Intermediate cr-adduct

Deoxygenative autoaromatization was reported to occur in the reaction of 3-amino-1,2,4-triazine 2-oxides 42 with alcohols in the presence of HCl or acetyl chloride. In this case the intermediate cr -adducts undergo elimination of water or acetic acid, resulting in 6-alkoxy-3-amino-l,2,4-triazines 75 (77JOC3498). 1,2,4-Triazine 1-oxides do not react with alcohols under these conditions (77JOC3498). 

Organolithium derivatives of arenes and hetarenes have been shown to react smoothly with l,2,4-triazin-4-oxides 26 in the presence of acetyl chloride to give 5-aryl- or 5-hetaryl substituted 1,2,4-triazines 88, as the Sn products. In this case, aromatization of the intermediate cr -adducts 87 takes place due to O-acetylation of the 1,2,4-triazine Af-oxides and elimination of OAc as the auxiliary group (Scheme 49). 

It is common knowledge that the reaction is a two-step process, which includes the addition of a nucleophile at an unsubstituted carbon of an arene or hetarene followed by the aromatization of the intermediate cr -adduct (94MI). Elimination of the hydride ion seems to be an improbable step compared to the elimination of a nucleofuge X from such cr -adducts. Thus the aromatization of a cr -adduct is the key step for the whole reaction, and it can proceed by several general paths, as shown in Scheme 1. 

The isolated cr -adducts 57 undergo oxidation with KMn04 easily, resulting in the corresponding 5-indolyl-1,2,4-triazine 4-oxides 60 (98ZOR429). Separating the nucleophilic addition step from the oxidative aromatization of the intermediate (T -adducts allows the use of such oxidant-sensitive nucleophiles as indoles. 

Another pathway for the aromatization of the cr -adducts was found in the reactions of 3-pyrrolidino-l,2,4-triazine 4-oxide 81 with amines. Thus the treatment of 1,2,4-triazine 4-oxide 81 with ammonia leads to 5-amino-1,2,4-triazine 4-oxides 54—products of the telesubstitution reaction. In this case the cr -adduct 82 formed by the addition of ammonia at position 5 of the heterocycle undergoes a [l,5]sigmatropic shift resulting in 3,4-dihydro-1,2,4-triazine 83, which loses a molecule of pyrrolidine to yield the product 54. This mechanism was supported by the isolation of the key intermediates for the first time in such reactions—the products of the sigmatropic shift in the open-chain tautomeric form of tiiazahexa-triene 84. The structure of the latter was established by NMR spectroscopy and X-ray analysis. In spite of its open-chain character, 84 can be easily aromatized by refluxing in ethanol to form the same product 54 (99TL6099). 

The isolation and/or NMR spectroscopic characterization of cr-complexes, as that shown by 1, have received considerable attention over the past two decades, because of the relationship between the formation of such adducts and that of the metastable cyclohexadienyl intermediates postulated in the S Ar mechanism. The detailed structures of these adducts are now well known, and their reactions, the kinetics and thermodynamics of their formation and decomposition, as well as their spectral properties have been investigated in detail5,11,12. Although these studies constitute an important contribution to the understanding of the intermediates involved in Ar, they will not be discussed in this chapter since they have been recently reviewed furthermore, most of the cr-adducts were formed by the addition of anionic nucleophiles13,5,11. 

Chloro-l,7-naphthyridine (110 X = Cl) gives on animation with KNH2/ NH3 the tele product 2-amino-1,7-naphthyridine (53) in addition to the ipso product 8-amino-l,7-naphthyridine (54).10 25 The formation of 53 involves as intermediates anionic cr-adduct 111 (X = Cl) (its existence has been proved by NMR spectroscopy see Section I1,B,1) and probably 2-amino-2,8-dihydro-8-chloro-1,7-naphthyridine (112). The latter undergoes a base-catalyzed dehydrochlorination, yielding 53. Because there are four atoms between position 2 and 8. the reaction is called an even tele substitution. 

Amination of 5-bromo-l,6-naphthyridine (113) gives as tele product 2-amino-l,6-naphthyridine (51 ),24 but in addition to the intermediacy of anionic cr-adduct (114) (as proved by H-NMR spectroscopy), its formation involves anionic cr-adduct 115, which is formed by a proton shift from 114. The number of atoms between positions 2 and 5 is five, thus this reaction is referred to as an odd tele substitution. Both types of tele substitution involve Addition of the nucleophile as the initial step and Elimination of the leaving group as the last step. However, in the even tele substitution the elimination can be described to take place from a neutral dihydro species, while in the odd tele substitution the elimination must occur from an anionic intermediate. In the naphthyridines several examples of even and odd tele substitutions are found, and in the following sections the results of studies concerned with tele amination are presented. 

The heats of formation of the intermediate methylamino-cr-adducts of 2-R-3-nitro- and 2-R-3,6-dinitro-l,8-naphthyridines (R = H, OCH3, OH, NH2, NHCH3, NHC6H5, Cl) and transition states of the SNH methylamina-tion reaction of these nitro-l,8-naphthyridines were calculated by the PM3 method. The agreement between the calculated and observed results was found to be satisfactory (97LAR2601,97MI4). 

Sigma adducts are ligands that are bound to a metal center via a cr-bond pair (an L-type ligand). The cr-adduct can be a reaction intermediate that arises prior to an oxidative addition step or subsequent to a reductive elimination step. In this way, a cr-adduct is a midpoint between a free molecule or substrate and an activated molecule that then serves as... 

Interception of the cr-adduct with an external hydride source, leading to an overall Michael-type addition is a synthetically useful variation of the Heck reaction (see Sect. IV.2.5). But there are also examples of a--intermediates that are relatively stable toward elimination due to chelation. One such intermediate as reported by Cheng and Daves Jr. is shown in Scheme This isolated complex underwent /8-elimination of hydrogen,... 

Acyclic dialkylamines are not very reactive as nucleophiles in the oxidative alkylamination, however they are very prone to oxidation and, therefore, they are capable for unexpected behavior. Presumably, transformation 33 41 starts from oxidation of dialkylamme into imine 42, that is in equilibrium with enamine 43 (Scheme 28). The latter, as bifunctional C,W-nucleophile, attacks C-4 atom of the pyridazine ring to form cr -adduct 44, which then undergoes oxidative aromatiza-tion. Subsequent intramolecular oxidative amination of the intermediate 45 yields pyrrole derivative 41. The participation of imines in this process has been confirmed experimentally. In the presence of AgPy2Mn04, pyrimidopyridazine 33 reacts with authentic aldimines and ketimines 42 to give pyrroles 41. Transformation 33 41 represents not only a rare example of the tandem processes but... 

This transformation starts with the addition of amine to C-5 of 94 resulting in the formation of the cr -adduct 96 (Scheme 62). Subsequent opening of the pyrimidine ring, rotation around C(4)-N(exo) in the intermediate 97, recyclization with participation of the triazole ring (97 98—>99), and elimination of HBr comprise the set of steps to form the final product 95. 

Strictly speaking, the intermediates in the Cri reductions are the Cr adducts of these complexes. 

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