[uglepik]

Hi guys!

I'm trying to couple an alcohol to an amine using carbonyldiimidazole (CDI). The amine is on a solid support, where the terminal amino acid containing the amine is a beta-alanine residue, making the amine primary. I have activated the alcohol (which is also primary) with CDI and isolated the activated compound. But... No matter how much I kick the mixture around (solvent is chloroform/DMF 3:1) with elevated temperatures and week-long agitation with or without base (DIPEA) the stuff doesn't seem to react fully. I monitor by Kaiser test and it DOES seem that there is some reaction occuring (the intensity of the Kaiser test goes down) and also, I can cleave my desired product off to some degree. So, reaction takes place, but for some reason the Kaiser test continues to give a significantly blue result.

So, now I'm starting to thinking if the carbamate could in some way hydrolyze during kaiser test (heating to around 100 degrees for a couple of minutes) and subsequently react with the ninhydrin. I consider it unlikely but my experience with carbamates is rather limited... Needless to say, I am super careful when I wash my resin before Kaiser test and I am careful not to leave traces of DMF - I wash twice with DCM and dry the resin before Kaiser test.

Any thoughts?

[discodermolide]

Hi guys!

I'm trying to couple an alcohol to an amine using carbonyldiimidazole (CDI). The amine is on a solid support, where the terminal amino acid containing the amine is a beta-alanine residue, making the amine primary. I have activated the alcohol (which is also primary) with CDI and isolated the activated compound. But... No matter how much I kick the mixture around (solvent is chloroform/DMF 3:1) with elevated temperatures and week-long agitation with or without base (DIPEA) the stuff doesn't seem to react fully. I monitor by Kaiser test and it DOES seem that there is some reaction occuring (the intensity of the Kaiser test goes down) and also, I can cleave my desired product off to some degree. So, reaction takes place, but for some reason the Kaiser test continues to give a significantly blue result.

So, now I'm starting to thinking if the carbamate could in some way hydrolyze during kaiser test (heating to around 100 degrees for a couple of minutes) and subsequently react with the ninhydrin. I consider it unlikely but my experience with carbamates is rather limited... Needless to say, I am super careful when I wash my resin before Kaiser test and I am careful not to leave traces of DMF - I wash twice with DCM and dry the resin before Kaiser test.

Any thoughts?

Carbamates react with ninhydrin but give a weaker response than amines

[Doc Oc]

You could try phosgene, although that stuff is pretty nasty and that's why most people prefer CDI.  Sometimes order of operations can make a big difference, so try reacting the CDI with the amine first, then add the alcohol.

[Honclbrif]

I don't have a ton of experience with CDI, but I like the thought of reacting the solid-supported amine with the CDI first, then adding the alcohol. Reacting the alcohol first may be generating a symmetric carbonate which probably isn't particularly reactive toward your amine.

Since your amine is solid-supported, the likelihood of forming a symmetric urea is probably pretty low, instead you would get the asymmetric imidazolyl-urea which would be ready to to capture your alcohol.

You might also be able to react your alcohol with p-nitrophenylchloroformate, then react that product with the amine to get your carbamate. As an added bonus, when the amine reacts, it spits out an equivalent of p-nitrophenol which allows you to monitor the course of the reaction spectroscopically.

I'd try this before screwing around with phosgene.

[uglepik]

Discodermilide: Interesting that the carbamate should react with ninhydrin. I haven't heard that before. Do have an idea as to what the mechanism for the reaction might be, does it involve hydrolysis? (I know it's difficult to explain here, without chemdraw and the like).

I did indeed try reacting the CDI with amine on the solid support first and then adding the alcohol - both with and without base - this didn't lead to any reaction. Kaiser tests were positive and quantification of the added alcohol indicated that nothing had coupled. I did not try to cleave the resin after this experiment, for which reason I cannot 100% rule out that it reacted. I only tried it once however, and it would indeed be a very facile approach. However, I do think that the higher nucleophilicity of the amine makes it better to have the amine attack than the alcohol.

As it turns out, I am actually able to cleave quite large amounts of product (desired) off my resin, in spite of the kaiser test being (slightly) positive. In light of what discodermilide said, that could mean that actually I achieve completion but the test still comes out positive. When I understand this better I might play around more with activating the amine on the resin, and perhaps other activating agents.

Thanks for your advice!

[discodermolide]

Discodermilide: Interesting that the carbamate should react with ninhydrin. I haven't heard that before. Do have an idea as to what the mechanism for the reaction might be, does it involve hydrolysis? (I know it's difficult to explain here, without chemdraw and the like).

I did indeed try reacting the CDI with amine on the solid support first and then adding the alcohol - both with and without base - this didn't lead to any reaction. Kaiser tests were positive and quantification of the added alcohol indicated that nothing had coupled. I did not try to cleave the resin after this experiment, for which reason I cannot 100% rule out that it reacted. I only tried it once however, and it would indeed be a very facile approach. However, I do think that the higher nucleophilicity of the amine makes it better to have the amine attack than the alcohol.

As it turns out, I am actually able to cleave quite large amounts of product (desired) off my resin, in spite of the kaiser test being (slightly) positive. In light of what discodermilide said, that could mean that actually I achieve completion but the test still comes out positive. When I understand this better I might play around more with activating the amine on the resin, and perhaps other activating agents.

Thanks for your advice!

Carbamates have a basic nitrogen atom which can react with other chloroformates or (Boc)2O. It also reacts with ninhydrin under forcing conditions, i.e. heat, which, depending on the carbamate, may involve some cleavage to the amine. The colour intensity is nowhere near that of an amine but they do give a response.