Nucleophilicity of amines

A completely different, important type of synthesis, which was developed more recently, takes advantage of the electrophilicity of nitrogen-containing 1,3-dipolar compounds rather than the nucleophilicity of amines or enamines. Such compounds add to multiple bonds, e.g. C—C, C C, C—O, in a [2 + 3 -cycioaddition to form five-membered heterocycles. 

The nucleophilicity of amine nitrogens is also differentiated by their environments. In 2,4,5,6-tetraaminopyrimidine the most basic 3-amino group can be selectively converted to a Schiff base. It is meta to both pyrimidine nitrogens and does not form a tautomeric imine as do the ortho- and /xira-amino groups. This factor is the basis of the commercial synthesis of triamterene. 

Both the basicity and the nucleophilicity of amines originate m the unshared electron pair of nitrogen When an amine acts as a base this electron pair abstracts a... 

Benzyl groups are one way of protecting secondary amines against strong bases that might depro-tonate them. But it is the nucleophilicity of amines that usually poses problems of chemoselectivity, rather than the acidity of their NH groups, and we come back to ways of protecting them from electrophiles when we deal with the synthesis of peptides in Chapter 25. 

Thus, as the nucleophility of amine is decreased (acid conditions, long chain substitutes), the probability of realization of random or uniform distribution of bonded molecules is increased. Promotion and stabilization of intermediate ionic structures (electrolyte) facilitates the island-like mechanism of surface coverage. 

The inductive effect of fluorination also reduces the basicity of organic bases by approximately the same order of magnitude (Table 1.6). In contrast with basicity, the nucleophilicity of amines is influenced much less by fluorinated substituents. 

Both the basicity and the nucleophilicity of amines originate in the unshared electron pair of nitrogen. When an amine acts as a base, this electron pair abstracts a proton from a Brpnsted acid. When an amine undergoes the reactions summarized in Table 22.4, the first step in each case is the attack of the unshared electron pair on the positively polarized carbon of a carbonyl group. 

Owing to the nucleophilicity of amines, the reaction of electrophiles, such as halogens, with olefinic amines may take a different course than that followed by alcohols or ethers, where concerted addition-cyclization normally occurs (see Chapter 4). For example, the bromination of 1-allylpyrazole (74) leads to the dibromide (75), which may be converted to diazapentalene (76) by N-5 cyclization and dehydrobromination. In... 

Because of the good nucleophilicity of amines, alkylation of amino acids is an important widespread reaction in both organic and biological systems. A simple methylation may proceed as follows ... 

The higher nucleophilicity of amines allows them to win the competition, as only amides are usually formed in carbonylation in the presence of amides and hydroxide ions or small amounts of water. However, for less-reactive arylamines, water puts up a stronger competition. Thus, in the carbonylation of p-nitroiodobenzene in the presence of p-iodoaniline, which gives only p-O2NQH4CONHC6H4I-P in DMF, the addition of only 5vol% H2O results not only in sharp acceleration of reaction, but also in the formation of considerable amounts of nitrobenzoic acid. No amide was formed in the carbonylation with such a weak nucleophile as diphenylamine [116]. 

The nucleophilicity of amines in the aminolysis of esters can be greatly improved by use of sodium hydride in DMSO or hexamethylphosphoramide the amine anion produced reacts smoothly with esters at room temperature to afford the desired amide in excellent yield. A similar use of n-butyl-lithium for amine anion production is recorded. ... 

When primary amines were used in this reaction instead of alcohols, cyclic carbamates 12 were formed (Scheme 7) [21]. Yields of 4-methyleneoxazolidin-2-ones 12 were foxmd to depend on the amine structiu e, while steric factors and nucleophilicity of amines were found to govern the reaction outcome. No product was formed in attempts to involve f-butylamine in the reaction. Yields of 4-methylene-3-phenyloxazolidin-2-ones (12, R3=Ph) obtained from aniline were also low (15-38%). Contrarily to the reaction of 10 with CO2 in the absence of external nucleophiles, under tire same condition in the presence of n-butylamine, an E-isomer of the corresponding cyclic carbamate was isolated in equal quantity with the Z-isomer (51% overall yield). 

Furthermore, these reactions are selective and avoid the use of protecting groups due to the high nucleophilicity of amines compared to alcohols. Fiowever, this method requires an excess of substrate and some purification. Typical examples of aminated sugars include N-acetyllactosamine [27], 2-amino-2-deoxy-D-glucose [145-147], glucosamine [148], galactosamine [148,149], lactosamine [150] and aminated mannose derivative [151]. 

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