Chichibabin Reaction

The Chichibabin reaction is a method for producing 2-aminopyridine derivatives by the reaction of pyridine with sodium amide. It was reported by Aleksei Chichibabin in 1914. The following is the overall form of the general reaction: The direct amination of pyridine with sodium amide takes place in liquid ammonia

1. NAMED REACTIONS IN ORGANIC SYNTHESIS:CHICHIBABIN REACTION By PRUTHVIRAJ K PRUTHVIRAJ K, MSc

2. Chichibabin Reaction In the early 1900s, A.E. Chichibabin reacted pyridine with sodium amide (NaNH2) in dimethylamine at high temperature (110 °C). After aqueous work-up, he isolated 2-aminopyridine in 80% yield.1 A decade later, he added pyridine to powdered KOH at 320 °C, and after aqueous work-up 2-hydroxypyridine was isolated.2 Similar reactions take place when pyridine or its derivatives are treated with strong nucleophiles such as alkyl- and aryllithiums to give 2-alkyl and 2-arylpyridines.11 The direct amination of pyridine and its derivatives at their electron-deficient positions via nucleophilic aromatic substitution ( SNAr ) is known as the Chichibabin reaction . This reaction is also widely used for the direct introduction of an amino group into the electron-deficient positions of many azines and azoles (e.g., quinoline is aminated at C2 & C4, isoquinoline at C1, acridine at C9, phenanthridine at C6, quinazoline at C4). Both inter- and intramolecular12-14 versions are available, but investigations have mainly focused on intermolecular reactions. There are two procedures for conducting the Chichibabin reaction : A ) the reaction is carried out at high temperature in a solvent that is inert toward NaNH2 (e.g., N,N - dialkylamines , arenes , mineral oil, etc.) or without any solvent; or B ) the reaction is run at low temperature in liquid ammonia with KNH2 (more soluble than NaNH2). PRUTHVIRAJ K, MSc

3. Procedure A proceeds in a heterogeneous medium and the reactions effected under these conditions show strong dependence on substrate basicity, while procedure B proceeds in a homogeneous medium and there is no substrate dependence. Frequently, an oxidant such as KNO3 or KMnO4 is added during procedure B to facilitate the amination by oxidizing the hydride ion (poor leaving group) in the intermediate ó-complex.9,6 The low temperature conditions make it possible to aminate substrates such as diazines , triazines , and tetrazines , which are destroyed at high temperatures, but pyridine itself does not undergo amination in liquid ammonia because it is not sufficiently electrondeficient . Mechanism The Chichibabin reaction is formally the nucleophilic aromatic substitution of hydride ion (H-) by the amide ion (NH2). In the first step, an adsorption complex is formed with a weak coordination bond between the nitrogen atom in the heterocycle and the sodium ion (Na+); this coordination increases the positive charge on the ring. This -complex is then aromatized to the corresponding sodium salt while hydrogen gas (H2) is evolved (a proton from an amino group reacts with the leaving group hydride ion   PRUTHVIRAJ K, MSc

4. In the laboratory of J.S. Felton, the synthesis of 2-amino-1-methyl-6-phenyl-1 H -imidazo[4,5- b ]pyridine (PHIP), amutagenic compound isolated from cooked beef, and its 3-methyl isomer have been accomplished.27 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. PRUTHVIRAJ K, MSc

5. M. Palucki and co-workers synthesized 2-[3-aminopropyl]-5,6,7,8-tetrahydronaphthyridine in large quantities for clinical studies via a one-pot double Suzuki reaction followed by deprotection and a highly regioselective intramolecular Chichibabin cyclization .14 This approach was amenable to scale-up unlike the traditional methods such as the Skraup and Friedländer reactions that involve carbon-carbon bond forming steps. The Chichibabin reaction was optimized and afforded the desired product in high yield, excellent regioselectivity , and a significant reduction in reaction time compared to literature precedent. PRUTHVIRAJ K, MSc

6. REFERENCES STRATEGIC APPLICATIONS OF NAMED REACTIONS IN ORGANIC SYNTHESIS By- Laszlo Kurti and Barbara Czako REACTIONS, REARRANGEMNTS AND REAGENTS By- S N Sanyal PRUTHVIRAJ K, MSc