3.4- Pyridynes nucleophilic addition

Substituted derivatives of 3,4-didehydropyridine have also been prepared, and these have been utilized in a variety of cycloaddition and nucleophilic addition reactions (82T427 89ACR275). A recent example involves the synthesis of azaanthraquinones by reaction of the pyridyne with the lithium salt of 3-cyanophthalide (Scheme 156), in a sequence that also involves the intermediacy of a 3-pyridyl carbanion (88H2643). 

Two other important modes of substitution require mention here. They are the SNAr and elimination-addition reactions. Actually, it is sometimes difficult to distinguish between true aromatic nucleophilic substitutions and addition-elimination processes. The second group involves pyridyne intermediates (Scheme 53). Both of these reaction types are discussed fully under substituent reactions (Chapter 2.06). 

Hydrogen attached to ring carbon atoms of neutral azines, and especially azinium cations, is acidic and can be replaced by a metal formally being removed as a proton. Alkyllithiums can be used as bases for this purpose however, the reaction can be accompanied by addition of the alkyl anion to the ring C=N bond. To avoid this, sterically hindered bases with strong basicity but low nucleophilicity can be utilized. Among these are lithium tetramethylpiperidide (LiTMP) and lithium diisopropylamide (LDA). If the anion contains an ortho halogen atom, then this can be eliminated to form a pyridyne (see Section 3.2.3.10.1). 

In some, apparently straightforward, displacements, more detailed mechanistic study reveals the operation of alternative mechanisms. For example the reaction of either 3- or 4-bromopyridine with secondary amines in the presence of sodamide/ sodium t-butoxide, produces the same mixture of 3- and 4-dialkylaminopyridines this proceeds via an elimination process (Sn(EA) - Substitution Nucleophilic Elimination Addition) and the intermediacy of 3,4-didehydropyridine (3,4-pyr-idyne)." That no 2-aminated pyridine is produced shows a greater difficulty in generating 2,3-pyridyne, it can however be formed by reaction of 3-bromo-2-chloropyridines with butyllithium" or via the reaction of 3-trimethylsilyl-2-trifluoromethanesulfonyloxypyridine with fluoride." ... 

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