Amination of pyridines

Tschitschibabin amination of pyridine, the mechanism of which has been established as involving an intermediate charge distribution of the thiazole molecule as well as of the thiazolium ion. 

Hydroxylamine-O-sulfonic acid for N-amination of pyridine, 43, 1 Hydroxylation of indene, 41, 53 2-Hydroxy-3-methylbenzoic add, oxidation to 2-hydroxyisophthalic acid by lead dioxide, 40, 48 Rydroxymethyleerrocene. 40, 52... 

Closure of the triazole ring can be achieved either by oxidative formation of the N-N bond, or condensation of an fV-aminopyridone. The latter was formed by iV-amination of pyridines with mesitylhydroxylamine (MSH), or by forming the pyridine ring, starting from cyanoacetic hydrazide with malononitrile or 2-cyanoacrylates. 

The results of some of the many aminations of pyridine and its derivatives that have been carried out appear in Table 14. Yields are quoted where possible but these should not be used for quantitative comparisons as reaction and work up conditions vary widely. 2-Alkylpyridines aminate at the vacant a-position, except when the substituent is very large. 2-f-Butylpyridine does not undergo the Chichibabin reaction, probably because the bulky 2-f-butyl group prevents adsorption on to the sodamide surface. In contrast, 2-phenylpyridine undergoes amination in very good yield. Aminations of 2- and 4-methyl-pyridines do not involve attack on the anhydrobases in aprotic solvents, but some ionization does take place in liquid ammonia. 4-Benzylpyridine forms a carbanion (148) which is only aminated with difficulty by a second mole of sodamide (equation 103). 

Nucleophilic substitution occurs in the 2, 4. and 6 positions of pyridine under relatively mild conditions. As an example, amination of pyridine with sodium amide in N, /V-dimethylaniline at I80°C gives 2-aminopyridine in good yield. 

The mechanism of the Chichibabin amination of pyridine has been discussed in terms of an addition-elimination mechanism via a covalent a-adduct.38 39 The possible formation of 2,3-didehydropyridine (2,3-pyridyne) as intermediate in the Chichibabin amination has been advocated, but this is now definitely rejected.38 39 In this section we discuss the Chichibabin amination of the parent naphthyridines and their derivatives and the products that are obtained in these aminations. The formation of their precursors (the covalent n-adducts) has already been discussed in Section II,A and II,B. 

Intermolecular aminations of pyridine 1-oxides with amide ions have not been as well investigated as those of the neutral molecules. Most of the examples studied involve halo JV-oxides, where a competition between Type B behaviour and pyridyne reaction compete (Scheme 91) (67RTC655). 

Chichibabin amination reaction Direct amination of pyridine via SNAr reaction. 80... 

In the amination of pyridine, only a very small amount of 4-aminopyridine is obtained (62HC(14,3)1). Acridine, with no available a-carbon atom, undergoes amination in the 9-position with extreme difficulty in aprotic solvents (72CHE1518). 

In aprotic solvents, the removal of a hydride ion from a cr-adduct requires elevated temperature. The hydride ion shows no tendency toward anionic stabilization and is difficult to remove from an sp carbon (76RCR454). Oxidants have frequently been used in low-temperature aminations in liquid ammonia (see Section II,A,4) to facilitate hydride ion elimination. However, only one instance has been reported of the use of an oxidant for aminating heterocycles under heterogeneous conditions. It was reported that reaction times were shortened and yields were improved for the amination of pyridine and 2- and 4-picolines in Tetralin or polyalky I benzenes by the addition of potassium or sodium nitrate (72MI1). 

Another approach to determine the relative reactivities was attempted. In a competitive amination of pyridine and 1-methylbenzimidazole, treat-... 

Improved procedures for the Chichibabin amination of pyridine derivatives have been reported (83JAP(K)58-208266, 83USP4386209, 83USP4405790). A general method has been developed for the conversion of 2-aminopyri-dines into 2-pyridones via 2-cthoxycarbonyl-l-(2-pyridyl)pyridinium ions 15. The pyridinium ions 15 are easily made from the 2-aminopyridines 14 and the corresponding pyrylium salt 13. On treatment with aqueous sodium hydroxide, pyridinium ions 15 are converted into the l-(substituted-2-pyridyl-carbonyl)-2-pyridones 16, which are readily hydrolyzed to the 2-pyridones 17 and the picolinic acid 18 (83JCS(P1)2623). 

The amination of pyridines to iV-amino quaternary salts (14) has not yet succeeded with chloramine, which is another typical reagent for ami-nations. However, amination of pyridones has been described, as in Eq. (1) 20,2 ... 

Grignard reagents RMgX into the amines RNH2 succeeds with the former but fails with the latter. The two reagents gave comparable yields in the iV-amination of pyridine and quinoline but for indole and carbazole the first was more effective. It was concluded that, in general, hydroxylamine-O-sulphonic acid was more versatile. 1,2,3-Triazole reacts with hydroxylamine 0-sulphonic acid in aqueous potassium hydroxide to yield a mixture of 53% 1-amino-l,2,3-triazole and 14% of the 2-amino isomer (equation 37) . ... 

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. 

Scheme 18 Macrocyclization exploiting amination of pyridine iV-oxides...

In contrast to quinoline N-oxides, the amination of pyridine N-oxides with NHqOH/TsCl or 2-aminopyridine/TsQ was unsuccessful due to a variety of side reactions nucleophilic addition at positiOTi 4, dimerization, tosylation of the amination product, and nucleophile itself [111]. 

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