Optimized amide binding reaction with heterocyclic compounds and carboxylic acid

A high-yield, scalable, one-pot reaction facilitates the preparation of biologically relevant amide compounds using less reactive nitrogen-containing heterocyclic compounds and carboxylic acid without the use of heat or special equipment.

Amide bonds are important functional groups in medicinal chemistry, accounting for approximately 16% of all reactions performed in drug discovery. Some amide binding reactions using pharmaceutically important nitrogen-containing heterocyclic compounds such as indole, carbazole and pyrrole instead of amines are not efficient using conventional manufacturing methods.

In a recent study, a team of leading chemists developed a novel one-pot reaction using 4-(N,N-dimethylamino)pyridine-N-oxide (DMAPO) catalyst and di-tert-butyl dicarbonate (Boc₂O) for the efficient formation of amide bonds using low-reactivity, nitrogen-containing heterocyclic compounds and carboxylic acid without special equipment or heat.

In an effort to improve the efficiency of N-acylation or amide bond formation of nitrogen-containing heterocyclic compounds or cyclic compounds composed of nitrogen and one or more other elements, a research team from Tohoku University previously reported the successful N-acylation of the heterocyclic compound Indole with carboxylic acid using the Boc₂O/4-(N,N-dimethylamino)pyridine (DMAP)/2,6-lutidine system. However, the reaction required a large excess of indole for a modest yield of the desired product.

In the current study, the research team used DMAPO as a catalyst and Boc instead₂O to generate a more efficient N-acylation reaction that: a) provided high chemical yield with a substrate ratio of 1:1, b) exhibited high functional group tolerance, c) allowed the direct use of carboxylic acid in a one-pot procedure, and d ) tolerated a variety of substrates, e) could be performed under mild and scalable conditions, and f) was easy to perform.

The team reported its findings on January 13 in ChemCatChem.

“Usually the [N-acylation] The reaction is carried out using a dehydrating condensing agent in the presence of an amine (primary amine, secondary amine or aniline) that is highly reactive with carboxylic acid. However, in reactions that use pharmaceutically important nitrogen-containing heterocyclic compounds such as indole, carbazole and pyrrole instead of amines, condensing agents do not efficiently promote the reaction,” said Atsushi Umehara, lead author of the publication and assistant professor in the Graduate School of Biological Sciences at Tohoku University.

“This is due to the low reactivity of nitrogen-containing heterocyclic compounds. Therefore, pre-activated derivatives such as acyl chlorides and acid anhydrides derived from carboxylic acids must be used, but this method is a two-step reaction involving reagent preparation and is inefficient. The use of strong metal bases is also often required, and the narrow range of substrate application is one challenge,” Umehara said.

The team recognized the utility of a more efficient N-acylation reaction for less reactive nitrogen-containing heterocyclic compounds, particularly for pharmaceutical research. Their optimized one-pot reaction produces amide compounds in high yields by reacting compounds such as indole, carbazole, and pyrrole with carboxylic acid, thereby addressing an important weakness in medicinal chemistry. “We have demonstrated the utility of this reaction in the synthesis of more than 120 amide compounds, achieving greater than 85% chemical yields for 104 compounds,” said Umehara.

Importantly, the reaction is efficient for heterocyclic compounds that show low reactivity under conventional reaction conditions, and the yields of the team’s new N-acylation reaction are high even with a 1:1 ratio of a nitrogen-containing heterocyclic compound to a carboxylic acid. The new one-pot reaction conditions also eliminate the lengthy purification steps that were necessary when strong metal bases were required for other N-acylation reaction conditions, and the new protocol requires no heat or special equipment.

Given the accessibility of these novel amide bond reaction conditions, the team predicts that the DMAPO/Boc2O-mediated system will be widely used to form amide bonds in medicinal chemistry. “We anticipate that the reaction developed in this research will have application to the production of a wide range of functional molecules in both industry and academia,” Umehara said. Increasing the efficiency of these amide binding reactions will reduce the cost and time associated with the development of amide compounds in both research and the pharmaceutical industry.