Acridine electrophilic substitution

Reactions of dibenzopyridines show analogies with pyridine, quinoline and isoquinoline. Acridine and phenanthridine are A-protonated by strong protic acids, iV-alkylated by alkyl halides and A-oxidized by peroxy acids. Electrophilic substitutions of acridine often result in disubstitution at the 2- and 7-positions (e.g. nitration giving 3), whereas those of phenanthridine occur at different positions (e.g. nitration mainly at the 1- and 10-position yielding 4 and 5) ... 

A-Methylacridones are synthesized from 2-(A-methyl-A-phenylamino)benzaldehydes in DMF using Sc(OTf)3 as the catalyst and Na2S04 as additive via dehydrogenative cyclization. There are two primary processes in the transformation the aldehyde first coordinates with Sc(OTf)3 and induces the aromatic electrophilic substitution (5eAt) reaction to form the active intermediate Af-methyl-acridin-9-ol, which is then quickly oxidized in situ to afford the acridones. ... 

Amino-2,1,3-benzothiadiazole (237) is convertible into its anthranilic acid derivative (238), which is cyclized by phosphorus oxychloride to 6-chloro-[l,2,5]thiadiazolo[3,4-c]acridine (239). Replacement of its 6-halogeno-substituent produces derivatives such as (240). An analogous series of reactions provides 7,8,9,10-tetrahydro-analogues. The condensation of (237) and alkyl 2-oxocyclopentanecarboxylate yields derivatives of the [1,2,5]-thiadiazolo[3,4-h]quinoline ring system such as (241)—(243). Electrophilic substitutions of naphtho[l,2-d][2,l,3]thiadiazole (244) have been studied in some detail. Nitration produces a mixture of the 6- and... 

Several routes to benz[c]acridines involve electrophilic aromatic substitution to form the heterocyclic ring. Thus, 9-nitrobenz[c]acridine results from the cyclisation of the 2-(l-naphtlylamino)benzaldehyde derived from 1-naphthylamine and 2-fluoro-5-nitrobenzaldehyde (J. Rosevear and J.F.K. Wilshire, Austral. J. Qiem., 1981, 34, 839). The reaction between a ff-aryl-l-naphthylamine and acetic anhydride has been used to synthesise 9- and ll-hydroxy-7-methylbenz[c]acridines and cyclisation of partially reduced 2-(l-naphtltylamino)benzoic acid by phosphorus oxychloride affords the 7-chloro-l,2,3,4-tetralydro derivative (B.V. Lap et ai,y J. heterocyclic Chem., 1983, 20, 281). 

The copper-catalyzed cascade annulation of nitriles, diaryliodonium salts, and alkynes was recently described by Chen and coworkers. N-Arylation of the nitrile resulted in an V-arylnitrilium intermediate, which was trapped by the aUcyne and subsequently underwent electrophilic annulation to yield substituted quinolines (Scheme 6d) [107]. The concept was later varied to reach polycyclic quinolines, quinazolines, quinazolinimine, and acridine scaffolds [108—110], A similar cascade reaction delivered iminobenzoxazines by N-aiylation of ort/io-cyanoanilides followed by C-O cyclization [111], and the reactimi of nitriles with [1,1-biphenyl]-derived iodonium salts resulted in phenanthiidines [112]. The corresponding C-arylation cascade reactions are discussed in Sect. 4.3. 

Sufficiently electrophilic aromatic compounds can effect substitution into pyrroles. Thus, acylpyridinium compounds give products formulated in the manner of (14), though the evidence for attachment at C(4> in the pyridine nucleus, rather than at C(2), is not conclusive - . In contrast, the product from 2-ethoxy-3,4-dimethylpyrrole, ethyl chloroformate and pyridine is formulated as the fully aromatized 3,4-dimethyl-2,5-di(4-pyridyl)pyrrole. Pyrroles react with acridine, giving either complexes of 9-(2-pyrrolyl)acridan with acridine, or 9-(2-pyrrolyl)acridine2 . 1-Methylpyrrole does not react with acridine, but 2,5-dimethylpyrrole reacts at both j8-positions. 

Ellman and coworkers reported a new [3+3] annulation reaction for the preparation of acridines and phenazines by Rh(III)-catalyzed C-H amination of aromatic imines and azobenzenes with aromatic azides. The reaction mechanism proceeds by C-H activation followed by intramolecular electrophilic aromatic substitution and aromatization to offer the respective products. Equations (5.81)-(5.83) illustrate that a broad range of acridines and phenazines can be generated with diverse functionality [44]. 

Scheme 39 shows a formal [3 + 3] annulation of aromatic azides 112 with aromatic imines proceeding through a cascade process of Rh(III)-cata-lyzed amination followed by an intramolecular electrophilic aromatic substitution and aromatization to prepare the acridines 113 and can be classified as a type B ring closure. The reaction can be performed starting from aldehydes 111 which form imines in situ, and these direct the CH amination. Benzyl-amine proved to be the best amine, and magnesium sulfate was appHed as a water scavenger. The substrate scope was examined, which is in part shown in Scheme 39 (2013JA12548). 

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