Hello, I am having trouble getting a sugar alcohol to be replaced with an azide, the substrate I am using is D-xylose which was reacted with acetone
and sulfuric acid over anhydrous copper sulfate to give (-)-1,2:3,5-Di-O-isopropylidene-a-D-xylofuranose. This was subjected to a .1M HCl solution and
stirred for 1.5 hours to hydrolyze the acetal on the side of the primary alcohol. The product was then benzoylated at 0 C with benzoyl chloride in DCM
with pyridine as the acid scavanger. Column Chromatography 2:1 hexanes ethyl acetate separates the mono benzoylated product from the dibenzoylated
product. going forward with the mono benzoylated product I have a few options to replace the remaining alcohol with an azide. I have tried mesylation
and tosylation followed by reactions with sodium azide in DMF or DMSO at room temperature and elevated temperature (80 C) to no avail ( cannot use 18
crown 6 to bind the sodium as azide forms a strong complex with 18 crown 6 and there isnt any 15 crown 5 laying around here). Mostly my starting
product just does not react. In an attempt to get at this another way I ran a reaction that was cited to be selective for the azidalation ( is that
even a word?) of a substrate specifically replacing a secondary alcohol. Bascially is it is a variation of a mitsunobu reaction using diphenyl
phosphoral azide. This showed the alcohol peak via nmr disappearing but the but another hydrogen was also missing, suggestive of elimination which is
an issue that sometimes goes along with mitsunobu reaction conditions. I am going to try reaction of the mesylate with TMS azide as I have seen this
cited in a thesis working for this substrate but with low yeild.
does anyone have any other Ideas I can try?
for the first two reactions that I mentioned the conditions were taken of the paper I have attached.
Thanks for the help.
Attachment: jo2600.pdf (1.1MB) This file has been downloaded 864 times
[Edited on 28-7-2011 by ThatchemistKid]
[Edited on 28-7-2011 by ThatchemistKid]AndersHoveland - 28-7-2011 at 10:31
Somewhat confused by your post. What exactly do you mean when you see the 1,2:3,5-Di-O-isopropylidene-a-D-xylofuranose was "benzoylated" ? could you
give some explanation of what the structure is of the resultant molecule?
Sounds like your intermediate molecule might be too delicate for mesylation/tosylation. Generally, the steps converting an alcohol to an organic azide
require strongly acidic conditions. Have you thought of the possibility of reacting the alochol with SCl2, then directly substituting the chlorine
atom, with an appropriate copper-ethylene diamine catalyst, using sodium azide in a propylene carbonate solvent? (reaction would take 48 hours)
might check this paper out: https://docs.google.com/viewer?a=v&pid=sites&srcid=Z...
I salute you for attempting a this mitsunobu-like reaction, but the long chain of steps before this final reaction may make it problematic, as much
can go wrong before you get there.
[Edited on 28-7-2011 by AndersHoveland]ThatchemistKid - 28-7-2011 at 10:53
Sorry to calarify the benzoylation was the addition of a benzoyl group to the primary alcohol, if you look at the paper I uploaded they add a pivalate
group on that alcohol instead of a benzoyl group. after that the mono benoylated (only on the primary alcohol) was separated from the dibenzoylated
product.. both the mono and the di benzoylated showed up on TLC and were characterized by NMR ..all products were characterized by NMR and are what I
suspected them to be. I have thought about chlorination or bromination, but halogenation followed by addition of the azide would give me the wrong
sterochemistry.
Thanks for the paper though I actually had not seen that one.GreenD - 28-7-2011 at 13:46
My only thought would be to use Lithium Azide, rather than sodium azide, as I have heard the lithium can complex better, thus giving better reaction
conditions. However if you have zero reaction going on with the sodium azide it may not be the case that Li Az helps at all.
I have seen 0 product from NaAz in benzene, toluene, and other non-polars, but near completion in DMF and DMSO but you have already stated you've
tried both.
My only real advice is the LiAzide... I've never tried it but I've heard that it is better for the formation. I wish I had the paper with me.
PS don't underestimate the use of the good ole IR machine. N3 is pretty easy to see if it is there.AndersHoveland - 28-7-2011 at 13:51
My only thought would be to use Lithium Azide, rather than sodium azide,
I agree. It depends, of course, on whether you have access to the lithium salt, or if you are willing to deal with the hazards of preparing it.
Lithium salts tend to be soluble in ether or THF.
Sounds like a really complicated reaction procedure.
[Edited on 28-7-2011 by AndersHoveland]ThatchemistKid - 28-7-2011 at 14:39
actually yes I have seen suggestions of Lithium azide but was not sure why. I have some lithium sulfate on hand that can be used to make it so I may
try that along with the TMS azide in the near future.
Thanks =)ThatchemistKid - 28-7-2011 at 14:49
the issue with the preparation of lithium azide is its tendency to explode apparently. AndersHoveland - 28-7-2011 at 15:42
the issue with the preparation of lithium azide is its tendency to explode apparently.
but it is actually less dangerous in this regard than hydroazoic acid. should not be too much of a problem so long as it is kept dissolved in the
solvent.Nicodem - 29-7-2011 at 11:07
You are trying to make an SN2 on a sterically hindered mesylate/tosylate of a secondary and furthermore cyclic alcohol. Your substrate has one
anti-hydrogen free, so E2 elimination is possible. All this is a against the reaction, so don't expect an easy/efficient reaction. Be ready for the
most extreme solutions, like using HMPA as solvent and/or temperatures above 100 C and severalfold excess of the azide salt (NaN3 can be used at 100 C
or even higher, though I would not comment on the safety so don't do this on anything more than 10 mmol and with proper precautions). If you are too
afraid of HMPA, you can try with sulfolane instead (though NaN3 might be troublesome to dissolve).
The reference on the use of LiN3 in DMF on a sugar tosylate is J. Org. Chem. 1985, 50, 891.
Using TMS azide with TBAF sounds like worth trying (Synthesis 1995, 376), but I can't say anything about how well it could work.
If I remember correctly, a true Mitsunobu reaction using HN3 and DEAD is actually known, but I don't have references at hand. This should not be prone
to E2 side reactions, but I doubt it would work in your case. It all depends on how desperate you are to get the product.
Obvious advice: Make sure you read the review article Chem. Rev. 1988, 88, 297.
