’t terribly competent at the time, so I didn’t think about reagent order, and since I didn’t realize it was eliminating, just that my product wasn’t there, I didn’t know what to do. I have assumed that the medium ring messes things up, and that it wasn’t the substitution per se.

    Azide: I didn’t rty phosphine cleavage because the product is water soluble and I was afraid of dealing with triphenylphosphine oxide. I don’t know whether Me3P would have worked better for me, because I wasn’t used to doing air-sensitive reactions.

    Comment by Hap — March 19, 2007 @ 1:41 pm

  23. Me3P is not super air-sensitive, and you can always add a little more…
    I like SnCl2 reductions, the unpleasant part is adding the huge amount of NaOH at the end to dissolve all Sn crap – this complicates things a bit on scaleup because the extraction volumes get large, and the product obviously has to be stable toward basic and acidic conditions.

    Comment by milkshake — March 19, 2007 @ 2:17 pm

  24. I used Staudinger reduction only once while reducing benzyl azide. Ph3P worked fine. I even did not care about moisture at all. For the first time I did not expect so fast evolution of nitrogen after adding solution of phosphine and had to wipe the foam from my hood :)

    Comment by petr — March 19, 2007 @ 2:40 pm

  25. Oh man. I HATE getting rid of Sn at the end of those. Such a pain to extract! Usually I get impatient and have to filter it (as opposed to waiting for several days to see clear phase separation).

    Comment by Ψ*Ψ — March 19, 2007 @ 5:32 pm

  26. ooops…the product of the 2nd paragraph is not the product in the 1st (EG-derived azide in 2nd paragraph – hence the water solubility of the product

    Comment by Hap — March 19, 2007 @ 5:56 pm

  27. Psi star, it sounds like you’re having about as frustrating of a time as I did. I would highly recommend that you check out the TL paper with hydrazine/graphite, I don’t know why it isn’t better known.

    Comment by dan — March 19, 2007 @ 6:10 pm

  28. I was usualy doing SnCl2.2H2O (5 equivs) in EtOH with some added AcOH (about 15 equivs) at reflux (1 hour) and if one adds then lots of NaOH (>50 equivs) and DCM and stirrs for about an hour or two the phases become separable.

    Comment by milkshake — March 19, 2007 @ 6:32 pm

  29. Dan, thanks much. I’ll definitely, definitely have to check that out…

    Comment by Ψ*Ψ — March 19, 2007 @ 9:26 pm

  30. I thought the most impressive substrate in the paper was 2,4-dinitrochlorobenzene, 88%Y unoptimized. Normally I would worry about the reactive chlorine because there is a procedure for dinitrophenyl hydrazine that uses exactly the same conditions (minus graphite). I think I will be using this procedure, for things like bromo-nitroaromatics.

    Comment by milkshake — March 19, 2007 @ 10:38 pm

  31. milkshake, you have once again rocked my (synthetic) world. If anyone is making hexaphenylbenzene or the like from a Diels-Alder, and it’s just not going as fast as you’d like, you can use benzophenone as a solvent. Boils at around 300C. Add some diphenyl ether before it cools to dissolve the benzophenone, or just distill off the benzophenone. No oxygen. Oxygen bad. There ya go. I sometimes fancy myself a synthetic chemist, but then I realize how little I really know…

    Comment by excimer — March 20, 2007 @ 12:08 am

  32. Oh I thought of another trick from my undergrad days. If you’re doing a reductive amination and imine formation isn’t going to plan, sonicate the solution for 20 minutes. We managed to get even very bulky amines to react after sonication in good yield.

    Comment by excimer — March 26, 2007 @ 2:02 pm

  33. Milkshake:

    Any hints for Knochel transmetallation?

    Comment by Klug — March 26, 2007 @ 8:19 pm

  34. No, not really – except that aryl iodides go nicely between -40 and -20C (although I was usualy lazy and did it on salt/ice bath at -20 to -15C), and a slight excess of iPrMgCl or cyclopentyl-MgCl is used. iPrMgCl is supposedly slightly superior to iPrMgBr (I did not find much difference). And in case of aryl bromides one has to add few equivs of LiCl to get the transmetallation going (esters are tolerated with ArI transmetallation but won’t survive ArBr transmetallation done in presence of LiCl – except for tert-Bu esters).

    Comment by milkshake — March 26, 2007 @ 9:24 pm

  35. Thanks, Milkshake!

    Comment by Klug — March 27, 2007 @ 9:20 pm

  36. In reduction of aryl nitros is very, very nice. Plus, the acid can be really mild, like NH4Cl if you’d like.
    Added bonus is that the In doesn’t really touch any of the other functional groups that you might worry about (like, say, nitriles).

    Comment by Matt J. — March 28, 2007 @ 2:39 pm

  37. Also, ethanol is a nice substitute for methanol when doing reductions using Pd/C. I have not had any issues with it at all, but then, I’ve also been very careful. I guess the big bonus is, if it goes up in flames, at least you can see the fire with ethanol.

    Comment by Matt J. — March 28, 2007 @ 3:15 pm

  38. Awesome post.

    A general option when all else fails is the sonicator. Good for initiating Grignards and can occasionally perform miracles for other reactions.

    I need help regarding the reduction of a nitrile to an aldehyde, (sulfonic acids also present). DIBAL has failed so I am on to the Stephen’s aldehyde synthesis. The standard method (Vogel’s) uses anhydrous Et2O or EtOAC. I need something a lot more polar. Any suggestions?

    Comment by agogmagog — March 30, 2007 @ 7:40 am

    • I would like to know the substitute to BF3/sulfolane combo for deacylation & moethoxylation, hopping you will suggest

      Comment by PLN — August 3, 2009 @ 3:18 am

      • unfortunately I have no experience with his reagent and I never heard of it – please what kind of deprotection are you doing?

        Comment by milkshake — August 3, 2009 @ 12:51 pm

  39. I have never done stephens reduction so I cannot be of much help. I would not do the reaction with free sulfonic acid because of the solubility problem, I would protect it with something that can be taken off easily (methyl, with NaI).

    Try saturated anhydrous HCl in dioxane, neat, >4M. It dissolves lots of stuff.
    For a more polar solvent alternative (that withstands anhydrous HCl) you can try sulfolane but good luck with isolating your stuff from the resulting high-boiling goo.

    Alternatively you can hydrolyze the nitrile to amide (NaOH + H2O2), reduce the primary amide to primary alcohol with Li or Na metal in refluxing n-propanol, then re-oxidize the alcohol to aldehyde.

    Comment by milkshake — March 30, 2007 @ 4:03 pm

  40. Milkshake…

    You’re just fuckin awesome. I swear to god. Can I be your postdoc?

    Comment by Kyle Finchsigmate — March 31, 2007 @ 10:06 pm

  41. Kyle, I am not bossing anyone – but you can become a postdoc at the institute in which case we end up as neighbours (and I might be ordering the bulk organic solvents for you – and eventually bullying you, if you do bad things to the lyo or my HPLC.)
    There is a total synthesis group which I would highly recommend if you can convince Bill to take you (you would have to contact him directly). There are also the medchem program postdoc positions here – and I think it could be a pretty good alternative, for someone interested in pharma industry career after the postdoc. We have lots of money to spend on research and the people here are nice and easy-going; though it is the usual medchem derivate-mania what we do here and not much of it gets published – we write patents. So you decide. I am quite friendly with most people in medchem program here so please let me know if I can be of any help. You have my e-mail.

    Comment by milkshake — April 1, 2007 @ 3:14 am

  42. Thanks Milkshake! I dunno if he would want a slacker like me tho.

    Comment by Kyle Finchsigmate — April 1, 2007 @ 10:43 pm

  43. Give him a try – the worst thing that can happen is that he will dump your resume on us.

    Comment by milkshake — April 1, 2007 @ 11:18 pm

  44. agogmagog:

    Try Raney Ni/NaH2PO2 in py/AcOH/H2O. Fast and clean, at least in my hands, and crashing out or extracting the product is relatively easy.

    Backeberg, O.G.; Staksun, B. J. Chem. Soc. 1962, 3961.

    Comment by Lucas — April 24, 2007 @ 7:14 am

  45. sir ,why 1)iodine only is used in g.r reactions ,what is its role 2) why thf is used , what is its role actually .

    how did the activity of the 2 nd nor nitrogen in 1 2 3 triazole can be stopped .

    Comment by ravi — April 25, 2007 @ 9:29 am

  46. Previous workers in my group unsuccessfully tried a Delepine transformation. I have converted the bromide to the azide (0.5M acetone, reflux, 2-3hr), then hydrogenated the azide in MeOH at about 30 psi for 30 min. I have to add acid, because my compound also contains a ketone, so the free product dimerizes to an imine.

    When I was taking organic chemistry, I learned that iodine reacted with the surface of magnesium metal, exposing more surface area for reactions. I have tried essentially the same Grignard technique as Naffer (only on alkyl Grignards). You will want a condenser, as the magnesium insertion is very exothermic.

    Speaking of Grignards, anybody ever added a Grignard to a nitrile?

    Comment by ed — April 27, 2007 @ 2:51 pm

  47. Milkshake, how long do you normally activate MnO2 in oven?
    I have finished copying of your marvels advises to chemknowhow.com
    Thanks a lot once again!

    Comment by Alexey — May 15, 2007 @ 11:47 am

  48. I don’t know, maybe overnight.

    Comment by milkshake — May 15, 2007 @ 3:43 pm

  49. Hey this thread is brilliant, am copying it all down now.

    Regarding MnO2 oxidations does anyone have a decent prep for making fresh and active MnO2 and BaMnO2??

    Comment by kirrasoul — June 11, 2007 @ 3:58 am

  50. I made my own BaMnO4 about 20 years ago and the procedure was simple: to mix KMnO4 solution with a slight excess of Ba(OH)2 or BaCl2 + hydroxide and to add slowly a solution of KI, exactly 0.125 equiv. (Iodide goes all the way to periodate). BaMnO4 precipitates out as a dark green powder. Then you wash it with water and dry in vacuo.

    I think I found the reference in old Fieser. If you are close to uni library you can also look for the much superior multi-volume Paquette compendium of organic reagents, it should be there.

    Comment by milkshake — June 11, 2007 @ 10:04 am

  51. Cheers.. thanks a lot for that.

    Off to the library i go then with a little detour to the inorganic labs to see if they want to “loan” me some barium salts.

    Comment by kirrasoul — June 12, 2007 @ 7:33 am

  52. Hi I’m desperate for a method for distilling oxalyl chloride

    Comment by khosi — July 14, 2008 @ 2:46 am

  53. what seems to be the problem? A fractional distillation at atmospheric pressure, preferably under Ar or nitrogen, through a short Vigreaux column should do it. Take the middle cut, etc.

    Comment by milkshake — July 14, 2008 @ 2:02 pm

  54. i want to solve sncl2+2H2O in water.I use HCl(5M),if i want to make less than 250cc solution, the used HCl exess from the volume i need and the PH of solution decresses to less than zero. i really don’t known what to do???

    Comment by mary — July 26, 2008 @ 4:11 am

  55. SnCl2.2H2O is freely soluble in water – but a poor-quality material that is oxidised contains Sn(IV) compounds that are insoluble (unless you add a lot of acid). You can dissolve the partly-oxidised stuff in acid but I suggest that you get hold of a new, better bottle of SnCl2.2H2O instead.

    Also, many times SnCl2 reduction is done in acidic conditions (to prevent the produced Sn(IV) stuff from precipitating) but you don’t need to use HCl – you can use acetic acid instead and work in ethanol.

    Comment by milkshake — July 27, 2008 @ 12:49 pm

  56. Hoi,

    i also have to reduce an azide to an amine but i also have a methyl protected acid in my molecule. Do you have a suggestion about the workup after SnCl2 reduction (i can’t just add NaOH cauce i don’t wont to deprotect my acid).

    thanks

    Comment by stefaan — October 8, 2008 @ 8:43 am

    • Hi all. I have solved in great extent my problems of work-up with SnCl2 reductions by centrifugating to help separate phases. Good luck!

      Comment by natysg — December 20, 2010 @ 4:53 am

  57. Stefaan, in your situation I would rather use Me3P as a reducing agent, in the presence of a small amount of water – trimethyl phosphine is much nicer than tin, and it works instantly at (or below) the room temperature.

    You can use very strongly acidic conditions to dissolve your tin crap (but your ester can be stil damaged by it). Or you can do workup with aqueous Rochelle salt (Na,K-tartrate), or with aqueous EDTA disodium salt with some added ammonia. Please try your workup first on a small scale, to see if you can get the tin stuff to dissolve.

    Comment by milkshake — October 8, 2008 @ 10:13 am

  58. Thanks for the advice milkshake.
    Anyway I did it otherwise. As I have to form an amide in the next step (and I can use acid chlorides). I just evaporate the EtOH after reduction. I redissolve the mixture in DCM and after addition of a large excess of solid NaHCO3 I ad the acid chloride dropwise.
    After reaction I filter everything over celite and purify the reaction via chromatography. The filtration goes very well, probably cause the tin crap is “coahulated” with the NaHCO3.
    Thanks anyway and keep up the good work

    Comment by stefaan — October 9, 2008 @ 9:49 am

  59. please,I have a Ar-NO2 to reduce,but there is also a NHBoc protected group..I can’t use H2 because the machine is broken..but i need to reduce as soon as possible my molecules..please help me!!I tried SnCl2 in Py/DMF,but HCl deprotect all…

    Comment by Diana — November 13, 2008 @ 3:33 pm

  60. You dont need a machine (Parr shaker) for hydrogenating aromatic nitro group – just double a normal baloon (baloon-in-baloon, so that if one ruptures there is no fire). The NO2 hydrogenation is fast even at atmospheric pressure under H2 baloon – especially when you use platinum on carbon.

    Comment by milkshake — November 13, 2008 @ 4:39 pm

  61. I’m looking to reduce an amino nitrile to an amino aldehyde, do you suppose aqueous Sn/HCl would do the job? I’ve seen a patent where they reduce amino nitriles to the aldehyde in h2o/hcl with Pd/C in high yield, and many times Pd/C reductions are in the same domain as metal+Hcl reductions. Amino nitriles can exist in solution as an Hcl salt, so perhaps they behave differently than regular nitriles with regard to aqueous dissolved metal reductions.

    Comment by Colin — January 27, 2009 @ 3:46 am

  62. You may need to protect the amino first. You can try DIBAL reduction of the protected nitrile. Please note that nitriles reduce with DIBAL at slightly higher temperatures than esters. I suggest you try DIBAL at -20C in toluene.

    Comment by milkshake — January 27, 2009 @ 4:44 pm

  63. What is a good method to work up a reaction for a nitro reduction with Sn/HCl…The strange thing is the paper stated the diamine could be filtered after basic workup with base but I dont see any solid…I am reducing 1,8-dinitronaphthalen with Sn/HCl

    Comment by Ed — December 2, 2009 @ 12:28 am

  64. Ed, you need a very large excess of NaOH or KOH to break up and dissolve all the tin crap. Count with me: for each nitro-to-amino group reduction you need theoretically 3 equivs of SnCl2 (Sn(II) goes to SnCl4). Each equiv of SnCl4 needs theoretically six equivs of NaOH to dissolve into disodium stannate… In reality you will need lot more. So I don’t know how much SnCl2 you are using but I guess its gonna end up like 50 equivs of NaOH for 1 equiv of your dinitronaphtalene, to liberate your product.

    Comment by milkshake — December 2, 2009 @ 2:33 am

    • Hmm… actually the diamine HCl salt will crystallize out of the rxn mixture. I then dissolve it in H2O and filter off any remaining Sn salts. Then i basify hopefully thinking i can get the diamine as a SOLID. In many cases after i extract and remove the solvent, I still get a sticky liquid like substance…

      Comment by Ed — December 8, 2009 @ 4:38 am

  65. Can you please give me suggestions for reduction homo coupled products during synthesis of Boronate ester by Pd (0) catalyzed reactions from aromatic iodo compounds. I am always ending up with Biphenyls when i arrempt synthesis of boronat ester by this method

    Comment by Prasad — May 21, 2010 @ 1:16 am

    • preparation of pinacolato boronate esters from aryl halide is usually done with aryl bromides, and AcOK as a base in DMSO with (pin)B-B(pin) and PdCl2(Dppf) as a catalyst. I suppose under these conditions the undesired Suzuki step is much slower than the borylation step, but the biphenyl formation still does happen, I remember always seing 10-20% of biaryl in the mix. Now with aryl iodides, the Suzuki is likely to go lot faster, so aryl iodides are probably not a very good class of substrates for this reaction.

      I think with your aryl iodide it would be probably more sensible to transmetalate the iodide to Grignard, with iBuMgCl or iPrMgCl in THF at -78 to -20C (20 min) and then trap the ayl Grignard at -78C with addition of freshly-distilled B(OMe)3

      [Also, there are some alternative to aryl halide borylation reactions, one of them uses HB(pin) as a reagent and gives supposedly better results in some cases, and then there is direct borylation of unsubstituted aromatic rings catalyzed with Ir catalyst. ]

      Comment by milkshake — May 21, 2010 @ 2:15 am

  66. Hey milkshake, this was a wicked read and DCC-in-MeCN is a much appreciated tip.

    I don’t suppose you have any experience opening oxazolones with amino acids to make dehydropeptides, do you? I feel like I’m doing something completely idiotic because whenever I use typical preps (oxazolone in acetone, AA in 1M NaOH, add AA solution slowly to oxazolone and magic ensues) I get hydrolysis instead of aminoacidolysis. Consequently, I’ve been using pretty rigorously anhydrous conditions to accomplish the same. Any insight on what I might be doing wrong?

    Thanks in advance.

    – HK

    Comment by HK — June 15, 2010 @ 8:32 pm

    • unfortunately I don’t have any experience with this particular acylation. I wonder what the role of NaOH is there – likely it only frees the NH2 of the aminoacid from its zwitterion with its carboxyl group. In theory one should need only 1 equiv of NaOH for the reaction and should avoid an excess of hydroxide. As you said there the opening reaction under anhydrous conditions would be a safer bet.

      Comment by milkshake — June 16, 2010 @ 8:56 am

      • Yeah, it’s weird… I strictly add 1 eq. of NaOH (sometimes a small excess of the amino acid), and it refuses to behave. With anhydrous conditions, I can isolate a small amount of my product but the reaction is abysmally slow. HOBt is supposed to accelerate the reaction, but it doesn’t seem to help much. Hmmm… Maybe I’ll have better luck of I use the AA-OMe instead of the carboxylate. Either way, thanks for the reply!

        – HK

        Comment by HK — June 16, 2010 @ 1:25 pm

        • If anyone’s interested, a mixture of THF/H2O/Acetone (roughly 5:1:2) with NEt3 or DIPEA works like a charm. Just make sure everything’s homogeneous and, if you see any solid crash out, add more base. I modified it from a Chinese Chem Lett, a journal I had no idea my institution had access to.

          Comment by HK — August 17, 2010 @ 4:13 pm

  67. In my suzuki reaction I have used Pd(dppf)cl2. My product and dppf-oxide(M.wt:587) are come in same Rf in TLC system 60%ETHYL ACETATE IN HEXANE. In coloumn I couldnot Isolated .It is final compound.Is there any option to Isolate it from compound. could you tell solubilty of Dppf-oxide.

    Comment by chakri — July 28, 2010 @ 4:57 am

    • you can 1) use a different system for elution, for example dichloromethane-ethyl acetate or run a separation on a prep HPLC 2) replace the catalyst with PdCl2(PPh3)2

      Comment by milkshake — July 28, 2010 @ 7:54 am

  68. how to prepare 4N-HCl in dioxane

    Comment by sunny — October 11, 2010 @ 10:07 am

    • The best is to buy it. If you cannot buy it you bubble anhydrous HCl gas into anhydrous dioxane with cooling on ambient water bath. You make a mark on the flask that indicates known volume, for example 100mL, put little less than 100mL of dioxane there, with a stirbar and septa. Weight the flask with dioxane, septa and all, then bubble HCl with cooling until you get the desired weight increase (in this case the weight of 400mmol of HCl). Then fill up the flask with some additional anh dioxane to the mark.

      Alternatively you can saturate dioxane as much as it takes, this will produce about 5-6M solution, then you measure acidity of the sample of known volume by simply diluting it with water and doing a titration with 0.100 M NaOH.

      4M HCl in dioxane has to be anhydrous. Store it in a tight bottle, preferably one with teflon-lined cap. HCl is very corrosive. For long-term storage it is probably better to keep it in a fridge (dioxane-HCl does not freeze in fridge, unlike pure dioxane).

      Comment by milkshake — October 11, 2010 @ 10:49 am

  69. […] pure (and beautiful spectra to match). I stumbled upon an old but interesting pair of posts (one from Org. Prep. Daily the other from In the Pipeline. Both discuss “lousy reactions” or […]

    Pingback by Difluorocarbene: We’re bringing it back « New Reactions — June 19, 2011 @ 11:52 am

  70. do you know how to prepare 4M HCl solution in dioxane? thanks a bunch. you are great?

    Comment by valentina bumbu — October 7, 2011 @ 1:59 am

    • you need to start with anhydrous dioxane and saturate it with anhydrous HCl gas in a hood while protecting it from the moisture. Since the HCl absorption is quite exothermic, you want to cool your dioxane flask with water (and later on you can add some ice to the bath – but not at the beginning because pure dioxane freezes easily). You store the prepared 4M solution in a bottle with well-sealing corrosion-resistant cap (polyethylene cap lined with teflon), preferably parafilmed. Since HCl is so corrosive you want to use a HCl gas inlet in the flask made either of glass or some insoluble plastic (teflon, polyethylene)

      Saturation point of dry dioxane with HCl gas is slightly above 4M, which is the concentration typically used in chemistry for cleaving acid-sensitive groups. If you want to have a precise concentration, you need to use a volumetric flask or a regular flask level-marked at the desired exact volume (for example 500mL). You fill it with dioxane only partially , leave some empty space (maybe 20%), weight the flask with dioxane, saturate and occasionally weight the flask to measure weight gain. Once you have all the HCl absorbed that you want (for example 2 mols of HCl) by weight, you fill up the volume with more dioxane to the mark

      Comment by milkshake — October 7, 2011 @ 11:40 am

  71. Any tips on how to remove boronic esters from reaction mixtures where the product is a liquid bi-aryl ketone?

    Comment by Frustrated — October 16, 2013 @ 11:43 pm

    • I would try aqueous wash with acidified (pH=1) 10% solution of fructose. Diluting store-bought high fructose corn syrup should work too. Galactose, lactose, sucrose should also work but I was reading somewhere that complexation of boronic acids with polyols is strongest in case of fructose/

      An alternative of this would be using sodium perborate solution to oxidize the boronic acid to a phenol, and try to separate it by extraction with NaOH

      Comment by milkshake — October 17, 2013 @ 6:02 pm

  72. Here is a tricky one for you! So I am using triethylamine as a base in an aqueous acetylation of a sugar. The reaction works, but the snag is that I can’t then remove the triethylamine hydrochloride and therefore can’t purify my product. The reaction is in water. The product is water soluble. I have tried swapping out triethylamine for tributylamine which is less soluble, but the reaction didn’t work, probably because it wasn’t soluble enough… I have also tried using inorganic bases with no luck, either the reaction doesn’t go, or it hydrolyses on vaccing down at the end of the reaction. Any help would be really great! What I want is a tertiary amine, that when you make the hydrochloride salt is organic soluble. I know one solution is to use a polymer supported base, but I’d rather find another way around the issue if possible.

    Thanks! You write a great blog!

    Comment by Andrew Watson — March 10, 2014 @ 9:55 pm

    • if you are running acetylation in water I presume you are using acetic anhydride, in which case the salt you get is triethylamine acetate…

      You may want to use a slurry of a bicarbonate salt of a quaternary ammonium ion exchanger, such as Amberlyst, either directly as a base or in the form of a column, for final de-salting. You can get bicarbonate salt by taking hydrochloride salt of Amberlyst of the formula Polystyrene-NMe3(+)Cl(-) and slurrying it in hot water, then washing with 5% NaHCO3 and finally with lots of deionized water until neutral reaction of eluates on pH paper.

      Evaporate water from your aqueous reaction mixture by lyophilization – becaus eevaporating water on rotovap is fairly harsh unless you have a very good pump and rotovap. Adjust the pH of your mix prior lyophilzation to pH below 8.5 and you should be fine.

      Comment by milkshake — March 17, 2014 @ 12:19 pm

  73. Any more information regarding the allylic oxidation with SeO2? What made you try tetrazole as an additive? Would triazole (1,2,3- or 1,2,4-) also work? In terms of working up the reaction what advice can you provide? So far I’ve seen significant selenium being carried over (the next step is a LiAlH4 reduction where red solids crash out). Perhaps reduction with SO2 could be effective prior to filtration through celite? Even easier would be metabisulfite addition, if that still reduces SeO2 to Se (and it’d quench the excess TBHP too…)

    Cheers in advance.

    Comment by Anon — June 25, 2014 @ 12:03 pm

    • If I remember correctly, the original procedure for catalytic SeO2 / tBuOOH oxidation from Sharpless group used salicylic acid as a co-catalyst, and when I was playing with the reaction (oxidation of geranyl acetate, it goes selectively to the prenyl group and only the methyl group that is trans gets oxidized) I noticed that salicylic acid got gradually lost during the course of the reaction, turned into some dark stuff. Also, with the original system a trace of moisture (up to about 1 mol%) had mildly accelerating effect but past that moisture was actually inhibiting the reaction. These results suggested that salicylic acid and water maybe acted as a nucleophile forming some sort of soluble adduct (SeO2 is polymeric in structure and poorly soluble) that was actually the active catalyst form. I worked with tetrazole previously, on unrelated project, and knew it is a mild acid, and the tetrazolato anion is a supernucleophile, and it is perfectly stable to oxidizing conditions, so I gave it a try as a surrogate of salicylic acid. In my hands, with tetrazole as a co-catalyst, the reaction was faster and there was no water-related acceleration. There could be water-related inhibition at the end though, when water produced during the oxidation accumulates…

      I think the reaction is best done with 4-5 equivalents of tBuOOH (anhydrous) in dichloromethane or dichloroethane, at 40C, with 5mol% of SeO2 and few % of tetrazole, overnight. You can later add some 3A or 4A activated sieves to the reaction mix, if the reaction stalls at partial conversion due to water formation. I think the workup was to dilute the reaction with ethanol, cool, add NaBH4 solid, then when the reduction was complete by TLC, acidify, evaporate to dryness, followed by aqueous workup. The reason for reductive workup is that the allylic oxidation typically produces a mixture of the overoxidized aldehyde (or ketone) in mixture with the allylic alcohol, but it is not easy to push it all the way to carbonyl compound. So usually the mix is reduced with borohydride to turn it into uniform product. Selenium is typically removed at this workup stage (it gets reduced to H2Se, exposure to air promptly turns it into red selenium)

      Comment by milkshake — June 25, 2014 @ 1:40 pm

      • Cheers for that. I also observe a mixture of allylic alcohol and unsaturated aldehyde as product, with the former being desired. How was the regioselectivity of the borohydride reduction? I was using lithal on the premise that it’s a harder nucleophile and will give almost exclusively the 1,2-reduction.

        Comment by Anon — June 26, 2014 @ 2:09 am

        • I think Na-borohydride is fairly safe with regards to the possible conjugate C=C reduction. But if you encounter any 1,4-reduction problem, you can do the Luche variant of NaBH4 reduction, by adding first an equivalent of CeCl3.7H2O (in ethanol or water-ethanol mix) before adding NaBH4. CeCl3 heptahydrate has large molecular weight (373) but it is fairly cheap, and does not complicate the workup

          Comment by milkshake — June 26, 2014 @ 12:05 pm

  74. I had considered a Luche reduction but opted for Lithal because its easier (/I’m lazy?). I’m unable to find tetrazole at the usual suppliers though (only as dil. solution in acetonitrile). Where did you find yours?

    Comment by Anon — June 30, 2014 @ 3:52 am

    • at that time (around 1998) tetrazole was available as a solid and the prices were reasonable, but since then the shipping DOT regulation changed (this affected whole bunch of previously commonly available endothermic compounds – Diazald, DEAD, picric acid, etc.) so in US it is now easy to buy only the overpriced tetrazole in acetonitrile solution, for nucleic acid synthesis. There are about 90 suppliers listed in Scifinder (CAS# 288-94-8) of tetrazole, so you may want to search them, to see if someone has better prices, and supplies it as solid, but it would be easiest just to buy the acetonitrile solution and use it as is. (You need only a tiny quantity of tetrazole, acetonitrile should not interfere in the oxidation,etc.) Or you can go with the original procedure that used salicylic acid as a co-catalyst

      Comment by milkshake — June 30, 2014 @ 10:22 am


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