Oxidants Chichibabin amination reaction

Table 12 Yields of 3-amino-1,2,4-triazine 4-oxides derived from the Chichibabin amination reaction at room temperature ...

Chichibabin amination refers to a reaction in which a hydrogen of an azaheteroarene is replaced by an amino group. The reaction is usually carried out by heating the heterocycle with a metal amide at elevated temperatures in an aprotic inert solvent. Potassium amide or sodium amide in liquid ammonia have also been found to be appropiate reagents for amination the presence of an oxidant seems to promote the reaction. Potassium nitrate is usually employed as an oxidant, 9 16 but other work shows that potassium permanganate can also successfully be used as an oxidizing agent in liquid ammonia.IO-20 17... 

Whereas metal hydride is eliminated from the o--complex intermediates (cf. 309) in Chichibabin aminations, which results in the subsequent reaction of the metal hydride with ammonia or amines and the evolution of hydrogen, the o--complex intermediates can also be oxidized to the corresponding amino-N-heterocycles. Thus, 5-azacinnoline (320) can be aminated with primary and secondary aliphatic or benzyl amines in the presence of potassium hydroxide/potassium ferricyanide to give the corresponding amino derivatives 321 in up to 65% yield. The... 

Amination of pyridine on heating with sodium amide in refluxing xylene observed by Chichibabin and Zeide nearly 100 years ago [132] was probably the first successful example of amino-dehydrogenation in the series of Jt-deficient aromatic systems. However, rather drastic reaction conditions and a requirement for an appropriate oxidant for the classic Chichibabin amination did not stimulate chemists in earlier days to enter this field of substitutions [23, 133, 134], Later on, van der Plas with coworkers [11, 19-21, 29, 35, 39, 40, 88], Vorbruggen [26], Pozharskii, Gulevskaya, and Maes [34, 45, 46, 48, 67, 68, 71, 72], McGill and Rappa [23], Pagoria, Mitchell, and Shmidt [59, 61, 63], Lopyrev [65, 66], Katritzky [58], and many other researches [11, 21, 45, 55, 58-74] contributed to the field of Sn amination reactions. 

The standard Chichibabin amination of quinoline with sodium amide in DMA gives 2-aminoquinoline in a low 7% yield and 2-amino-3,4-dihydroquinoline in a 24% yield. Not until the introduction of the Chichibabin oxidative amination variant (e.g., in the presence of KMn04) were these yields improved. Regio-chemical outcome depends on reaction temperature (kinetic or thermodynamic control). 2-aminoquinoline (39) forms at -65 °C, i.e., the kinetic adduct, and is isolated in a 50-55% yield with no evidence of 4-amino adduct formation, whereas 4-aminoquinoline (40) forms in 60-65% yield at 15 °C, i.e., the thermodynamic adduct (oxidant added at -45 C), with 6-7% of 39. Substituted quinolines give various... 

The most common nncleophiles that are resistant toward oxidation are ammonia and hydroxide anion. Indeed, such strong oxidant as KMnO is soluble in liquid ammonia and forms solutions that are stable even at room temperature (under pressure). These solutions are efficient agents for amination of electron-deficient nitroarenes and azines that proceeds via addition of ammonia to the ring, followed by oxidation of the o -adducts with KMnO. This amination process of azines is often referred to as the oxidative Chichibabin reaction [7]. For instance, the reaction... 

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. 

The examples shown are illustrative of the many easy nucleophilic additions to the polyaza-azines both 3-phenyl-l,2,4,5-tetrazine and 1,3,5-triazine itself add ammonia and simple amines (contrast the requirement for hot sodamide (Chichibabin reaction) for pyridine (8.3.1.2)) and thus amino and alkyamino derivatives can be obtained via oxidative trapping with permanganate. 

However, significant chemistry, particularly the application of ammonia/amide reactions has been reported since 1984. Thus, while pyridazine is resistant to the Chichibabin reaction, a variety of pyridazines form u-adducts in ammonia/potassium amide which can be oxidized by the addition of potassium permanganate to yield 4(5)-aminopyridazines, often in excellent yields. For example, dissolution of pyridazine in ammonia/potassium amide leads to the almost complete formation of the anionic adduct, which can be oxidized to give 4-aminopyridazine in excellent yield, while reaction of 3-phenylpyridazine (Scheme (9)) gives a mixture of the three isomeric amination products in which the 4- and 5-amino isomers predominate <82JHC1285>. 

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