Nucleophilic aromatic substitution heterocyclic systems

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]. 

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. 

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. 

Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds Polyfluoroaromatic nitrogen heterocyclic systems are all activated, relative to the corresponding benzenoid compounds, towards nucleophilic aromatic substitution. The magnitude of this activation is illustrated by the effects of a ring nitrogen, relative to C—F at the same position, for attack by ammonia [91] (Figure 9.32). 

In the following discussion, reactions of each perfluoroaromatic heterocyclic system are discussed in turn after a more general description of the mechanism of nucleophilic aromatic substitution that underpins the majority of the chemistry presented here. 

Multifunctional systems from perfluorinated heterocycles by nucleophilic aromatic substitution processes 12THC(27)1. 

Besides the applications of the electrophilicity index mentioned in the review article [40], following recent applications and developments have been observed, including relationship between basicity and nucleophilicity [64], 3D-quantitative structure activity analysis [65], Quantitative Structure-Toxicity Relationship (QSTR) [66], redox potential [67,68], Woodward-Hoffmann rules [69], Michael-type reactions [70], Sn2 reactions [71], multiphilic descriptions [72], etc. Molecular systems include silylenes [73], heterocyclohexanones [74], pyrido-di-indoles [65], bipyridine [75], aromatic and heterocyclic sulfonamides [76], substituted nitrenes and phosphi-nidenes [77], first-row transition metal ions [67], triruthenium ring core structures [78], benzhydryl derivatives [79], multivalent superatoms [80], nitrobenzodifuroxan [70], dialkylpyridinium ions [81], dioxins [82], arsenosugars and thioarsenicals [83], dynamic properties of clusters and nanostructures [84], porphyrin compounds [85-87], and so on. 

M n Part II we spend a lot of time and pages on aromatic systems, starting with benzene. You examine benzene s structure, its resonance stabilization, and its stability. Next you study benzene derivatives and heterocyclic aromatic compounds, and then we address the spectroscopy of these aromatic compounds. And in Chapters 7 and 8 we introduce you to aromatic substitution by both electrophiles and nucleophiles, and you get to see a lot of reactions and a lot of examples. In this part you also start working with many more named reactions. 

Since there are no extensive studies on the relative aromaticity of the heterocycles covered in this chapter, the relative order of aromaticity of these systems has been gleaned from disparate studies. A priori, the combined effects of the 7i-electron-deficient five-membered heterocycles annelated to a pyridine nucleus provides a series of bicyclic heterocycles with low reactivity towards electrophiles. In the presence of suitable leaving groups, they are prone to undergo nucleophilic substitution. Since these heterocycles are readily obtained from either appropriately substituted pyridines or five-membered heterocycles, methods for direct functionalization of the parent heterocycles are not frequently studied. Based on the diversity of reactions these heterocycles undergo, it can be inferred that the pyridofuroxans are the least aromatic. 

It is important to recall that the reactivity pattern of phosphoies is very different from that of the related S, N, and O ring systems due to their limited aromatic character. For example, electrophilic substitution takes place only with a handful of phosphoies that have been specifically tailored via increasing the bulkiness of the P substituent (see Section 3.15.10.4, Scheme 83). In fact, electrophiles react at the phosphoms atom affording a panel of neutral and cationic CN 4 derivatives (Scheme 8). Phosphoies are also versatile synthons for the preparation of other heterocyclic systems via Diels-Alder reactions. The cycloaddition can involve the dienic moiety of the phosphole ring or can occur following a 1,5-shift of the P-substituent (Scheme 8). Finally, phosphoies can be transformed into phospholide ions, which are powerful nucleophiles that have found a variety of applications (Scheme 8). All these facets of phosphole reactivity are presented in this section. It should also be noted that CN 3 phosphoies exhibit a rich coordination chemistry toward transition metals (see Section 3.15.12.2). 

This chapter describes in general terms the types of reactivity found in the typical six- and five-membered aromatic heterocycles. We discuss electrophilic addition (to nitrogen) and electrophilic, nucleophilic and radical substitution chemistry. This chapter also has discussion of orf/to-quinodimethanes, in the heterocyclic context. Organometallic derivatives of heterocycles, and transition metal (especially palladium)-catalysed chemistry of heterocycles, are so important that we deal with these aspects separately, in Chapter 4. Emphasis on the typical chemistry of individual heterocyclic systems is to be found in the summary chapters (7, 10, 13, 15, 19 and 23), and a more detailed examination of typical heterocyclic reactivity and many more examples for particular heterocyclic systems are to be found in the chapters - Pyridines Reactions and Synthesis , etc. 

Addition of electron-rich aromatic systems to the 1,2,4-triazine ring can easily be achieved by preliminary activation of the heterocyclic system by protonation or alkylation. Addition of the following nucleophiles to the 1,2,4-triazinium ion (129) has been observed indoles, pyrroles, anilines, phenols, and aminothiazoles. The 1,6-dihydro-1,2,4-triazines (130) can be isolated in most cases and oxidized in a second step to the aromatic 1,2,4-triazine system (Scheme 20). 1,2,4-Triazin-5(2i/)-ones also undergo this reaction. 5-Unsubstituted 1,2,4-triazine 4-oxides (131) can be transformed into 5-substituted 1,2,4-triazine 4-oxides (Equation (14)) <86KGS1535, 92H(33)93l, 95UP 611-01>. 

Examples of the completely unsaturated 10 -electron hetero-aromatic ring system are known for all the above heterocycles. The chemical reactivity of these heterocyclic systems can be viewed as a microcosm of heterocyclic chemistry. Although little explored, the literature on these compounds is already replete with examples of imaginative synthetic entry, nucleophilic and electrophilic substitution reactions, mechanistically intriguing molecular rearrangements and compilations of spectral data, which now allow structure assignment to new reaction products with relative certainty. 

This method has been exploited for the synthesis of a variety of condensed heterocyclic systems through awto-aromatization of the intermediate o -adducts derived from the reactions of nitro-substituted azoloazines with nucleophiles [104, 105]. 

In addition to well-known routes to fused heterocyclic systems which are based on displacement of two leaving groups in an aromatic ring, it has been suggested to exploit tandem nucleophilic addition-addition (A —An), addition-substitution of hydrogen (An-Sn ), and double substimtion of hydrogen reactions (Sn -Sn ) on two neighboring carbons (Scheme 54) [11,114-116, 169-176]. 

Abstract After a short presentation of major variants of nucleophilic substitution of hydrogen, application of these reactirais to introduction of substituents into aromatic and heteroaromatic rings and construction of heterocyclic systems are discussed. 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

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