[pianoteam]

Hi everyone,

This is my first time posting here and I wanted to kindly ask for some advice on getting an oxidation reaction to work. The substrate is very simple (5-hexen-1-ol) but it has plagued me with countless difficulties. I am trying to synthesize an aldehyde from this alcohol and have tried using PCC, the Swern oxidation and DMP. This substrate has been used with all these reagents successfully in the literature although I am having a hard time pinpoint my problem. The Swern oxidation seems to give me either the thioacetal side product or carboxylic acid and I am not interested in pursuing this further because of the difficulty in set-up and bad smell. PCC and DMP I got to work before with dilute conditions (0.1 M) but with low yield (<25 %) although I could not purify the crude product as it seemed to degrade/autoxidize in a day or two (even under vacuum or N2) so I plan to use the crude product in my following reaction. I have decided to stick with DMP just because with PCC it is challenging to remove all of the chromium salts. Unfortunately with DMP I am still seeing the carboxylic acid as the major product (lately less than 10 % yield) and am quite perplexed as I use anhydrous DCM as well as an oven dried flask/stir bar and perform the reaction under an inert nitrogen atmosphere. Also the DMP was purchased about a month ago and I am the only one using it. The conditions I use are 1.2 eq DMP and 1 eq alocohol (0.1 M solution in DCM). Does anyone know where I could be going wrong with this? It is very frustrating as this should be a simple reaction to carry out yet it is giving me a very difficult time. My supervisor suggested converting this substrate to the methyl ester and using DIBAL to generate the aldehyde - would this be a better route despite having more steps?

[Babcock_Hall]

I am not a synthetic specialist, but what about the Dess-Martin oxidation?

[rolnor]

That is the DMP described.

[sjb]

I don't know if it's of any consequence, but from memory 4-methylpent-4-enal is quite volatile?

[kriggy]

I had some experience with oxidation of alcohols to aldehyde using MnO2. Either in toluene or neat, just mix your alcohol with excess of MnO2, heat it to boiling point and its done. Then extract with organic solvent.
You can also try MnO2 on carbon which is prepared by mixing KMnO4 with activated charcoal (there is a lit procedure for that).

Also, if your aldehyde is being over oxidized, you can do it in acetic anhydride and your product with then be isolated as acylal. I think I saw a procedure using CrO3 + Ac2O.

If your oxidation work but you are losing product on workup, we purified some aldehyde by reaction with sodium bisulfite. The adduct was highly crystaline and did precipitate out of the solution as nice crystals

[pianoteam]

Thanks for everyone's feedback so far. DMP is Dess-Martin periodinane for those who don't know. With regard to being volatile, the boiling point is roughly 128 °C so I do not think it is being lost during rotovaping. In fact, I use a low temperature to rotovap since I find that heating causes it to overoxidize (autoxidation). I do not recover very much of the product from the reaction (only at most 25-50 mg out of 200 mg) and it is not in the aqueous layer during extraction although the acid is present. I have been running my oxidation reactions overnight since they seemed to take longer at 0.1 M but somebody in my lab suggested monitoring every half hour since it may not be stable for longer periods of time. Most people in the literature seem to do the reaction for 3-4 hours and use it crude (though mostly pure since the DMP gets hydrolyzed in the basic work-up) so I will likely do the same since I do not think this compound is very stable over time. I have also noticed that other aliphatic aldehydes are often sold in their acetal form since they can be prone to oligomerization or degradation/over-oxidation.

[clarkstill]

I don't have any difficulty believing that the aldehyde is unstable - Stuart Warren once described aldehydes as "barely on the verge of existence"... so yeah, make it and use it.

Since you're not getting mass-balance out of your reactions there must be an issue with the work up - maybe hemiacetal formation which then sits in the aqueous layer? How do the reactions look by TLC prior to the addition of anything aqueous? Can you just pass the reaction mixture over a plug of silica or something, rather than doing an aqueous workup?

I think MnO2 only works for allylic/benzylic alcohols, although maybe MnO2 on carbon is different.

Other oxidations to try: TPAP, TEMPO/BAIB or TEMPO/bleach, PDC (should be milder than PCC), Oppenauer.

Good luck!

[rolnor]

What is the nest step in your reaction scheme? Maby you can avoid the tricky aldehyde-step or use it without purification?

[pianoteam]

The TLC is always clean - if the reaction goes better I see an intense band around the middle corresponding to the aldehyde. I always see the iodo species on the baseline and likely the carboxylic acid is present here too if it is ever formed. I could definitely try passing the reaction mixture through a pad of silica although I don't think the aqueous work-up is the problem and I have never observed hemiacetal/diol formation in the aqueous layer or elsewhere. I think the issue is letting the reaction run for too long so I will monitor my next attempt very closely. There are many DMP oxidations of this compound in the literature and most take 3-4 hours with 50%+ yields so I think I can resolve the issue. On another note, DMP should be quite stable in bottle I believe? I have it stored in a -20 °C freezer currently.

I don't have any difficulty believing that the aldehyde is unstable - Stuart Warren once described aldehydes as "barely on the verge of existence"... so yeah, make it and use it.

Since you're not getting mass-balance out of your reactions there must be an issue with the work up - maybe hemiacetal formation which then sits in the aqueous layer? How do the reactions look by TLC prior to the addition of anything aqueous? Can you just pass the reaction mixture over a plug of silica or something, rather than doing an aqueous workup?

I think MnO2 only works for allylic/benzylic alcohols, although maybe MnO2 on carbon is different.

Other oxidations to try: TPAP, TEMPO/BAIB or TEMPO/bleach, PDC (should be milder than PCC), Oppenauer.

Good luck!

[pianoteam]

I will probably avoid doing a column however I need to do some kind of work-up to remove the iodo species. The next reaction is a condensation reaction that forms a phosphonate Michael acceptor under thermodynamic conditions.

What is the nest step in your reaction scheme? Maby you can avoid the tricky aldehyde-step or use it without purification?

[wildfyr]

I like the bisulfite adduct trick. It should stabilize your aldehyde and make it easier to separate from the muck.

That compound should be very bench stable, then you can convert it back right before use.

[rolnor]

Is the next step a Wittig-reaction? Then you could make it one-pot or?

[pianoteam]

It is not a Wittig, it is a condensation analogous to enone formation with two carbonyls but a phosphonate is used in place of one.

[rolnor]

So its more a Knoevenagel-reaction? It could be possible to do it one-pot. The enone is more stable and has higher boiling-point so isolation is easier. What base are you using for the condensation?

[pianoteam]

It is exactly like that reaction but the starting marterial is a bisphosphonate, tetraethyl methylene diphosphonate. In addition, the bisphosphonate moiety is maintained rather than cleaved as in the decarboxylation event in the Knoevengal reaction. The reaction conditions use N-methyl moropholine as a base (added dropwise over an hour) and TiCl4 as a Lewis acid catalyst. The solvent is CCl4 but the base is dissolved in THF and added to the flask. I can provide a reference if interested.