Nucleophilic substitution derivatives

Nucleophilic substitution of benzene itself is not possible but the halogeno derivatives undergo nucleophilic displacement or elimination reactions (see arynes). Substituents located in the 1,2 positions are called ortho- 1,3 meta- and 1,4 para-. 

The Peterson reaction has two more advantages over the Wittig reaction 1. it is sometimes less vulnerable to sterical hindrance, and 2. groups, which are susceptible to nucleophilic substitution, are not attacked by silylated carbanions. The introduction of a methylene group into a sterically hindered ketone (R.K. Boeckman, Jr., 1973) and the syntheses of olefins with sulfur, selenium, silicon, or tin substituents (D. Seebach, 1973 B.T. Grdbel, 1974, 1977) illustrate useful applications. The reaction is, however, more limited and time consuming than the Wittig reaction, since metallated silicon derivatives are difficult to synthesize and their reactions are rarely stereoselective (T.H. Chan, 1974 ... 

As is broadly true for aromatic compounds, the a- or benzylic position of alkyl substituents exhibits special reactivity. This includes susceptibility to radical reactions, because of the. stabilization provided the radical intermediates. In indole derivatives, the reactivity of a-substituents towards nucleophilic substitution is greatly enhanced by participation of the indole nitrogen. This effect is strongest at C3, but is also present at C2 and to some extent in the carbocyclic ring. The effect is enhanced by N-deprotonation. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Piperazinothiazoies (2) were obtained by such a replacement reaction, Cu powder being used as catalyst (25. 26). 2-Piperidinothiazoles are obtained in a similar way (Scheme 2) (27). This catalytic reaction has been postulated in the case of benzene derivatives as a nucleophilic substitution on the copper-complexed halide in which the halogen possesses a positive character by coordination (29). For heterocyclic compounds the coordination probably occurs on the ring nitrogen. 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

Illustrate the stereochemistry associated with unimolecular nucleophilic substitution by con structmg molecular models of cis 4 tert butylcyclohexyl bromide its derived carbocation and the alcohols formed from it by hydrolysis under S l conditions... 

Ethylene oxide is a very reactive substance It reacts rapidly and exothermically with anionic nucleophiles to yield 2 substituted derivatives of ethanol by cleaving the car bon-oxygen bond of the nng... 

As we ve just seen nucleophilic ring opening of ethylene oxide yields 2 substituted derivatives of ethanol Those reactions involved nucleophilic attack on the carbon of the ring under neutral or basic conditions Other nucleophilic ring openings of epoxides like wise give 2 substituted derivatives of ethanol but either involve an acid as a reactant or occur under conditions of acid catalysis... 

Rifamycin S also undergoes conjugate addition reactions to the quinone ring by a variety of nucleophiles including ammonia, primary and secondary amines, mercaptans, carbanions, and enamines giving the C-3 substituted derivatives (38) of rifamycin SV (117,120,121). Many of the derivatives show excellent antibacterial properties (109,118,122,123). The 3-cycHc amino derivatives of rifamycin SV also inhibit the polymerase of RNA tumor vimses (123,124). 

The apphcation of bimolecular, nucleophilic substitution (S ) reactions to sucrose sulfonates has led to a number of deoxhalogeno derivatives. Selective displacement reactions of tosyl (79,85), mesyl (86), and tripsyl (84,87) derivatives of sucrose with different nucleophiles have been reported. The order of reactivity of the sulfonate groups in sucrose toward reaction has been found to be 6 > 6 > 4 > 1. ... 

Nucleophilic Substitutions of Benzene Derivatives. Benzene itself does not normally react with nucleophiles such as haUde ions, cyanide, hydroxide, or alkoxides (7). However, aromatic rings containing one or more electron-withdrawing groups, usually halogen, react with nucleophiles to give substitution products. An example of this type of reaction is the industrial conversion of chlorobenzene to phenol with sodium hydroxide at 400°C (8). 

The most useful syntheses of pyridazines and their alkyl and other derivatives begins with the reaction between maleic anhydride and hydrazine to give maleic hydrazide. This is further transformed into 3,6-dichloropyridazine which is amenable to nucleophilic substitution of one or both halogen atoms alternatively, the halogen(s) can be replaced by hydrogen as shown in Scheme 110. In this manner a great number of pyridazine derivatives are prepared. 

Broadly speaking, nucleophilic substitution may be divided into (a) the direct displacement of hydrogen and (b) the displacement of other substituents. Displacements of type (a) are rare and are typified by the Tschitschibabin reaction. Pyrazine reacts with NaNHa/NHs to yield 2-aminopyrazine, but no yield has been quoted (46USP2394963). Generally, the synthesis of aminopyrazines, aminoquinoxalines and aminophenazines is more readily accomplished by alternative methods, particularly displacement of halogen from the corresponding halo derivatives, which are themselves readily available. 

In those reactions where the fV-oxide group assists electrophilic or nucleophilic substitution reactions, and is not lost during the reaction, it is readily removed by a variety of reductive procedures and thus facilitates the synthesis of substituted derivatives of pyrazine, quinoxaline and phenazine. 

In this section three main aspects will be considered. Firstly, the basic strengths of the principal heterocyclic systems under review and the effects of structural modification on this parameter will be discussed. For reference some pK values are collected in Table 3. Secondly, the position of protonation in these carbon-protonating systems will be considered. Thirdly, the reactivity aspects of protonation are mentioned. Protonation yields in most cases highly reactive electrophilic species. Under conditions in which both protonated and non-protonated base co-exist, polymerization frequently occurs. Further ipso protonation of substituted derivatives may induce rearrangement, and also the protonated heterocycles are found to be subject to ring-opening attack by nucleophilic reagents. 

Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position (80AHC(27)241). Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. These reactions have been reviewed (74AHC(i6)123) the mechanism involves an intermediate cr-complex. 

Alkylthio groups are replaced in nucleophilic substitutions. Such reactions are easy in cationic derivatives for example, in the 1,2-dithiolylium series (539), substituted cydopen-tadienyl ion gives fulvene derivatives (540) (66AHC(7)39). 2-Methylthio groups in... 

Isoquinoline, l-(dimethylamino)-methylation, 2, 179 Isoquinoline, halo-lithium derivatives, 2, 363 Isoquinoline, 3-halo-nucleophilic substitution, 2, 59 Isoquinoline, l-halo-3-hydroxy-synthesis... 

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