Tschitschibabin synthesis

With the two starting compounds, the picolylsulfone and the a-bromoketone we applied the well known Tschitschibabin synthesis (ref. 10). The first step of this synthesis is the formation of a quaternary pyridinium salt. 

Broadly speaking, nucleophilic substitution may be divided into (a) the direct displacement of hydrogen and (b) the displacement of other substituents. Displacements of type (a) are rare and are typified by the Tschitschibabin reaction. Pyrazine reacts with NaNHa/NHs to yield 2-aminopyrazine, but no yield has been quoted (46USP2394963). Generally, the synthesis of aminopyrazines, aminoquinoxalines and aminophenazines is more readily accomplished by alternative methods, particularly displacement of halogen from the corresponding halo derivatives, which are themselves readily available. 

In the case of pyridine, Tschitschibabin s synthesis proceeds with special ease. An intermediate addition product of NH2Na to the —N=C double bond with the grouping —NNa—C(NH2)— is doubtless formed. The net result is as follows ... 

Galatasis, P. Chichibabin (Tschitschibabin) Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 308-309. (Review). 

This synthesis, originally devised by Tschitschibabin,8 is still the most widely used because it can easily be modified to yield substituted indolizines. The synthesis involves the quaternization of a 2-substituted pyridine, normally using an a-halo carbonyl compound, followed by intramolecular cyclization of the quaternary salt with a mild base, usually aqueous sodium bicarbonate (Scheme 1). 

The base-induced cyclization of Ar-(oxoethyl(pyridinium salts of 2-picolines, known as the Tschitschibabin indolizine synthesis, is a classical method of preparation of indolizines from pyridines. The ready isolation of the products by decanting or filtration has allowed for the recent development of a parallel synthesis of a wide range of 2-substituted indolizines <2003SL2086>. 

The known preparative methods for the synthesis of imidazo[l,2-6]pyridazines prior to 1983 have been extensively reviewed <84CHEC-I(5)607>. This section will review new methods of syntheses published since 1983. The most common synthesis of this ring system is closure of the imidazole ring via the Tschitschibabin cyclization between a 3-aminopyridazine and an a-halocarbonyl compound. 

The structures assigned to the alkaloids and their breakdown products on the basis of the degradative evidence have been confirmed by the S3Tithetic investigations of N. A. and W. A. Freobrashenski and their collaborators. The first step, the synthesis of pilopic and isopilopic acids, was achieved in 1930 by A. E. Tschitschibabin and N. A. Freobrashenski... 

The Stadel and Rugheimer synthesis is also poorly suited for the preparation of pyrazine, see Tschitschibabin, A. E. Schtschukina, M. N. Chem. Ber. 1929, 62, 1075-1080. 

Guareschi-Thorpe pyridine synthesis Chichibabin (Tschitschibabin) pyridine synthesis Bohlmann-Rahtz pyridine synthesis Krohnke pyridine synthesis... 

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