Amide bonds without a coupling reagent

A carboxylic acid and an amine become an amide in the hands of one catalyst, with water as the only stoichiometric byproduct, and the isolated yield matches a coupling-reagent reaction run beside it. The same written procedure is used for an unhindered primary amine, a secondary amine, an electron-poor aniline, and a hindered acid.

Amide formation is one of the reactions a medicinal-chemistry project runs most often, and it is still usually done with a stoichiometric coupling reagent. That reagent is the waste, the cost, and a common cause of epimerization. A catalyst that matches it on the pairs people actually submit, rather than on the pairs a scope table was built around, is the result that would retire the reagent.

Borate and boronic-acid catalysts already make many amides with water as the byproduct. They do not yet do it as one locked procedure across the four classes below.

Procter, Alamillo-Ferrer, Shabbir, Britton, Bučar, Dumon, Rzepa, Burés, Whiting, and Sheppard reported a fluorinated borate, B(OArF)₃, for difficult amides (doi:10.1039/D4SC07744J (opens in a new tab)). On 3-fluorophenylacetic acid with 2-aminopyridine, that borate gave 43 percent yield in an 18-hour screen. Extending the same reaction to 66 hours gave amide 4 in 57 percent isolated yield. Changing the solvent to tert-butyl acetate raised the isolated yields of amides 3 and 4 above 80 percent in 20 hours. The scope that follows is not one recipe: the footnotes use 2 mol percent or 5 mol percent of the isolated borate, or 10 to 15 mol percent of borane–dimethyl sulfide to generate it, in tert-butyl acetate or in toluene, for 20 hours, 24 hours, 40 to 45 hours, or 72 hours. Electron-poor anilines and hindered secondary anilines are reported to react, with toluene chosen for some of them because of side reactions in tert-butyl acetate. 1-Adamantylamine showed low reactivity. Aromatic carboxylic acids, including heterocyclic ones, “proved less reactive, giving low yields even after prolonged reaction times.” A multigram run of one amide gave 59 percent yield at 5 mol percent catalyst, and another gave 71 percent. In the same screen, 2-chlorophenylboronic acid gave no amide from the aminopyridine pair, and a DATB catalyst gave 20 percent. On the easier pair of benzoic acid and benzylamine, 10 mol percent of 2-chlorophenylboronic acid gave 79 percent.

That is a real advance on coordinating and electron-poor amines, bought with a change of solvent, loading, and time, and with aromatic acids left at low yield. It is not one procedure, frozen before the pairs are known, matched against HATU on a blinded set.

The grading laboratory already runs amide couplings. A laboratory that would be learning the workup during the test does not grade this problem.

The laboratory preregisters 12 acid–amine pairs. At least three pairs use a primary aliphatic amine, three a secondary amine, three an aniline or other electron-poor amine, and three a hindered acid, either α,α-disubstituted or an ortho-substituted benzoic acid. The pairs are disclosed together. No pair is one of the example numbers in the 2025 Sheppard scope.

Within 24 hours, and with no experiment on the test pairs, the attempt submits one catalyst system and one procedure: identity, loading at or below 5 mol percent, solvent, temperature, time, and workup. The procedure may name a drying agent. It may not name a stoichiometric activator. One backup procedure may be submitted at the same time. The backup, if it is used, is applied to every pair or to none. A footnote that changes the solvent for the anilines and the loading for the hindered acids is a second procedure, and it is not allowed unless it was the single backup and is then used for the whole set.

The laboratory runs that procedure, and runs a HATU comparison on the same pair, same scale, same day. The HATU conditions are fixed so they cannot be weakened: 1.1 equivalents of HATU, 2 equivalents of N,N-diisopropylethylamine, N,N-dimethylformamide, 0 °C to room temperature, 12 hours, then the same chromatography conditions used for the catalytic product. Both products are isolated. The catalytic product is at least 95 percent pure by quantitative proton NMR. Yields are isolated masses of amide divided by theoretical mass.

On at least 10 of the 12 pairs, the isolated yield of the catalytic amide is at least the isolated yield of the matched HATU reaction and at least 40 percent, at the purity above, and no stoichiometric byproduct other than water is formed. The 10 include at least 2 pairs from each of the four classes.

Ten of twelve, the class floors, 5 mol percent, 40 percent, and 95 percent purity are pass marks defined here. The comparison with HATU is the side-by-side experiment, not a universal percentage copied from a paper. Forty percent is a floor so that matching a failed HATU reaction does not count. It sits below the yields above 80 percent, and below the 59 and 71 percent multigram yields, that Procter and co-workers report for individual amides after per-substrate adjustment. A HATU reaction that was run badly does not help: if the HATU yield on an unhindered primary amine is below 70 percent, that pair is repeated. Seventy percent is a pass mark for the control on that subclass only.

Each pair has a no-catalyst reaction, same solvent, temperature, and time. It must not reach the catalytic yield. If the uncatalyzed reaction matches the catalyzed one, that pair does not count as catalysis.

The HATU product and the catalytic product must be the same amide by NMR and high-resolution mass spectrometry. A rearranged product fails even if the mass is high. Where the acid or the amine has a stereocenter that can epimerize, the enantiomer or diastereomer ratio of the catalytic amide must be at least that of the HATU product run beside it. A more epimerized catalytic product fails that pair.

Water is the stoichiometric byproduct required by the procedure’s equation. A hidden activator that is consumed one-to-one with the acid fails the pair. The laboratory checks the spent reaction for the coupling reagents named in “Not allowed” if the procedure’s mass balance suggests one was present.

Any catalyst, including an enzyme, within the loading rule. A drying agent that is not a coupling reagent. Molecular sieves. One backup procedure submitted before any experiment on the test pairs, used for every pair or for none.

Carbodiimides, uronium salts, phosphonium salts, and other stoichiometric coupling reagents. Preforming an acid chloride or a mixed anhydride with a stoichiometric activator and then calling the acylation step catalytic. More than 5 mol percent of catalyst, including a borane precursor counted as the boron it delivers. A different solvent, temperature, or loading for one class unless that change is the single backup procedure applied to every pair. Editing conditions after the first yield is known. Choosing the twelve pairs from a published scope table of the same catalyst.

At least 8 of the 12 pairs meet the yield, purity, and HATU comparison, every failure is one of the hindered acids, and each of the other three classes has at least two passes. Eight of twelve, confined to that class, is the lesser bar. It shows a general unhindered amidation and an unsolved hindered one. It is not a solution.

Yields are judged against the side-by-side HATU experiment rather than against a published yield. The 5 mol percent ceiling, the 10-of-12 count, the class floors, the 40 percent absolute floor, the 70 percent floor on unhindered HATU controls, and the partial-success rule are pass marks defined here.

The 2025 scope is Procter and co-workers, Chemical Science, 2025, 16, 4718–4724, doi:10.1039/D4SC07744J (opens in a new tab). The 43 percent screen yield, the 57 percent isolated yield at 66 hours, the yields above 80 percent after the solvent change, the low yields on aromatic acids, the low reactivity of 1-adamantylamine, the 59 and 71 percent multigram yields, the 0 percent and 20 percent comparison catalysts, and the 79 percent yield with 10 mol percent 2-chlorophenylboronic acid are taken from that paper. The variation in loading, solvent, and time is taken from the footnotes of its scope scheme.

Purity uses the quantitative proton NMR assay of Pauli and co-workers, Journal of Medicinal Chemistry, 2014, 57, 9220–9231, doi:10.1021/jm500734a (opens in a new tab).