Ullmann acridine synthesis

What is Ullmann acridine synthesis?

In 1902, Ullmann (University of Geneva) first reported a reaction that involves the preparation of acridine derivatives. The reaction utilizes N-arylanthranilic acid as the starting material, which is treated with an acylating agent like polyphosphoric acid (PPA), followed by reduction and dehydration.

Ullmann acridine synthesis - general reaction scheme
Ullmann acridine synthesis

R1, R2 = H, alkyl, aryl, etc. (see list of acronyms)

Although the reaction for the preparation of acridone and acridine derivatives is distinct, it is often associated with the preparation of N-arylanthranilic acid since Ullmann was also involved in the preparation of the latter. Various acylating agents, such as POCl3, H2SO4, (CF3CO)2O, HCl, TFA, or PPA, can be used in this reaction. However, the type of acylating agent used has little effect on the product composition, indicating that the cyclization proceeds via an acylcarbonium ion.

It is worth noting that the preparation of acridines with a substituent at position 3 is challenging since the cyclization of the resulting diphenylamine yields a mixture of 1- and 3-substituted products that cannot be easily separated. Furthermore, acridones can be converted into acridines by reduction with Na/BuOH or Al/Hg/NaOH followed by dehydration with FeCl3/HCl. Alternatively, acridones can react with a Grignard reagent, followed by dehydration, to form 9-substituted acridines. Direct formation of acridines is also possible by cyclizing N-aryl-2-aminobenzaldehyde or 2-(N-aryl)aminophenylketoacid.