Amines aromatic nucleophilic substitution

G. Aromatic Nucleophilic Substitution with Amines in which the... 

The dichotomy of amine effects in aromatic nucleophilic substitution... 

TABLE 19. Aromatic nucleophilic substitution in non-polar aprotic solvents. Third-order in amine kinetic law144. Reprinted with permission from Reference 144. Copyright (1983) American Chemical Society... 

Some heteroarylamines have been prepared by aromatic nucleophilic substitution of suitable support-bound arylating agents with amines (Table 3.27). This technique has been successfully employed in the synthesis of 2-(alkylamino)pyrimidines [507,508], 2-(arylamino)pyrimidines [509], aminopurines [510-512], and 1,3,5-triazines [513]. When the heteroarene is bound to the support as a thioether, nucleophilic clea-... 

Aryl- and heteroaryl halides can undergo thermal or transition metal catalyzed substitution reactions with amines. These reactions proceed on insoluble supports under conditions similar to those used in solution. Not only halides, but also thiolates [76], nitro groups [76], sulfinates [77,78], and alcoholates [79] can serve as leaving groups for aromatic nucleophilic substitution. 

Non-activated aryl bromides (but not fluorides) can be used as substrates for palla-dium(0)-catalyzed aromatic nucleophilic substitutions with aliphatic or aromatic amines. These reactions require sodium alcoholates or cesium carbonate as a base, and sterically demanding phosphines as ligands. Moreover, high reaction temperatures are often necessary to achieve complete conversion (Entries 7 and 8, Table 10.4 Experimental Procedure 10.1). Unfortunately, the choice of substituents on the amine... 

Support-bound benzimidazoles can be N-arylated by treatment with arylboronic acids in the presence of Cu(OAc)2 (Entry 3, Table 15.15). Benzimidazolones, which can be prepared from resin-bound 1,2-diaminobenzenes and di-iV-succinimidyl carbonate (Entry 8, Table 15.14), can also be N-alkylated on insoluble supports (Entry 4, Table 15.15). Benzimidazole-2-thiones, on the other hand, are generally cleanly S-alkylated (Entry 5, Table 15.15). Examples of amination by aromatic nucleophilic substitution at resin-bound halopurines are given in Section 10.1.2. 

Reactions of 5f/-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-one 71, prepared by reaction of 1,2-diaminobenz-imidazole 72 with acetoacetic ester 73, with different reagents was described, in the search of new heterocycles with biological activity <2002CHE598>. When lactam 71 was treated with aromatic aldehydes in boiling 1-BuOH with addition of piperidine 74, 577-3-arylidene-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-ones 75a-c were obtained (Scheme 7). Coupling lactam 71 with phenyldiazonium chloride 76 in dioxane afforded the 3-phenylazo-substituted tricycle 77. When 71 was treated with phosphorus pentasulfide 78 in boiling dioxane or pyridine, its thio analog 79 was obtained. The reaction proceeded most efficiently when lactam 71 was refluxed with twofold excess of 78 in dry dioxane. These thiones 79 react with ammonia and amines by nucleophilic substitution. When 79 was refluxed with ammonia, benzylamine, piperidine, or morpholine, the 4-amino-substituted tricycles 80a-d were obtained. All the described compounds were identified by NMR, mass spectrometry, and IR spectroscopy. 

Another field of application for active esters is solid-phase synthesis. Some polymer-supported reagents are available commercially (see Fig. 9). The acid is first immobilized on a polymer support as an active ester and the excess reagents are washed away conveniently. Finally, the amide is released by amine treatment. During the cleavage, a limited amount of amine can be used to avoid the presence of excess amine in the final mixture. The acid is loaded onto the resin using classic ester condensation methods for TFP resin 35 (66), HOBt resin 36 (67), and oxime resin 37 (68). In the case of the triazine resin 38, the acid is loaded via an aromatic nucleophilic substitution in the presence of a base (69). 

The effect of a solvent on the rate of the two-step aromatic nucleophilic substitution reactions of primary or secondary amines are sometimes complicated by the acid-base equilibrium (30) and by the fact that the transition state,... 

One of the most historically significant examples of aromatic nucleophilic substitution is the reaction of amines with 2,4-dinitrofluorobenzene. This reaction was used by Sanger " to develop a method for identification of the N-terminal amino acid in proteins, and the process opened the way for structural characterization of proteins and other biopolymers. 

Aromatic nucleophilic substitution An expeditious microwave-assisted S Ar reaction with cyclic amines has been reported for activated aromatic substrates [141] (Eq. 55) ... 

Microwave-assisted solid-phase synthesis of purines on an acid-sensitive meth-oxybenzaldehyde (AMEBA)-linked polystyrene has been reported [50]. The heterocyclic scaffold was first attached to the polymer support via an aromatic nucleophilic substitution reaction by conventional heating in l-methyl-2-pyrrolidinone (NMP) in the presence of N,N-diisopropylethylamine. The key aromatic nucleophilic substitution of the iodine with primary and secondary amines was conducted by microwave heating for 30 min at 200 °C in l-methyl-2-pyrrolidone (Scheme 16.28). After reaction the products were cleaved from the solid support by use of trifluoroacetic acid-water at 60 °C. 

As seen with pyridazines, palladium catalyzed coupling reactions were also frequently applied in the phthalazine field. For example, commercially available 1,4-dichlorophthalazine 185 was aminated to give 186 in good yield by aromatic nucleophilic substitution with A -methylpiperazine <01S699>. Then, 186 was coupled with various substituted arylboronic acids to obtain 187 by Suzuki-type cross-coupling reactions. Best results were obtained with electron-donating substituents on the arylboronic acid. 

There have been a large number of detailed studies, especially involving kinetic measurements, that have helped to determine the reactivity of various nucleophiles, solvent effects, and the finer details of aromatic nucleophilic substitutions proceeding via the addition-elimination mechanism. We will not attempt to summarize these results here, since reviews are available. Carbanions, alkoxides, and amines are all reactive in nucleophflic aromatic substitution and provide most of the cases in which this reaction has been used preparatively. Some examples are given in Scheme 7.7. 

The use of organic microheterogeneous systems for developing new or improving known kinetic-based determinations is progressing well. Many micellar kinetic determinations based on uncatalyzed reactions have involved aromatic nucleophilic substitutions, e.g., reactions between l-fluoro-2,2-dinitrobenzene and primary and secondary amines, phenolic compounds, and thiols. These reactions... 

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