Acridines => carboxylic acids

Vinyloxy)butyl-9-acridinecarboxylate, cf.. Figure 3.27, is synthesized from 9-acridine carboxylic acid hydrate and 1,4-butanediol vinyl ether. 

To a solution of oxalic chloride (5 g) in dichloromethane, a solution of diphenyl amine (5 g) in dichloromethane was added dropwise and refluxed for 30 min. The solution was concentrated (50%) and aluminum trichloride (8 g) added in portions. The mixture was refluxed for 45 min and the solvent evaporated. To this residue hydrochloric acid in ice water (1 M) was added and the red-colored precipitate filtered. The precipitate was dissolved in potassium hydroxide (10% in water), refluxed overnight, and poured into hydrochloric acid in ice water (5 M). The yellow acridine-9-carboxylic acid was filtered, washed with water, and dried. 

Acridine-9-carboxylic acid (1 g) was mixed with thionyl chloride (20 mL) and refluxed until a clear solution was obtained. The solution was concentrated and... 

Scheme 4.8 Rebek s trifunctional enolization catalyst including a general base (acridine nitrogen), hydrogen bond donor (carboxylic acid), and a binding group (carboxylate).

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... 

Alkyl radicals for such reactions are available from many sources such as acyl peroxides, alkyl hydroperoxides, particularly by the oxidative decarboxylation of carboxylic acids using peroxy-disulfate catalyzed by silver. Pyridine and various substituted pyridines have been alkylated in the 2-position in high yield by these methods. Quinoline similarly reacts in the 2-, isoquinoline in the 1-, and acridine in the 9-position. Pyrazine and quinoxaline also give high yields of 2-substituted alkyl derivatives <74AHC(16)123). 

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

Subsequent investigations have reinforced earlier evidence for the wide occurrence of hydrogen bonding of azines. Bonding of all the monocyclic azines,many substituted azines, and azinones with water, alcohols, and dilute acids has been studied by electronic absorption spectra and the variation of the effect with changes in the position of the substituent noted. Quinolines and acridines with chloroform, alcohols, phenols, carboxylic acids, aniline, and pyrrole show the influence of hydrogen bonding on... 

Hexahydronicotinic acid (90%) is obtained by catalytic hydrogenation of nicotinic acid at 3 atm. pressure over colloidal platinum. Preparation of the catalyst is described. The 9,10 double bond in the acridine nucleus is reduced at 10° by sodium amalgam in dilute sodium carbonate solution to give 9,10-dihydroacridine-S>-carboxylic acid in 70% yield. 2-Phenyl-cyclohexanecarboxylic acid (96%) is prepared by the selective reduction, of 2-phenylbenzoic acid by a large excess of sodium in refluxing amyl alcohol. ... 

Decarbonylation and Decarboxylation - The photochemical reactions between carboxylic acids such as formic and trifluoroacetic acid and silica surfaces have been studied. The irradiation of diphenylacetic acid in acetonitrile with acridine results in the decarboxylation and the formation of the adduct (102). When the two achiral compounds, acridine and diphenylacetic acid, are cocrystallized a chiral two component molecular crystal is obtained in which the components are present in a 1 1 ratio. Both (—)- and (+)- crystals can be obtained. This crystalline material is photochemically reactive and irradiation brings about decarboxylation and formation of the adduct (102) with an ee of 35%. This compound is accompanied by a low yield of (103) which is formed exclusively on irradiation of the reactants in acetonitrile solution.Photochemical decarboxylation can be brought about by the irradiation of benzilate (104)/ methyl viologen pairs. ... 

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

Reductive alkylation of N-methylacridinium (87) occurs when it is irradiated with carboxylic acid salts. The reaction is thought to proceed by electron transfer from the carboxylate to the excited acrldinium ring followed by decarboxylation of RCOO coupling of the alkyl radical produced with the acridinyl radical then gives (88). A very similar sequence probably occurs in a reaction proposed as a synthetic procedure for decarboxylation of carboxylic acids.In this case an aza-aromatic compound such as acridine is irradiated with a carboxylic acid in benzene in the presence of tert-butyl thiol. The authors propose that a hydrogen bonded acridine-acid complex is excited and that adiabatic proton transfer is followed by electron transfer. This produces RCOO which decarboxylates, and reduction of the alkyl radical then ensues. The major fate of the acridine is coupling to (89) if the reaction is perfonned in the absence of oxygen. 

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).

Fig. 22. Conversion via the acid chloride of a substituted acridine-9-carboxylic acid into an ester...

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