Syntheses Involving Nucleophilic Substitution

FIGURE 22.2 Nucleophil ic substitution in a synthesis of a cyclic amine. 

FIGURE 22.3 Amine synthesis by ring opening of a hindered epoxide. 

FIGURE 22.4 Amino acid synthesis by nucleophilic substitution. 

1(a) The first step here is the epoxidation of the alkene, which is then opened to give the traKS-azido alcohol. The azide is then reduced to the amine by lithium aluminum hydride  

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III. SYNTHESES INVOLVING NUCLEOPHILIC SUBSTITUTION REACTIONS OF AZIDE ION... 

The Williamson synthesis involves nucleophilic substitution of alkoxide ion or phenoxide ion for halide ion it is strictly analogous to the preparation of alcohols by treatment of alkyl halides with aqueous hydroxide (Sec. 15.7). Aryl halides cannot in general be used, because of their low reactivity toward nucleophilic substitution. 

The Williamson synthesis involves nucleophilic substitution of the alkoxide ion for the halide ion. 

Yang J, Gibson HW (1999) A polyketone synthesis involving nucleophilic substitution via carbanions derived from bis(a-aminonitrile)s. 5. A new, well-controlled route to long bisphenol and activated aromatic dihalide monomers. Macromolecules 32 8740-8746... 

The Gabriel-Cromwell aziridine synthesis involves nucleophilic addition of a formal nitrene equivalent to a 2-haloacrylate or similar reagent [29]. Thus, there is an initial Michael addition, followed by protonation and 3-exo-tet ring-closure. Asymmetric variants of the reaction have been reported. N-(2-Bromo)acryloyl camphor-sultam, for example, reacts with a range of amines to give N-substituted (azir-idinyl)acylsultams (Scheme 4.23) [30]. 

A certain amount of phenol, as well as the cresols, is obtained from coal tar (Sec. 12.4). Most of it (probably over 90%) is synthesized. One of the synthetic processes used is the fusion of sodium benzenesulfonate with alkali (Sec. 30.12) another is the Dow process, in which chlorobenzene is allowed to react with aqueous sodium hydroxide at a temperature of about 360°. Like the synthesis of aniline from chlorobenzene (Sec. 22.7), this second reaction involves nucleophilic substitution under conditions that are not generally employed in the laboratory (Sec. 25.4). 

Complexes of the type (ri -arene)Cr(CO)3 are very important from the viewpoint of selective organic synthesis involving aromatic substitution reactions since the tricar-bonylchromium moiety attached to the arene ring can modify its reactivity. Interesting stereo- and regioselective organic syntheses have been developed based on the specific properties of (ri -arene)Cr(CO)3 [32]. A typical example of nucleophilic substitution on the aromatic ring by a carbanion is shown in eq (12). 

There are also many syntheses that involve nucleophilic substitution using a synthon for ammonia. Thus, the azide anion is an excellent nucleophile, and alkyl azides are readily reduced to amines (Figure 22.5), either by hydrogenation, as in this example, or by reduction with lithium aluminum hydride. Hexamethylenetetramine is also an excellent nucleophile and a synthon for ammonia in this case, the final product is released by hydrolysis (Figure 22.6). In the Gabriel synthesis, phthalimide acts as a synthon for ammonia (Figure 22.7). 

Nucleophilic Substitution Route. Commercial synthesis of poly(arylethersulfone)s is accompHshed almost exclusively via the nucleophilic substitution polycondensation route. This synthesis route, discovered at Union Carbide in the early 1960s (3,4), involves reaction of the bisphenol of choice with 4,4 -dichlorodiphenylsulfone in a dipolar aprotic solvent in the presence of an alkaUbase. Examples of dipolar aprotic solvents include A/-methyl-2-pyrrohdinone (NMP), dimethyl acetamide (DMAc), sulfolane, and dimethyl sulfoxide (DMSO). Examples of suitable bases are sodium hydroxide, potassium hydroxide, and potassium carbonate. In the case of polysulfone (PSE) synthesis, the reaction is a two-step process in which the dialkah metal salt of bisphenol A (1) is first formed in situ from bisphenol A [80-05-7] by reaction with the base (eg, two molar equivalents of NaOH),... 

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl halides, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom imdeigoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

The synthesis of nitro dyes is relatively simple, a feature which accounts to a certain extent for their low cost. The synthesis, illustrated in Scheme 6.5 for compounds 140 and 141, generally involves a nucleophilic substitution reaction between an aromatic amine and a chloronitroaromatic compound. The synthesis of C. I. Disperse Yellow 14 (140) involves the reaction of aniline with l-chloro-2,4-dinitroaniline while compound 141 is prepared by reacting aniline (2 mol) with compound 144 (1 mol). 

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) [76]. Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization. 

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