Heterocycles radical acylation

The numerous amino-adds which are met in the products of advanced tryptic hydrol)rsis are of quite different constitution. Some possess only an add function and an amine function others are di-adds and mono-amines, or mono-adds and di-amines. Some have an alcohol function others are sulphur products. Finally, these compounds are sometimes of straight chain, sometimes of dosed chain constitution. Yet, we may say that all answer to the general formula, R — CHCNHj) — COjH, which shows that there is at least a grouping NHj fixed on the C adjacent to carboxyl, R bdng an acyl, an aromatic or heterocyclic radical. The following is a list of these compounds ... 

The resulting nucleophilic acyl radical adds onto the protonated heterocycle and the resulting heterocyclic radical is reduced by the Fe(II) salt into the corresponding dihydropyridine derivative that is subsequently oxidized into the corresponding products. The use of a TBHP/ri(in) redox system allowed for the isolation and charaeterization of the dihydropyridine intermediate. - ... 

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. 

In agreement with MO calculations (V-acylation of 5H- dibenz[6,/]azepine alters considerably the pattern of electrophilic substitution. In the N-unsubstituted heterocycle the sites of electrophilic substitution are at C-2 and C-8 i.e. ortho and para to the free NH see Section 5.16.3.9.1). However, as predicted theoretically, IV-acylation deactivates the car-bocyclic nuclei towards substitution via mesomers of structure (32). As a result Friedel-Crafts acetylation furnishes the 5,10-diacetyl derivative (108). Electrophilic bromination (Br2/CHC13), unlike the free radical process (see Section 5.16.3.7), yields the 10,11-dibromo compound. In contrast, nitration of the (V-acetyl derivative at low temperature affords only the 3-nitro isomer (74CRV101). 

Acyl radicals obtained by the oxidation of aldehydes or the oxidative decarboxylation of a-keto acids react selectively at the a- or y-position of the protonated heterocyclic nitrogen. Pyridines, quinolines, pyrazines and quinoxalines all react as expected yields are typically 40 to 70%. Similarly, pyridines can be carbamoylated in acid media at C-2 (Scheme 38). 

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). 

A new process for the homolytic acylation of protonated heteroaromatic bases has been developed by Minisci et al. An A-oxyl radical generated from iV-hydroxyphthalimide by oxygen and Co(ll) abstracts a hydrogen atom from an aldehyde. The resulting nucleophilic acyl radical adds to the heterocycle which is then rearomatized via a chain process. Under these conditions, quinoline and benzaldehyde afford three products (Equation 108) <2003JHC325>. A similar reaction with 4-cyanopyridine gives 2-benzoyl-4-cyanopyridine in 96% yield. 

An alternative method for the substitution of a hydrogen atom in -electron deficient heterocycles is using the nucleophilic character of radicals in homolytic aromatic displacement reactions <74AHC(16)123>. Acylation with acyl radicals derived from aldehydes is an especially important approach since Friedel-Crafts-type reactions are not applicable to pteridines. 

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. " ... 

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. 

Radical cycUzations. Closure of carbocycles and heterocycles can be achieved by this method using HSi(SiMe3)3 and an initiator (e.g., AIBN, EtjB) to act on halides, thionocarbonates, or acyl selenides. ... 

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 ... 

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... 

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