Sodium borohydride/iodine reduction

Lately I’ve been doing quite a few asymmetric Michael additions using a chiral oxazolidinone, or one of the thio variants, as a chiral auxiliary. Some of the auxiliaries are commercially available but far too expensive for my taste. They can be easily synthesized from amino alcohols which are also commercially available but they too cost more then I’m willing to pay. So, the only option is to make them myself, which is not that bad a choice considering that the corresponding amino acids are not that expensive, especially the L ones. The D ones can be quite pricey. This is how the auxiliaries look like:

Chiral auxiliaries

There are many ways to reduce amino acids to amino alcohols but my favourite by far is sodium borohydride/iodine combination (.pdf), which is not only non-expensive alternative but also convenient compared to, for example, lithium aluminum hydride (see, I don’t like burning labs). Below is how it looks like chemically written:

sodium borohydride / iodine reduction

So, what is actually happening there? This is how I understand it:

Reaction of sodium borohydride with iodine

First, iodine is reacting with one sodium borohydride, so you get borane, sodium iodide, and hydrogen iodide. Then hydrogen iodide is reacting with another sodium borohydride, so you get another borane and another sodium iodide, plus some hydrogen. All that borane is actually the stuff that reduces the acid to alcohol. Very nice and convenient. I’ve been doing it in 200 mmol scale and works just great, giving the amino alcohol in good >70% yield after recrystallization from toluene.

That’s it for today. Feel free to stop by again and comment if you like.

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47 Comments on “Sodium borohydride/iodine reduction”

  1. Milo Says:

    Not only is this a great route from a cost and safety perspective, but the workup is much easier, no nasty salts to monkey with, like in LiAlH4 reactions.

  2. sks Says:

    I guess Ralph Salvatore has been using similar conditions, methyl iodide instead of iodine. He uses it on heterocycles. In a rather colourful garish slide show replete with mistakes, he gave a very good talk about the reduction of various heterocycles, i wonder if it would work under the current situation.

  3. Gaussling Says:

    I LOVE this reaction. The I2 oxidizes hydride giving a mole of H2 and generating BH3 in situ. I have reduced a lot of amino acids to the amino alcohol with this process. I fell into this reaction years ago after I had an LAH reduction of valine in THF go sideways on me, blowing the apparatus apart and splashing me with the reaction mixture. I tried warming the reaction with a warm water bath too soon and ended up paying for my impatience. I recall the taste and the sensation of H2 bubbling from my lips. Yikes. I did get in the habit of quenching LAH mixtures with powdered Na2SO4-10 H2O. Add xs hydrate and stir for 4 hrs or until the slurry is snow white. No fireworks and no silly Fieser workup to do. Filter, strip, and go have a beer.

  4. JR Says:

    Very nice protocol, and it brings up a point which I have wondered about for a while. Whenever I’ve used BH3/THF in the past, my product would always have residual THF signals in the NMR which were very difficult to purify away. Has anyone else come across this, and know what it is due to? I just moved on to a different reducing agent but this seems like a convenient method of producing BH3 in situ.

  5. milkshake Says:

    I think the active reagent is iodoborane actually, IBH2.

    There is a nice alternative using a solution of 96%H2SO4 in THF dropwise added into a slurry od aminoacid and NaBH4 in THF at 0C. Worked very nicely for me with tert-leucine.

    JR: are you sure it was THF signals and not butanediol? THF/Borane slowly goes bad because of a ring-opening reaction – although I don’t know how would this would produce butane1,4-diol in absence of a peroxide workup.

  6. JR Says:

    That would certainly explain the tenacity of the impurity…

  7. cru jones Says:

    milkshake… can you elaborate a little more on that prep? is exactly as the I2 prep, but with 96% H2SO4? the reason i ask is because i will be doing a t-leucine reduction here soon and would like to try this! thanks.

  8. milkshake Says:

    I don’t have the procedure with me anymore but if I remember it correctly (after nine years) it was as follows: tert-leucine+several molar eqivivalents of NaBH4 was suspended in THF, cooled on ice bath, an excess of 96% H2SO4 dissolved in THF (with cooling on water bath) was then very slowly added dropwise (using an addition funnel) to the borohydride-tert-leucine slurry over 1 hour with intense stirring on ice (gas evolution), the mixture was then stirred at RT overnight, pH adjusted with NaOH to about 10-11 and some saturated NaCl was added, the mixture was extracted several times with dichloromethane (the tert-leucinol is quite water-soluble). I think I took the crude tert-leucinol directly to the next step.

  9. anilpatel Says:

    i want to chloro to iodo reation cl is remove and iodine is attach which type of catlyst use with sodium iodide

  10. Panoramix Says:

    I had bad experiences with I2/NaBH4. 3,5-Dimethoxybenzoic acid was quantitatively destroyed, neither acid nor alcohol were recovered, the same thing happened with a substituted 4,6-Dihydroxy-2-pentyl-benzoic acid.

    For reduction of beta-amino acids Zn(BH4)2 works great, >70%.

  11. Lee Says:

    If borane is actual reductant, why not use borane directly? Is it more expensive?

  12. Samantha Wimala Says:

    Actually, sodium borohydride and sulfuric acid works as well, if you’re not a fan of iodine.

  13. java Says:

    I found that by first making the ethyl ester from the amino acid and refluxing it in 50% ethanol/water for 4.5.hours using 4 equiv of Nabh4 with yields 81% to be best since it doesn’t require any I2 or THF

  14. Lowprofile Says:

    Hi @all,
    nice write-ups, could anyone tell about the work-upo procedure a little bit of the Bh3*THF?
    I would filter the salts of NaI and then simply strip off the solvent and do an acid base.
    Does one need to boil the mixture after strippig the solvent?

  15. pmgb Says:

    I did the same like java-reduction of ethyl esters to alcohols using NaBH4 alone (in ethanol)…

  16. Sachin M.S; Ph.D Says:

    The THF traces in the reaction mixture can be easily removed by taking product in organic solvent and giving it a water wash. The organics is then dried over anhydrous sodium sulphate and evaporated, dried further over vaccum for about half an hour under warm heating. This is rally a good way of doing this reaction…one naother option is use BH3/DCM as an alternate of BH3/THF(dry).
    Thanks & Regards,

  17. tulasi Says:

    Dear sir,
    I tried reduction 0f Phenyl alanine with NaBH4(1.0 eq) in THF and H2So4(1.25eq) in ether,but i didnt get the product,and also i t is difficult to check tlc after fomation of BH3 comlex.

  18. Peter Piper Says:

    But how does one reduce an amino alcohol, to an amine?
    Any refs would be great!

  19. Roger Says:

    You would react the alcohol with thionyl chloride (SOCl2), or PBr3 to create the alkyl halide (R-X). The X (Halogen; Cl or Br)is then replaced using any number of hydrogenation methods (LAH, H2& Ni, H2 & Pb).

    My question is simple; Has anyone any information on any CNS effects of the compound given above as an example (the reduction product of phenylalanine – referred to as phenylalinol, or alpha-methoxy phenylethylamine?)

    • java2 Says:

      “you would react the alcohol with thionyl chloride (SOCl2), or PBr3 to create the alkyl halide (R-X). The X (Halogen; Cl or Br)is then replaced using any number of hydrogenation methods (LAH, H2& Ni, H2 & Pb).

      My question is simple; Has anyone any information on any CNS effects of the compound given above as an example (the reduction product of phenylalanine – referred to as phenylalinol, or alpha-methoxy phenylethylamine?)”

      ….How about using NaBH4 /NiCl since the catalyst would be the NiCl and NaBH4 would generate the Hydrogen, also,

      “Transitional metal compound mediated reductio of alpha -amino acids to 1,2-amino alcohols with nabh4 in water”
      ….Turk. J. Chem, 1999, 23, 123-126

      The above study is much better without having to first synthesise the ester as in the study…

      “Studies of opticall active amino acids synthesis of optically active alpha-aminoalcohols by the reduction of alpha-amino acids esters by sodium borohydride”

      …Chem. Pharm. Bull. 1965, 13,(8), 995-1000

      …..and so I wonder if NaBH4 /NiCl would dehalogenate the now halogenated former primary aliphatic alcohol …….any comments with some references please….java

  20. Akash Says:

    I am trying to reduce an pyrimidin ester / pyrimidin acid but no common reducing agent works well, always getting over reducing product, is there any one who did reduction of ester of acid having pyrimidin moiety??

  21. Leda Says:

    Hello, I’m trying to reduce an nitrile ( phenoxyacetonitrile moiety) in the presence of pyrimidine group.Moreover i have problems with the solubility of the compound…in diethyl ether it is not soluble, in THF: 50mg in 5ml…I tried the reduction LAH/THF but it didn’t give me good result. :(.Do you have any idea for a reducing nitrile agent in the presence of pyrimidine moiety? The nitrile group is very reactive and in the in case of pyridine derivatives the nitrile group reacts with LiAlH4 a 0°C in only 10 minutes? Is the problem the pyrimidine or the solubility of the compound…Thank you very much.

  22. virendra tiwari Says:

    this reaction is very helpful

  23. Akash Says:

    u can try LiBH4

  24. anu Says:

    how can we reduce nitrile group follwing same approach

  25. anu Says:

    plz do imform if method available

  26. Aditya Bhattacharyya Says:

    Can anyone suggest how to reduce cyclic imines?

  27. kirandep kaur Says:

    please tell the mechanism when reduction of imine by sodium borohydride in ethanol with few drops of sodium hydroxide. what is the purpose of sodium hydroxide.

  28. kirandep kaur Says:

    please tell the mechanism when reduction of imine by sodium borohydride in ethanol with few drops of sodium hydroxide. what is the purpose of sodium hydroxide

  29. Paul F Says:

    Has anyone tried reduction of tryptophan? I’ve done several methods including borane in situ from iodine/sodium borohydride and sulphuric acid in ether/sodium borohydride in THF. Both produced little yields.

  30. Santosh Pagire Says:

    Tryptophan is the only amino acid having indole side chain so this ring always cause steric hindrance to the hydride nucleophile, better to try BH3-DMS (May be work well)

  31. ravikumar.r Says:

    hellow sir cyno to amine can i do in sodium borohydred/ sulphric acid?

  32. Dave Says:

    I personally disagree with the idea that I2 + NaBH4 gives BH3. The original paper states that refluxing a boc amine in NaBH4/I2 does not reduce the boc, which would definately get reduced by BH3 under reflux in THF

  33. Curtis Says:

    In non-coordinating solvents like heptane, it’s pretty clear that I2 and MBH4 (M = Li, Na, K) react to give borane and mixed iodoboranes. The reaction has been investigated as a way to make boron triiodide. To complete the reduction of iodine, ~10 equiv. KBH4 need to be used. Some of this doesn’t react, but when the effluent gasses of the reaction are passed through water, boric acid is among the hydrolysis products.

    Briggs, A. G.; Simmons, R. E. Naturwissenschaften 1990, 77, 595–597.


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  35. DNG Says:

    it is very good concept.

  36. Milk Says:

    I try to find this method, so can you give me the experimental flow chart for reducing amino acid, such as glycine, methionine etc.
    I had read this from many journals but I still not cleared in the experimental method.

    Thanks in advance.

  37. Giuseppina Cheroki Says:

    Phenylalanine is necessary for the neurotransmitter production in our brain. It also helps with anxiety and depression by synthesizing serotonin which calms the mind and makes us feel good. .”;*.

    With appreciation
    http://www.healthmedicinelab.com/symptoms-of-mono/


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