[Dan]

Apologies for being cagey with details... you know how it is.

I am trying to oxidise a primary alcohol to an aldehyde. The substrate is an advanced and delicate synthetic intermediate, which is very sensitive to acid (unstable in the presence of carboxylic acids) and quite sensitive to base (e.g. unwanted base-catalysed reactions with TBAF, but can can be suppressed with careful temperature control).

I have run a few reactions with Dess-Martin periodinane (DMP) in DCM, and while they do basically work, the yields are moderate(~60%) due to an acid-promoted side reaction. Given that DMP oxidations generate AcOH as a stoichiometric byproduct, I have been looking at adding an external base to keep it in check.

Today I tried K₂CO₃(S) as a buffering agent. This did suppress the unwanted acid-catalysed reaction, but the carbonate is clearly reacting with the DMP - I see copious precipitate (perhaps IBX?) and the reaction rate much slower than usual. Conversion did eventually reach ~90%, at which point I processed the mixture and obtained the desired aldehyde in 60% yield, the remaining mass balance being composed of a complex and as yet unidentified mixture.

I wonder if this buffering strategy is really compatible with DMP or whether I am wasting my time. If anyone has any insight or suggestions, I would be interested to know. I will probably have a look at TEMPO and TPAP systems and maybe Swern as well.

[TheUnassuming]

I've had good luck with sodium bicarbonate (3-4 equiv.) as an additive to take care of the acid.  Never tried K2CO3, but if your compound is base sensitive could that be the source of some of your problems?

I like the Swern oxidation even if its not a quick/easy as the DMP oxidation... then there is also the DMS smell that always seems to escape the hood .

[phth]

TPAP is the mildest to both sides of A/B protecting groups.  DMP is pretty damn sensitive.  Putting it in acetonitrile will kill the activity towards oxidation of alcohols up to 8 eq reported.  Those authors suggested that the best result they found was 8:1:1 DCM:MeCN:H₂O.  These authors did some work on its activity in different systems, even if it's not a similar substrate I think it can make things more clear: http://pubs.acs.org/doi/abs/10.1021/ol027518n

[Babcock_Hall]

I made my contribution to the field of organic synthesis by leaving it.  I am guessing that pyridine is not compatible with your compound.  What about using a hindered base, such as potassium dimethylpropanoate?

[Dan]

I've had good luck with sodium bicarbonate (3-4 equiv.) as an additive to take care of the acid.

Good to know. I was originally going to do that but went with pot carb instead - a bad call I suppose. Bicarb was next on the list.

I am guessing that pyridine is not compatible with your compound.  What about using a hindered base, such as potassium dimethylpropanoate?

Pyridine or PivOK would probably be fine, but I think their conjugate acids will be too acidic

[Babcock_Hall]

Here is where I got the idea for pyridine:  "It is possible to perform an oxidation with Dess-Martin periodinane under almost neutral conditions by adding pyridine to the reaction flask in order to neutralize the acetic acid, which is generated during the oxidation, and performing the work-up by treatment with sodium thiosulfate in the presence of a sodium bicarbonate buffer.²"  http://download.springer.com/static/pdf/224/chp%253A10.1007%252F0-387-25725-X_3.pdf?auth66=1426287711_2c86059ca0bd69183c595fe91f536bcf&ext=.pdf  "Chapter 3: Hypervalent Iodine Compounds"

2,6-Lutidine is more basic than pyridine, and it has been used in Dess Martin reactions (26 Reiser, U.; Jauch, J.; Herdtweck, E.; Tetrahedron: Asymmetry 2000, 11, 3345).  I am used to thinking of buffers in the context of aqueous, as opposed to non aqueous, solutions.  An excess of base in the presence of acetic acid might generate a kind of buffer, I suppose.  It looks as if bicarbonate is frequently used.

[Dan]

http://download.springer.com/static/pdf/224/chp%253A10.1007%252F0-387-25725-X_3.pdf?auth66=1426287711_2c86059ca0bd69183c595fe91f536bcf&ext=.pdf  "Chapter 3: Hypervalent Iodine Compounds"

Thanks for the follow up. The link doesn't work for me, can you post the doi or citation and so I can find it?

[Babcock_Hall]

The link is not working for me, either, and even when it was, there was no information given as to what I was looking at, other than that it was apparently Chapter 3 of some book.  I am not 100% certain, but it may have been a chapter in this book:  Hypervalent Iodine Chemistry: Preparation, Structure, and Synthetic Applications of Polyvalent Iodine Compounds, Viktor V. Zhdankin, ISBN: 978-1-118-34103-2, December 2013.  However, the link says Springer, not Wiley.  It might also be this book:  ISBN 978-3-540-46114-2

Here are some papers where they apparently used bicarbonate:  a) Gonza ́lez, I. C.; Forsyth, C. J.; J.Am.Chem.Soc. 2000, 122, 9099. (b) Nicolaou, K. C.; Snyder, S. A.; Simonsen, K. B.; Koumbis, A. E.; Angew. Chem. Int. Ed. 2000, 39, 3473. (c) Harris, J. M.; O’Doherty, G. A.; Tetrahedron 2001, 57, 5161. (d) Trost, B. M.; Gunzner, J. L.;
Dirat, O.; Rhee, Y. H.; J. Am. Chem. Soc. 2000, 124, 10396

[Dan]

I've had good luck with sodium bicarbonate (3-4 equiv.) as an additive to take care of the acid.

Forgot to post a follow up: This worked very well for me too. Using 4 equiv of bicarb relative to DMP, the side product is suppressed to ~2% and the isolated yield is consistently 85-90%.

[TheUnassuming]

Great news!

I don't know what it is about sodium bicarb, but straight carbonate or swapping the metal seems to not work as well.

[qazwsxedc]

Hey,
Useful topic, guys. I have a very quick question about DMP so I don't want to create a new topic just for it.
I was trying to dissolve DMP at 15 wt% in dichloromethane (0.4g to 2mL CH2Cl2) but it doesn't seem to work well, I still see a lot of undissolved DMP after sonication for 30 minutes. Are there any tricks to solubilise it?

[pgk]

1). If you draw up the mechanism of the Dess–Martin oxidation, will see that 1 mole of acetic acid is generated per 1 mole of alcohol. Thus, buffering is absolutely necessary, if your intermediate is sensitive to carboxylic acids
2). Buffering by NaHCO3 is preferred as being a milder base than K2CO3, but quite effective.
3). However, carbonate and bicarbonate salts are thickening agents to chlorinated solvents (DCM is dichloromethane, right?) and therefore, they affect the reaction time by increasing the viscosity of the reaction medium. In other words, you need a longer reaction time and a higher dilution. The best is to add the adequate amount of NaHCO3, according stoichiometry (and a little excess).
4). In addition, concentrated carbonate and bicarbonate suspensions might salt the DCM:MeCN:H2O  solvent system and cause separation of the aqueous phase. Besides, carbonate and bicarbonate suspensions in chlorinated solvents, form strong emulsions in presence of water and might affect the reaction time and the expected yield. Thus, a higher dilution and addition of only the adequate amount of NaHCO3 might be necessary, in this case, too.
5). What about Bu4N+, HSO4- or (Bu4N+)2, SO4 2-, as phase transfer catalysts?

[Dan]

Hey,
Useful topic, guys. I have a very quick question about DMP so I don't want to create a new topic just for it.
I was trying to dissolve DMP at 15 wt% in dichloromethane (0.4g to 2mL CH2Cl2) but it doesn't seem to work well, I still see a lot of undissolved DMP after sonication for 30 minutes. Are there any tricks to solubilise it?

Pure DMP us DCM soluble, but the reagent is very sensitive to hydrolysis. The products of hydrolysis by atmospheric moisture and/or water in the solvent will form I(V) compounds with low DCM solubility. The good news is that these partially hydrolysed I(V) are active oxidising agents. In fact there are studies that show they are the active oxidants, and pure DMP has much lower activity in strictly anhydrous conditions. I don't have the papers to hand, sorry, but it should be easy to find them. Run your reaction with the suspension of "DMP", it will probably work.