[Babcock_Hall]

We have previously used 4-nitrophenylesters of nicotinic acid to make amide bonds, following some work by Karl Folkers and collaborators.  We are trying to do the same with isonicotinate esters, but we are having less success.  We follow the reaction by quantitating the production of 4-nitrophenolate ion by spectrophotometry.  The first attempt produced about 75% of the theoretical amount of 4-NP, but the product was not seen in the extractions.  The second attempt is proceeding very slowly.  We are considering adding DMAP to this reaction and/or future reactions.  DMAP has been used as a catalyst in amide bond formation from acyl chlorides.  Does anyone have any thoughts on the wisdom of this approach?  Thanks in advance.

[discodermolide]

We have previously used 4-nitrophenylesters of nicotinic acid to make amide bonds, following some work by Karl Folkers and collaborators.  We are trying to do the same with isonicotinate esters, but we are having less success.  We follow the reaction by quantitating the production of 4-nitrophenolate ion by spectrophotometry.  The first attempt produced about 75% of the theoretical amount of 4-NP, but the product was not seen in the extractions.  The second attempt is proceeding very slowly.  We are considering adding DMAP to this reaction and/or future reactions.  DMAP has been used as a catalyst in amide bond formation from acyl chlorides.  Does anyone have any thoughts on the wisdom of this approach?  Thanks in advance.

DMAP is quite effective as a catalyst in these reactions. I believe it proceeds via an "acycl dmap" intermediate.
It is certainly worth a shot.
You may be able to use imidazole as a catalyst for this as well.

[OC pro]

DMAP may help. But i would convert your acid into acid chloride using e.g thionyl chloride. You will obtain isonicotinic acid chloride hydro chloride (should precipitate out). The acyl chloride will react easily with amines (in presence of base).

[BobfromNC]

It should work, and you don't have to worry about racemization, so DMAP should be OK.   You might also consider the pentafluorophenyl esters, they also work well like the nitrophenyl ones, but I believe they might be more reactive.  We used to use them for just that type of reaction.  

[Babcock_Hall]

OC Pro,

Our amine is alpha-BOC-protected lysine, and we chose this route so that we could leave the carboxylic acid group of lysine unprotected.  We would have to protect this group if we went to the acid chloride.  We have previously protected carboxylic acids as the 4-methoxybenzylesters and had modest success with that tactic.  We did not have any luck trying to make tert-butylesters, however.

BobfromNC,

I have seen that group used on occasion but never studied it.  We'll have to check into the cost of pentafluorophenylphenol, which could be an issue.

[Babcock_Hall]

We prepared a large amount of 4-nitrophenyl isonicotinate, and we are currently using BOC-ornithine or lysine as nucleophiles and DMF as the solvent.  The reactions seem more sluggish than the same reactions with the nicotinate ester which seemed to be complete in about a week.  We have added DMAP to two of our reactions and imidazole to a third reaction.  We set up a fourth reaction without a catalyst.  The effect of the catalyst seems modest (33% completion versus 18% completion w/o DMAP).

In retrospect I wish that we had used different conditions altogether (or even a different strategy).  However, we committed enough material to these reactions to make it worth our time to make them work, if possible.  I was thinking of adding heat (60-80 °C).  Does anyone have any suggestions or ideas.  Thanks in advance.

[Babcock_Hall]

I just worked with my students to uncover the actual problem with the reactions.  Much of the mass of the 4-nitrophenyl isonicotinate was actually ethyl acetate, a solvent used in its purification.  We first began to suspect this when we tried a complete hydrolysis of a few milligrams of material and did not get anywhere near the theoretical change in absorbance that 4-nitrophenolate was expected to produce.  BTW the ability to quantitate the extent of reaction is one nice feature of 4-nitrophenol-based esters.

[Dan]

You might also be able to do the coupling with the free acid and the free amine with a tris-(2,2,2-trifluoroethyl)borate catalyst. See the work of Tom Sheppard (UCL, London).

They have definitely managed to use Boc-protected amino acids in these reactions. Not sure about (iso)nicotinates. I'm not intimately familiar with the scope, I just saw a poster on it yesterday at a conference so some of this may still be unpublished. Here is a reference from last year:

http://pubs.rsc.org/en/content/articlelanding/2011/ob/c0ob01069c