George Varvounis

Chapter 2 Pyrazol-3-ones. Part IV: Synthesis and Applications

Publisher Summary This chapter focuses on the synthesis and applications of Pyrazol-3-ones. The chapter also highlights the reactions of the ring atoms of pyrazol-3-ones. It explores the reactivity of the ring substituents of pyrazol-3-ones. This chapter illustrates that the majority of pyrazol-3-ones have been synthesized from open chain precursors, and relatively few from5-,6-, 5,6-, 6,6-and 5,6,7-membered rings. Due to the growing use of combinatorial chemistry in various applications, use of polymer-supported methodologies have increased. The oxidation potentials as well as the hydroxyl radical scavenging activities for some pyrazol-3-ones have been detected and compared with edavarones. The Schiff base 4-[(4-hydroxy-3-hydroxymethylbenzylidene) amino]-1,5-dimethyl-2-phenyl-1,2 dihydropyrazol-3-one retards the corrosion of steel. The chapter concludes that certain azopyrazol-3-ones may prove useful as labels for chromatographic analysis of carbohydrates.

Synthesis, Chemistry, and Biological Properties of Thienopyrimidines

Publisher Summary Various aspects of the chemistry and biology of thienopyrimidines are described in the chapter. The chapter attempts to group the ring syntheses according to the type of starting material used and thienopyrimidine produced. The most widely used method for the synthesis of thieno[2,3-d]pyrimidines is condensation of 2-aminothiophene-3-carboxylates with reagents that provide the remaining C−N fragment required for pyrimidine fusion. The majority of thieno[3,2-d]pyrimidines are synthesized from alkyl 3-aminothiophene-2-carboxylates. The C−N fragment required for pyrimidine fusion is introduced either directly or stepwise. A general approach to the synthesis of thieno[3,4d]pyrimidines comprises the reaction of alkyl 3-aminothiophene-4-carboxylates with electrophilic and/or nucleophilic reagents that furnish the remaining C and N atoms of the pyrimidine ring. The chapter presents reactions, physicochemical properties, and the applications of thieno[2,3-d]pyrimidines, thieno[3,2-d]pyrimidines, and thieno[3,4-d]pyrimidines.

Abnormal Nucleophilic Substitution in 3-Trichloromethylpyridine, its N-Oxide and 3,5-Bis(trichloromethyl)pyridine

Abstract The scope of abnormal reactions of nucleophiles with β-trichloromethylazines is further explored: reactions of 3-trichloromethylpyridine with nucleophiles other than methoxide, and reactions of 3-trichloromethylpyridine N-oxide and 3,5-bis(trichloromethyl)pyridine with methoxide. Attack at a ring carbon, followed by hydrogen migration to the side-chain, occurred in most cases, though attack at the trichloromethyl carbon was also sometimes observed. We now report further studies on this type of interesting, and potentially useful, reaction. These involved reactions of 3-trichloromethylpyridine (1) with nucleophiles other than methoxide, comparative reactios of 3-trichloromethylpyridine-N-oxide (4), and reactions of 3,5-bis(trichloromethyl)pyridine (5) with methoxide.

Pyrazol-3-ones. Part III: Reactivity of the Ring Substituents

Publisher Summary All pyrazolones are named according to the International Union of Pure and Applied Chemistry (IUPAC) recommendations as pyrazol-3-ones and not as pyrazol-5-ones. The IUPAC nomenclature numbers the ring clockwise, whereas most organic chemists are used to an anti-clockwise numbering. Alkylation of pyrazol-3-ones usually occurs not only on side-chain substituents, such as primary amino groups, but also on the nitrogen atom of the unsubstituted lactam group. Alkylation can also occur on a stabilized carbanion generated from a methyl group by a strong base. Most of the acylation reactions are carried out with 4-amino-1,2-dihydro-1,5-dimethyl-2- phenyl-3H-pyrazol-3-one (4-aminoantipyrine). The acid chlorides are prepared separately or generated in situ from the corresponding carboxylic acid in the presence of the aminopyrazol-3-ones. The only halogenation reactions of the ring substituents of pyrazol-3-ones known are those with bromine, N-bromosuccinimide, and hydrogen bromide. Sulfonation of 5-aminopyrazol-3-ones is described. Coupling the diazonium salts with carbon nucleophiles is the most common reaction. Condensation reactions are discussed. One of the categories of reactions may involve nucleophilic addition either by or to the pyrazol-3-one side-group. A variety of nucleophilic substitution reactions are discussed. Pyrazol-3-ones are oxidized by a variety of oxidizing agents. The reduction of functional groups, such as aldehyde, nitro, nitroso, alkene, and imino as well as deamination of amines and cleavage of amides are accomplished by various reducing agents without affecting the pyrazol-3-one ring. Some miscellaneous reactions are discussed.

Pyrazol-3-ones. Part II: Reactions of the Ring Atoms

Publisher Summary This chapter examines the reactions of the ring atoms of pyrazol-3-ones, in particular 1,2-dihydro-3 H -pyrazol-3-one and 2,4-dihydro-3 H -pyrazol-3-one. The chapter describes reactions of pyrazol-3-ones with alkyl halides, esters of sulfonic and carbonic acids, trimethyloxonium tetrafluoroborate, diazo compounds, Mannich or Mitsunobu conditions or miscellaneous reagents. Pyrazol-3-ones are known to be ambient compounds and depending on the solvent in which they are dissolved can exist in several tautomeric forms. Usually in less polar solvents such as chloroform pyrazol-3-one tautomers are dominant, whereas in more polar solvents such as dimethylsulfoxide 3-hydroxypyrazole tautomers are dominant. It is noted that pyrazol-3-ones are weak acids and can be titrated with strong bases. 2,4-Dihydro-3H-pyrazol-3-ones are stronger acids than 1,2-dihydro-3H-pyrazol-3-ones, which are very weak. The outcome of acylation of the ring atoms of pyrazol-3-ones with acid chlorides depends on the type of substitution on the pyrazol-3-one ring. Both C- and N acylation are possible. With 2-aryl-4-(or 5)-substituted pyrazol-3-ones and reaction with acid chlorides occurs in 1,4-dioxane with calcium hydroxide.

Reduction of 2- and 3-Acylpyrroles. A New Synthesis of the Pyrrolo[1,2-b]cinnolin-10-one Ring System from 1-(4-Methylphenyl)sulfonyl-1H-pyrrole

Abstract Reduction of (2-nitrophenyl)(1H-pyrrol-2-yl)methanone 4 with zinc and ammonium chloride gave 5,10-dihydro-pyrrolo[1,2-b]cinnolin-10-one 5 and (2-hydroxylaminophenyl)(1H-pyrrol-2-yl)methanone 6 whereas reduction of 4 with zinc and sodium hydroxide gave only 5. Reaction of (2-nitrophenyl)(1H-pyrrol-3-yl)methanone 10 with zinc and ammonium chloride or zinc and sodium hydroxide afforded (2-nitrosophenyl)(1H-pyrrol-3-yl)methanone 11 and 2-aminophenyl)(1H-pyrrol-3-yl)methanone 12 or 12 as a single product, respectively. Sodium borohydride reduction of (2-nitrophenyl)(1-methyl-1H-pyrrol-2-yl)methanone 13 or (2-nitrophenyl)(1-methyl-1H-3-pyrrolyl)methanone 19 gave a mixture of the corresponding alcohols 15 or 21 and nitroso-ketones 18 or 22. Reduction of alcohols 15 or 21 with zinc and sodium hydroxide afforded nitroso-ketones 18 or 22, respectively.

Oxidation of 1-acyl-2-naphthol oximes: peri- and o-cyclisation and spiro cyclodimerisation of naphthoquinone nitrosomethide intermediates

Abstract The oxidation of 2-hydroxynaphthaldehyde oxime with lead(IV) acetate (LTA) gave a mixture of naphtho[1,8-de][1,2]oxazine and a spiro dimer. LTA oxidation of 6-bromo (or nitro)-2-hydroxynaphthaldehyde oximes provided only spiro dimers. Similar treatment of (2-hydroxy-1-naphthyl)keto oximes with LTA gave naphtho[1,8-de][1,2]oxazines and benzo[cd]indol-3(1H)-ones. Low temperature oxidation of 1-(2-hydroxy-1-naphthyl)propan-1-one oxime furnished 2-ethylbenzo[cd]indol-3(1H)-one and 1-ethylnaphtho[1,2-d]isoxazole-2-oxide. peri- and o-Naphthoquinone nitrosomethides are invoked as intermediates that undergo peri- and o-cyclisation and intermolecular cyclodimerisation.

Tele Nucleophilic Aromatic Substitutions in 1-Nitro-3- and 1,3-Dinitro-5-trichloromethylbenzene, and 3-Trichloromethylbenzonitrile. A New Synthesis of the 1,4-Benzothiazine-3(4H)-one Ring System from 3-Nitrobenzoic Acid

Abstract 3-Trichloromethylnitrobenzene 2 , 1,3-dinitro-5-trichloromethylbenzene 13 and 3-trichloromethylbenzonitrile 18 react with sodium methoxide to give 4-methoxy-3-nitrobenzaldehyde 6 , 4-methoxy-3,5-dinitrobenzaldehyde 15 and 5-dimethoxymethyl-2-methoxybenzonitrile 19 , respectively. Compounds 2 and 13 react with methyl thioglycolate to afford dichloromethylacetates 7 and 16 , respectively. These products are the result of tele nucleophilic aromatic substitution. Compound 18 reacted with methyl thioglycolate to give acetate 20 resulting from nucleophilic displacement of cyanide. Reductive cyclisation of 7 afforded benzothiazine 11 .

An update on the synthesis of pyrrolo[1,4]benzodiazepines

Pyrrolo[1,4]benzodiazepines are tricyclic compounds that are considered “privileged structures” since they possess a wide range of biological activities. The first encounter with these molecules was the isolation of anthramycin from cultures of Streptomyces, followed by determination of the X-ray crystal structure of the molecule and a study of its interaction with DNA. This opened up an intensive synthetic and biological study of the pyrrolo[2,1-c][1,4]benzodiazepines that has culminated in the development of the dimer SJG-136, at present in Phase II clinical trials. The synthetic efforts have brought to light some new synthetic methodology, while the contemporary work is focused on building trimeric pyrrolo[2,1-c][1,4]benzodiazepines linked together by various heterocyclic and aliphatic chains. It is the broad spectrum of biological activities of pyrrolo[1,2-a][1,4]benzodiazepines that has maintained the interest of researchers to date whereas several derivatives of the even less studied pyrrolo[1,2-d][1,4]benzodiazepines were found to be potent non-nucleoside HIV-1 reverse transcriptase inhibitors. The present review is an update on the synthesis of pyrrolo[2,1-c][1,4]benzodiazepines since the last major review of 2011, while the overview of the synthesis of the other two tricyclic isomers is comprehensive.

Synthesis and reactions of 1-aryl-2-nitropyrroles. Structural and conformational study of ethyl N-[2′-[1′-(2-nitropyrrolyl)]phenyl]-N-toluene-4-sulfonamide glycinate

Nitration of 1-aryl(or 1-benzyl)pyrroles 1, 2 and 7 has provided the corresponding 2- and 3-nitropyrroles 3 and 5, 4 and 6, and 8 and 9 in a 1:2 ratio. Reductive cyclisation of 3 and 8, gave pyrrolo[1,2-a]quinazolines 11 and 12, and pyrrolo[1,2-b][2.4]benzodiazepine 13, respectively. A conformational study of 5 in the solid and liquid state using X-ray diffraction analysis, molecular dynamics calculations and NMR spectroscopy, is described.