Heterocycles, acylation radical alkylation

In the first step, the carbon centered radical is generated. The second step involves the addition of this radical to the protonated ring. The third step consists of the rearomatization of the radical adduct by oxidation. The rates of addition of alkyl and acyl radicals to protonated heteroaromatic bases are much higher than those of possible competitive reactions, particularly those with solvents. Polar effects influence the rates of the radical additions to the heteroaromatic ring by decreasing the activation energy as the electron deficiency of the heterocyclic ring increases. 

The introduction of an acyl group activates the heteroaromatic ring towards further acylation, which however always takes place exclusively at the positions X and y to the heterocyclic nitrogen (the protonated nitrogen is by far the main activating factor, which determines the positional selectivity). Thus, if a heterocyclic compound has two reactive positions, it is easy to obtain diacyl derivatives, but only one isomer (for example 2,4-diacylderivatives in the case of quinoline), whereas the monoacylderivatives prevail only at very low conversions. Due to the nucleophilic character of alkyl and acyl radicals, the behavior of homolytic... 

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). 

The homolytic acylation of protonated heteroaromatic bases is, as with alkylation, characterized by high selectivity. Only the positions a and y to the heterocyclic nitrogen are attacked. Attack in the position or in the benzene ring of polynuclear heteroaromatics has never been observed, even after careful GLC analysis of the reaction products. Quinoline is attacked only in positions 2 and 4 the ratio 4-acyl- to 2-acylquinoline was 1.3 with the acetyl radical from acetaldehyde, 1.7 with the acetyl radical from pyruvic acid, and 2.8 with the benzoyl radical from benzaldehyde. 

The Friedel-Crafts alkylation and acylation are of very little, if any, synthetic interest when applied to heterocyclic aromatic bases the substitution of protonated heterocycles by nucleophilic carbon-centered radicals is instead successful. This reaction, because of the dominant polar effect which is mainly related to the charge-transfer character of the transition state (Scheme 1), reproduces most of the aspects of the Friedel-Crafts aromatic substitution, but reactivity and selectivity are the opposite. 

With unprotonated heterocyclic bases, nucleophilic radicals either do not react (t-alkyl, benzyl, acyl, a-oxoalkyl, a-N-amidoalkyl) or react more slowly (3 to 6 orders of magnitude less) leading poor synthetic value (low yields and low chemo- and regioselectivity). 

The silver-catalyzed decarboxylation of a-oxo acids (carboxylic acids " ) by peroxy-disulfate leads to acyl " (alkyl radicals, which can effect selective homolytic acylation (alkylation of quinoxaline. This procedure is effective in monoacylation when multiple positions of high nucleophilic reactivity are available in the heterocyclic ring. " ... 

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 heterocycies 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 ... 

Scheme 38. The use of protonated heterocyclic bases as alkene traps for alkyl radicals from 0-acyl thiohydroxamates [41]...

Alkylation and Acylation by Free-radical Reactions. Heteroaromatic bases, being electron-deficient compounds, readily react with nucleophilic reagents, particularly when protonation enhances their electron-deficient nature. Because of the nucleophilic character of the wide range of available alkyl radicals, homolytic alkylation of heteroaromatics is of interest comparable to that of electrophilic alkylation in the homocyclic series. Homolytic acylation is of no less importance because of the wide applicability of this general reaction in the heterocyclic field. 

Alkylations. Treatment of 1 with various primary alkyl halides provides the corresponding substituted dithianes (eqs 3-5 ). Removal of the dithiane under the Lewis acid conditions, illustrated in eqs 3-5, unmasks the acyl silane for subsequent transformations such as photolysis, radical reactions, and heterocyclic synthesis. Other conditions for removing the dithiane moiety of 2-substituted-2-f-butyldimethylsilyl-l,3-dithianes include anodic oxidation, ceric ammonium nitrate (CAN)/NaHC03 in CH3CN/H2O, iodomethane/CaC03 in THF/H20, 8 and l2/CaC03 in THF/H2O. The formyl sUane of 2-t-butyl-dimethylsilyl-l,3-dithiane has also been reported." ... 

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