[Sam30]

Hello!

I'm trying to synthesize a substituted styrene derivative. I have the aldehyde precursor and have been trying to obtain the Wittig product but the reaction doesn't seem to proceed even at low temperatures.

I have carried out the reaction at a whole range of temperatures ( -78 - 0 degrees). The ylide was formed by addition of n-BuLi to a solution of dry THF or dry ether at low temperatures. This was followed by addition of the aldehyde. The conversion is lower than 10%.

Any recommendation on how I can modify the process to obtain a better yield?

[Dan]

Try room temperature or higher if necessary. Depending on the hinderance of the ylid and the carbonyl, it might need to be heated.

[Sam30]

Hi Dan,

I'm using triphenylphosphine methylbromide as my wittig salt.

[Dan]

It also depends on how hindered and electrophilic the aldehyde is.

Let the reaction mixture warm to RT after addition of the aldehyde and monitor it by TLC.

[Sam30]

Hi Dan,

Here's some more information about my reagent: The substrate is benzaldehyde substituted in the 3,4 position  (one alkoxy in the para position and one alkyl in the meta position).

After addition of the n-BuLi, the solution turned yellow. I allowed the solution to stir for 30 minutes and then added the aldehyde. The mixture was stirred overnight to room temperature. I then worked up a small fraction of the solution but the product was still not formed.

[subro]

If you have a very hindered substrate you should use phosphonate carbanions (Horner-Wadsworth-Emmons) or even Julia.

Anyway, try to use another base, like LDA, hydrides or even KOtBu, because N-BuLi can nucleophilically attack the aldehyde.

[Dan]

The mixture was stirred overnight to room temperature.

OK, so try reflux. Can I request that you provide accurate information from the beginning? You initially say that you tried temperatures between -78 °C and 0 °C, but now it's RT...

It does seem quite surprising that the reaction does not proceed at RT.

I then worked up a small fraction of the solution but the product was still not formed.

You say previously that you observe <10% conversion - can I check that this is is the case, i.e. you observe >90% starting material? There is a question here about whether you might be getting side reactions (e.g. BuLi addition, as mentioned by subro). I personally favour tBuOK/THF because I always seem to get BuLi addition when using BuLi (presumably because I am too impatient for quantitative ylid formation).

[pgk]

There is phase transfer modification of the Witting reaction, effectuated in dichloromethane/water:
Synthesis, (5), 295-297, (1973), in German
As well as, an application of the phase transfer Witting reaction, for hindered substrates:
Synthesis, (12), 869-870, (1974), in English
Just take a look if you have access to this journal. It might be helpful.

[Sam30]

@Dan:

The ylide formation was carried out at low temperature, followed by addition of the aldehyde. These processes were all carried out at low temperatures. The reaction mixture was allowed to warm up to RT after addition of the aldehyde and stirred overnight at RT.

You say previously that you observe <10% conversion - can I check that this is is the case, i.e. you observe >90% starting material? There is a question here about whether you might be getting side reactions (e.g. BuLi addition, as mentioned by subro). I personally favour tBuOK/THF because I always seem to get BuLi addition when using BuLi (presumably because I am too impatient for quantitative ylid formation).

I have the NMR spectra after working up and purification. The n-BuLi does not form an addition product
with my aldehyde. I recovered my starting material (~90% was recovered) from the reaction mixture (aldehyde still intact).

I have tried using t-BuOK/THF as well, again with no significant yield.

@subro

Thanks for the suggestions, I have tried t-BuOK but had the same result - no alkene formation. My aldehyde is sterically quite unhindered however I think the electron donating nature of my substituents seems to be reducing the aldehydes reactivity.

@pgk:
Thank you for the references, I'll look through them to see if I can apply them to my substrate.

[Sam30]

Just an update:

I tried the wittig reaction on a more electron deficient benzaldehyde substrate with the same synthetic procedure as discussed. The product formed in high yields. It seems that the substrate is preventing the product formation.

[Dan]

Hmmm. I had a ketone once that was very reluctant to condense with Ph₃P=CHCO₂Me. In the end, I found heating them solvent free at 150 °C worked well. Maybe you could try something similar?

In my case the stabilised ylid could be generated prior to the olefination reaction, with yours I'm not sure that is easy. You could heat your aldehyde with the ylid salt and tBuOK solvent free. Or perhaps you could use your BuLi procedure to generate the ylid, add aldehyde and then remove the THF under vacuum and heat the resulting solvent-free mixture? Or conduct the reaction in a higher boiling solvent - e.g. xylene.