Heterocycles, acylation alkylation

Diazadienes have been used in organic synthesis for the preparation of various heterocyclic compounds. Alkylation of 1,3-diazadienes 207 and the benz-fused analog 210 at the nitrogen atom by aryl acyl bromides provided the iV-alkyl amidinium bromides 208 and 211, which underwent annulation to the 2,3-dihydro-imidazo[2,l-A]thiazole 209 and imidazo[2,l- ]benzothiazoles 212, respectively (Equations 92 and 93) <2001S741, 2002J(P1)741>. 

Acyl peroxides of structure (16) are known as diacyl peroxides. In this structure R1 and R2 are the same or different and can be alkyl, aryl, heterocyclic, imino, amino, or fluoro. Acyl peroxides of structures (17), (18), (19), and (20) are known as dialkyl peroxydicarbonates, OO-acyl ((-alkyl monopcroxycarbonatcs. acyl organosulfonyl peroxides, and di(oiganosulfonyl) peroxides, respectively. R1 and R2 in diesc structures are the same or different and generally are alkyl and aryl. Many diacyl peroxides (16) and dialkyl peroxydicarbonates (17) are produced commercially and used in large volumes. 

To expand the diversity of their libraries Brill et al.16 also modified various heterocycles by alkylation, acylation, or metal-mediated coupling reaction prior to resin capture. A remaining chloro substituent was still available for nucleophilic displacement or a palladium-mediated coupling reaction with anilines, phenols, and boronic acids on solid phase [see Fig. 10 for the preparation of purine derivative (62)]. 

Lateral chain modifications on QDO and PDO have been well documented in the literature. The described reactions have shown modifications in specific functional group—i.e., acylations, alkylations, decarboxylations, hydrolysis, rearrangements, substitutions—or the production of a new heterocycle, fusioned or not. Examples of the most recent descriptions are depicted in Fig. 6 [64-66],... 

Enaminones were obtained from lactam acetals by reaction with active methylene compounds610. Heterocyclic / -enaminoesters are synthons in the preparation of condensed systems611. Acylated alkyl aminoisobutyrylmalonates (145) can be converted to 3-oxo-2-pyrrolines (146)612,613. 

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 gas phase, alkylation of five-membered heterocycles by alkyl cations usually occurs via the usual addition-elimination mechanism of aromatic electrophilic substitution. The phenyl cation behaves differently, however although its substrate discrimination is limited, in accord with its exceedingly high reactivity, it has marked selectivity for the a position, which does not conform with the hard character of this cation. It has, therefore, been suggested that an electron-transfer mechanism is followed this is thermodynamically allowed for the phenylium, and likewise for the methyl cation, but not for other alkyl cations (Scheme 28). This SET mechanism applies also for acyl cations [87]. 

Oxonium fiuoroborate Preferential N-alkylation of N-heterocyclics Acyl as N-protective group... 

Reaction of 2-aminothiazoles with alkyl isocyanates yields 2-thiazolylureas (256) (Scheme 153) (479-483). This reaction is general and works with acyl isocyanates (484. 485). These heterocyclic ureas are also prepared by the reaction of H2O on 2-thia2olylcyanamide (486) or by action of HjOj on the corresponding thiourea (303, 481). 

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

A surpnsing feature of the reactions of hexafluoroacetone, trifluoropyruvates, and their acyl imines is the C-hydroxyalkylation or C-amidoalkylaOon of activated aromatic hydrocarbons or heterocycles even in the presence of unprotected ammo or hydroxyl functions directly attached to the aromatic core Normally, aromatic amines first react reversibly to give N-alkylated products that rearrange thermally to yield C-alkylated products. With aromatic heterocycles, the reaction usually takes place at the site of the maximum n electron density [55] (equaUon 5). 

The reaction of the enamines of cyclic ketones with alkyl isocyanates, acyl isocyanates, phenyl isothiocyanates, and acyl isothiocyanates has also been reported 112). The products are the corresponding carboxamides. The products from the isothiocyanates have been utilized as intermediates in the preparation of various heterocyclic compounds 113). 

Acylation of heterocyclic enamines is to a great extent similar to alkylation, and usually occurs on the /3-carbon atom of the enainine grouping. 

As noted earlier (see Chapter 10), 4-acyl piperidines separated from benzimidazole by a three carbon chain often show antipsychotic activity. The heterocycle can apparently be replaced by a pyridopyrimidine ring. Thus alkylation of piperidine 41 with halide 42 affords pirenperone (43). ... 

These alkylation and acylation reactions are important because Friedel-Crafts alkylation and acylation (11-12, 11-14) cannot be applied to most nitrogen heterocycles. See also 13-15. 

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can be converted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40-70% yield, in a Reissert-Henze reaction, by activation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followed by treatment with aqueous alkali metal cyanide in H2O or dioxane. 

The aerobic reduction of aryl and alkyl carboxylates to the corresponding aldehydes. The reaction involves formation of an acyl-AMP intermediate by reaction of the carboxylic acid with ATP NADPH then reduces this to the aldehyde (Li and Rosazza 1998 He et al. 2004). The oxidoreductase from Nocardia sp. is able to accept a range of substituted benzoic acids, naphthoic acids, and a few heterocyclic carboxylic acids (Li and Rosazza 1997). 

The alkylation of formazan anions (166) with methyl iodide yields the A-methylformazan (202) which cannot be prepared by direct methods (Scheme 31).4 However, formazans that contain hydroxyaryl (203) or heterocyclic groups (205) alkylate preferentially on these groups to yield the alkylation products 204349 and 206,346-348 respectively (Eqs. 24,25). Although formazans are resistant to acylation,334,350 351 it can be accom-... 

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). 

R1 = H, alkyl, aryl R4 = aryl, alkyl, heterocycle E = ester, acyl, amide nitro... 

These methods involve the modification of the C-4 atom in (539) by its alkylation products (547) and A -acylation of (539) in the presence of bases, which is accompanied by the double-bond transfer in heterocyclic system (products (548)). 

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