Electron-poor heterocycle

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. 

The electroactive species A is generated by a reaction, generally an equilibrium displaced toward Z, that precedes the electron transfer step. Z is the reactant introduced in the cell or the predominant form of the reactant in the reaction medium. These reaction schemes were introduced to rationalize the various electrochemical phenomena observed during the reduction of certain aldehydes in aqueous solutions. Indeed, in water, formaldehyde, r-electron-poor heterocyclic aldehydes, and a few aldehydes with strongly electron-attracting groups exist as their nonreducible hydrated form in rapid equilibrium with the reducible carbonyl ... 

As with the azoles, oxa- and thiadiazoles are very weak bases due to the inductive effects of the extra heteroatoms, although A-quatemisation reactions can be carried out. For similar reasons, electrophilic substitutions on carbon are practically unknown, apart from a few halogenations and mercurations - it is an intriguing paradox that mercurations, with what is generally thought of as a weak electrophile, are often successful in electron-poor heterocycles. Another important difference from other azoles is of course the absence of A-hydrogen, so that A-anion-mediated reactions are not available. 

Nucleophilic radicals carry cation-stabilising groups on the radical carbon, allowing electron density to be transferred from the radical to an electron-deficient heterocycle they react therefore only with electron-poor heterocycles and will not attack electron-rich systems examples of such radicals are CH20H, alkyl-, and acyl-. Substitution by such a radical can be represented in the following general way ... 

Generally speaking the electron-poor heterocycles are more resistant to oxidative degradation than are electron-rich systems - it is usually possible to oxidise alkyl side-chains attached to electron-poor heterocycles whilst leaving the ring intact this is not generally true of electron-rich, five-membered systems. 

Both electron-rich and electron-poor heterocyclic rings are susceptible to substitution of H by radicals. Although electrically neutral, radicals exhibit varying degrees of nucleophilic or electrophilic character and this has a very significant effect on their reactivity towards different heterocyclic types. These electronic... 

Intermolecular oxidative dimerisation of electron-poor arenes as well as electron-rich and electron-poor heterocycles proceeds in high yields in the... 

The groups of Hu and You reported a remarkable palladium-catalyzed oxidative cross-coupling of Af-containing heteroarenes 62 with diversely substituted thiophenes 47 to afford products 63A-D (Scheme 10.19). The Af-containing heteroarenes included electron-rich heterocycles such as xanthines and azoles as weU as electron-poor heterocycles such as pyridine IV-oxides. In cases where heteroarenes demonstrated sluggish reactivity, CuBr was used as an additive to assist C—H bond activation. A computational study provided support for a two-fold C—H activation pathway via a CMD mechanism. 

The examples shown demonstrate that the process tolerates the presence of a variety of functional groups most notably protic functionalities, which are not typically compatible with nucleophilic aromatic substitution methods owing to the high basicity of the fluoride ion in the anhydrous solvents typically used in these reactions. Additionally, electron rich atyl fluorides, which cannot be accessed through late stage nucleophilic displacement, are obtained in a regiospecific manner. Furthermore electron-poor, heterocyclic and ort/zo-substituted aromatics all perform well in the process. 

Because fluorine can affect drug properties so dramatically, a variety of monomers containing fluorine should be incorporated in to any monomer collection. Aryl fluorides, allq l fluorides, difluoromethyl variants and tri-fluoromethyl variants are all available from many commercial sources. Recently, a number of methods have been developed that allow a wider variety of bespoke monomers to be prepared by relatively simple means thus increasing the diversity of a monomer set. For instance, both the Baran and MacMillan groups have developed methods to introduce both CHF2 and CF3 moieties via CH insertion into both electron-rich and electron-poor heterocycles and unactivated arenes (Scheme 18.29). ... 

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