Nucleophilic substitution, ANRORC

Although the final products of the amination of 5-bromo-4-R-pyrimidines are the 6-amino-4-R-pyrimidines,106 107 two mechanisms, by which these same products are formed, have been recognized. The substrate is converted in part to the product via C-6 adduct 41, whereas the remaining part follows an ANRORC mechanism requiring attack of the reagent at C-2.105 Evidence for the existence of C-2 adducts as intermediates in nucleophilic substitutions is hard to obtain. However, the formation of an adduct of this kind (34) from 4,6-diphenyIpyrimidine was definitely proved by H-NMR measurements (Table XI).98 C-6 adducts such as 42-44 have also been described (see also Table XI) and shown to be the sole intermediates in the amination of 5-chIoro-4-te/T-butyIpyrimidine and 5-X-2,4-di-tert-butyIpyrimidines (X = Cl, Br), the ANRORC mechanism remaining excluded with the latter substrates.98... 

Just as in phenyl halides, the halogen can be replaced by hydrogen, by a metal, or be coupled. Two of the four mechanisms of such nucleophilic substitutions are also familiar from benzene chemistry via arynes and by the SRN1 mechanism. However, of the two further mechanisms of nucleophilic replacement, the ANRORC is unique to heterocycles, and SAE reactions occur only with strongly activated benzenoid systems. 

Dehydroheteroarenes like (10) and (11) have also been proposed as intermediates in nucleophilic substitution.23-25 Some of these reactions were evaluated uncritically and operation of other mechanisms like addition-elimination (AE) and ring opening-ring closure (ANRORC) can now be demonstrated in many such cases. Nevertheless, there is conclusive evidence for heteroaryne intermediacy in some reactions of heterocyclic halides. From the preparative point of view, nucleophilic coupling of such intermediates has found only limited applications.26-28 Reactive intermediates with an additional formal bond between nonadjacent atoms, like (12) and (13), have also been postulated but again hold little synthetic interest. 

Hetero substitutents exchange readily, though it has been shown that substitution of bromine by amide ion occurs through the Sn (ANRORC) mechanism. Replacement of an amino group with ammonia or hydrazine occurs by both and Sn (ANRORC) mechanisms (84MI5). The only example of this type of nucleophilic substitution in the current literature is the displacement of halogens in tetrazine 288 by alkoxide 289 to yield 290 (85TL4355). 

Nucleophilic substitution in azines, Sn(ANRORC) mechanism 78ACR462. Photochemical addition-substitution reactions of azines 74KGS867. Polyazaphenanthrenes 79H (12)529. 

The amination of 2.4-diphenyl-1,3,5-triazine (7, X = H) with potassium amide in anhydrous liquid ammonia at -33°C occurs by a Chichibabin-type reaction, i.e. replacement of H" by NH via nucleophilic substitution involving an addition-elimination process (SsAE). In contrast, the 2-methylsulfanyl derivative 7 (X = SMe) is aminated nearly exclusively by a ringopening-ring-closing sequence [Sn(ANRORC)].52... 

The initially formed adducts can be converted into products of nucleophilic substitution of hydrogen in a variety of ways oxidation with external oxidants, conversion into nitrosoarenes according to intramolecular redox stoichiometry, vicarious substitution, cine- and fe/e-elimination, ANRORC, etc. These processes have been discussed in a concise way in our preceding reviews [4,6-10]. The major message of those reviews is that nucleophilic substitution of hydrogen, in its many variants, is the main, primary process, whereas the conventional nucleophilic substitution of halogens X, the SnAt process, is just a secondary ipso reaction [9, 10]. 

It should be stressed that although outcome of these reactions is identical to that of classical Sj Ar of halogens, the substitution proceeds at the carbon atom of the ring connected with hydrogen thus, it is fully justified to consider cZwe-, tele-, and ANRORC substitutions as processes of nucleophilic substitution of hydrogen Sj H. 

Reactions with strongly basic nucleophiles such as potassium amide in liquid ammonia may prove much more complex than direct substitution. 2-Chloro-4,6,7-triphenylpteridine reacts under these conditions via an S ANRORC mechanism to form 2-amino-4,6,7-triphenylpteridine and the dechlorinated analogue (78TL2021). The attack of the nucleophile exclusively at C-4 is thereby in good accord with the general observation that the presence of a chloro substituent on a carbon position adjacent to a ring nitrogen activates the position meta to the chlorine atom for amide attack. 

A new variant of the Sn(ANRORC) substitutions was found in reactions of A-methylpyrimidinium salts with bifunctional nucleophiles, such as S-methylisourea, O-methylisourea, and cyanamide. 

Nucleophilic attack is faster at unsubstituted ring positions than at similarly activated but substituted ring positions.8-15-43 5 Since the addition is in most cases reversible, the opportunity exists for competing reactions. Indeed an extremely varied spectrum of reactivities is found in these systems, depending on reactants and reaction conditions. Examples are known of competing SNAr and cine substitution,46 NAr and tele substitution,47 SnAt and cine and tele substitution (equation l),5 SsAr and VNS,16 and SnAt and Sn(ANRORC).48... 

The reaction of strongly basic amide anions, R -N-R, with chloro- or bromopyridines, -pyrimidines, and other heterocycles can lead to ring opening and subsequent ring closure to result in substituted amino-N-heterocycles (addition of nucleophile, ring opening, ring closure = ANRORC). 

Ring-degenerate transformations initiated by the nucleophilic addition at C-5 of the 1,2,4-triazine ring have also been reported to occur in reactions of 4-aryl-substituted 3-methylthio-l,2,4-triazine-3,5-diones with hydrazine hydrate (Scheme 80). This ANRORC mechanism involves the open-chain compound 138 as intermediate (80JHC1733 81JHC953). 

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