Acridine-9-carboxylic acid synthesis

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

Many acridines and benzacridines have been synthesized by the Bernthsen reaction (l884LA(224)l) in which a diphenylamine is heated with a carboxylic acid and zinc chloride, with or without aluminum chloride. The reaction has been reviewed (73HC(9)141), and will be outlined here. The yields are not generally high one of the better examples is the synthesis of 2-chloro-9-methylacridine (312) (63BCJ1477). In the synthesis of the... 

In the Bernthsen synthesis, diphenylamine 61 and carboxylic acids form 9-substituted acridines 62 (Scheme 31). 

BERNTHSEN Acridine Synthesis Acridine synthesis from diphenylamine and carboxylic acids (see 1st edition). 

Ironically, the synthesis and chemiluminescent properties of some of these important compounds were first reported in the 1920s i.e., acridine-9-carboxylic acid, a precursor of acridinium esters, was synthesized in 1928 (L7), which was the same year that Albrecht described the chemiluminescence of luminol (A8). The emission from lucigenin, a 6is-acridinium analog, was reported 7 years later by Gleu and Petsch (G7). 

Fig. 21. Synthesis of acridine-9-carboxylic acid in a two-stage reaction starting with acridine. This method was adopted by Weeks et at. (W6), based on the original scheme by Lehmstedt and Wirth (L7).

Acridines are an important structural feature of many natural products and medicinally important compounds. They can be produced in a straightforward manner by a Friedel-Crafts reaction, the Bernthsen acridine synthesis, 1 9 which couples diaryl amines (such as diphenylamine) with a carboxylic acid (such as benzoic acid) in the presence of a Lewis acid (zinc chloride, ZnCl2, is a typical reagent). Heating to 260°C (10 h) gave a 48% yield of acridine 317.1 9 ... 

Diphenylamine reacts with carboxylic acids in the presence of Lewis acids (e.g. AICI3, ZnCl2) forming 9-substituted acridines 20 (Bernthsen synthesis) ... 

This reaction was first reported by Bernthsen in 1878It is one of the earliest methods for the synthesis of acridine by heating diphenylamine hydrochloride with benzonitrile. Therefore, this reaction is generally known as the Bernthsen reaction. In the modified method, the mixture of diphenylamine, an aromatic or aliphatic carboxylic acid, and zinc chloride is heated at 200-270°C for 20 Heating zinc chloride with fV-acyldiphenylamine or a mixture of diphenylamine and acyl chloride also affords acridines. ... 

A possible way to induce selectivity in the photodecarboxylation process could be through photosensitized reactions in the soHd state. In fact, when a two-component molecular crystal of phenanthridine and 3-indoleacetic acid is irradiated at low temperature (-70°C), 3-methyHndole is formed in high yield as the sole product by contrast, when the same reaction is carried out in acetonitrile solution, four products are obtained.Furthermore, irradiation of two-component molecular crystals of arylalkyl carboxylic acids with stoichiometric amounts of electron acceptor causes decarboxylative condensation between the two components with important selectivities. " Thus, irradiation of (S)-naproxen in a chiral crystal with 1,2,4,5-tetracyanobenzene produces a decarboxylated condensation product retaining the initial chirality." Photolysis of an enantiomorphous bimolecular crystal of acridine with the R or S enantiomer of 2-phenylpropionic acid causes stereoselective condensation to give three optically active products. An absolute asymmetric synthesis has also been achieved by the enantioselective decarboxylative condensation of a chiral molecular crystal formed from achiral diphenylacetic acid and acridine (Scheme 9). ... 

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