Amination of 4-Substituted Pyridines

When the amination of 3-picoline was run in an autoclave in toluene with sodium amide, under a partial pressure of 30 psi of ammonia and pressurized further with nitrogen to a total pressure of 350 psi, the ratio of isomers was reversed to give a predominance of the 2,5-substituted isomer 53 in a ratio of 3.9 1. 

Even though it has been shown that the S fANRORC) mechanism did not operate in the amination of 4-phenylpyrimidine (29) in m-xylene (83RTC367), a ring-opening and ring-closure mechanism cannot be excluded in the pres- 

The effect of temperature and pressure on the amination of 3-picoline is shown in Fig. 1. It is seen that the higher temperature gave lower yields of 2-amino-5-methylpyridine (53). This was probably due to thermolysis playing an important role. 

Other 3-substituted pyridines behaved the same way as 3-picoline under pressure. The results are given in Table 11. 

The amination of 3,4-lutidine (60) under pressure gave 6-amino-3,4-dimethylpyridine (61) and 2-amino-3,4-dimethylpyridine (62) in a ratio of 

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The question still remaining to be settled is that of the observed preferential attack at C-2 in the aminations of 3-substituted pyridines. This preferred orientation does not seem to depend on the electrical effect of the 3-substituent (see Table VII). Since an attempted kinetic study of the reaction has, until now, been thwarted by the insolubility of sodamide in the reaction medium,268 a somewhat related system was investigated,10 namely that involving the reaction between methoxide ion in methanol and 2-chloro-, 2-chloro-3-methyl-, and... 

Amination of 3-substituted pyridines occurs preferentially at the a-position, i.e., 2(6) position. One example is the amination of 3-phenylpyridine (9) which gives the 2-amino isomer 10 in a 52% yield under the classical Chichibabin amination conditions. ... 

Butylamination of 3-picoline is shown in Scheme 35. The ratio of the 2-amino-5-isomer (89) to the 2-amino-3-isomer (90) was 16 L The yield of both isomers was 72%, which is about the same as obtained with sodium amide. The predominance of 89 is due most likely to steric hindrance caused by the bulkiness of the aminating agent. The situation is similar to the amination with sodium amide of 3-substituted pyridines at atmospheric pressure, in which the bulk of the 3-substituent directs the amount of 2-amino-5-isomer formed (Section IV), except that in this case, it is the size of the aminating group that decides the ratio of isomers. Additional alkylaminations of 3-substituted pyridines are shown in Table III. 

For [CoII(2,3,17,18-TDC)]+, the association constant Kt was found to increase in the range 102-104M 1 as the pKa of 4-substituted pyridines increased.254,265 The Kx is linearly correlated to the pATa in the [Co11 (ODC)]+-N-donor system (equation 3V).269 Though the for L = Im fits the equations, aliphatic amines show lower Kx values than expected from their pK values, suggesting some metal-axial ligand n interaction. The steric hindrance of the 2-methyl group lowers K by a factor of 103. 

The initiation by aromatic tertiary amines is affected by the type of substituent and its position in the ring. A series of meta-substituted pyridines show a higher activity than ortho- or para-substituted derivatives with electron-releasing substituents. 3-Aminopyridine is much more reactive than 2-aminopyridine and 3-methylpyridine is more effective than 2- or 4-methylpyridine 19). The strong electron-withdrawing substituent of 2-bromopyridine and its steric hindrance eliminate the effect of this amine. A 2,6-Dimethylpyridine was also found to display a steric effect. Thus, in the presence of this amine, the rate of copolymerization decreases by a factor of 4 compared with 3-methylpyridine 69). 

The reaction of 1,2,4-triazines with ketene derivatives, such as 0,0-acetals, 0,A-acetals, N,N-aminals and A V-aminals has been studied intensively. In all cases pyridines are isolated, as the reaction follows the usual cycloaddition route (see p 648 and Houben-Weyl, Vol. E 7 b, p 471 ff). Again it is found that the orientation is dominated by secondary orbital interactions, leading either to 4-substituted or 3-substituted pyridines. The keten Af/V-aminals give predominantly the orientation opposite to the other ketene derivatives.407,408 The effect of the solvent on these reactions has also been studied.408... 

Ring expansion can be drawn in various ways. There is a direct route from the neutral amine, or its anion, that doesn t look very convincing, or you can ionize one of the chlorides first and open the cyclopropyl cation in an electrocychc reaction. However you explain it, this is a good way to make 3-substituted pyridines. 

Adolf Pinner (1842-1909), Professor of Chemistry at the Veterinary Institute in Berlin, elucidated the structure of nicotine in 1893 by oxidative degradation with bromine. [528] In addition to nicotinic acid, he also found methylamine and malonic acid. With the knowledge ofthe overall chemical formula, and the fact that nicotine had to contain two tertiary amine functions, he postulated it as a 3-substituted pyridine linked to a 2-substituted N-methylpyrrolidine. 

Pyridine iV-oxides can be aminated with isocyanides (Scheme 33). The reaction proceeds through an N-formylaminopyridine intermediate that can be isolated or hydrolyzed with acid to provide the aminopyridines.The reaction works with a number of substituted pyridines however, with electron-withdrawing groups the yields are lower. With C-3 substituted pyridine iV-oxides, a mixture of regioisomers was produced. The C-2 product predominated with aryl isocyanides. Steric hindrance did appear to impact the yield for both aryl and aliphatic isocyanides. Finally, isoquinoline AT-oxide reacted under these conditions to form the aminoisoquinoline in good yield (60%). If both the two and six positions were blocked, the reaction failed to proceed (14JOC2274). 

In the 3-substituted pyridines, the 2-amino regio-isomer can form selectively. In 3-dimethylaminopyridine (14) case, amination gives 15 exclusively in a 62% yield the product is favored due to the strong ion-dipole interaction of the sodium amide with the dimethyl amino-substituent. ... 

A number of papers have been concerned with substitution reactions of Vitamin B12 model compounds. Kinetics of the substitution of the alkylaquo-l,3-bis(acetyl monoximeimino)propanato-cobalt ions (MH2O) by L are consistent with formation of an intermediate MH20,L only when L contains an aromatic group. Sjxl substitution reactions of the axial aquo-ligand in methyl aquo-cobaloxime by thiols, primary amines, and 4-substituted pyridines have been described. 

Benzenesulphonyl chloride reacts with primary and secondary, but not with tertiary, amines to yield substituted sulphonamides (for full discussion, see Section IV,100,3). The substituted sulphonamide formed from a primary amine dissolves in the alkaline medium, whilst that produced from a secondary amine is insoluble in alkali tertiary amines do not react. Upon acidifying the solution produced with a primary amine, the substituted sulphonamide is precipitated. The reactions form the basis of the Hinsberg procedure for the separation of amines see Section IV,100,(viii) for details. Feebly basic amines, such as o-nitroaniline, react slowly in the presence of allcali in such cases it is best to carry out the reaction in pyridine solution see Section IV,100,3. ... 

In spite of the potential complexity of the general problem, even when restricted to the reagent family of amines, the nucleophilicities of such series as meta- and pom-substituted pyridines and anilines appear to correlate very closely with the expected substituent effects and with the basicities. This has been verified in the following cases (i) The reaction of pyridines (R = H, m- andp-CHs) with 2-chloro-3-nitro-, 2-chloro-5-nitro-, and 4-chloro-3-nitro-pyridines. ... 

A special type of ammonio group is represented by 4-( 1 -pyridinium)-pyridine and other azinium analogs. Such products often result from self-quaternization of highly reactive derivatives. A -(4-Pyridyl)-and A -(3-nitro-4-pyridyl)-pyridinium chloride hydrochlorides (121) react with aniline, chloride ion, and water to give 4-substituted pyridines plus pyridine. l-(2-Quinolyl)- and l-(4-quinolyl)-pyridinium salts undergo 2- and 4-substitution, respectively, with amines, anilines, hydroxylamine, phenols, alkoxides, mercaptans, and chloride... 

An extensive study of the amination of halopyridines has been carried out by den Hertog and co-workers.A comparison of their results with studies in inert solvents using primary and tertiary amines should permit some evaluation of the postulated factors. 2,4-Dichloropyridine in concentrated aqueous ammonia (180°, 5 hr) resulted in the formation of 4-amino- (60% yield) and 2-amino-chloropyridines (20% yield). Under similar conditions, only 4-substitution of 3,4,6-trichloro- and of 2,3,4,5-tetrabromo- and -tetrachloro-pyridines was observed. However, in these and the other polyhalo pyridines, the appreciable and unequal mutual activation by the halogen substituents needs to be emphasized. 

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