[hairygorillaz]

Hey guys,

Firstly, thanks to all of you guys. I've been a lurker, but learnt lots from you guys so far.

Now for the problem. I am attempting a synthesis pathway. And the first step is the reduction of a ketone to an alcohol via NaBH₄ in MeOH.

The alcohol formed decomposes too quickly. I lost approximately 50% in about 2 hours. The only solution that I have is to quickly run it through a column and then convert it to a bromide via PBr₃

What I need at the end is a primary amine (-NH₂ in place of the -OH as seen in (2)). I have tried converting it to an azide via NaH and then reducing via LiAlH₄ but the reaction doesn't proceed well, often yielding the alcohol. Any suggestions of alternative synthesis pathways?

Thanks a lot

[hairygorillaz]

Now is there a way to get the diagram embedded into the main post? I tried, but I can't seem to scale it so that it will fit.

[discodermolide]

Try a reductive amination with sodium cyanoborodhydride and ammonium acetate. Note you will get some of the dimer formed, but the main product should be the amine.
What is the alcohol decomposing to? Are you getting elimination to the styrene?

[hairygorillaz]

Try a reductive amination with sodium cyanoborodhydride and ammonium acetate. Note you will get some of the dimer formed, but the main product should be the amine.
What is the alcohol decomposing to? Are you getting elimination to the styrene?

Hmm. I really have no idea what its decomposing to. When it was left overnight, its just disappeared. And when I left it for two hours, it turned an ugly black.

[discodermolide]

Try a reductive amination with sodium cyanoborodhydride and ammonium acetate. Note you will get some of the dimer formed, but the main product should be the amine.
What is the alcohol decomposing to? Are you getting elimination to the styrene?

Hmm. I really have no idea what its decomposing to. When it was left overnight, its just disappeared. And when I left it for two hours, it turned an ugly black.

Then do not leave it overnight!
Do the reductive amination.

[hairygorillaz]

Try a reductive amination with sodium cyanoborodhydride and ammonium acetate. Note you will get some of the dimer formed, but the main product should be the amine.
What is the alcohol decomposing to? Are you getting elimination to the styrene?

Hmm. I really have no idea what its decomposing to. When it was left overnight, its just disappeared. And when I left it for two hours, it turned an ugly black.

Then do not leave it overnight!
Do the reductive amination.

Haha! The overnight one was the first time. But the one where the mass decreased to about 50% of the original in 2 hours shocked me. Reductive amination? I'll give it a shot!

Any idea as to why it happens? I've replaced the -CF₃ group with -Cl, -ⁱPr and -^tBu and most of the reactions run fine. Would the strongly electron withdrawing group affect it so much more than the chloride analog?

[discodermolide]

Very probably, perhaps go down with the temperature?

[hairygorillaz]

Thanks a lot! I'll try it out!

[Borek]

Now is there a way to get the diagram embedded into the main post? I tried, but I can't seem to scale it so that it will fit.

First - you should be able to export it in the more reasonable resolution before posting. If not, you can resize it using picture editing programs (some are free, some are expensive - your choice).

Second - using tiff format for web is not a best idea, as tiffs are not always supported. jpg, png and gif are much better. In this case I would go for a two-color png or gif, as jpg leaves compression artifacts in the case of the line drawings.

[hairygorillaz]

Now is there a way to get the diagram embedded into the main post? I tried, but I can't seem to scale it so that it will fit.

First - you should be able to export it in the more reasonable resolution before posting. If not, you can resize it using picture editing programs (some are free, some are expensive - your choice).

Second - using tiff format for web is not a best idea, as tiffs are not always supported. jpg, png and gif are much better. In this case I would go for a two-color png or gif, as jpg leaves compression artifacts in the case of the line drawings.

Thanks Borek. I'll take note the next time

[hairygorillaz]

Try a reductive amination with sodium cyanoborodhydride and ammonium acetate. Note you will get some of the dimer formed, but the main product should be the amine.
What is the alcohol decomposing to? Are you getting elimination to the styrene?

Sorry, a couple more questions. Would NaBH₄ work in a similar fashion? Or is there a reason most reductive aminations use NaBH₃CN?

And the NH₄OAc is basically an ammonium source right? So if my target now is a tertiary amine, I can just use something like dimethylamine am I right?

[discodermolide]

Try a reductive amination with sodium cyanoborodhydride and ammonium acetate. Note you will get some of the dimer formed, but the main product should be the amine.
What is the alcohol decomposing to? Are you getting elimination to the styrene?

Sorry, a couple more questions. Would NaBH₄ work in a similar fashion? Or is there a reason most reductive aminations use NaBH₃CN?

And the NH₄OAc is basically an ammonium source right? So if my target now is a tertiary amine, I can just use something like dimethylamine am I right?

NaBH4 is too strong a reductant as you are observing. NH4OAc is the ammonia source. All you are doing if forming the imine and reducing it with NaCNBH3.
If your target is a tertiary amine I see no reason not to use dimethylamine, the reaction will be cleaner.

[hairygorillaz]

Try a reductive amination with sodium cyanoborodhydride and ammonium acetate. Note you will get some of the dimer formed, but the main product should be the amine.
What is the alcohol decomposing to? Are you getting elimination to the styrene?

Sorry, a couple more questions. Would NaBH₄ work in a similar fashion? Or is there a reason most reductive aminations use NaBH₃CN?

And the NH₄OAc is basically an ammonium source right? So if my target now is a tertiary amine, I can just use something like dimethylamine am I right?

NaBH4 is too strong a reductant as you are observing. NH4OAc is the ammonia source. All you are doing if forming the imine and reducing it with NaCNBH3.
If your target is a tertiary amine I see no reason not to use dimethylamine, the reaction will be cleaner.

Thanks lots! Now to find NaCNBH₃ or some suitable alternative... Maybe will try to cook up a batch of NaB(OAc)₃H

[discodermolide]

Try a reductive amination with sodium cyanoborodhydride and ammonium acetate. Note you will get some of the dimer formed, but the main product should be the amine.
What is the alcohol decomposing to? Are you getting elimination to the styrene?

Sorry, a couple more questions. Would NaBH₄ work in a similar fashion? Or is there a reason most reductive aminations use NaBH₃CN?

And the NH₄OAc is basically an ammonium source right? So if my target now is a tertiary amine, I can just use something like dimethylamine am I right?

NaBH4 is too strong a reductant as you are observing. NH4OAc is the ammonia source. All you are doing if forming the imine and reducing it with NaCNBH3.
If your target is a tertiary amine I see no reason not to use dimethylamine, the reaction will be cleaner.

Thanks lots! Now to find NaCNBH₃ or some suitable alternative... Maybe will try to cook up a batch of NaB(OAc)₃H

NaBH3CN is commercially available. I'm not sure your alternative will work (still to strong an reductant).
You can form the imine and reduce it over Pd/C and hydrogen.