[Messi]

Do you generate the thioketene in situ, from what?

Yes, I do. From 1-heptyne + nBuLi + sulfur I get my thioketene. Once I have this, I add an acid TFA and react it with my amine with the hope of getting a thioamide.

My final goal is to add LDA to this thioamide to generate an enolate with the hope that the enolate will attack the electrophilic carbon bonded to the bromine and create a heterocyclic system.

If it has a precursor then you mix them together and add a base such as triethylamine or Hünig's base.
Triethylamine should not add to the thioketene.

So you suggest I add 1-heptyne + nBuLi + sulfur + amine + triethylamine all together in one pot to start off? Would it be fine to forgo the addition of triethylamine and simply add two equivalents of nBuLi?

The free amine and the bromomethyl groups are not compatible.

Why is this? Intramolecular reaction? Won't the ring size be unfavorable?

[discodermolide]

In that case 2 equivalents of BuLi should do the same thing as triethylamine.
I would pre-make the solution of thioketene and add it to a suspension of the amino alcohol.

Do you know if your thioketene is stable to another equivalent of BuLi (by the way TFA is used to quench the reactions you have been doing)

p.s. BuLi is quite nucleophillic and coule displace the bromine from your primary halide! Just so you are aware of this.

[Messi]

I would pre-make the solution of thioketene and add it to a suspension of the amino alcohol.

Pre-make the solution of thioketene with two equivalents of nBuLi?

Do you know if your thioketene is stable to another equivalent of BuLi

Yes, I believe it is.

p.s. BuLi is quite nucleophillic and could displace the bromine from your primary halide! Just so you are aware of this.

How about this work around:

Create my thioketene by reacting my 1-heptyne + 1 equivalence of nBuLi + sulfur then add my salt form of my amine + triethylamine then add my TFA. Would this work? Or would the triethylamine simply get neutralized by TFA?

But the free amine and the bromomethyl groups are not compatible.

Why is this exactly?

[discodermolide]

I would add the thioketene solution to a suspension of the amine hydrobromide. Then I would add triethylamine or Hünig's base.
As I said the TFA is there for the work up, do not add it until the reaction is finished.

Amines are readily alkylated by alkyl halides.
If you make the free base of your amine it will react with the primary bromide. So you generate the free base in the presence of your other reaction partner, the thioketene. This should ensure the amine will react as desired.

[Messi]

Great, awesome stuff! Thanks!

When you say suspension, do you simply mean add my thioketene solution to my amine hydrobromide salt? Any reason why not vice-versa? Sorry, just me trying to understand what is going on more deeply

PS: Are you a professor/supervisor? You would be awesome to work for

[discodermolide]

I'm having real problems connecting here this morning.
Anyway:
It is easier to add the solution to a solid than a solid to a solution. AND you must get the free base of the amine. By adding the thioketene to the amine hydrobromide and then adding a base you will set the amine free and it should react with the thioketene.
As I said if you set the amine free first it will react with itself, before it can react with the thioketene.

[Messi]

Thanks discodermolide! If chemicalforums is correct, happy birthday to you!

[discodermolide]

Thank you very much

[Messi]

I found this procedure:

A mixture of (S)-amino alcohols 5 (0.15 mol) dissolved in 20% HBr aqueous solution (130 mL) was concentrated to dryness under reduced pressure. Owing to complete removal of water, the residue was dissolved in hot EtOH (40 mL) and the solvent was evaporated in vacuum to give amino alcohol hydrobromides. The obtained hydrobromide salts were then mixed with PBr3 (25.44 g, 0.093 mol) and refluxed for 10 min. After cooling, an excess of PBr3 was then removed by washing the mixture with Et2O several times and the residue was recrystallized from i-PrOH to afford 6a–e (over 86% yields).

I am trying to translate this procedure to layman terms. Does the above procedure translate to:

1) Dissolve amino alcohol in an HBr solution in an RBF
2) Add hot EtOH to RBF (Any reason why hot?)
3) Throw mixture on rotavap (How long?)
4) Add PBr₃ to RBF and reflux for ten minutes
5) Throw RBF contents in a buchner funnel and aspirate via vacuum filtration
6) Collect crystal/salts and undergo next step in my reaction (Purification not necessary?)

Great... I did my vacuum filtration.... and got no crystals... AWESOME... 

Not sure what happened... I'm so confused.

[discodermolide]

Then evaporate the filtrate.
In that procedure you posted what were the amino-alcohols 5?

[Messi]

Then evaporate the filtrate.
In that procedure you posted what were the amino-alcohols 5?

They included 5a-e which one of them was prolinol!

The solution of the amino alcohol in HBr/water was evaporated to dryness, then hot ethanol was added.

When you said was evaporated to dryness, how do you know when it is dry? I had rotovapped my solution for a good 15 minutes and still had all my solvent so decided to proceed to the next step. Maybe this was my mistake?

Also, I never saw one crystal. Everything was always liquid. Maybe I added too much solvent?

[discodermolide]

You rotavaped for 15 minutes and STILL had all the solvent?
Did you apply a vacuum? It is more or less dry when the weight of the flask and contents is a constant weight.

So effectively you added the PBr₃ to the ethanolic solution?

[Messi]

I added my HBr solution to my amine and the HBr solution didn't evaporate after 15min. under the rotavap under a 30mm Hg vacuum.

I then added warm ethanol and tried rotavapping again and nothing came off. I then added my PBr₃ as per procedure.

I just ran another reduction of proline now, should be ready by tomorrow. I will have a second batch of prolinol. Hopefully this time my reaction will work...

[discodermolide]

Right throw it away.
The first evaporation is the removal of water. This takes time, a good vacuum and a warm water bath, 40°C or more.
Here it is important that you get almost all the water removed. The step with the ethanol evaporation removes the rest of the water. This is also important and gets it dry before adding the PBr₃.

You have been lucky as PBr₃ and water and or ethanol react violently!

You must take your time and do not rush things, think carefully, but don't rush.

[Messi]

You have been lucky as PBr₃ and water and or ethanol react violently!

Yes, I agree. I didn't see any "violent" reaction. Where do you think I "messed" up however. This is quite odd. I did everything and literature told me to do and I still didn't get any crystals!

I thought I did indeed make my prolinol as per the NMR shown below...