Came across two interesting articles. Boric acid is cheap and useful stuff, and apparently it can catalyse formation of amides from carboxylic acids and amines. What's more, it seems to cause little racemisation. The yields are good, not perfect, but the procedure is so simple and could probably be optimised very nicely.
Boric Acid Catalyzed Amidation in the Synthesis of Active Pharmaceutical Ingredients concerns refluxing boric acid, the carboxylic acid and amine in toluene or xylene, for extended periods of time but even so it's interesting.
Am I right in thinking that a solid dehydration agent, magnesium sulphate maybe, might improve the yield or speed? Also if microwaves dramatically improve the yield of simply heating the carb. acid with amine, they might be useful here.
The thermal and boron-catalysed direct amide formation reactions: mechanistically understudied yet important processes goes into more detail about the mechanism (obviously) and talks about the fancier versions of boron reagent. By their reckoning, R-CO-OB(OH)2 type intermediates are responsible. There was this interesting mention:
- But I figure if boric acid itself can do the job in some situations (above) then catecholboric acid might be useful stuff. It ought to form rather easily, reflux in solvent perhaps simply fusing the dry materials together; http://www.fpl.fs.fed.us/documnts/pdf1999/chen99a.pdf wherein catechol and boric acid can be refluxed in DMF to form "Biboric Acid B" and an adduct from the DMF.
Also, it mentions the tetrachlorocatechol boric acid derivative. This here (4,5,6,7-Tetrachlorobenzo[d][1,3,2]dioxaborol- 2-ol as an Effective Catalyst for the Amide Condensation of Sterically Demanding Carboxylic Acids) mentions it can be formed in situ from the tetrachlorocatechol and boric acid. Fairly good yields, using xylene and water removed by azeotropic reflux.
Hope you folks find this method useful. To my knowledge it hasn't been brought up in this context. [EDIT - attached files]
Boric Acid Catalyzed Amidation in the Synthesis of Active Pharmaceutical Ingredients concerns refluxing boric acid, the carboxylic acid and amine in toluene or xylene, for extended periods of time but even so it's interesting.
Quote
The liberated water was continuously removed from the reaction. It was observed that aromatic acids or amines require a longer time and higher temperatures, while aliphatic acids and amines require a relatively shorter time and lower temperatures for the completion of reactions. Additionally, the boric acid catalyzed amidation has several advantages over other processes in terms of eliminating byproducts, minimizing the number of impurities, and affording products in good yields and purity.
Am I right in thinking that a solid dehydration agent, magnesium sulphate maybe, might improve the yield or speed? Also if microwaves dramatically improve the yield of simply heating the carb. acid with amine, they might be useful here.
The thermal and boron-catalysed direct amide formation reactions: mechanistically understudied yet important processes goes into more detail about the mechanism (obviously) and talks about the fancier versions of boron reagent. By their reckoning, R-CO-OB(OH)2 type intermediates are responsible. There was this interesting mention:
Quote
Ganem et al. (27) reported that carboxylic acids and amines condense readily to form amides in the presence of stoichiometric amounts of catecholborane 12, but under much milder conditions, i.e. THF, ?78 °C to room temperature as outlined in Scheme 6.
- But I figure if boric acid itself can do the job in some situations (above) then catecholboric acid might be useful stuff. It ought to form rather easily, reflux in solvent perhaps simply fusing the dry materials together; http://www.fpl.fs.fed.us/documnts/pdf1999/chen99a.pdf wherein catechol and boric acid can be refluxed in DMF to form "Biboric Acid B" and an adduct from the DMF.
Also, it mentions the tetrachlorocatechol boric acid derivative. This here (4,5,6,7-Tetrachlorobenzo[d][1,3,2]dioxaborol- 2-ol as an Effective Catalyst for the Amide Condensation of Sterically Demanding Carboxylic Acids) mentions it can be formed in situ from the tetrachlorocatechol and boric acid. Fairly good yields, using xylene and water removed by azeotropic reflux.
Hope you folks find this method useful. To my knowledge it hasn't been brought up in this context. [EDIT - attached files]
The thermal and boron catalysed direct amide formation reactions mechanistically understudied yet important processes.htm