Amines and Nitrogen Heterocyclic Compounds

A. Lattes, Afinidad 1972, 2953 -2970 . .Application of Organometallic Compounds to the Synthesis of Amines and Nitrogenated Heterocycles". 

In recent years, direct amination of tautomerizable heterocycles with amines via phosphonium coupling has been widely utilized in the synthesis of various heterocychc compounds used for chemical building blocks or medicinal chemistry. The reaction rate of the direct amination is usually dependent upon the electronic and steric nature of the amine nucleophiles. In principle, electron-richer and sterically less-hindered alkyl amines are much more reactive than aryl amines and nitrogen heterocycles (04AP702,05JOC1957). 

One extra disconnection is all we need to cope with misaturated heterocycles. If a nitrogen atom is joined to a double bond in a ring, we have a cyclic enamine. This is made from an amine and a carbonyl compound in the same way as ordinary enamines ... 

Addition compounds form with those organics that contain a donor atom, eg, ketonic oxygen, nitrogen, and sulfur. Thus, adducts form with amides, amines, and A/-heterocycles, as well as acid chlorides and ethers. Addition compounds also form with a number of inorganic compounds, eg, POCl (6,120). In many cases, the addition compounds are dimeric, eg, with ethyl acetate, in titanium tetrachloride-rich systems. By using ammonia, a series of amidodichlorides, Ti(NH2) Cl4, is formed (133). 

Arylations of amines and nitrogen-containing heterocycles require the presence of a copper catalyst, usually 10% copper(ll) acetate. For example, the reaction of 4-MeC6H4Pb(OAc)3 with the benzimidazole 20 affords the arylation product 21 in 98% yield.39 40 Similarly, the arylation of the amino groups of heteroaromatic compounds 22 and 23 gives rise to the corresponding products 24a and 25 in good to excellent yields (Equations (7)-(9)).41 42... 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

Organic chemicals that are susceptible to oxidation and are of concern from the perspective of contamination and environmental degradation include aliphatic and aromatic hydrocarbons, alcohols, aldehydes, and ketones phenols, polyphenols, and hydroquinones sulfides (thiols) and sulfoxides nitriles, amines, and diamines nitrogen and sulfur heterocyclic compounds mono- and di-halogenated aliphatics linear alkybenzene-sulfonate and nonylphenol polyethoxylate surfactants and thiophosphate esters. Table... 

It has long been observed that some aromatic nitrogen heterocyclic compounds aminate more easily than others. For instance, 1-methylbenzimidazole is aminated in a matter of a few minutes, whereas pyridine requires about 2 hr. In order to explain this, chemists in the U.S.S.R. have considered four factors they believe are most responsible for causing different rates of amination in aprotic solvents at elevated temperatures (heterogeneous conditions). They are (1) basicity of the heterocycle (2) positive charge on the carbon atom adjacent to the nitrogen (3) polarizability of the C=N bond and (4) ease of aromatization of the a-adduct (76CHE210). The first three pertain to the addition step of the Chichibabin reaction and the last factor depends upon the hydride-ion elimination step. 

For the moment accept that amine ends in -ine and any heterocyclic compound whose name ends in -ine is a nitrogen heterocycle. The syllable azo- also implies nitrogen and pyr- (usually) implies a six-membered ring (except in pyrrolel). 

Compounds with reducible functional groups predominate. Polyaromatic hydrocarbons, aromatic hydroxy compounds and amines, as well as amides and various nitrogen heterocyclic compounds can be determined anodically. These processes are in many cases pH dependent. Determinations based on redox processes are therefore carried out in buffered solutions. The composition and concentration of the buffer systems generally has no influence on the position of the half-wave or peak potentials. If its concentration is sufficiently high, the buffer simultaneously performs the function of the supporting electrolyte. 

Also values of alcohols(22,31,33), ethers(11b,34,35a), amines(34, 35b), ketones(11b,36), amides(11b,32,36,37a,b), pyridines and others heterocyclic compounds containing nitrogen(38), phenols (22,39), benzene and derivatives(llc,22b,40), esters(llb), polyethers (28,41), polyamines(35b,41), polyols(42-44), polycarboxylic acids (43), aminoalcohols(41), aminoethers(31,35b,41), hydroxyethers(11a, 28), xanthines(45), ureas(46) have been preferably obtained from direct measurements of the heat capacity of the solutions, but in some cases also by differentiation of the heats of solution with respect to temperature(22a,b,28,43,45) or as second derivatives with respect to temperature of solubility data(33,47). 

The nitrogen atom in compounds is often threefold coordinated and has a tetragonal structure with the free electron pair in one comer of the tetrahedron. Nitrogen occurs in varied forms in organic molecules, e.g. in amines (R-NH2), amides (R-C(=0)-NH2), nitriles (R-C=N), oximes (R2C=N-OH) and nitrogen-heterocycles (e.g. pyridine) [2.3]. 

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