Fertile
Bluelighter
- Joined
- Mar 31, 2022
- Messages
- 1,627
Having searched through a stack of patents, when presented with a secondary amine on a scaffold MW around 400, their seems to be 2 general routes to adding an N-phenylethyl:
1-Alkyl bromide i.e. phenylethylbromide
2-Acid halide (usually acid chloride) which forms the amide that is then reduced to the product.
The former is used in earlier works but yield seems to be 55-70% depending on conditions and the aromatic involved (2-(2-furanyl)-ethyl) is also found. Yield of amide is usually 83% to 90%. Then the amide is reduced.
The problem here is selectively reducing the amide without reducing a ketone (also on scaffold) to alcohol or even possibly reducing a phenolic -OH.
I have read through the many selective reductions of amides but none of them seem to be appropriate. I know the ketone can be protected but then it all gets too complex.
Now the use of an alkyl bromide will tend to leave some unreacted secondary amine which it is possible to make non-basic so that in an A/B wash, the unreacted material does not pass through the cleaning.
I did also wonder of one could perform an Eschweiler–Clarke reaction to N-methylate the secondary amine. I have often wondered about the scope of the Eschweiler–Clarke reaction on the basis of can it form ANY amide and then the formaldehyde reduce it?
Lots of ideas.
1-Alkyl bromide i.e. phenylethylbromide
2-Acid halide (usually acid chloride) which forms the amide that is then reduced to the product.
The former is used in earlier works but yield seems to be 55-70% depending on conditions and the aromatic involved (2-(2-furanyl)-ethyl) is also found. Yield of amide is usually 83% to 90%. Then the amide is reduced.
The problem here is selectively reducing the amide without reducing a ketone (also on scaffold) to alcohol or even possibly reducing a phenolic -OH.
I have read through the many selective reductions of amides but none of them seem to be appropriate. I know the ketone can be protected but then it all gets too complex.
Now the use of an alkyl bromide will tend to leave some unreacted secondary amine which it is possible to make non-basic so that in an A/B wash, the unreacted material does not pass through the cleaning.
I did also wonder of one could perform an Eschweiler–Clarke reaction to N-methylate the secondary amine. I have often wondered about the scope of the Eschweiler–Clarke reaction on the basis of can it form ANY amide and then the formaldehyde reduce it?
Lots of ideas.
