By Direct Amination

The direct amination of pyrazine and alkylpyrazine has been discussed in Sections IV. 1C and 1V.2C (8), respectively. 

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Aromatic amines can be produced by reduction of the corresponding nitro compound, the ammonolysis of an aromatic haUde or phenol, and by direct amination of the aromatic ring. At present, the catalytic reduction of nitrobenzene is the predominant process for manufacture of aniline. To a smaller extent aniline is also produced by ammonolysis of phenol. 

Treatment of a-hydroxy-ketones or -aldehydes with ammonium acetate (65BSF3476, 68BSF4970) results in the formation of dihydropyrazines, presumably by direct amination of the hydroxyketone followed by self-condensation (79AJC1281). Low yields of pyrazines have been noted in the electrolysis of ketones in admixture with KI and ammonia, and again it appears probable that the a-aminoketone derived by way of the a-iodoketone is the intermediate (69CI(L)237>. 

In the presence of zinc chloride, stereoselective aldol reactions can be carried out. The aldol reaction with the lithium enolate of /-butyl malonate and various a-alkoxy aldehydes gave anti-l,2-diols in high yields, and 2-trityloxypropanal yielded the syn-l,2-diol under the same conditions.633 Stoichiometric amounts of zinc chloride contribute to the formation of aminoni-tropyridines by direct amination of nitropyridines with methoxyamine under basic conditions.634 Zinc chloride can also be used as a radical initiator.635... 

The amino group of 10H-benzo[i7]thieno[2,3-e][l,4]diazepin-4-amine 253 can be substituted with N-methyl piperazine by direct amination under thermal conditions (Scheme 53, Section 3.1.3 (1997BMCL25)). 

In gas phase reactions the size of catalyst libraries can be over couple of thousands. For instance, in the synthesis of aniline by direct amination of benzene around 25000 samples were screened in about a year [15], however, the optimization method used was not discussed. In contrast, in liquid phase reactions taking place at elevated pressure and temperature, due to technical difficulties the rational approach does not allow testing libraries containing more than 200 250 catalysts. Consequently, the informatic platform and the strategy used to design catalyst libraries for high-pressure liquid phase reactions should have very unique optimization tools. 

Many amino-1,5-naphthyridines have been made by primary synthesis (see Chapter 1), by aminolysis of halogeno-1,5-naphthyridines (see Section 3.2.2), or by aminolysis of 1,5-naphthyridinones (see Section 4.1.2). Others have been made by direct amination, as illustrated in the following examples. 

All known examples of such amines have been made by primary synthesis (see Section 30.1), by direct amination (see Section 30.2.3), or by aminolysis of halogeno substrates (see Sections 30.2.1 and 30.3.2). 4-Phenyl-2,7-naphthyr-idin-1-amine (lophocladine B) was isolated from a red alga.1435... 

The Hell-Volhard-Zelinsky reaction (Section 22-6) is an effective method for introducing bromine at the a position of a carboxylic acid. The racemic a-bromo acid is converted to a racemic a-amino acid by direct amination, using a large excess of ammonia. 

The Gabriel-malonic ester synthesis is used to make many amino acids that cannot be formed by direct amination of haloacids. The following example shows the synthesis of methionine, which is formed in very poor yield by direct amination. 

Tris(organoamino)boranes have been utilized to prepare, in reasonable yields,4,5 mono- and dihalo(organoamino)boranes which are often difficult to obtain by direct amination of the boron trihalides. Carboxylic acids, 1,3-diketones, ketones, and /3-ketoesters have been converted into carboxamides, enamino-ketones, enamines, and j -enamino-amides, respectively, by reaction with an appropriate tris(organoamino)borane under very mild conditions.6 Sulfenamides (R2NSC6H5) have also been prepared in high yield from selected tris(organoamino)boranes and sulfenic esters under relatively mild conditions.7... 

Numerous substituted and benzo-fused quinazoline-2- and -4-amines are accessible by direct amination via the Chichibabin reaction. Quinazoline is aminated at position 4 on heating with sodium amide in iV,A-dimethylaniline or by a mild amination oxidation procedure using potassium amide, liquid ammonia, and potassium permanganate. The latter method comprises oxidation with potassium permanganate of an anionic c-adduct w hich is easily formed when quinazoline is dissolved in liquid ammonia containing potassium amide. 

Dimethylaniline has been prepared by reduction of the corresponding nitro compound, either chemically or catalyti-cally. It has been prepared from 3,4-dimethylphenol by heating with ammonia, ammonium bromide, and zinc bromide from w-toluidine hydrochloride by alkylation with methanol at high temperatures from anhydro-4-amino-2-methylbenzyl alcohol by dry distillation from calcium hydroxide from 2-methyl-S-aminobenzyl alcohol by reduction with sodium from 2-methyl-5-nitrobenzyl chloride and 2-methyl-S-nitrobenzyl acetate by catalytic reduction from o-xylene by direct amination with hy-droxylamine hydrochloride in the presence of aluminum chloride and from 3,4-dimethylacetophenone by the Beckmann rearrangement of the oxime.i" The present method has been published. ... 

Aminoindole exists mainly as the 3H-tautomer, presumably because of the energy advantage conveyed by amidine-type resonance. 3-Aminoindole is very unstable, and easily autoxidised. Both 2- and 3-acylamino-indoles are stable and can be obtained by catalytic reduction of nitro-precursors in the presence of anhydrides. 1-Amino-indoles can be prepared by direct amination of the indolyl anion. ... 

Synthetic approaches that have been developed or extended in the review period and have the potential for general use include radical alkoxycarbonylation to give 4-alkoxycarbonylpyridazines (Section 6.01.5.6) preparation of 4(5)-aminopyridazines by direct amination with ammonia or amide ions followed by oxidation (Section 6.01.5.4.3) C—C bond formation by palladium catalyzed coupling reactions of pyridazine O-triflates (Section 6.01.7.12.2) and halopyridazines (Section... 

The 1 H-NMR spectra have been used to assign the structures of benzo-diazine N-imines obtained by direct amination in which two isomeric... 

An alternative fatty acid was introduced into position 2 following phospholipase A hydrolysis, and final conversion to phosphatidylcholine or phosphatldylethanolamine was accomplished by direct amination. Cytidine diphosphate diacylglycerols are essential Intermediates in the biosynthesis of several... 

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