Nitrogen-containing heterocycle synthesis compounds

This method is the basis for synthesis of nitrogen-containing heterocyclic compounds when Z is a carbonyl-containing substituent.290... 

The synthesis of nitrogen containing heterocyclic systems by photocylo-addition processes is virtually limited to examples involving [ 2 + 2] cycloaddition of imines, nitriles, and azo compounds. Successful additions are few in number and the requirements for success uncertain. The reactions do not proceed with the facility with which carbonyl containing compounds undergo photocycloaddition to alkenes to give oxetans, and various explanations have been advanced to account for this observed lack of reactivity.226... 

Strecker reactions provide one of the most efficient methods for the synthesis of a-amino nitriles, which are useful intermediates in the synthesis of amino acids and nitrogen-containing heterocycles. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a cyano anion source provides promising and safer routes to these compounds.133-351 Consequently, we focused our attention on tributyltin cyanide (Bu3SnCN), because Bu3SnCN is stable in water and is also a potential cyano anion source. Indeed, the Strecker-type reactions of aldehydes, amines, and Bu3SnCN proceeded smoothly in water (Eq. 9).1361 It should be noted that no surfactants are required in this reaction. Furthermore, Complete recovery of the toxic tin compounds is also possible in the form of bis(tributyltin) oxide after the reaction is over. Since conversion of bis(tributyltin) oxide to tributyltin cyanide is known in the literature, this procedure provides a solution to the problem associated with toxicity of tin compounds. 

The synthesis of oxygen- and nitrogen-containing heterocyclic compounds by anionic cyclization of unsaturated organolithium compounds has been reviewed recently. " Broka and Shen reported the first intramolecular reaction of an unstabilized a-amino-organolithium compound using reductive lithiation of an A,5-acetal derived from a homoaUylic secondary amine (Scheme 21). Just one example was reported treatment with lithium naphthalenide gave the pyrrolidine product, predominantly as the cis isomer. 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

The most usable and well-known pathway for the synthesis of five-membered nitrogen-containing heterocycles is condensation involving a,P-usaturated carbonyls and 1,2-binucleophilic compounds, e.g., derivatives of hydrazine and hydroxylamine (Scheme 2.8). The procedure based on these reactions was successfully applied for a long period [45, 46, 47, 48, 49, 50, 51, 52, 53]. 

The main aim of this monograph is a comprehensive review and organization of the known literature data devoted to the reactions of o,/3-unsaturated ketones, their synthetic equivalents and their precursors utilized in the synthesis of nitrogen-containing heterocycles. The book is separated into four chapters and an Addendum, and contains nearly 900 literature references. Each chapter describes the synthesis and chemical and other interesting properties and features of certain classes of heterocyclic compounds. 

Cazes et al. reported the Pd-catalyzed intermolecular hydroamination of substituted allenes using aliphatic amines in the presence of triethylammonium iodide leading to allylic amines [19]. In a way similar to the Pd-catalyzed hydrocarbona-tion reactions we reported that the hydroamination of allenes [20], enynes [21], methylenecyclopropanes [22], and cyclopropene [10] proceeds most probably via oxidative addition of an N-H bond under neutral or acidic conditions to give allylic amines. The presence of benzoic acid as an additive promotes the Pd-medi-ated inter- and intramolecular hydroamination of internal alkynes [23]. Intramolecular hydroamination has attracted more attention in recent years, because of its importance in the synthesis of a variety of nitrogen-containing heterocycles found in many biologically important compounds. The metal-catalyzed intramolecular hydroamination/cyclization of aminoalkenes, aminodienes, aminoallenes, and aminoalkynes has been abundantly documented [23]. 

Electronically excited carbonyl chromophores in ketones, aldehydes, amides, imides, or electron-deficient aromatic compounds may act as electron acceptors (A) versus alkenes, amines, carboxylates, carboxamides, and thioethers (D, donors). In addition, PET processes can also occur from aromatic rings with electron-donating groups to chloroacetamides. These reactions can be versatile procedures for the synthesis of nitrogen-containing heterocyclic compounds with six-membered (or larger) rings [2],... 

The Stork s aza-annulation method with acrylamide180,181 has been used frequently for the synthesis of six-membered nitrogen-containing heterocycles. Recently, this reaction was applied to the synthesis of 315 and 316 from protected enamine 314 (equation 68)182. Compound 315 is a key intermediate in the synthesis of the alkaloid Huperzine A and its analogues. 

Meyers and Garcia-Munoz64 assume that the cyclization of the -ketonitriles 67 by the action of concentrated sulfuric acid may be regarded as a still further extension of the Ritter reaction to the reactions of carbonyl compounds in the synthesis of nitrogen-containing heterocycles (equation 25). In this case the cyano-group reacts as a nucleophile with the positively charged center of the carboxonium intermediate J L... 

Besides N-acylated enamines, enamides containing a functional group in the carbon skeleton are obtained in the acid-catalyzed reactions of carbonyl compounds with nitriles. Some of them were shown in equations 18, 28, 31, 33, 38, 58, 59, 63, 65, 75 and 87 and they are mainly the polyacylated enamines (e.g. /Lacylaminovinyl ketones 79, 87, 93, 200, 207 and 278). Most of them are intermediates in the synthesis of oxygen and nitrogen containing heterocycles or products of further conversions of the latter. 

B. S. Drach, V. S. Brovaretz and O. B. Smolij, Synthesis of Nitrogen-containing Heterocyclic Compounds using an amidoalkylation reagent, Naukova Dumka, Kiev, 1992 (in Russian), pp. 62-76. 

Prof. F. Sficzewski is currently the head of the Department of Chemical Technology of Drugs, Medical University of Gdansk, Poland. His research interests are focused on the design and synthesis of nitrogen-containing heterocyclic compounds with potential circulatory, anticancer and anti-HIV activities. 

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