[columbo123]

Hello everybody,
I am currently planning a synthetic route and the fourth step is planned as shown below.
I am now suspicious of where the lithiation with LDA (or optionally BuLi) is likely to happen. Literature states that H_A is favoured over H_B in the similar molecule without a OMe group on the phenyl ring. Does anybody have more knowledge on wheter alpha-lithiation at the H_A site or ortho-lithiation at H_C, promoted by the direct-metallating group OMe, is favoured?

[rolnor]

Ha and Hb is much more acidic then Hc. Its more difficult to know if Ha is more acidic then Hb, I think you have to just try.

[Guitarmaniac86]

In my group where we synthesise polyaromatic and polyheteroaromatic compounds we have deprotonated at Hc but definitely not with LDA, we use nBuLi.

Though Hb and Ha have similar PKa, I would expect LDA would favour Ha because there is less steric hindrance there.

Sorry I can't be of more help than that.

[rolnor]

If you want to lithiate methoxybenzene you do it at 21°C and with BuLi. Its much easier to lithiate thiophene. I guess Hb is on a carbon that is more conjugated, less "thiophene-like" and therefore less acidic than Ha.

[wildfyr]

21°C? how do you maintain that temp? haha

[columbo123]

Thank you for all the suggestions.
I will conduct the experiment somewhen next week and post the result, if any of you are curious too.

[wildfyr]

please do!

[columbo123]

Better late than never,

for those of you who were curious: With LDA at -78 °C in THF anh., H_A gets deprotonated selectively. A second, very small TLC spot probably indicates partwise attack on H_B, but in a neglectable ratio.

Greetings.

[rolnor]

Interesting, thanx!