Unsaturated Nitrogen Heterocycles Research Articles

HARC as an open-shell strategy to bypass oxidative addition in Ullmann–Goldberg couplings

The copper-catalyzed arylation of unsaturated nitrogen heterocycles, known as the Ullmann-Goldberg coupling, is a valuable transformation for medicinal chemists, providing a modular disconnection for the rapid diversification of heteroaromatic cores. The utility of the coupling, however, has established limitations arising from a high-barrier copper oxidative addition step, which often necessitates the use of electron-rich ligands, elevated temperatures, and/or activated aryl electrophiles. Herein, we present an alternative aryl halide activation strategy, in which the critical oxidative addition (OA) mechanism has been replaced by a halogen abstraction-radical capture (HARC) sequence that allows the generation of the same Cu(III)-aryl intermediate albeit via a photoredox pathway. This alternative mechanistic paradigm decouples the bond-breaking and bond-forming steps of the catalytic cycle to enable the use of many previously inert aryl bromides. Overall, this mechanism allows access to both traditional C-N adducts at room temperature as well as a large range of previously inaccessible Ullmann-Goldberg coupling products including sterically demanding ortho-substituted heteroarenes.

On the Basicity of Organic Bases in Different Media

The basicities of simple organic bases – aliphatic and aromatic amines, amidines, phosphazenes, as well as saturated and unsaturated nitrogen heterocycles – are examined in acetonitrile, dimethyl sulfoxide, tetrahydrofuran, water and the gas phase. The basicities (pKaH values) of conjugate acids of a large variety of bases in these media are presented and discussed. Equations employing easily usable structural descriptors have been derived for approximately converting basicities from acetonitrile to other solvents. Recommendations are given on their practical use and a number of pKaH values that are experimentally unavailable are estimated from these relationships. An important part of the minireview is a large compilation of pKaH and GB values of the compounds in solvents and the gas phase, respectively, as well as the revised basicity scale in acetonitrile, now containing more than 270 pKaH values.

Recent advances in the application of ring-closing metathesis for the synthesis of unsaturated nitrogen heterocycles.

This short review summarizes recent advances relating to the application of ring-closing olefin-olefin and carbonyl-olefin metathesis reactions towards the synthesis of unsaturated five- and six-membered nitrogen heterocycles. These developments include catalyst modifications and reaction designs that will enable access to more complex nitrogen heterocycles.

Transfer hydrogenation of nitrogen heterocycles using a recyclable rhodium catalyst immobilized on bipyridine-periodic mesoporous organosilica

Transfer hydrogenation of unsaturated nitrogen heterocycles using a rhodium catalyst immobilized on bipyridine-periodic mesoporous organosilica (BPy-PMO) is described.

Asymmetric Allylic Alkylation in Combination with Ring-Closing Metathesis for the Preparation of Chiral N-Heterocycles

Asymmetric copper-catalyzed allylic substitution with methylmagnesium bromide is employed in combination with ring-closing olefin metathesis or ene-yne metathesis to achieve the synthesis of chiral, unsaturated nitrogen heterocycles. The resulting six- to eight-membered chiral heterocycles are accessible in high yields and with excellent enantioselectivities.

3H-Pyrroles, Alkylidene-Pyrrolines and Functionalized Pyrrolidines by Radical Cyclization of β-Allenyliminyl Radicals

In this work, we show that the tin hydride-mediated reaction of allene-tethered dithiosemicarbazides 4 is a convenient method for the preparation of five-membered unsaturated nitrogen heterocycles. The sulfur-directed intermolecular attack of the tin radical at the semicarbazide moiety leads to an allene-tethered iminyl radical, which then undergoes a 5-exo-dig cyclization leading to both the 3H-pyrroles 5 and the alkylidene pyrrolines 6; thermal isomerization of 5 to 6 occurs in some cases.

Development of a Packed Precolumn for Capillary Gas Chromatographic Analysis of Amines in Acidic Aqueous Solution

This paper describes an optimization of the analysis of amines in aqueous solution. Direct injection of the acidic sample (HCl 0.12 N) is performed by the coupling of packed precolumn with a capillary column. The basic support efficiently traps residual vapors of hydrochloric acid and water at the injection time; the capillary chromatographic performance is maintained. The precolumn coupling with PoraPLOT Amines capillary column enables a separation and quantification of the lower volatile aliphatic amines (methylamine, dimethylamine, trimethylamine and ethylamine). The ammonia addition to the solution (200 ppm NH3) reduces amine adsorption in the column. The analysis repeatability is about 5% for a 50μM amine mixture and 21% for the quantification limit of 0.5 μM with a sensitive and specific nitrogen phosphor detector. The precolumn avoids using split injection (sensitivity increased). Other nitrogen compounds can be analyzed by this system: aromatic amines (aniline) and unsaturated nitrogen heterocycles (pyridine). This new technique increases the chromatographic performances in comparison with usual methods; its automation is possible.

Development of a packed precolumn for capillary gas chromatographic analysis of amines in acidic aqueous solution

This paper describes an optimization of the analysis of amines in aqueous solution. Direct injection of the acidic sample (HCl 0.12 N) is performed by the coupling of packed precolumn with a capillary column. The basic support efficiently traps residual vapors of hydrochloric acid and water at the injection time; the capillary chromatographic performance is maintained. The precolumn coupling with PoraPLOT Amines capillary column enables a separation and quantification of the lower volatile aliphatic amines (methylamine, dimethylamine, trimethylamine and ethylamine). The ammonia addition to the solution (200 ppm NH 3 ) reduces amine adsorption in the column. The analysis repeatability is about 5% for a 50μM amine mixture and 21% for the quantification limit of 0.5 μM with a sensitive and specific nitrogen phosphor detector. The precolumn avoids using split injection (sensitivity increased). Other nitrogen compounds can be analyzed by this system: aromatic amines (aniline) and unsaturated nitrogen heterocycles (pyridine). This new technique increases the chromatographic performances in comparison with usual methods; its automation is possible.

Effects of some unsaturated nitrogen-heterocycles on the polymerization of methyl methacrylate initiated by benzoyl peroxide

The rate of polymerization at 60°C of methyl methacrylate initiated by benzoyl peroxide is almost unaffected by the presence of a small amount of 4-styrylpyridazine, 1-(2-pyridyl)-2-(4-pyridyl)ethylene or 2,6-distyrylpyridine. Examination of polymers made using peroxide suitably labeled with carbon-14 and tritium shows that these additives increase the ratio of benzcate to phenyl end-groups derived from the initiator. This effect arises because the additives are effective in capturing the benzoyloxy radical; in this respect, they are however considerably less reactive than the corresponding compounds containing groups derived from benzene in place of the nitrogen heterocycles.

Dialkylindium derivatives of unsaturated nitrogen heterocycles—preparation, spectroscopic properties and the use in MOVPE

A series of dialkylindium azolides of the type R 2In(NR′) (with R = Me and Et) have been synthesized by the reaction of InR 3 with various N-heterocycles (pyrrole, pyrazoles, imidazole and 1,2,4-triazole) or by treatment of R 2InCl with a lithiated azolide, Li(NR′) in an inert solvent. The compounds have been characterized by NMR ( 1H, 13C) and vibrational (IR and Raman) spectroscopy, and their mass spectra are discussed. The pyrazole derivatives are dimeric in solution and in the gas phase, whereas, as indicated by the mass spectral data, the triazole compound is trimeric in the gas phase, and the imidazole derivative seems to be polymeric. The spectroscopic data suggest that the dimethylindium-pyrrole compound has an unusual structure, which is not comparable with those of the other organoindium azolides. Dimethylindiumpyrazole was used in metalorganic vapor phase epitaxy (MOVPE) experiments to grow in InP layers.

Inhibition of microsomal lipid peroxidation and cytochrome P-450-catalyzed reactions by nitrofuran compounds.

(5-Nitro-2-furfurylidene)amino compounds bearing triazol-4-yl, benzimidazol-1-yl, pyrazol-1-yl, triazin-4-yl or related groups (a) stimulated superoxide anion radical generated by rat liver microsomes in the presence of NADPH and oxygen; (b) inhibited the NADPH-dependent, iron-catalyzed microsomal lipid peroxidation; (c) prevented the NADPH-dependent destruction of cytochrome P-450; (d) inhibited the NADPH-dependent microsomal aniline 4-hydroxylase activity; (e) failed to inhibit either the cumenyl hydroperoxide-dependent lipid peroxidation or the aniline-4-hydroxylase activity, except for the benzimidazol-1-yl and the substituted triazol-4-yl derivatives, which produced minor inhibitions. Reducing equivalents enhanced the benzimidazol-1-yl derivative inhibition of the cumenyl hydroperoxide-induced lipid peroxidation. The ESR spectrum of the benzimidazol-1-yl derivative, reduced anaerobically by NADPH-supplemented microsomes, showed characteristic spin couplings. Compounds bearing unsaturated nitrogen heterocycles were always more active than those bearing other groups, such as nifurtimox or nitrofurazone. The energy level of the lowest unoccupied molecular orbital was in fair agreement with the capability of nitrofurans for redox-cycling and related actions. It is concluded that nitrofuran inhibition of microsomal lipid peroxidation and cytochrome P-450-catalyzed reactions was mostly due to diversion of reducing equivalents from NADPH to dioxygen. Trapping of free radicals involved in propagating lipid peroxidation might contribute to the overall effect of the benzimidazol-1-yl and substituted triazol-4-yl derivatives.

Generation of Radical Anions of Nifurtimox and Related Nitrofuran Compounds By Ascorbate

Nifurtimox analogues bearing triazol-4-yl, benzimidazol-1-yl, triazin-4-yl or related groups as counterpart of the (5-nitro-2-furfurylidene) amino group were reduced to their nitro anion radicals by ascorbate in anaerobic solutions at high pH. The ESR spectra of the radical anions showed hyperfine spin couplings restricted to the nitrofuran moiety. With these compounds, the spin density at the nitro group was greater than with nifurtimox, nitrofurazone and nitrofurantoin. At neutral pH, solutions containing ascorbate and nitrofuran derivatives consumed oxygen, the compounds bearing unsaturated nitrogen heterocycles being the most effective. Superoxide dismutase and catalase decreased the rate of oxygen consumption, thus demonstrating the production of superoxide and hydrogen peroxide, respectively. NMR spectra of the triazol-4-yl and triazin-4-yl nitrofuran derivatives showed a deshielding effect for the azomethine proton, which was undetectable with nifurtimox and nitrofurazone.

Palladium phosphine catalyzed hydroesterifications of unsaturated nitrogen heterocycles

Results of PdCl 2(PPh 3) 2-catalyzed hydroesterifications of unsaturated nitrogen heterocycles under moderate conditions are reported. Although basic amine substrates are unreactive, hydrochloride salts of N-methyl-1, 2,3,6-tetrahydropyridine, 1, 1,2,3,6-tetrahydropyridine, 7, and tropidine, 20, gave moderate to good conversions to mixtures of isomeric methyl esters. The weakly basic substrate, N-ethoxycarbonylnortropidine, 23, gave high conversion to two major methyl esters but N-ethoxycarbonyl-1,2,3,6-tetrahydropyridine, 12, and N-acetyl-1,2,3,6-tetrahydropyridine, 13, gave low conversions to esters due to competing reactions.

Rhodium-catalyzed hydroformylations of unsaturated nitrogen heterocycles: regio- and stereoselectivity in the synthesis of tropane and pdperidine carboxaldehydes

Results of the RhH(CO)(PPh 3) 3-catalyzed hydroformylations of several unsaturated nitrogen heterocycles under moderate conditions are reported. Substrates included N-methyl-1,2,3,6-tetrahydropyridine, 8, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 9, N-ethoxycarbonyl-1,2,3,6-tetrahydro-pyridine, 10, tropidine, 11, 4-phenyltropidine, 12, and N-ethoxycarbonyl-nortropidine, 13. The relative reactivity was found to vary in the order: 13 $ ̆ 11⋍ 10 $ ̆ 8, with 12 and 9 being essentially unreactive. Conversion was high for the bicyclic olefins, 11 and 13, with the regio- and stereoselectivity favoring the symmetrical 3β-carboxaldehyde isomers. Conversion was high for 10 with the regioselectivity favoring the unsymmetrical, 3-substituted isomer. Low conversion and little selectivity were observed in the reaction of 8. Olefin hydrogenation was extensive for substrate 8 only, and alcohol formation was a minor secondary reaction for all substrates. The temperature dependence of the product distributions is discussed along with results of competitive reactions between pairs of substrates.