[Parathormon]

Good evening,

I hav a question about such reaction:

alpha-bromoacetophenone + n-methyl tertbutoxycarbamate or n-methyl methylcarbamate

Does any reaction occure? Theoretically such type of amine has one more free electron, but it is protected so it can affect inductive effect of whole molecule making it unreactive on amine group;

Can anyone help with this?

I can do it in practice and just figure it out but maybe someone knows?

[rolnor]

Is there perhaps a way to make the nitrogen more nucleophilic?

[Parathormon]

ethylcarbamate has pkA around 13 so.. it is base

Conclusion is that alkyl carbamate esters are bases...

But it os theory..

[rolnor]

Yes, with strong base like sodium hydride it is possible to alkylate it I think. You have to consider that bromoacetophenone has twoo electrophilic groups though.

[Parathormon]

Thank You

I will try to do it somewhat...

To avoid substitution on carbonyl it must be done in rather low concentration of base i think..

But wait - on carbonyl there is no option to form imine - nucleophill is secondary amine...

[rolnor]

Thank You

I will try to do it somewhat...

To avoid substitution on carbonyl it must be done in rather low concentration of base i think..

But wait - on carbonyl there is no option to form imine - nucleophill is secondary amine...

Yes, thats true. There is acidic protons on the bromoacetophenon also so this could be rather messy Im am afraid.

[Parathormon]

It not works... I made it and .. nope

Amide is not a suitable nucleophil  to treat it like amine in this situation...

Better way is to substitute witn amine and protect afterwards whole aminoketone

[rolnor]

It not works... I made it and .. nope

Amide is not a suitable nucleophil  to treat it like amine in this situation...

Better way is to substitute witn amine and protect afterwards whole aminoketone

You know that amines also react with ketones? It might be possible to react the bromoacetophenone with sodium azide and the reduce the azide by catalytic hydrogenation. You can do this with the Boc2O present and trap the amine as it formes.

[wildfyr]

Easier to reduce with PPh₃ (Staudinger reduction).

[rolnor]

Easier to reduce with PPh₃ (Staudinger reduction).

When you use PPh3 you get a aza-Wittig reagent as intermediate and this can react with ketone-carbonyl I think. The point with my suggestion is that you dont need to isolate the amino-ketone, it is probably not stable because amine can react with ketone-carbonyl. Maybe I am  too carefull but I see problem with isolation of the amino-ketone.

[rolnor]

Actually this aminoketone is realated to the drug "Cat" and this drug is not stable as free base;

https://en.m.wikipedia.org/wiki/Methcathinone

[kriggy]

You know that amines also react with ketones? It might be possible to react the bromoacetophenone with sodium azide and the reduce the azide by catalytic hydrogenation. You can do this with the Boc2O present and trap the amine as it formes.

The bromoketone reacts on the bromine preferentialy AFAIK. For example, one of the salbutamol synthesis reacts reacts the bromoketone with tBuNH2 followed by the ketone reduction

[rolnor]

You know that amines also react with ketones? It might be possible to react the bromoacetophenone with sodium azide and the reduce the azide by catalytic hydrogenation. You can do this with the Boc2O present and trap the amine as it formes.

The bromoketone reacts on the bromine preferentialy AFAIK. For example, one of the salbutamol synthesis reacts reacts the bromoketone with tBuNH2 followed by the ketone reduction

Yes, maybe I am too worried about the aminoketone. Perhaps one could work quickley and do the next step fast and not isolate the aminoketone. In the case with Salbutamol the t-BuNH2 is stericaly hindered and that could be important to avoid dimerisation of the aminoketone.

[rolnor]

You can buy the aminoacetophenone;

https://www.sigmaaldrich.com/catalog/substance/2aminoacetophenonehydrochloride17162546837111?lang=en&region=SE

Its easy to put on a Boc on this with Boc2O and a little base.