[JimCronshaw]

Hi there. First post so I'll introduce myself. I'm Jim, an honours student working on an open science project involving the synthesis (and subsequent evaluation) of potential anti-malarial drug candidates. Link to our work here.

I'm trying to remove a proton from the thienopyrimidine compound. The reaction shown below:

I've tried n-BuLi at -78, -40 and -15, and sec-BuLi in these conditions also. In all reactions 3 equiv of BuLi was used. All reactions were quenched with D₂O, and all reactions show that the only proton being removed belongs to the primary amine.

I'm trying to rule out possibilities, such as the starting material being tainted with water (the HNMR indicates that there's water present, but not in unusual quantities). I might do a recrystallisation and see if that eliminates that problem. I've also synthesised a version of this compound where the primary amine is replaced by morpholine.

My question is, what other possibilities might be leading to the right proton not coming off? What conditions do you guys know of that would lead to the removal of this proton? The ultimate reaction that this is leading towards is the replacement of the α-thiophene proton with iodine, followed by a Suzuki coupling.

Should the abstraction of this proton not be possible I suppose that I'll have to do the BuLi step before introducing that amine, I suppose.

[discodermolide]

Did the desired reaction work with the morpholine derivative?

[orgopete]

What is the solvent? Are you deprotonating it? Does the anion suppress metallation?

[JimCronshaw]

re morpholine derivative: no, i'll be doing that tomorrow (if time permits). i'm assuming at this point that it will work, because there's precedent for it all over the literature. but then, there was precedent in the literature for the original reaction with n-buli.

the solvent is THF. admittedly it doesn't dissolve the starting material spectacularly, but with sonification it at least forms a suspension. might this be a problem?

[discodermolide]

re morpholine derivative: no, i'll be doing that tomorrow (if time permits). i'm assuming at this point that it will work, because there's precedent for it all over the literature. but then, there was precedent in the literature for the original reaction with n-buli.

the solvent is THF. admittedly it doesn't dissolve the starting material spectacularly, but with sonification it at least forms a suspension. might this be a problem?

The lack of solubility may very well be the problem, especially as the alkyllithiums are solutions in hexane, decreasing the solubility even more. What about adding some HMPA just enough to get a solution?

[OC pro]

I think alkyllithiums are not an option here due to solubility problems? Have you tried LDA or even better lithiumdiethylamide? Especially the second one worked wonders for me in the past.
Another point: why not do a simple bromination/iodination using NBS or NIS (start at 0 °C)? From my point the 5-position at the thiophene should be the most activated.

[discodermolide]

I think alkyllithiums are not an option here due to solubility problems? Have you tried LDA or even better lithiumdiethylamide? Especially the second one worked wonders for me in the past.
Another point: why not do a simple bromination/iodination using NBS or NIS (start at 0 °C)? From my point the 5-position at the thiophene should be the most activated.

I think the S atom may be halogenated to give R₂S⁺--I I^-
(Meant to be an S-I bond)

[orgopete]

Certainly, the combination of low solubility and the decomposition of THF (see Wikipedia) with n- or sec-butyllithium will hinder this reaction. I don't know the solubility of these compounds or their derivatives, but I would consider preparing some kind of derivative. I think you can still succeed in deprotonation to form a dianion.

[JimCronshaw]

The solubility is a problem. I can't just dissolve it in hexane because the starting material is incredibly polar (although it doesn't dissolve spectacularly in THF anyway...). The thing is, the solvent (THF) hasn't been a problem according to the literature examples. Admittedly, only one of them is from a journal...

We'll see how the morpholine goes. If that succeeds, I think that a protected amine might be the way to get this done.

I might try NIS just to say I gave it a go as well. The more ideas I can say I've used, the better.

Here's one last point. I have to write a thesis for this stuff at the end of the year. Appealing to the internet for ideas is fine in my case because it's open source, but I still need to reference ideas that aren't my own. To that end, can I request that those of you who gave ideas (orgopete, discodermolide and OC pro) provide me with real names? If you think this sounds a little suspect I'd agree. So here's my university email:

jcro3392@uni.sydney.edu.au

And our groups website for verification:

http://openwetware.org/wiki/Todd

And my online lab book, once again, for verification:

http://malaria.ourexperiment.org/aminotpseries

Feel free to email me if you don't want to do it here.

THANKS! 

[buRnINGbeND]

THF shouldn't be a problem unless you do it at ~RT.  at low T it won't react.  i'd definitely try adding some sort of amine like disco suggested, but i'd suggest DMPU over HMPA just for toxicity reasons.

have you tried adding something other than D2O?  if you're SM isn't too expensive, try doing like a 150mg reaction and add MeI or something and seeing if you methylate that spot.  it might just be that the D2O is contaminated or there are just random issues.

[JimCronshaw]

The D2O quench does indicate that a proton is being removed (and replaced with D) on the primary amine though.

[buRnINGbeND]

also, someone suggested LDA.  is that going to be basic enough?  what's the pKa of the proton in question?  like 30 maybe?

[buRnINGbeND]

The D2O quench does indicate that a proton is being removed (and replaced with D) on the primary amine though.

yeah that's kind of why i'm just like "handwaving!" to explain it.

[JimCronshaw]

also, someone suggested LDA.  is that going to be basic enough?  what's the pKa of the proton in question?  like 30 maybe?

yeah about 30. LDA is 36, right?

[buRnINGbeND]

yeah, 36