Nucleophilic aromatic heterocycles

Palladium(0)-catalyzed allylation of ambident nucleophilic aromatic heterocycles 96AHC(66)73. 

Nucleophilic aromatic amination by the action of unsaturated N-heterocycles 99T11399. 

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

It has also been argued10,40 that the second mechanism (rapid, reversible interconversion of II and IV) cannot be general. The basis for this contention is the fact that electrophilic catalysis is rare in nucleophilic aromatic substitution of non-heterocyclic substrates, an exception being the 2000-fold acceleration by thorium ion of the rate of reaction of 2,4-dinitrofluorobenzene with thiocyanate... 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

In more recent work by other researchers, sealed-vessel microwave technology has been utilized to access valuable medicinally relevant heterocyclic scaffolds or intermediates (Scheme 6.120) [240-245]. Additional examples not shown in Scheme 6.120 can be found in the most recent literature (see also Scheme 6.20) [246-249]. Examples of nucleophilic aromatic substitutions in the preparation of chiral ligands for transition metal-catalyzed transformations are displayed in Scheme 6.121 [106,108]. 

A wide variety of other heterocyclic ring systems can conceivably serve as the conjugated backbone in nonlinear organic molecules. We will give examples from preliminary work on two of these, the thiazole and pyrimidine heterocycle derivatives 65-72 in Table VIII. These two heterocycles were chosen because the appropriate haloderivatives are commercially available as starting materials for nucleophilic aromatic substitution. The pyrimidine derivatives are of particular interest since their absorption edges ( 400 nm) are shifted hypsochromically an additional 30 nm relative even to the pyridines. 

Most syntheses of naturally occurring phenazines, though, are based on a two-step elaboration of the central heterocycle of the phenazine [78]. The first key step involves the generation of orf/zo-monosubstituted 88 or orf/zo, ortho -disubstituted diphenylamines 89-91 via nucleophilic aromatic substitution. Ring formation is then achieved by means of reductive or oxidative cyclization, for which a number of efficient methods are available. The main flaw of this approach is the synthesis of the substituted diphenylamines via nucleophilic aromatic substitution, as this reaction often can only be performed under strongly basic reaction conditions and at high temperatures. In addition, the diphenylamines required may only be achieved with certain substitution patterns with high yields. 

Gradually it was recognized that nucleophilic aromatic photosubstitution is a fairly general reaction (Havinga et al., 1967 Havinga and Kronenberg, 1968). It can be realized also with polycyclic and heterocyclic aromatic systems. Various solvents (water, alcohols. 

Halopyridines and other re-deficient nitrogen heterocycles are excellent reactants for nucleophilic aromatic substitution.112 Substitution reactions also occur readily for other heterocyclic systems, such as 2-haloquinolines and 1-haloisoquinolines, in which a potential leaving group is adjacent to a pyridine-type nitrogen. 4-Halopyridines and related heterocyclic compounds can also undergo substitution by nucleophilic addition-elimination but are somewhat less reactive. 

In a separate report, the regioselectivity and reactivity problems in the substitution of pyrimidines were avoided using 4,6-dichloro-5-nitropyrimi-dine as starting material,17 a very electron-poor heterocycle, which is highly reactive in nucleophilic aromatic substitutions. It reacts readily with the free amino group of the (trialkoxybenzhydrylamine) Rink linker on solid phase. This heterocycle could serve as a scaffold by itself and could also be used as a building block (precursor) to make other heterocycles such as purines. 

As mentioned earlier, Ding et al.15 captured a number of dichlorohetero-cyclic scaffolds where one chloro atom is prone to nucleophilic aromatic substitution onto resin-bound amine nucleophiles (Fig. 1). Even though it was demonstrated that in many cases the second chlorine may be substituted with SNAr reactions, it was pointed out that palladium-catalyzed reactions offer the most versatility in terms of substrate structure. When introducing amino, aryloxy, and aryl groups, Ding et al.15 reported Pd-catalyzed reactions as a way to overcome the lack of reactivity of chlorine at the purine C2 position and poorly reactive halides on other heterocycles (Fig. 10). 

Moreno-Manas, M., Pleixats, R., Palladium (O)-Catalyzed Allylation of Ambident Nucleophilic Aromatic Heterocycles,... 

Nucleophilic Aromatic Substitution of Hydrogen as a Tool for Heterocyclic Ring Annulation... 

A.V. Gulevskaya and A.F. Pozharskii (Rostov State University, Russia) write on nucleophilic aromatic substitution of hydrogen, concentrated on the use of this reaction for heterocyclic ring annulation. It covers particularly the recent extension of the general SnH reaction to effect ring annulation. 

So far we have concentrated on making complete heterocycles with substituents. So indomethacin 87 was made with one substituent (OMe) on the benzene ring and two on the pyrrole ring. Only the substituent on nitrogen was added after the indole was formed. Now we shall consider what reactions can be used to add substituents to heterocycles after they are formed. This will usually be by electrophilic or nucleophilic aromatic substitution. The most important distinction between... 

The use of transition-metal arene complexes to facilitate nucleophilic aromatic substitution features in a route to derivatives of thiosalicylic acid and hence to thioxanthone. The cyclopentadienyl iron complex of 2-chlorobenzoic acid is converted into the benzamide prior to displacement of the chloride by thiophenoxide. Photolytic decom-plexation followed by directed remote metallation of the diaryl sulfide yielded the heterocycle (Scheme 207) <2000SL975>. 

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