Patentamt 0 098 684 JJEuropaisches European Patent Office (fi) Publication number: B1 Office europeen des brevets ® EUROPEAN PATENT SPECIFICATION 06) Date of publication of patent specification: 16.01.91 (g) Int. CI.5: C 07 D 213/73, C 07 D 213/80, (3) Application number: 83301960.7 C 07 D 213/803, C 07 D 213/82, w(8) Date of filing: 07.04.83 C 07 D 215/38, C 07 D 401/04 (54) Modified chichibabin reaction, and novel pyridine derivatives. (§) Priority: 08.04.82 US 366598 (73) Proprietor: REILLY INDUSTRIES, INC. 23.03.83 US 478138 1510 Market Square Center Indianapolis Indiana 46204 (US) (§) Date of publication of application : 18.01.84 Bulletin 84/03 (72) Inventor: McGill, Charles K. 4343 Broadway Street Indianapolis Indiana 46205 (US) (§) Publication of the grant of the patent: Inventor: Sutor, James J. 16.01.91 Bulletin 91/03 287 Meander Way Greenwood Indiana 46142 (US) (8) Designated Contracting States: BECHDEFRGBITLINL (74) Representative: Bannerman, David Gardner etal Withers & Rogers 4 Dyer's Buildings Holborn References cited: London, EC1N 2 JT(GB) CHEMISCHES ZENTRALBLATT, vol. 86, 1915 1, Berlin A. TSCHITSCHIBABIN et al. "Eine neue @ References cited: Reaktion der Verbindungen, welche den Chemical Abstracts vol. 59, no. 13, 1963, Pyridinring enthalten", pages 1064-1065 Columbus, Ohio, USA L.S. LEVITT et al. Evidence for aryne intermediates in the direct Chemical Abstracts vol. 55, no. 2, 1961, amination of pyridine", columns 15150h-15151d 00 Columbus, Ohio, USA K. KOVACS et al. "New Chemical Abstracts vol. 60, 13, 1964, to methods for the direct substitution of the no. pyridine ring by alkylamines", column 1608b-e Columbus, Ohio, USA R.A. ABRAMOVITCH et al. CO "Aromatic substitution. VI. On the mechanism O) of the amination of pyridine", columns 15699h- o 15700b Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall CL be filed in a written reasoned statement.. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1 ) European convention). IU patent Courier Press, Leamington Spa, England. EP 0098 684 B1 56) References cited: Chemical Abstracts vol. 62, no. 12, 1965, Columbus, Ohio, USA R.A. ABRAMOVITCH et al. "Aromatic substitution. VIII. Aspects of the mechanism of the Chichibabin reaction", columns 14618g-h Chemical Abstracts vol. 62, no. 5, 1965, Columbus, Ohio, USA R.A. ABRAMOVITCH et al. "Mechanism of the Chichibabin reaction", column 5169e-g :P 0 098 684 B1 Description been studied which are not neterocycies, dui nave a N=CH group such as Schiff bases. Pozharskii, This invention relates to a modified Chichibabin Simonov and Doron'kin, Russ, Chem. Rev., 47, reaction of a nitrogen-containing heterocyclic 1042 (1978). Translated from Uspekhi Khim., 47, base by sodamide in an organic solvent at an 5 1933 (1978). The result of these efforts is that the slevated temperature. predictability of Chichibabin aminations is In 1914, Chichibabin and Seide first reported thought to be high for a given base compound, as that a-picoline, or more commonly 2-methylpy- are the expected product or products of the ridine, underwent direct amination in the free a- reaction. Although such certainty is helpful, situa- position on the ring when treated with sodium w tions arise where a partial or complete change in amide in toluene at elevated temperatures. the Chichibabin result is desirable. For example, Chichibabin and Seide, J. Russ. Phys. Chem. Soc, expected products may not be desired, or new 46, 1216 (1914). This reaction was later extended products may be wanted, or isomer ratios may be by Chichibabin and his contemporaries to amina- preferably reversed. is tion of many pyridine, quinoiine and isoquinoline is An important example of this last category bases. It has since been recognized as one of the the case of 3-substituted pyridine bases, and more important and influential developments in particularly 3-alkyl derivatives, which are known pyridine chemistry, so much so that the reaction to undergo Chichibabin amination to produce itself has become synonymous with the name of predominantly 2-amino-3-alkylpyridine ("2,3- its discoverer. Its commerical importance should 20 isomer") and to a much lesser extent 2-amino-5- also not be discounted as, for example, the 2- alkylpyridine ("2,5-isomer"). The amination of 3- amino amination product of pyridine itself has methylpyridine, also known as 3- or p-picoline, is become an enormously important and useful an excellent example, which reportedly yields the starting material for further synthesis in many 2,3- and 2,5-isomers in a ratio of about 10.5:1. areas. 25 Abramovitch, Advan. Heterocycl. Chem., 6, 294 The Chichibabin reaction has been the subject (1966); Abramovitch, Helmer and Saha, Chem. & of much study and comment through the years, Ind., 659 (1964); Abramovitch, Helmer and Saha, both as to scope and as to the mechanism of the Can. J. Chem., 43, 727 (1965). This is highly amination. For example, although first carried out unfortunate as the 2,5-isomers are much pre- in toluene, the reaction has since been carried out 30 ferred because of their usefulness as starting in other aprotic solvents of which dialkylanilines, materials and intermediates for the preparation of liquid paraffin and other hydrocarbons such as herbicides, insecticides and pharmaceuticals. benzene, xylene, cumene, mesitylene and Chemical manufacturers are hard-pressed to petroleum fractions are most common. Similarly, meet the demand for 2,5-products since they are although first accomplished using sodium amide, 35 left with very large quantities of largely unusable or more commonly sodamide, the reaction has 2,3-isomer at this time. Understandably, there is since been carried out with other metal amides thus a substantial need to change the classic such as potassium amide, barium amide, etc., Chichibabin amination in this case in a way that particularly when using low temperatures and improves the.yield of these 2,5-products, of which long reaction times in attempting to slow the 40 2-amino-5-methylpyridine is most preferred, at reaction to study the mechanism of its amination least at this time. of the process. The Chichibabin mechanism remains Notwithstanding the many years of study one of the least understood nucleophilic substitu- Chichibabin reaction, until now no significant tion reactions in heterocyclic chemistry owing to breakthrough has been reported which teaches or the difficulty in handling the alkali metal amides 45 suggests a methodology to change the reaction's and in studying kinetics of a process which takes classic mechanism or its anticipated results given place under heterogeneous conditions at high a particular heterocyclic base compound. temperatures. Classicly, those conditions have According to this invention the applicants included heating the mixture at atmospheric therefore provide a Chichibabin reaction of a with pressure and at temperatures between about so nitrogen-containing heterocyclic base 100— 200°C. Another characteristic feature has sodamide in an organic solvent at an elevated been the evolution of hydrogen gas and ammonia temperature, characterised by being modified in of gas which signals the start of the reaction and that the reaction is conducted under a pressure identifies its progress toward completion. at least 50 psi (3.40 bars) in the gas phase above Novikov, Pozharskii & Doron'kin, Translated from 55 the reaction mixture and in the presence of a Khim. Geterotsikl. Soedin., No. 2, 244 (1976); partial pressure of added ammonia of at least 5 Levitt & Levitt, Chem. & Ind., 1621 (1963). psi (0.34 bars). The base compound which undergoes amina- The gas phase in the vessel is perferably main- tion has also received much study. Reports docu- tained at a pressure of at least 100 psi (6.80 bars), ment the amination of mono and diazines such as 60 and the autogenous pressure of gases evolved pyridines, quinolines, isoquinolines, benzoquinol- during the reaction may contribute to that ines, phenanthridines, acridines, benzimidazoles, pressure. quinazolines, naphthyridines, pyrimidines, pyrazi- The gas phase above the mixture may be nes and other heterocyclic systems. Reactions placed under a pressure of at least 100 psi (6.80 related to the Chichibabin amination have also 65 bars) prior to commencement of the reaction, and 3 3 EP 0 18 684 B1 4 the pressure of the gas phase may be increased to After the reactants were combined in a pressure at least 300 psi (20.40 bars) and maintained at such vessel the gas phase above the mixture was a pressure during the reaction. initially pressurized to at least about 50 psi and The reaction may be conducted in a sub- ammonia was added to the vessel sufficient to stantially inert atmosphere at temperatures 5 produce an initial partial pressure of ammonia of between 100— 250°C and without refluxing the at least about 5 psi in this gas phase. The mixture reaction solvent as is common in the classic was brought to a temperature sufficient to cause Chichibabin reaction. The added ammonia may be reaction to occur, and pressure was maintained at injected in gaseous form, or left as liquid ammonia or above this initial 50 psi level during the course of in the reaction mixture as when sodamide is 10 the reaction until hydrogen evolution had sub- prepared in situ by reacting sodium in excess stantially ceased. Although the autogenous liquid ammonia priorto conducting the amination. pressure of gases evolved in situ during amination The temperature and pressure in the vessel are was used to assist in maintaining pressure during preferably maintained for a period sufficient to the reaction, it was preferred to initially purge the cause substantial reaction to occur as measured 15 vessel of air and pressurize it using an inert gas by the production of hydrogen gas by the reaction, such as nitrogen and then to conduct the reaction although both may vary from their initial settings.