[kriggy]

Hi guys, I have several questions about amide reactivity and stuff:

a) is there a way to selectively alkylate amidic nitrogen in presense of free amino group in the molecule? (I dont think so but hey..)

b) what amine-protecting group would be the best if I wanted to do the beforementioned alkylation? I suppose acyl wont change the reactivity that much compared to the other amide

c) Is there a way to selectively protect N1 of indazole in presence of amidic nitrogen in the molecule? I found DHP+ptsa works fine but the method requires chromathographic purification and I would like to avoid that because I need the compound on larger scale than few miligrams (probably gram scale). The separation works but I got realy low yields after colum, like 30% or something

[Dan]

a) is there a way to selectively alkylate amidic nitrogen in presense of free amino group in the molecule? (I dont think so but hey..)

Not that I'm aware of. Stoichiometric deprotonation of the amide (e.g. with NaH) prior to introduction of the electrophile might result in faster alkylation of the amide anion vs the neutral amine. But I've never tried and haven't checked the lit.

b) what amine-protecting group would be the best if I wanted to do the beforementioned alkylation? I suppose acyl wont change the reactivity that much compared to the other amide

You may also struggle to deprotect NAc in the presence of other amides. I presume then that this is a primary amine? Phthalimide or benzylidene spring to mind first.

c) Is there a way to selectively protect N1 of indazole in presence of amidic nitrogen in the molecule? I found DHP+ptsa works fine but the method requires chromathographic purification and I would like to avoid that because I need the compound on larger scale than few miligrams (probably gram scale). The separation works but I got realy low yields after colum, like 30% or something

What's the reason for the low yield? Sounds like an isolation issue. MOM is similar to THP but more robust. Trifluoroacetyl or a carbamate perhaps?

[kriggy]

b) It is primary amide. I can deprotect it quite easily in refluxing KOH, the other amide is part of the cycle,in fact its a δ-lactam (my apologies for not being correct, I have sometimes trouble differentiating between them when Im not careful)

c) It seems. THe conversion was about 70% so I was expecting maybe 230-250 mg of product but I got some 130 mg of oily substance. There comes to mind another question, how to get rid of the traces of DCM in my product? It seemst that thats the reason why it is oily.. I tried rotovaping it for some time but it didnt help at all. Any chance there are solvents that behave better in case of evaporation?

Anyway to facilitate the discussion:

Im trying to alkylate compound 4 on the benzimidazolone nitrogen but im getting the mixture of products (tried Benzylbromide with various bases and mitsunobu reaction, my friend tried chan-lam coupling) so thought that I could protect the indazole part of the molecule OR run the alkylation before I do the cyclization (ie. alkylate either the compound 1 OR its precursor that is the same molecule but acylated at the primary amino group). It seems that weak bases (acetate) are able to get the mono alkylated compound i want but there is maybe 20% conversion and by increasing amount of benzylbromide i get mixture again.
Im fan of the protection because then the derivatization is in the last step and I have quite big amounts of compound 4 in my hands so I can try a lots of stuff.

[Dan]

b) It is primary amide. I can deprotect it quite easily in refluxing KOH, the other amide is part of the cycle,in fact its a δ-lactam (my apologies for not being correct, I have sometimes trouble differentiating between them when Im not careful)

Aah ok - I'd call this a quinoxalinone and an aniline.

c) It seems. THe conversion was about 70% so I was expecting maybe 230-250 mg of product but I got some 130 mg of oily substance. There comes to mind another question, how to get rid of the traces of DCM in my product? It seemst that thats the reason why it is oily.. I tried rotovaping it for some time but it didnt help at all. Any chance there are solvents that behave better in case of evaporation?

Check that the protected product is stable on silica with a 2D TLC. If not, you could try alumina, or switch to MOM. I would see what 4 does with Ac₂O/pyridine as well.

For the DCM: high vac with a (preweighed) stirrer bar and warm it. The stirrer provides nucleation sites.

It seems that weak bases (acetate) are able to get the mono alkylated compound i want but there is maybe 20% conversion and by increasing amount of benzylbromide i get mixture again.

This is in the protection of 4 or 1?

Acetate may be too weak - the acetic acid byproduct may protonate and deactivate your substrate. A carbonate may be a better option, or a combination of an insoluble carbonate and acetate (the poorly soluble carbonate regenerates acetate from acetic acid).

Benzylidene protection of the aniline in 1 might be worth a shot.

[kriggy]

2) good point, it might decompose on silica since its acid labile group. I didnt realize that.How do you choose the mobile phase for alumina? Are there TLCs with alumina instead of silica?

3) tallking about 4. Im alkylating it using benzyl bromide and acetate/carbonate/bicarbonate/KOH as a model reaction for other derivatives. I will try the mix of the bases

[Dan]

2) good point, it might decompose on silica since its acid labile group. I didnt realize that.How do you choose the mobile phase for alumina? Are there TLCs with alumina instead of silica?

Generally the mobile phase is similar - Rf tends to be higher on alumina vs silica with the same eluent (but that will depend on particle size I imagine). I've only had to use alumina a couple of times (for enol ethers) - and yes, you can get alumina TLC plates.

3) tallking about 4. Im alkylating it using benzyl bromide and acetate/carbonate/bicarbonate/KOH as a model reaction for other derivatives. I will try the mix of the bases

What is the product distribution like with bicarbonate, carbonate or hydroxide? Beware that the acetate reaction might be clean at low conversion, but as conversion increases so will the rate of formation of the dialkylated product (because the concentration of monoalkylated product is increasing).

[kriggy]

Ok I dont know from top of my head exact numbers (and I have my notes at lab and I wont be there for month so)
with hydroxide I got mixture of products - roughly 40%SM, 40% monoalkylated, 10%another mono alkylated and the rest are di-alkylated.
With carbonate its roughly the same
with acetate i got maybe 20% of the product and rest is starting material so I could probably run a column and then regenerate the starting material