Amides Chichibabin amination reaction

PROBLEM 15.88 Isoquinoline (1) undergoes the Chichibabin amination reaction when treated with potassium amide in liquid ammonia to yield 1-aminoisoquinoline (2) (p. 676). 

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... 

Extensive investigation of amide-induced amination of purine and its derivatives has shown that the parent compound (purine) as well as its 2-methyl and 8-methyl derivatives react with potassium [ - Njamide in ammonia to undergo exclusive amination at C6 without incorporation of the N label into the ring (Chichibabin reaction). Amination of 2-fluoro-, 2-chloro-, and 2-(methylsulfanyl)purine 7, and 2-chloro-6-phenylpurine with potassium [ N]amide in ammonia, however, gives purin-2-amines with complete incorporation of the N label in the pyrimidine ring. 

The reactivity of pyridine toward nucleophilic substitution is so great that even the powerfully basic hydride ion, H", can be displaced. Two important examples of this reaction are amination by sodium amide (Chichibabin reaction), and alkylation or arylation by organolithium compounds. 

The amination of 2.4-diphenyl-1,3,5-triazine (7, X = H) with potassium amide in anhydrous liquid ammonia at -33°C occurs by a Chichibabin-type reaction, i.e. replacement of H" by NH via nucleophilic substitution involving an addition-elimination process (SsAE). In contrast, the 2-methylsulfanyl derivative 7 (X = SMe) is aminated nearly exclusively by a ringopening-ring-closing sequence [Sn(ANRORC)].52... 

The Chichibabin amination (see p 277) proceeds with alkali amides in liquid ammonia. In this reaction, quinoline provides a mixture of the 2- and 4-amino compound 14 and 15, whereas 2-phenylquinoline yields the 4-amino compound ... 

Similar to that of pyridine, the Chichibabin amination on quinoline and isoquinoline proceeds with alkali metal amides in liquid ammonia. In accordance to that, the reaction of quinoline with liquid ammonia initially forms a complex, which allows amide anion to add to the heterocyclic core of quinoline and isoquinoline bicycle, obtaining 2- or 4-aminoquinolines and 1-aminoisoquinolines, respectively, in good yields. ... 

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... 

Reactivity of 5,6,7,8-tetrafluoroquinoline 130 with the fully fluorinated benzene ring towards the amide anion has been studied [104]. The Chichibabin amination at C-2 has been shown to occur by action of sodium (potassium) amide in liquid ammonia in the presence of potassium permanganate, however only a low yield of the corresponding 2-aminoquinoline has been reached due to concurrent amino-defluorination reactions, taking place at positions 6 and 7 (Scheme 69). 

Amines are insufficiently nucleophilic to react with most azoles which do not contain a ring oxygen, and the stronger nucleophile NH2 is required. When treated with amide ions, thiazoles can be aminated in the 2-position by NaNHa at 150 °C. Only TV-substituted condensed imidazoles such as 1-alkylbenzimidazole react in such Chichibabin reactions. Imidazoles are aminated by alkaline NH2OH. 

Pyridine and other heterocyclic nitrogen compounds can be aminated with alkali metal amides in a process called the Chichibabin reaction The attack is always in the 2 position unless both such positions are filled, in which case the 4 position is attacked. Substituted alkali metal amides (e.g., RNH and R2N ) have also been used. The mechanism is probably similar to that of 13-15. The existence of intermediate ions such as 15... 

Pyridine and other heterocyclic nitrogen compounds an be aminated with the alkali-metal amides by chichibabin reaction. The attack is always in the 2 position unless both such positions... 

The Chichibabin reaction is exemplified by the amination of 2-methylpyridine (308) by sodium amide in toluene via intermediate 309 to yield 6-amino-2-methylpyridine (310). This reaction has been applied to pyridines, quinolines, isoquinolines, and naphthyridine as well as to benzimidazole, and was reviewed in great detail (66AHC229 78RCRI042 88AHC1). 

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. 

Purine and its derivatives undergo amination with potassium amide in liquid ammonia. Under these conditions, two different mechanisms may be followed (1) the Chichibabin reaction, and (2) the Sn(ATSIRORC) (Addition of Nucleophile, Ring Opening, Ring Closure) reaction. 

In the laboratory of J.S. Felton, the synthesis of 2-amino-1-methyl-6-phenyl-1/-/-imidazo[4,5- i]pyridine (PHIP), a mutagenic compound isolated from cooked beef, and its 3-methyl isomer have been accomplished. The synthesis of PHIP began with the commercially available 3-phenylpyridine, which was aminated at the 6-position with sodium amide in toluene by the Chichibabin reaction in 58% yield. 

Simig, G., Van der Plas, H. C. The SN(ANRORC) mechanism. XVII. An SN(ANRORC) mechanism in the amination of phenyl-1,3,5-triazine with potassium amide in liquid ammonia. A novel mechanism for the Chichibabin reaction. Red. Trav. Chim. Pays-Bas 1976, 95,125-126. 

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