N-heterocycles reactions

Entry Copper source Ligand N-heterocycle Reaction conditions Ref. 

The more challenging asymmetric iV-alkylation reactions of amines with alcohols was also developed in recent years. In 2009, by employing an Ir-catalyzed N-heterocyclization reaction as the key step, Trudell and co-workers first achieved the enantioselective total synthesis of both enantiomers of noranabasamine with >30 % overall yields and >80 % ee (Eq. 53) [175]. 

N -Heterocyclic Sulfanilamides. The parent sulfanilamide is manufactured by the reaction of A/-acetylsulfanilyl chloride with excess concentrated aqueous ammonia, and hydrolysis of the product. Most heterocycHc amines are less reactive, and the condensation with the sulfonyl chloride is usually done in anhydrous media in the presence of an acid-binding agent. Use of anhydrous conditions avoids hydrolytic destmction of the sulfonyl chloride. The solvent and acid-binding functions are commonly filled by pyridine, or by mixtures of pyridine and acetone. Tertiary amines, such as triethylamine, may be substituted for pyridine. The majority of A/ -heterocycHc sulfanilamides are made by simple condensation with A/-acetylsulfanilyl chloride and hydrolysis. 

Studies on covalent hydration of N-heterocycles (67AG(E)919,76AHC(20)117) have revealed the diagnostic value of alkyl substituents in structural assignments due to their steric hindrance effects in addition reactions. C-Methyl substituents are therefore also considered as molecular probes to solve fine-structural problems in the pteridine field. The derivatives... 

The thiotrithiazyl cation in [S4N3]C1 was one of the first S-N heterocycles to be prepared and structurally characterized. It is obtained as a reasonably air-stable, yellow solid by the reaction of S4N4 or [SsNaClJCl with S2CI2 in CCI4 (Eq. 5.12)." ... 

Generation and reactions of nonstabilized a-aminocarbanions, derivatives of saturated N-heterocycles 98T2647. 

High pressure and selectivity in reactions with formation of O- and N-heterocycles 97T2669. 

Heminal-activated haloolefins with heterocyclic fragments in reactions with N-heterocycles as nucleophiles 98UK317. 

Oxidative addition reactions of platinum(II) complexes with N-heterocyclic ligands 97CRV1735. 

Syntheses of natural O- and N-heterocycles via stereocontrolled Pd-catalyzed reactions 99PAC1065. 

Radical reactions of Hoffmann-Loffler-Freytag type with participation of iodine(III) compounds leading to five-member N-heterocycles 97YGK90. 

Synthesis of multisubstituted furan rings using silyl protection 99CSR209. Synthetic applications of furan Diels-Alder chemistry 97T14179. Transformation of furans to N-heterocycles by aza-Achmatovicz reaction 98SL105. 

Comparison of the reactivity of conjugated ynaminocarbonyl compounds (N—C —C=0), their vinylacetylene analogs (N—C —C=C—C=0), and acetylenic ketones (C —C=0) in the heterocyclization reactions provides evidence for the highest activity of the former (92KGS867). 

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

The surprising stability of N-heterocyclic carbenes was of interest to organometallic chemists who started to explore the metal complexes of these new ligands. The first examples of this class had been synthesized as early as 1968 by Wanzlick [9] and Ofele [10], only 4 years after the first Fischer-type carbene complex was synthesized [2,3] and 6 years before the first report of a Schrock-type carbene complex [11]. Once the N-heterocyclic ligands are attached to a metal they show a completely different reaction pattern compared to the electrophilic Fischer- and nucleophilic Schrock-type carbene complexes. 

Independently, Caddick et al. reported microwave-assisted amination of aryl chlorides using a palladium-N-heterocyclic carbene complex as the catalyst (Scheme 99) [lOlj. Initial experiments in a domestic microwave oven (reflux conditions) revealed that the solvent is crucial for the reaction. The Pd source also proved very important, since Pd(OAc)2 at high power in DMF gave extensive catalyst decomposition and using it at medium and low power gave no reaction at all. Pd(dba)2/imidazohum salt (1 mol% catalyst loading) in DME with the addition of some DMF was found to be suitable. Oil bath experiments indicated that only thermal effects are governing the amination reactions. 

Developments in the synthesis and characterization of stable silylenes (RiSi ) open a new route for the generation of silyl radicals. For example, dialkylsilylene 2 is monomeric and stable at 0 °C, whereas N-heterocyclic silylene 3 is stable at room temperature under anaerobic conditions. The reactions of silylene 3 with a variety of free radicals have been studied by product characterization, EPR spectroscopy, and DFT calculations (Reaction 3). EPR studies have shown the formation of several radical adducts 4, which represent a new type of neutral silyl radicals stabilized by delocalization. The products obtained by addition of 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO) to silylenes 2 and 3 has been studied in some detail. ... 

All these steps proceed to afford free or N -substituted crystalline cytidines 6 in high yields [11] (cf. the preparation of N (tetramethylene)cytidine 6b in 95.4% yield in Section 1.1.). This simple one-pot reaction is also very easy to perform on a technical scale, as are the subsequently discussed analogous silylation-aminations of purine nucleosides and other hydroxy-N-heterocycles (cf. Sections 4.2.4 and 4.2.5). The concept of silylation-activation while simultaneously protecting hydroxyl groups in alcohols, phenols, or phosphoric acids by silylation was subsequently rediscovered and appropriately termed transient protection [16-18]. 

The amination of aromatic hydroxy-N-heterocycles is a standard reaction in medicinal and agricultural chemistry and has heen reviewed [36]. The hitherto commonly used two-step procedure for amination of hydroxy-N-heterocycles, starts with conversion into the chloro-N-heterocycles, e.g. by treatment of the hydroxy-N-heterocycle with POCI3, PCI5, or SOCI2, followed by reaction with the amine moiety. This methodology has several drawbacks however, for example ... 

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