Nucleophilic addition nitrogen nucleophiles

Nucleophilic Addition—Nitrogen Nucleophiles I mine Formation... 

Substitution of an additional nitrogen atom onto the three-carbon side chain also serves to suppress tranquilizing activity at the expense of antispasmodic activity. Reaction of phenothia zine with epichlorohydrin by means of sodium hydride gives the epoxide 121. It should be noted that, even if initial attack in this reaction is on the epoxide, the alkoxide ion that would result from this nucleophilic addition can readily displace the adjacent chlorine to give the observed product. Opening of the oxirane with dimethylamine proceeds at the terminal position to afford the amino alcohol, 122. The amino alcohol is then converted to the halide (123). A displacement reaction with dimethylamine gives aminopromazine (124). ... 

Moreover, Alder et al. (10) have shown that, with the appropriate substituents, it is possible to isolate acyclic nucleophilic carbenes, 7. Polyfunctional nucleophilic carbenes have also been prepared (6, 11), as have carbenes that feature additional nitrogen atoms or heteroatoms other than nitrogen (12). 

The influence of additional nitrogen atoms in the azines sometimes allows new reactions. An example of this is that of nucleophilic displacement of a cyano group, as in (561) — (562) this does not normally occur in the pyridine series, but is analogous to a reaction of acyl cyanides (RCOCN). 

Formal replacement of a CH unit in pyridine 5.1 by a nitrogen atom leads to the series of three possible diazines, pyridazine 10.1, pyrimidine 10.2, and pyrazine 10.3. Like pyridine they are fully aromatic heterocycles. The effect of an additional nitrogen atom as compared to pyridine accentuates the essential features of pyridine chemistry. Electrophilic substitution is difficult in simple unactivated diazines because of both extensive protonation under strongly acidic conditions and the inherent lack of reactivity of the free base. Nucleophilic displacements are comparatively easier. 

All positions on each of the diazines, with the sole exception of the 5-position of a pyrimidine, are a and/or 7 to an imine ring nitrogen and, in considering nucleophilic addition/substitution, it must be remembered that there is also an additional nitrogen withdrawing electron density. As a consequence, all the monohalodiazines are more reactive than either 2- or 4-halopyridines. The 2- and 4-halopyrimidines are particularly reactive because the anionic intermediates (shown below for attack on 2-chloropyrimidine) derive direct mesomeric stabilisation from both nitrogen atoms. 

The development of this version of the Schmidt reaction predates the experience of anyone working in organic chemistry today (Schmidt s original report was in 1924) but the extension of the concept to nucleophilic alkyl azides is a decidedly contemporary development. For example, if one compares the two reactions shown in Scheme 7.2, it is clear that the direct insertion of an alkyl azide into cyclohexanone allows for the introduction of additional nitrogen atom substitution and, in the case of an alkyl azide tethered to a carbonyl substrate, the possibility of an intramolecular reaction. The goal of this chapter... 

The reaction of isatin, 3-methyl-l-phenyl-5-aminopyrazole 111, and diketones 112 afforded the spiro-pyrazolo[3,4-b]pyridine-oxindoles 113 (Scheme 37). There could be two possible products 115 and 116 from the latter two N-rmsubstituted pyrazoles 114 due to the presence of an additional nitrogen nucleophilic center but the reaction was completely regioselective and afforded only product 115 (Scheme 38). This outcome of the reaction was explained by high nucleophilicity of the C-4 in comparison to N-1 in 3-phenyl- and 3-methyl-5-aminopyrazoles. 

Addition of Carbon, Oxygen, Nitrogen, and Sulfur Nucleophiles... 

Small amounts of salt-like addition products (85) formed by reaction on the ring nitrogen may be present in the medium. (Scheme 60) but. as the equilibrium is shifted by further reaction on the exocyclic nitrogen, the only observed products are exocyclic acylation products (87) (130. 243. 244). Challis (245) reviewed the general features of acylation reactions these are intervention of tetrahedral intermediates, general base catalysis, nucleophilic catalysis. Each of these features should operate in aminothiazoles reactivity. 

The reaction of propiolic acid or its esters with 2-aminothiazole yields 7H-thiazolo[3.2o]pyTimidine 7-one (109) (Scheme 74) (273), The reaction probably proceeds by initial nucleophilic attack of 2-aminothiazole on the sp C followed by intramolecular addition of ring nitrogen to spC. 

Nucleophiles other than water can also add to the carbon-nitrogen triple bond of nitriles In the following section we will see a synthetic application of such a nude ophilic addition... 

The carbon-nitrogen triple bond of nitriles is much less reactive toward nucleophilic addition than is the carbon-oxygen double bond of aldehydes and ketones Strongly basic nucleophiles such as Gngnard reagents however do react with nitriles in a reaction that IS of synthetic value... 

In addition to being more basic than arylammes alkylammes are also more nucleophilic All the reactions m Table 22 4 take place faster with alkylammes than with arylammes The sections that follow introduce some additional reactions of amines In all cases our understanding of how these reactions take place starts with a consideration of the role of the unshared electron pair of nitrogen... 

In acid the nitnle is protonated on nitrogen Nucleophilic addition of water yields an imino acid... 

Nitrogen bears a portion of the negative charge in the anionic intermediate formed m the nucleophilic addition step m 4 chloropyndme but not m 3 chloropyndme... 

This addition is general, extending to nitrogen, oxygen, carbon, and sulfur nucleophiles. This reactivity of the quinone methide (23) is appHed in the synthesis of a variety of stabili2ers for plastics. The presence of two tert-huty groups ortho to the hydroxyl group, is the stmctural feature responsible for the antioxidant activity that these molecules exhibit (see Antioxidants). 

Chemical Properties. The presence of both a carbocycHc and a heterocycHc ring faciUtates a broad range of chemical reactions for (1) and (2). Quaternary alkylation on nitrogen takes place readily, but unlike pyridine both quinoline and isoquinoline show addition by subsequent reaction with nucleophiles. Nucleophilic substitution is promoted by the heterocycHc nitrogen. ElectrophiHc substitution takes place much more easily than in pyridine, and the substituents are generally located in the carbocycHc ring. 

The importance of steric effects in determining the oxidation state of the product can be illustrated by a thioether linkage, eg (57). If a methyl group is forced to be adjacent to the sulfur bond, the planarity required for efficient electron donation by unshared electrons is prevented and oxidation is not observed (48). Similar chemistry is observed in the addition of organic nitrogen and oxygen nucleophiles as well as inorganic anions. 

Polyurethane Formation. The key to the manufacture of polyurethanes is the unique reactivity of the heterocumulene groups in diisocyanates toward nucleophilic additions. The polarization of the isocyanate group enhances the addition across the carbon—nitrogen double bond, which allows rapid formation of addition polymers from diisocyanates and macroglycols. 

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