[ronholes7059]

Hi all,
I am trying to carry out the reaction below, I am new to this so I hope it comes out okay, I am having trouble pasting the image. If not I will try again but here is my question

     

I am starting with 3-chloro-1,2-propanediol commercially available from Sigma, and reacting with sodium azide in water under reflux to get 3-azido-1,2-propanediol. I am pretty confident I was able to get this reaction to work, based on some TLC staining for azides, although I think I need to let the reaction go longer, but that is not the point. 

For the second step I am treating 3-azido-1,2-propanediol with 2 molar equivalents of 0.3 M DMP in CH₂Cl₂(from sigma) and reacting at RT for a few hours.  When I do this I see a shift in Rf on the TLC that has a positive stain for azides so I think I might be getting the product, but when I stain for carbonyls I do not see the spot (although I think the carbonyl stain may not be as sensitive as the azide stain).  However, my main issue is that during the reaction workup I get a large amount of precipitate that forms, and gets more as the reaction goes on, which I am thinking is perhaps the used up DMP that is precipitating out of solution?

I have tried the reaction with 3-chloro-1,2-propanediol and DMP as well, under the same conditions just to see if I see the same effect and if I can get the oxidation to work, but again I see the precipitate form as the reaction progresses. 

Any ideas on what the precipitate could be or has anyone had a similar experience?  If it is the reacted DMP precipitating out, I guess I can extract it with an aqueous buffer or water??

Thanks

[Guitarmaniac86]

I always had trouble with DMP. I found using 3 equivs and adding water helped the reaction. Take a look at this ref: Meyer, S.D; Schreiberm S.L. J Org Chem, 1994, 59, page 7549

You stated you are using 2 molar equivs. Up it to 4 equivs. I found for a single -OH I had to use between 2 - 2.5 equiv per -OH group. So increase the number of molar equivalents first before you go to the paper ref with water.

Edit:

I have never experienced a precipitate but have you taken an NMR of it or isolated it to see what it could be? Also, what is your work up procedure?

[ronholes7059]

So I have very little experience with oxidations, but my concern is that I do not want to over-oxidize the aldehyle to a carboxylic acid. I know wit other oxidizing agents this can occur, not sure with DMP but I know it prefers the alcohol to the carbonyl so that is why I am trying to not add too much.  For the same reason I would prefer to leave water out of the reaction. 

I have not gotten a chance to analyze the precipitate, we don't have NMR here (Cedars-Sinai) but I am working on getting access at UCLA.  I tried an extraction of the preipicate with ethyl acetate and water, keeping the organic layer and it cleaned it up, but putting the ethyl acetate layer in the cold room overnight cause some precipitate to form. 

Here is my workup, I have only done it once so far:

Step 1: 3-Chloro-1,2-propanediol in water treated with slight excess of sodium azide. React under reflux for 3 hrs (I think this needs to go slightly longer, I am basing this on a previous publication by Namba et al, J. Am. Chem. Soc. 2011, 133, 11466–11469.  I then extracted the product with ethyl acetate, and dried in speedvac, no further isolation

Step 2: 3-azido-1,2-propanediol (product from step 1) treated with 2 molar equivalents of DMP in CH2Cl2 and reacted for 3 hrs at RT. Added ethyl acetate to the reaction and then Extracted eith water, sat. sodium carbonate, then sat. NaCl. keeping the organic layer.  About as far as I have gotten, did some TLCs on the product, there is an azide there with an Rf shift on TLC consistent with oxidation from OH to C=O, but not sure if it is the right product or something else.   

[kamiyu]

I have a couple of concerns regarding your reaction:

1. if you consider the mechanism of this DM oxidation, there is a alpha-proton abstraction by acetate group to facilitate the formation of the carbonyl group. Here, (please note that your azide group in the drawing seems to be problematic because it is +ve charged, but it should be neutral; thus the terminal proton should be absent and -ve charged nitrogen atom), there is a -ve charge on the nitrogen atom of the azide group, which might compete with the acetate. You may need to find out which is more basic (azide vs. acetate) to figure out this complication.

2. I am wondering if it is possible to do the DM oxidation first, then SN2 with azide. It seems primary chloride should survive in the oxidation

3. This DM oxidation is very mild and should not produce COOH

[AWK]

There are surplus hydrogen atoms in azidogroups. Starting compound contained chlorine, on the scheme is bromine.
I suggest symmetrical dioxin.

[ronholes7059]

thanks, yes structure was wrong, it should be Cl not Br in the starting material.  I have thought about doing the oxidation first, but wasn't sure if the azide would reaction with the aldehyde. Yes the azide should be a zwitterion, just having an issue drawing it with the SMILES function.  I will try the oxidation first and see if that helps, main problem I think is going to be getting rid of the precipitate that is formed. 

Never used dioxin, how does it compare to DMP?

[AWK]

I mean (N₃CH₂)₂C₄H₂O₂

Oxidation of -CH₂OH, cyclization (dimer), dehydration.

[ronholes7059]

Oh I see, you mean as a side product of the reaction, you think it could be the precipitate?

[AWK]

I would expect soluble dioxin rather in solution, and IBA as precipitate (since water is formed during reaction)
 IBA properties
http://onlinelibrary.wiley.com/doi/10.1002/047084289X.rn00605/abstract

[kamiyu]

thanks, yes structure was wrong, it should be Cl not Br in the starting material.  I have thought about doing the oxidation first, but wasn't sure if the azide would reaction with the aldehyde. Yes the azide should be a zwitterion, just having an issue drawing it with the SMILES function.  I will try the oxidation first and see if that helps, main problem I think is going to be getting rid of the precipitate that is formed. 

Never used dioxin, how does it compare to DMP?

You reminded me the reaction between azide and aldehyde. This is the Schmidt reaction. But I personally think this is OK because this reaction needs acid as the catalyst, which is absent in the trivial SN2 reaction between primary chloride and sodium azide.

[ronholes7059]

Thanks for the help, I will try all the suggestions. 

I will try to work out the oxidation conditions using the Chlorinated diol since that is commercial, I assume the oxidation should be the same regardless of functional group.  I will also *Ignore me, I am impatient* up the equivalents of DMP as suggested.  Once I get this worked out I will try making the desired product using both methods of starting off with SN2 displacement first and also trying it with the oxidation step first.

Will post an update later this week/early next with my findings

[orgopete]

Can you afford to buy 3-chloro-2-oxopropanal from a supplier?

[Dan]

A few years ago I did quite a lot of work with alpha-azidolactones. They were quit prone to decomposition and side reactions via facile enolisation, and had to be handled with care. An alpha-azidoketone is going to be even more reactive in this respect, and a flanking aldehyde will activate it even more. Then you also have the complication of hydrates, dimers and/or oligamers associated with the pyruvaldehyde system.

I'd be fairly surprised if you could isolate that compound (but chemistry throws up plenty of surprises).

I think I'd do the oxidation first as well - the azide displacement on the pyruvaldehyde system will be much faster compared with the diol. Depending on what your next step is, it may be possible to perform the next reaction in the same pot rather than attempting isolation of azidomethylpyruvaldehyde (this is less likely to be a viable option if you perform the DMP oxidation as the second step).

[rolnor]

I also think this compound will be very sensitive, I have worked with aldehydes with a alpha alkoxygroup an they look fine freschly prepared but decompose/dimerize/hydratisize rapidly. It would be interesting to know what you are going to use this material for, perhaps you could avoid it alltogether if it is a intermediate and change your synthetic route?

[ronholes7059]

So I am trying to make an analogue to methylglyoxal (MG), which is the same structure except a H replacing the Azido group.  I know MG exists in equilibrium in three forms, the dicarboyl, the mono-hydrate and di-hydrate.

So we are interested in MG modifications of proteins and analyzing them by MS, we do a lot of proteomics work on our lab, so I wanted to try and come up with an analogue that we could treat the cells/animals with then pull out the mods using click chemistry. 

So, the final product I listed above (the dicarbonyl azido) is the final product.

I looked for the 3-chloro-2-oxopropanal that Orgopete suggested, but I can't seem to find it commercially available. I did a structure search on Sigma but could not find it, but if it (or something similar) is available commercially that someone knows about please point me in the right direction and I will just buy it, unless it is super expensive the cost is not an issue. 

Yeah, I know it is going to be tough to isolate and like I said there will be a mixture of the mono and di-hydrates as well, but I thought I would give it a try.  I think doing the oxidation first is maybe the better route so I will try that way for now.