Amination, Chichibabin

It has been reported (39JPJ18) that the Chichibabin amination of 4-methylpyrimidine, using sodium amide in boiling deealine, affords a mixture of 2-amino-4-methylpyrimidine and 2,6-diamino-4-methylpyrimidine. In light of the results mentioned in this section, it certainly eannot be excluded that in this aminodehydrogenation an Sn(ANRORC) meehanism is (partly) involved in the formation of these produets. 

The application of the Chichibabin amination to effect a direct amination of quinazoline has been reported. It gives 4-aminoquinazoline (60MII) as well as 2,4-diaminoquinazoline (59GEP958197). No mechanistic details were discussed, but it can be expected (based on the experience with the amination with 4-phenyl- and 5-phenylpyrimidine) that amination of quinazoline would also involve, at least partly, participation of the Sn(ANRORC) mechanism. Amination with N-labeled potassium amide/liquid ammonia will certainly shed some light on the mechanism operative in this Chichibabin amination. 

The Chichibabin amination of phenylpyrazine with N-labeled potassium amide/liquid ammonia gave two products, 3-amino- and 5-amino-2-phenylpyrazine in both products the label is only present in the amino group, and no label was found to be incorporated into the pyrazine ring (82MI1). This result proves that in the aminodehydrogenation of phenylpyrazine, no Sn(ANRORC) mechanism is involved. This result is confirmed by the fact that amination of phenylpyrazine in the presence of the radical scavenger azobenzene, a compound that has been found to prevent the Sn(ANRORC) mechanism in the Chichibabin amination of 4-phenylpyrimidine, still yields both aminopyrazines. 

Furthermore, it was pointed out that, whereas the formation of the amino adduct is fast and the formation of the product slow, it is possible that an equilibrium exists among the starting materials, their 1 1 a-amino adducts, and their open-chain amidines (Scheme 11.54). When this is the case, one may expect that, if the amination of phenyl-1,3,5-triazine is stopped before complete conversion, the retrieved starting material should be N-labeled. This has indeed been found. This behavior is in agreement with that observed with the Chichibabin amination of 4- and 5-phenylpyrimidine. 

A. E Pozharskii and A. M. Simonov, Chichibabin Amination of Heterocydes. Izd. Rost. Univ., Rostov-on-Don, USSR, 1971. 

Nucleophilic substitution occurs at C-2, and to a lesser extent C-4, as might be predicted from similar reactions with pyridine. Chichibabin amination occurs rather more readily than with pyridine, giving 2-aminoquinoline. A typical hydride abstraction process occurs when qninoline is heated with sodinm... 

A classic reaction of this type is Chichibabin amination. leading mainly to 2-aminopyridine (Scheme 2.12a). This takes place when a pyridine is heated at 140 °C with sodamide (NH2 is a very strong nucleophile). Although hydrogen gas is certainly evolved during the reaction, the initial proton donor is not known. However, once some 2-aminopyridine is formed this product could function as the donor (Scheme 2.12b), and the process may then become a form of chain reaction. 

Derivatives of 23 undergo Chichibabin amination under comparatively mild conditions in the presence of an oxidant (Equation 12) the major product results from amination at C-4, but is accompanied by up to 10% of the 3,4-diamine <2000MC150>. 

Alkynes, obtained as above, also undergo Chichibabin amination in this case, cyclization occurs in situ to form a pyrrole <2003RCB441>. Although pyrrole formation is expected to involve attack at followed by cyclization onto the acetylene, the possibility of initial attack occurring at the acetylene cannot be excluded, in view of the isolation of ketone 28 (Scheme 11) <2005JHC413>. 

The 7-unsubstituted 6-bromopyrazino[2,3- ]-l,2,6-thiadiazine 41 behaved in a different manner, yielding the product 42 of Chichibabin amination at C-7 when reacted with ammonia, a process that is shown in Equation (6) <2003HCA139>. 

H.C. van der Plas u. M. Wozniak, Croat. Chem. Acta 59, 33-49 (1968) . .Potassium Permanganate in Liquid Ammonia. An Effective Reagent in the Chichibabin Amination of Azines". 

Carboxamidation of heteroaromatic compounds, promoted by fluorine, provides a convenient alternative to the well-known Chichibabin amination reaction (Fig. 86) [228]. The mechanism of this reaction was suggested to proceed via a carbene intermediate (Fig 87). 

Naphthyridine undergoes NH2" attachment at position 1 at -30°C. The NMR spectrum of the resulting adduct does not change at 20°C. Accordingly, the amination of the same substrate yields 1-amino-2,6-naphthyridine.110 A similar behavior is displayed by 2,7-naphthyridine, attachment of the reagent occurring at position l.110 Also in this case the Chichibabin amination occurs at room temperature at the same position. 

A. Replacement of Hydrogen by an Amino Group (Chichibabin Amination). .. 117... 

Chichibabin amination refers to a reaction in which a hydrogen of an azaheteroarene is replaced by an amino group. The reaction is usually carried out by heating the heterocycle with a metal amide at elevated temperatures in an aprotic inert solvent. Potassium amide or sodium amide in liquid ammonia have also been found to be appropiate reagents for amination the presence of an oxidant seems to promote the reaction. Potassium nitrate is usually employed as an oxidant, 9 16 but other work shows that potassium permanganate can also successfully be used as an oxidizing agent in liquid ammonia.IO-20 17... 

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. 

Chichibabin amination of 1,6-naphthyridine (4) with KNH2/NH3 at room temperature gives 2-amino-l,6-naphthyridine (51) in 33% yield.19 When the... 

The most striking example of these reactions is the Chichibabin amination performed in its classical variant under heterogeneous conditions. The reaction is accompanied by the evolution of hydrogen gas that is conveniently monitored. Presumably, on elimination, the hydride ion is combined with an acidic proton, likely from an amino group 4, to form a hydrogen molecule the reaction mechanism without details is shown in Scheme 3. 

This type of cyclization has been already illustrated by the formation of 7-azaindole on Chichibabin amination of 3-ethynylpyridine (Scheme 2). Similarly, 6-alkynyl-l,3-dimethyllumazines 137 (03RCB1403, 05JHC413) and 3-alkynyl-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6//,8//)-diones 140 (05JHC413, 03RCB441)... 

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