Amide couplings are one of the least problematic b...

2012-01-18T18:22:35.573-06:00

Amide couplings are one of the least problematic bond-forming reactions in general but anyone who worked on peptidomimetics and or in combichem can confirm that combination of hindered substrates and especially acylation of amines with electron-withdrawing substituents is a problem. I remember using a combination of acyl chloride and several equivalents of silver cyanide in DMEU in one particularly nasty acylations, this being the only one method that worked. Yet another problem is with unstable substrates that crap up during activation/coupling.

With regards to atom economy, I find it disingenuous when people obsess about the molecular weight of a reagent while at the same time running large-column chromatographic purification of their products, a method that consume gallons of organic solvents per gram of purified product. Also I remember once using triphenyl phosphine for reduction of arylsulfonyl chloride to arylthiol. This requires about 3.5-4 equivs of PPh3 and with molecular weight of 250+ a reduction done on a moderate scale meant that I loaded a kilo of PPh3 into the flask and then had to remove a kilo of PPh3O from the reaction mix, but it was not a major problem once I found a system where the phosphine crap was soluble and the thiol product was not.

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Amide couplings are one of the least problematic b...