[kriggy]

Hello guys,
Im having a bit struggle with this proedure:
.

It was reported in Paz, M. M.; Sardina, F. J. J. Org. Chem. 1993, 58 (25), 6990–6995.

Dimethyl N-(9-Phenylfluoren-9-yl)-3,4-Didehydro- glutamate (1). A solution of glutamate 2 (2.150 g, 5.18 mmol) in THF (11 mL) was added dropwise (10 min) to a solution of KHMDS (9.4 mL, 10.36 mmol, 1.1 M in THF) at -78 °C. The resulting pale-yellow solution was stirred for 1.5 h at -78 °C and then transferred via cannula (cooled to -78 °C) onto a solution of PhSeCl (2.182 g, 11.4 mmol, 220 mol %) in THF (9 mL) at -78 °C. THF (5 mL) was added to the flask that contained the enolate solution, cooled to -78, and cannulated to the PhSeCl solution. The reaction mixture was stirred for 2h at -78 °C, HOAc (1.5 mL) was added, and the resulting suspension was allowed to warm up to rt, diluted with EtOAc/hexane (2:1,100 mL), washed with saturated aqueous NaHCOa (2 x 50 mL), dried over MgS04, filtered, and concentrated to give 3 as a sticky yellow oil...

the procedure then continues by mcpba oxidation to yield dehydroglutamate which I followed and in the end got maybe 10% yield instead of 85%.

I did not have KHMDS so I used NaHMDS instead. But this was used in similar reactions as well, together with LDA... I did try LDA and LiHMDS as well but in all cases I still see lots of unreacted starting material and PhSeCl.

Could the choice of base really have such an impact on the reaction? I would warm it up after adding the base but since its diester, Im worried about side reactions such as ester Dieckman condensations.

I also try to isolate the selenyl derivative which I was able to get but also in small yield (around 30%) with lots of unreacted starting material and bunch of impurities.

From this it seems the formation of the enolate is not going to completion. Can you please offer any insight or help? I never did chemistry like this so Im bit struggling on where to go next and what conditions to try.

thx

[rolnor]

Are the reagents fresch? The selenyl chloride also? Its a bit tricky to keep canulas coold, did this work well? My experience is that these metal-HMDS reagents are typically less popular then BuLi and LDA, therefore bottles are often opened and tend to be old, you dont see this from outside but they can be bad quality. Same with the selenyl reagent. I would by new KHMDS and selenyl chloride.

[kriggy]

My selenyl chloride is new, the base is probably older but I used LDA which just appeared in the fridge but it seems new as well. I did not keep the canulas cold, I did cool the solution to -78 and then add it via syringe at once. I was maybe 10 seconds total, it could not possibly warm up significantly. The XHMDS were probably not as fresh but the septa were still looking very good.

Im going to borrow KHMDS on  monday to see if it works. Just  read a paper on process developement where LiHMDS was giving much better results than LDA or KHMDS so maybe there is something specific to my case that needs KHMDS

[rolnor]

Its probably no coincidence that they use very specific method here, I think its important to follow the procedure. You get a di-anion and this, as you point out, can react with itself or polymerize if not kept cold. Also the adding of the di-anion to the selenyl chloride can be very critical. To keep canulas cold can be important but its hard to say. You could contact the authors and ask them.

[kriggy]

Its probably no coincidence that they use very specific method here, I think its important to follow the procedure. You get a di-anion and this, as you point out, can react with itself or polymerize if not kept cold. Also the adding of the di-anion to the selenyl chloride can be very critical. To keep canulas cold can be important but its hard to say. You could contact the authors and ask them.

how do I get dianion? I dont follow. I think you are right but I saw many examples of this reaction on various esters with various bases so I did not thing at first it could be an issue to  use different base

how do I keep canulas cold? I never did anything like this...

[rolnor]

They use 2equv. base, its both the alpha proton and the amide proton that is picked.
You can pack dry-ice around the canula, place a sheet of aluminiumfoil on the bench, place a few sheet of cleaningpaper on top of this, then a layer of crusched dry-ice. Then you wrap this around the canula.

[kriggy]

They use 2equv. base, its both the alpha proton and the amide proton that is picked.
You can pack dry-ice around the canula if you use some cleaning-paper and around this aluminiumfoil.

Its not, the Pf groups specifically prevents deprotonation of the alpha proton. Thats the whole point of the protecting group othewise I would use Boc or others but then the alpha carbon is easy to racemize

[rolnor]

Maybe I am unclear, I mean the alpha proton on the ester that has no amino group in the alpha position and the proton on the nitrogen.

[kriggy]

That makes sense.

Anyway, I discarded all the advice which was supplemented by my colleagues at work and got the correct base and run it again under the literature conditions and somehow, TLC shows clean conversion of the diester into the selenide. Guess it was the choice of the base or possibly my technique.

Thanks for all the advice Rolnor

[rolnor]

Great!