Tele substitution

An abnormal (tele) substitution of chlorine in both 2,3- and 2,6-dichloropyrazines 91, 92 occurred on reaction with dithiane anion, while morpholine gave the normal //wo-substitution <06TL31>. Another paper described the highly selective ipso monosubstitution of the 2,3-dichloro compound by enolates in toluene <06T9919>. 

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... 

There is an alternate mechanism for halide replacement, following the sequence of nucleophile addition, protonation and elimination of HX (Scheme 9). In this pathway, the addition of the nucleophile need not be at the ipso position it can be ortho to halide leading to cine substitution or it can be at the meta or para positions, leading to tele substitution.69,70 The mechanism is the same for both cine and tele substitution and the different names reflect a differentiation in the IUPAC naming schemes. 

An important example of indirect substitution utilizes alkoxy leaving groups the intermediate (28) from the reaction of the [(diphenyl ether)Cr(CO)3] complex and the 2-methyl-1,3-dithiane anion can be induced to eliminate phenol by protonation at low temperature the result is tele substitution (equation 17). 

The directing effects of F (strong meta) versus Cl (weak, ortho-meta discussed below) allow control over the site of tele substitution the chloro analog leads to (30), with the 1,3,5-substitution pattern (equation 19).71... 

Substitution with amine nucleophiles in the series of chlorotoluene complexes showed that the substitution is direct no cine or tele substitution was observed.75 The analogous [(fluoroarene)FeCp]+ complexes are known, but less well developed. Kinetic studies show that the fluoro derivatives are more reactive compared to the chloro analogs.47... 

III,B,1 we will deal with reactions in which both cine and ipso products are formed. The mechanism according to which these products are formed has been explained by the occurrence of a didehydronaphthyridine (naphthyri-dyne) intermediate.44 In Section III,B,2 the occurrence of aminodehalogena-tions involving tele substitutions are discussed and in Section 1II,B,3 the reactions in which the aminodehalogenation occurs in an ipso position are examined. 

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. 

One example has been reported of the occurrence of an even tele substitution within one ring of the 1,7-naphthyridine system. Amination of 5-halogeno-l,7-naphthyridines (27) with potassium amide gave 8-amino-1,7-naphthyridine (54).28 This reaction bears a close analogy to the formation... 

Tele substitutions that occur with the halogen derivatives of naphthy-ridines, which are characterized by a high degree of symmetry, cannot simply be recognized by the structure of the products obtained. For example, the amination of l-halogeno-2,6-naphthyridines (121, R = H)yields 1-amino-2,6-naphthyridine (123 R = H) (5-amino-2,6-naphthyridine 60).21 It is evident that this compound can be formed either by an Sm(AE) ps0 or SN(AE),elc pathway or by both mechanisms. 

An odd tele substitution also occurring in one ring has been observed on amination of 2-bromo-l,5-naphthyridine, yielding 4-amino-1,5-naphthyridine.21... 

An interesting case of an odd tele substitution has been found when aminating 2-X-l,8-naphthyridine (X = Cl, Br) with liquid ammonia containing potassium amide.10 29,30 The product obtained in the amination was 2-(or 7-) amino-1,8-naphthyridine (58). However, carrying out the amination with 2-X-7-deutero-l,8-naphthyridine (138), the 2-amino product had a deuterium content considerably less than was present in the starting material. From the amount of deuterium present in the 2-amino compound, it was calculated that for X = Br, 45% of the amino compound was formed according to the SN(AE) ele process and that for X = Cl, this percentage was considerably lower (10%).58... 

CHMe2). The steric hindrance for nucleophilic attack on position 1, in addition to approximately equal charge densities in positions 1 and 3, facilitates attack by the hydroxide ion to position 3 in 108, with simultaneous elimination of a CN anion (a kind of tele-substitution (78JHC731). Then, a thermally allowed 1,5-hydrogen transfer in 122 leads to stable l-alkylidene-3-hydroxy-isochromanes 123 (88T6217). 

Supposedly cyanoisochromene 108 reacts by tele-substitution, with intermediate formation of l-alkylidene-3-hydroxyisochromanes 123 (Section III,C,2). Indeed, on heating with aqueous alkaline solutions, these intermediates are quantitatively converted into the corresponding a- (204) or /3-naphthols (208) (88T6217). 

Dicyanopyridazine may react with pyrrole and indole systems as a heterocyclic azadiene in IEDDA Diels-Alder reactions. However, in acetic acid as solvent reaction occurs by substitution of CN at the 4-position and intermediates such as (10) may be isolated.50 Reaction of dichloropyrazines with a dithiane anion in THF may result in a tele-substitution process, as shown in Scheme 5, in which initial nucleophilic attack occurs at an unsubstituted ring position. Deprotection of the substituted product yields the corresponding aldehydes.51... 

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