Substitution N-heterocycles

V-Eluoro-substituted N-heterocycles as fluorinating reagents 98MI40, 99T12431,99UK725. 

The enantioselective hydrogenation of prochirai heteroaromatics is of major relevance for the synthesis of biologically active compounds, some of which are difficult to access via stereoselective organic synthesis [4], This is the case for substituted N-heterocycles such as piperazines, pyridines, indoles, and quinoxa-lines. The hydrogenation of these substrates by supported metal particles generally leads to diastereoselective products [4], while molecular catalysts turn out to be more efficient in enantioselective processes. Rhodium and chiral chelating diphosphines constitute the ingredients of the vast majority of the known molecular catalysts. 

Different synthetic routes have been used to prepare these carbenes (Scheme 8.6). The most common procedure is the deprotonation of the conjugate acid. In early experiments, sodium or potassium hydride, in the presence of catalytic amounts of either f-BuOK or the DMSO anion were used. ° Then, Herrmann et al. showed that the deprotonation occurs much more quickly in liquid ammonia as solvent (homogeneous phase), and many carbenes of type IV have been prepared following this procedure. In 1993, Kuhn and Kratz" developed a new and versatile approach to the alkyl-substituted N-heterocyclic carbenes IV. This original synthetic strategy relied on the reduction of imidazol-2(3//)-thiones with potassium in boiling tetrahydrofuran (THF). Lastly, Enders et al." reported in 1995 that the 1,2,4-triazol-5-ylidene (Vila) could be obtained in quantitative yield from the corresponding 5-methoxy-l,3,4-triphenyl-4,5-dihydro-l//-l,2,4-triazole by thermal elimination (80 °C) of methanol in vacuo (0.1 mbar). 

From a retrosynfhetic viewpoint, N-aryl-l,2-diimine Ni precatalysts are synthesized by (i) reaction of 1,2 diimines with nickel halides from (ii) 1,2-diimine ligands which in turn are obtained by (iii) condensing 1,2-dicarbonyl substrates with two equivalents of primary aromatic amines, usually under acidic conditions [11]. In analogy, the synthesis of N-hetaryl 1,2 diimine catalysts starts from the corresponding substituted N-heterocyclic primary amines as the amine building blocks. The synthesis of three types of such heterocycles, N-amino-pyrroles, -indoles and -carbazoles, and their corresponding diimine derivatives is presented in the following sections. 

A Grignard type of addition of alkynes to in situ generated imines from aldehyde and amines, catalyzed by CuBr, provides an efficient solvent-free approach for the synthesis of substituted N-heterocycles such as propargyla-mines in excellent yields (Scheme 8.17). ... 

The formation of four-membered chelate rings involving N and S donors is not unusual and has been observed in several complexes of 2-thiol- or 2-thione-substituted N heterocycles. Foye and Lo reported this form of coordination for a variety of metal chelates of antibacterial heterocyclic thiones. 2-Mercaptobenzimidazole (35 X = NH) was reported to form such chelates with Cu , Al and Fe . Complexes of 2-thiouradl (36), and substituted forms, also have been reported with this bonding mode to these metal ions. The tetrakis chelate of W" with 2-mercaptopyrimidine has been shown to adopt a symmetrical dodecahedral geometry. The mercapto S atom is thought to act as the better t-electron donor with the corresponding aromatic N atom acting as a tc acceptor. 

Influence of Symmetrically 1,3-Substituted N-Heterocyclic Carbene in Metathesis 313... 

Mercapto-substituted N-heterocycles have been extensively studied by Kwiatkowski et ai PPP-type calculations have been used to predict the TT - JT electronic transition energies, oscillator strengths, and transition polarizations of monomercapto-substituted pyridines (n)," - pyrimidines (13), pyrazines (14), purines (15), and 1,3,8-triazaindolizines (16) and... 

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. 

Heterocyclization by catalytic formation of N—Car bond to give indoles, amino-pyridines, and N-aryl-substituted saturated heterocycles 98ACR805. 

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. 

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]. 

Although several methods are used to aminate heterocyclic aromatic hydroxy-N-heterocycles [36], some additional, special, amination procedures are used for nucleoside modification. When we planned to synthesize a series of N -substituted cytidines 5 starting from uridine 1 we considered known classical methods, which imply (Scheme 4.14) ... 

N-heterocycles are a class of neutral ligands with strong coordination affinity to many metal ions. Since a number of neutral N-donors ligands are available, a wide range of oxo-centered triruthenium complexes with various N-heterocyclic ligands have been prepared through axial ligand substitution. By judicious selection of the N-heterocyclic type and modification of the substituents with different electronic and steric effects, the electronic, redox, and spectroscopic properties in these oxo-centered triruthenium derivatives are controllable. 

Relevant examples of enantioselective hydrogenation of aromatic N-heterocycles are given below. Scheme 16.21 shows the hydrogenation of a 2-ester substituted piperazine to the corresponding 2-substituted pyrazine with a catalyst... 

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