[geckosan]

Please let me start off by saying that I am not a synthetic chem major, but a Natural Products guy.  That being said, I am in awe of you synthetic jockeys...I don't know how you do, nor keep up with it all. 

We have to do one synthetic project as part of our dissertation however and I am sort of at a stump point.  I have my isolate synthesis almost completely finished, save a single step.  I need to cyclize an ethyl-5-aminopentanoate derivative (i.e. amine attack the carbonyl to form the ring) to produce a piperidin-2-one ring.  I fear there will a decomposition and loss of the amine functionality instead of the amide formation. 

Is this step possible and what conditions could facilitate its occurrence?

Thanks for reading and any help you can give me.

Chris

[salteen]

Hi,

The compound you named would probably be very prone to cyclization on its own.  Do you have the compound isolated right now?  If so, is it possible you have the ammonium salt rather than the free amine?

Simple treatment with mild base would neutralize the amine and likely cause cyclization quite easily.

[geckosan]

I have completed 13 of the 15 steps I needed to do.  the compound has two amines, both protected by Cbz at the moment (according to the NMR).  I had planned to use HBr to deprotect, then hopefully cyclize and be done.  I am truly excited by your suggestion!  that should mean after deprotection and all I need to do is neutralize the acid and go slightly basic to get my result.

Thanks for the suggestion!  I'll be working on the last few steps next week and try to get back to everyone with the results.

Chris

[Doc Oc]

This can be a simple procedure, but a lot depends on the complexity of your starting material.

HBr is a very strong acid and not necessary to remove CBz.  One of the big upsides of CBz is that it can be easily removed by hydrogenolysis and your product recovered in high yield simply by filtration.  If you have anything else sensitive in your starting material the HBr could cause a lot to go wrong with it.

You said you have 2 amines, does it matter which one reacts to close the lactam?  If the answer is yes, you have a serious problem that may require re-working your synthesis.

The cyclization will likely not proceed spontaneously with a free acid/free amine, you will need to activate the carboxylic acid.  A peptide coupling agent like EDC will be sufficient.  Again, this depends a lot on what type of functionalities are on your starting material.

[geckosan]

I do have 2 amines, but one is sterically hindered and would form a 3 atom heterocycle versus the more stable 6 atom.  I had considered hydrogenolysis but HBr was suggested by Greene's book (protective groups in organic synthesis) mainly because it was easier and more economical. 

You do pose a new thought for me as well...would that ethoxy group leave under acidic or mildly basic conditions?

I really wish we had a dedicated synthesis position here, I am SO glad for you guys right now... 

Chris

[salteen]

In theory, your ethoxy group could leave under both acidic and basic conditions (same principle as esterification, which can also proceed under both conditions).  Doc Oc is right, you may need to use a coupling agent to induce cyclization, but this will add an extra step because you will have to first saponify your ethyl ester to the carboxylic acid.  So if it were me, I'd try refluxing with KOH/H2O to remove the ester -  if it ends up cyclizing in the process, bonus, but if not, you can always go ahead and try any number of coupling agents.

I also strongly recommend hydrogenolysis to remove your Cbz group, as it is a much milder procedure than HBr and works every time for me. In my version of Greene, it's listed as option number 1

[geckosan]

I have the 2nd edition.  so I think I need to requisition the latest anyway.  I think I'll see if its in the budget and go for hydrogenolysis to be safer.

Thanks again for all the help everyone.  I realized I could go directly to the carboxyl thereby removing a step and eliminating the ethoxy completely. 

I'll post the results as soon as I get it finished, worked up and complete the spectroscopy work.

Chris

[Dan]

I once did a similar reaction involving an isopropyl ester and an azide (see scheme below). Reduction of the azide with H₂, Pd/C gave the free amine and then all I did was filter out the Pd/C and heat the aminoester in EtOH at 40^oC for a couple of hours to get quantitative lactam formation. No basic additives were necessary.

Now, in my reaction I was forming a γ-lactone, which is kinetically much faster than forming δ-lactones as you are doing, but I also had a substantially bulkier ester than you do. I would start by just warming the aminoester with no basic additives and see what you get.

[geckosan]

Thank you again.  I definitely have a new direction to take and I think a much clearer plan now.

I say this only in jest, but I hate you guys.   You are making me THINK! and possibly replan this synthesis to be much more efficient....and probably more successful.  next natural product target for you all to work on is on me.

Chris

[Doc Oc]

Excellent tips all around.  I especially like Dan's example proving you can go directly from ester to lactam.

I agree that between the 2 amines the one forming the 3-membered ring is highly unfavored, so you should be okay there.  HBr and HI are commonly used to remove methyl protecting groups from alcohols.  If you were to use that, there is definitely the possibility that you would hydrolyze your ester as well.  Keep in mind that the product of this deprotection would be the ammonium bromide salt, so you'd need to neutralize and extract your product out (extracting amines from aqueous phase can be a painful process).  However, you might be able to just go directly to Glycomaster's suggestion and add a bunch of base and see if the product cyclizes on its own rather than doing a neutralization/extraction.