Aromatic nucleophilic substitution synthesis

The first step in this scheme is a classical aromatic nucleophilic substitution. Details of the method have been expounded (14—17). References 14 and 15 are concerned with the synthesis of the diaryl hahde intermediate whereas References 16 and 17 discuss the synthesis of the polymers, with emphasis on the polymerisation of PPSF by this route. 

Synthesis of the first of the antileprosy drugs, dapsone (219), starts with aromatic nucleophilic substitution of the... 

Scheme 13.13 Examples of aromatic nucleophilic substitutions used in the synthesis of1 sF-labeled radiopharmaceuticals.

Monomer/Oligomer Synthesis. The first two steps in the four step reaction sequence of Figure 1 are capable of producing both monomer and oligomer. The first step, aromatic nucleophilic substitution, is a polymer forming reaction under the correct stoichiometric conditions. In order to favor the formation of monomer with a small amount of oligomer, the substitution was carried out at a 4 1 ratio of diol to dichlorodiphenyl sulfone. This led to a predominantly monomeric product (IV) with only the requirement that the excess diol be removed from the product to eliminate the potential presence of low molecular weight species in later reactions. 

For a review of copper-assisted aromatic nucleophilic substitution, sec Lindley Tetrahedron 1984, 40. 1433-1456. "For a review of the Ullmann ether synthesis, see Moroz Shvartsbcrg Russ. Chem. Rev. 1974, 43. 679-689. Wcingarten J. Org. Chem. 1964, 29. 977. 3624. 

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-... 

Acceptor-substituted haloarenes have been successfully used to O-arylate phenols by aromatic nucleophilic substitution (Table 7.14). The most common arylating agents are 2-fluoro-l-nitroarenes, 2-halopyridines, 2-halopyrimidines, and 2-halotriazines. When sufficiently reactive haloarenes are used, the reaction proceeds smoothly with either the arylating agent or the phenol linked to the support. The thallium(III) nitrate catalyzed arylation of phenols with aryl iodides has been used for macrocycli-zations on solid phase [184], Burgess and co-workers have developed a solid-phase synthesis of 3-turri mimetics based on ring-closure by aromatic nucleophilic substitution (Entry 4, Table 7.14 see also Table 10.5). Phenols, alkylamines, and thiols have been successfully used as nucleophiles for this type of macrocyclization [185],... 

In addition to sulfone, phenyl units, and ether moieties, the main backbone of polysulfones can contain a number of other connecting units. The most notable such connecting group is the isopropylidene linkage which is part of the repeat unit of the well-known bisphenol A-based polysulfone. It is difficult to clearly describe the chemical makeup of polysulfones without reference to the chemistry used to synthesize them. There are several routes for the synthesis of polysulfones, but the one which has proved to be most practical and versatile over the years is by aromatic nucleophilic substitution. This polycondensation route is based on reaction of essentially equimolar quantities of 4,4,-dihalodiphenylsulfone (usually dichlorodiphenylsulfone (DCDPS)) with a bisphenol in the presence of base thereby forming the aromatic ether bonds and eliminating an alkali salt as a by-product. This route is employed almost exclusively for the manufacture of polysulfones on a commercial scale. 

It is comparable to crown ethers or R4NBr for phase-transfer catalyzed aliphatic nucleophilic substitutions in addition it catalyzes aromatic nucleophilic substitutions such as the Ullmann synthesis. 

A much more general method for acyl silane synthesis involving silyl diazo intermediates is illustrated in Scheme 1688. The lithiated derivative of trimethylsilyl diazomethane reacts smoothly with alkyl halides in THF solution to give a-trimethylsilyl diazoalkanes in good yields. Oxidative cleavage of the diazo moiety is effected using 3-chloroperbenzoic acid in benzene solution, to give access to a wide variety of acyl silanes in yields of up to 71%. A phosphate buffer (pH 7.6) is used to prevent side reactions. Aromatic acyl silanes clearly cannot be prepared by this chemistry since an aromatic nucleophilic substitution reaction would be required. 

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). 

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