Replacement Reactions with Nitrogen Nucleophiles

Replacement of Hydrogen by an Amino Group (Chichibabin Amination) 

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. 

Amination of 1,5-naphthyridine (1) with sodamide in liquid ammonia at room temperature was reported by Hart40 togive2-amino-l,5-naphthyridine (48). Other work has shown that under the conditions described by Hart, 

Other work has been carried out concerning the amination of 3-nitro-1,5-naphthyridine (46a) with liquid ammonia containing potassium permanganate.27 The 4-amino-3-nitro- 1,5-naphthyridine (50) is obtained in 50% yield. Its precursor, the covalent rr-adduct (47a), has been detected by NMR spectroscopy (see Section II,B,3). 

Other work has been carried out concerning the amination of 3-nitro- 

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Polycarbophosphazenes possess a backbone of phosphorus, nitrogen, and carbon atoms and can be regarded as derivatives of classical polyphosphazenes (1) in which every third phosphorus atom is replaced by carbon. The first examples of these materials were discovered in 1989 (88). Thermal ROP of a cyclic carbophos-phazene was used to prepare the chlorinated polymeric species (23), which im-dergoes halogen replacement reactions with nucleophiles such as aryloxides and aniline to yield hydrolytically stable poly(aryloxycarbophosphazenes) (24) (Afw = ca 10 , Mn = 10 ) (eq. 23) (88-91). The polymer backbone in these materials was found to be less flexible than in classical polyphosphazenes. For example, the halo-genated polymer (23) possesses a Tg of —21°C compared to a value of —66°C for poly(dichlorophosphazene) (2). 

Carrying out the same reaction with N-labeled potassium amide/liquid ammonia, the aminodechlorination leads to 100% incorporation of the label in the ring of 95. This exclusive enrichment of the nitrogen of the ring in 95 means that the replacement of the 2-chloro substituent starts by an exclusive nucleophilic attack at C-4 and formation of the C-4 adduct 93. Ring opening to 2-iminobenzoyl-3-cyanamino-5,6-diphenylpyrazine (94) and subsequent recyclization yield 95. 

An important prerequisite in these reactions is the nucleophilicity of the imine nitrogen. Indeed, electron-withdrawing substituents in the aryl ring of (159) retard the reaction with isothiocyanates, whereas such substituents in the R group of the isothiocyanates enhance the reaction. No reaction occurs under the above chosen conditions (reflux in chloroform), when the aryl ring of (159) is replaced by a sulfonyl group <88BSB83>. 

This diazotization reaction is compatible with the presence of a wide variety of substituents on the benzene ring. Arenediazonium salts are extremely important in synthetic chemistry, because the diazonio group (N=N) can be replaced by a nucleophile in a radical substitution reaction, e.g. preparation of phenol, chlorobenzene and bromobenzene. Under proper conditions, arenediazonium salts react with certain aromatic compounds to yield products of the general formula Ar-N=N-Ar, called azo compounds. In this coupling reaction, the nitrogen of the diazonium group is retained in the product. 

More general solutions come from the replacement of alkylations by reactions with carbonyl compounds. These generally occur once only and in many cases cannot occur twice as the products—amides 12 or imines 15 for example—are much less nucleophilic than the starting amine. The products are reduced to the target amines. The amide route is restricted to amines with a CH2 group next to nitrogen 13 but the imine route is very general and is known as reductive animation.1 It is the most important way to make amines and a recent survey showed that the majority of amines made in the pharmaceutical industry are made this way. 

Reactions of vinyliodonium salts with nitrogen, oxygen, sulfur and phosphorus nucleophiles have been reported only sporadically and have not been examined in a systematic way. The earliest studies are qualitative, while later investigations are based on rather atypical vinyliodonium structures. Such reactions usually result in the replacement of iodobenzene by the nucleophile (equation 184). The MC pathway, a common mode of reactivity for alkynyliodonium salts, has not been documented for any vinyliodonium compound. 

In this sense Organ and coworkers [80] have developed intriguing syntheses of polysubstituted olefins based upon consecutive intermolecular reactions such as allylic and allylic-vinylic halide coupling sequences. Therefore, l-acetoxy-4-chloro but-2-ene can be readily submitted as a template for Pd-catalyzed allylic substitutions with two different carbon or nitrogen nucleophiles, leading to unsymmetrically substituted butene derivatives 66-70 in good yields (Scheme 22). Mechanistically, the chloro substituent is replaced... 

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