[Messi]

You the best Dan!

Finally got it! Picture below!

[discodermolide]

The chloroformate will also react with the alcohol.
You need to protect the nitrogen first. Using Schotten-Baumann conditions.

[Messi]

Ahh, how about this!

Btw guys, I really appreciate the *delete me*

[discodermolide]

The Boc will get reduced by LiAlH₄.
Make the ester and then try LiBH₄ reduction, the Boc should survive.
You could also make the acid chloride, do a Rosenmund reduction and reduce the aldehyde to the alcohol.

[Messi]

What if instead of the Boc I used Cbz? Would the reaction still work?

[discodermolide]

You mean the LiBH₄ reduction of the ester? If so then it should work.
I have references but unfortunately no experimental that I have found yet on this PC.

[Dan]

A couple of things:

1. The Boc group replaces the H in the NH, i.e. R₂NH R₂NBoc
2. Boc is not usually written backwards, i.e. R₂NBoc and BocNR₂ look normal, but coBNR₂ is never used. This is true of all abbreviated groups that do not show atom connecivity.
3. HCl will not displace a tosylate. You need a nucleophile, i.e. chloride ion. Bromide or iodide would be better (more nucleophilic). HCl will just remove the Boc group.

I see what you're trying to do, and it seems feasable. However, it can be done more efficiently:

You can "protect" the amine by forming the hydrobromide salt:



Then heat it with PBr₃ to get the alkyl bromide.

Alternatively, you could make the hydrochloride salt and then make the alkyl chloride.

These compounds would normally be handled as salts or N-protected because they are relatively unstable in free-base form.

[Messi]

Ok, wow this isn't easy...

Make the ester and then try LiBH₄ reduction, the Boc should survive.

This? Shown below? I used LiBH₄

You could also make the acid chloride, do a Rosenmund reduction and reduce the aldehyde to the alcohol.

That's an extra step because I need to turn my proline into an acyl chloride then into a primary alcohol when I could simply turn my proline carboxylic acid functional group directly into a primary alcohol via reduction

[Messi]

A couple of things:

1. The Boc group replaces the H in the NH, i.e. R₂NH R₂NBoc
2. Boc is not usually written backwards, i.e. R₂NBoc and BocNR₂ look normal, but coBNR₂ is never used. This is true of all abbreviated groups that do not show atom connecivity.
3. HCl will not displace a tosylate. You need a nucleophile, i.e. chloride ion. Bromide or iodide would be better (more nucleophilic). HCl will just remove the Boc group.

Thanks Dan! I appreciate this!

I see what you're trying to do, and it seems feasable. However, it can be done more efficiently:

You can "protect" the amine by forming the hydrobromide salt:



Then heat it with PBr₃ to get the alkyl bromide.

Alternatively, you could make the hydrochloride salt and then make the alkyl chloride.

These compounds would normally be handled as salts or N-protected because they are relatively unstable in free-base form.

I like this one, nice quick and easy! I'll try it that way and the other way and see what I get it! I am mainly trying to get lab experience at this stage of my career. Thanks for the *delete me*

[discodermolide]

LiBH₄ will not reduce the acid to the alcohol, you need to go through the ester.
I have a procedure for pyroglutamate (ethyl ester) to the alcohol with LiBH₄.

[Messi]

I've decided to first do it Dan's way. I found a nice procedure for the reduction step with LiAlH₄ on this website:

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0530

For the set-up, it says: An oven-dried three-necked flask equipped with a mechanical stirrer, a Friedrich condenser, and a nitrogen-inlet tube. Based on this, I am not sure how I will be adding my proline to my mixture. Proline is a solid, and I was told to use a plastic sleeve to add my proline. How exactly am I going to do that!  Would anyone mind telling me how I will set-up for such a reaction?

Would the set-up look like something shown below?

[Corribus]

Based on this, I am not sure how I will be adding my proline to my mixture. Proline is a solid, and I was told to use a plastic sleeve to add my proline. How exactly am I going to do that!

If the whole reaction vessel is under positive pressure, you can remove the stopper and add it quickly, followed by replacing the stopper.  You will want to have nitrogen constantly cycling (using a septum and needle, say) afterwards to remove residual oxygen.  Just be careful you don't blow off all your solvent.  But the better way to do it is to do a cannula transfer of dissolved proline, supposing it is soluble in the reaction solvent.  Even if it isn't, you can usually transfer a suspension over this way if the reactant is in excess.

This will all be much easier to do on a Schlenk line.

[Messi]

Thanks Corribus, thumbs up!

I do have access to a Schlenk line, and I do agree that doing a cannula transfer would be much easier (just saw a video on the process - looks very neat). Regarding having nitrogen or argon constantly cycling via a septum and needle, where should I place my septum and needle in my previously posted picture?

Also, as a side note, how should I measure my desired amount of LiAlH₄. I can't simply use a balance and expose my LiAlH₄ to air... wouldn't that be dangerous!

[discodermolide]

That is not a three-necked flask.
Where is the mechanical stirrer?
Is your LiAlH₄ in solution or a solid?
What scale are you doing this reaction on?

[Messi]

That is not a three-necked flask.

I thought my apparatus would have the same effect as a three-necked flask.

Where is the mechanical stirrer?

I was going to use a magnetic stir bar.

Is your LiAlH₄ in solution or a solid?

A solid. So, I will add my THF in my RBF, then add my LiAlH₄ after. Not sure how I will weigh my solid however.

What scale are you doing this reaction on?

Small scale. Probably on 50-60 mmol of LiAlH₄

Anything wrong with my set-up Discodermolide? I have big plans once I create my product(s)