Recent Advances in the Synthesis of Piperazines: Focus on C–H Functionalization

Piperazine ranks as the third most common nitrogen heterocycle in drug discovery, and it is the key component of several blockbuster drugs, such as Imatinib (also marketed as Gleevec) or Sildenafil, sold as Viagra. Despite its wide use in medicinal chemistry, the structural diversity of piperazines is limited, with about 80% of piperazine-containing drugs containing substituents only at the nitrogen positions. Recently, major advances have been made in the C–H functionalization of the carbon atoms of the piperazine ring. Herein, we present an overview of the recent synthetic methods to afford functionalized piperazines with a focus on C–H functionalization.

Copper catalyzed late-stage C(sp3)-H functionalization of nitrogen heterocycles

Nitrogen heterocycle represents a ubiquitous skeleton in natural products and drugs. Late-stage C(sp3)-H bond functionalization of N-heterocycles with broad substrate scope remains a challenge and of particular significance to modern chemical synthesis and pharmaceutical chemistry. Here, we demonstrate copper-catalysed late-stage C(sp3)-H functionalizaion of N-heterocycles using commercially available catalysts under mild reaction conditions. We have investigated 8 types of N-heterocycles which are usually found as medicinally important skeletons. The scope and utility of this approach are demonstrated by late-stage C(sp3)-H modification of these heterocycles including a number of pharmaceuticals with a broad range of nucleophiles, e.g. methylation, arylation, azidination, mono-deuteration and glycoconjugation etc. Preliminary mechanistic studies reveal that the reaction undergoes a C-H fluorination process which is followed by a nucleophilic substitution.

Promotion of C-S Bond Scission over Solid Catalytic Sulfides by Aromatics and Nitrogen Heterocycles

The competitive adsorption of aromatics and nitrogen heterocycles on the active sites of solid catalytic sulfides (Ni(Co)-MoS2 dispersed over oxidic carriers) typically causes inhibitory effects during the hydropurification of sulfur heterocycles. Contrary to this typical behavior, we report herein that it is possible to promote the scission of the C-S bond of refractory dibenzothiophene by co?feeding the above compounds during hydropurification over a conventional Ni-MoS2/Al2O3 catalyst. Particularly, we prove that at temperatures between 240 and 300°C and concentrations of dibenzothiophene between 1.0 and 3.7 wt.%, the desulfurization of dibenzothiophene is promoted by increasing its conversion up to 370% when either naphthalene, indole, or quinoline are co-fed to the reaction system. The work highlights the following: (i) lower temperatures and higher concentrations of the sulfur heterocycle enhanced the cleavage of the C-S bond from dibenzothiophene; (ii) it is possible to promote hydropurification reactions regardless of the nature of the of co-reactants; namely: a fused aromatic ring -naphthalene-, or a fused nitrogen heterocycle with a lone pair belonging to the pi-system -quinoline- or not -indole-.<br><p><a></a></p>

Promotion of C-S Bond Scission over Solid Catalytic Sulfides by Aromatics and Nitrogen Heterocycles

The competitive adsorption of aromatics and nitrogen heterocycles on the active sites of solid catalytic sulfides (Ni(Co)-MoS2 dispersed over oxidic carriers) typically causes inhibitory effects during the hydropurification of sulfur heterocycles. Contrary to this typical behavior, we report herein that it is possible to promote the scission of the C-S bond of refractory dibenzothiophene by co?feeding the above compounds during hydropurification over a conventional Ni-MoS2/Al2O3 catalyst. Particularly, we prove that at temperatures between 240 and 300°C and concentrations of dibenzothiophene between 1.0 and 3.7 wt.%, the desulfurization of dibenzothiophene is promoted by increasing its conversion up to 370% when either naphthalene, indole, or quinoline are co-fed to the reaction system. The work highlights the following: (i) lower temperatures and higher concentrations of the sulfur heterocycle enhanced the cleavage of the C-S bond from dibenzothiophene; (ii) it is possible to promote hydropurification reactions regardless of the nature of the of co-reactants; namely: a fused aromatic ring -naphthalene-, or a fused nitrogen heterocycle with a lone pair belonging to the pi-system -quinoline- or not -indole-.<br><p><a></a></p>

Direct and indirect photochemical aging of organic aerosol components as a function of temperature

&lt;p&gt;The chemical composition of aerosols, in both gas and particle phase, is an important factor regarding their properties influencing air quality, weather, climate, and human health. Organic compounds are a major fraction of atmospheric aerosols and their composition depends on chemical processing by atmospheric oxidants and photochemical reactions. These processes are complex due to the abundance of potential reactions and rarely studied over a wider range of atmospheric temperatures. To achieve a better understanding of three different photochemical processes relevant for the atmosphere as well as the capabilities to investigate such processes in our simulation chamber we studied three different organic aerosol systems between 213 K and 293 K in the AIDA simulation chamber at the Karlsruhe Institute of Technology.&amp;#160; With the first system we studied the direct photolysis of 2,3-pentanedion which is a typical carbonyl compound emitted by the food industry but also by trees. In the second system we studied the depletion of pinic and pinonic acid by radicals formed through photolysis of an iron oxalate complex, which acts as the photosensitizer in this system, all present in aqueous aerosol particles. Furthermore, we studied the photolysis of a nitrogen heterocycle in aerosol particles, which can form in the atmosphere by the reaction of dicarbonyls and shows strong absorption in the visible [1].&lt;/p&gt;&lt;p&gt;Photochemical reactions were studied using a new LED light-source simulating solar radiation in the UV and visible. The organic aerosols were generated by nebulizing aqueous solutions containing the aerosol components. &amp;#160;The aerosols were analysed by a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS), a proton transfer mass spectrometer (CHARON-PTRMS) and a high&amp;#8211;resolution time-of-flight chemical ionization mass spectrometer (FIGAERO-HR-ToF-CIMS). &amp;#160;The latter two allow to study the composition of gas phase and particle phase separately.&lt;/p&gt;&lt;p&gt;In this presentation, we will discuss the changes that these organic compounds undergo in gas and particle phase, during photochemical aging at temperatures between 213 and 293 K.&lt;/p&gt;&lt;p&gt;&amp;#160;&lt;/p&gt;&lt;p&gt;[1] C. J. Kampf, A. Filippi, C. Zuth, T. Hoffmann and T. Opatz, Secondary brown carbon formation via the dicarbonyl imine pathway: nitrogen heterocycle formation and synergistic effects, Phys. Chem. Chem. Phys, 2016, 18, 18353&lt;/p&gt;

Potential Hexokinase II Inhibition by Benzimidazole Anthelmintics: Albendazole, Mebendazole and Fenbendazole

The nitrogen heterocycle benzimidazoles have been known to be anthelmintic drugs. Beyond that role, the benzimidazoles exhibit other pharmacological potential as anti-inflammatory, antiulcer, anti-hypertensive and anticancer agents. A growing body of evidence supports the anticancer efficiency via treatment with benzimidazoles. The target proteins for pharmacological effect appear to be cell microtubules. However, it has been reported that the benzimidazoles could inhibit hexokinase II, which is a critical factor in the glycolysis pathway in humans. Here, we discuss on the most common benzimidazoles such as albendazole, mebendazole and fenbendazole and focus on the potential anticancer activities of the target enzyme hexokinase II. This review would give better insight in development of target-specific benzimidazole derivatives as potential anticancer therapeutics.