Saturated Nitrogen-containing Heterocycles Research Articles

Synthesis of 1-azabicyclo[2.1.1]hexanes via formal single electron reduction of azabicyclo[1.1.0]butanes under photochemical conditions.

C(sp3)-rich heterocycles are privileged building blocks for pharmaceuticals and agrochemicals. Therefore, synthetic methods that provide access to novel saturated nitrogen-containing heterocycles are in high demand. Herein, we report a general synthesis of 1-azabicyclo[2.1.1]hexanes (1-aza-BCH) via a formal cycloaddition of azabicyclo[1.1.0]butanes (ABB) with styrenes under photochemical conditions. To overcome the challenging direct single electron reduction of ABBs, we designed a polar-radical-polar relay strategy that leverages a fast acid-mediated ring-opening of ABBs to form bromoazetidines, which undergo efficient debrominative radical formation to initiate the cycloaddition reaction. The reaction is applicable to a broad range of ABB-ketones and we demonstrate the 1-aza-BCH products can be further functionalised to access larger saturated, conformationally rigid heterocycles.

Hexafluoroisopropanol-assisted selective intramolecular synthesis of heterocycles by single-electron transfer

Intramolecular amination of remote aliphatic C–H bonds via hydrogen-atom transfer reactions has become a powerful tool for accessing saturated nitrogen-containing heterocycles. However, the formation of six-membered rings or oxa-heterocycles remains a formidable challenge for Hofmann–Löffler–Freytag reactions. Here we show how by simply combining bench-stable (bis(trifluoroacetoxy)iodo)benzene and hexafluoroisopropanol (HFIP) we can switch from the well-established Hofmann–Löffler–Freytag mechanism to a different versatile reaction pathway that enables selective C(sp3)–H bond functionalization. We have exploited the facile formation of radical cations via single-electron transfer, in the presence or absence of light, to synthesize pyrrolidines and piperidines, including drug-type molecules, along with O-heterocycles. Experimental and computational mechanistic studies support two distinct mechanistic pathways, depending on the electron density of the substrate, in which the HFIP plays a multifunctional role.

Straight-chain ω-amino-α,β-unsaturated carbonyl compounds: versatile synthons for the synthesis of nitrogen-containing heterocycles via organocatalytic reactions

In this review, we elaborate and discuss the recent applications of straight-chain amino-α,β-unsaturated carbonyl compounds as versatile synthons in organocatalytic reactions for the creation of five- and six-membered saturated nitrogen-containing heterocycles.

Design, synthesisand antiviral evaluation of novel conjugates of the 1,7,7-trimethylbicyclo[2.2.1]heptane scaffold and saturated N-heterocycles via 1,2,3-triazole linker.

A new series of heterocyclic derivatives with a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment was designed, synthesised and biologically evaluated. Synthesis of the target compounds was performed using the Cu(I) catalysed cycloaddition reaction. The key starting substances in the click reaction were an alkyne containing a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment and a series of azides with saturated nitrogen-containing heterocycles. Some of the derivatives were found to exhibit strong antiviral activity against Marburg and Ebola pseudotype viruses. Lysosomal trapping assays revealed the derivatives to possess lysosomotropic properties. The molecular modelling study demonstrated the binding affinity between the compounds investigated and the possible active site to be mainly due to hydrophobic interactions. Thus, combining a natural hydrophobic structural fragment and a lysosome-targetable heterocycle may be an effective strategy for designing antiviral agents.

Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Lactams: Enantioselective Construction of All-Carbon Quaternary Stereocenters in Saturated Nitrogen-Containing Heterocycles.

Stereogenic nitrogen-containing heterocycles are ubiquitous in natural products and pharmaceutical compounds, but methods for their enantioselective construction have remained elusive. We report a general method for the asymmetric conjugate addition of arylboronic acids to β-alkyl/aryl α,β-unsaturated lactams that affords chiral β,β-disubstituted lactams. The transformation is operationally simple and air- and moisture-tolerant and uses a commercially available (S)-t-Bu-PyOx ligand. The method is high-yielding (up to 95% yield) and enantioselective (up to 97% ee) for a wide range of arylboronic acids and α,β-unsaturated lactams, including those with different ring sizes.

Structure-based design of novel melanin-concentrating hormone receptor-1 ligands based on saturated nitrogen-containing heterocycles

Melanin Concentrating Hormone (MCH) receptor is a G protein-coupled receptor (GPCR) with two subtypes R1 and R2. MCH-R1 is involved in the control of energy homeostasis, feeding behavior and body weight. Many studies have proved that administration of MCH-R1 antagonists significantly reduces food intake and causes weight loss in animal models. Herein, we report the optimization of our previously reported virtual screening hits into novel MCH-R1 ligands with chiral aliphatic nitrogen-containing scaffolds. The activity was improved from the micromolar range of the initial leads to 7 nM. We also disclose the first MCH-R1 ligands based on a diazaspiro[4.5]decane nucleus with sub-micromolar activity. A potent MCH-R1 antagonist with acceptable pharmacokinetic profile could represent a new hope for the management of obesity.

Non-Directed β- or γ-C(sp3)–H Functionalization of Saturated Nitrogen-Containing Heterocycles

AbstractReactions that take place via C–H functionalization are valuable tools in organic synthesis because they can be used for the synthesis of target compounds and for the late-stage functionalization of bioactive compounds. Among these, non-directed C(sp3)–H functionalization reactions of saturated nitrogen-containing heterocycles have been developed in recent years. However, most of these lead to functionalization at the α-position relative to the heteroatom, and reactions at the β- or γ-positions are limited since these bonds are stronger and less electron-rich. Hence, in this review, we will discuss non-directed β- or γ-C(sp3)–H functionalization reactions of saturated nitrogen-containing heterocycles, which are of recent interest to medicinal chemists. These methods are attractive in order to avoid the pre-functionalization of substrates, and to reduce the number of synthetic steps and the formation of byproducts. Such non-directed β- and γ-C(sp3)–H functionalization reactions can be divided into enamine-intermediate-mediated processes and other reaction types described in this review. 1 Introduction2 Non-Directed β-C(sp3)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles via an Enamine Intermediate2.1 Non-Directed β-C(sp3)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Acidic, Basic or Thermal Conditions2.2 Non-Directed β-C(sp3)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Oxidative Conditions2.3 Non-Directed β-C(sp3)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Redox-Neutral Conditions3 Strategies for Non-Directed β- or γ-C(sp3)–H Functionalization of Saturated Heterocycles Excluding Examples Proceeding via an Enamine Intermediate 4 Summary

A Stereoselective aza-Prins Reaction: Rapid Access to Enantiopure Piperidines and Pipecolic Acids

The aza-Prins reaction is a widely employed and highly efficient method for the preparation of saturated nitrogen-containing heterocycles. Its major drawback has always been a lack of diastereoselectivity and the formation of racemic products. Herein, we address these problems and report, for the first time, the synthesis of both diastereomerically and enantiopure multiply substituted piperidines via the aza-Prins reaction. This method is widely applicable for natural product synthesis and is exemplified here by the synthesis of enantiopure pipecolic acid derivatives.

Design, synthesis and bio-evaluation of novel 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazoles as the tubulin polymerization inhibitors

A series of 2-aryl-4-(3,4,5-trimethoxybenzoyl)-5-substituted-1,2,3-triazoles were designed, synthesized and evaluated for the anticancer activities. Based on the model of DMAM-colchicine-tubulin complex interactions, various saturated nitrogen-containing heterocycles were introduced to the C5-position of 1,2,3-triazol to interact with a tolerant region at the entrance of the binding-pocket and increase the aqueous solubility of the compounds. All designed compounds were concisely synthesized by one-pot oxidative cyclization. Most compounds exhibited moderate antiproliferative activity with IC50 values in the micromolar to sub-micromolar range. Among them, 5g posed N-acyl-piperazine moiety at the C5-position of B-ring showed most potent against cancer cells, with IC50 values of 0.084–0.221 μM 5g potently disrupted microtubule/tubulin dynamics, induced cell cycle arrest at G2/M phase in SGC-7901 cells. In addition, molecular modeling studies suggested that 5g probably binds to the colchicine site of tubulin.

Dual C(sp3 )-H Bond Functionalization of N-Heterocycles through Sequential Visible-Light Photocatalyzed Dehydrogenation/[2+2] Cycloaddition Reactions.

Herein we describe a mild method for the dual C(sp3 )-H bond functionalization of saturated nitrogen-containing heterocycles through a sequential visible-light photocatalyzed dehydrogenation/[2+2] cycloaddition procedure. As a complementary approach to the well-established use of iminium ion and α-amino radical intermediates, the elusive cyclic enamine intermediates were effectively generated by photoredox catalysis under mild conditions and efficiently captured by acetylene esters to form a wide array of bicyclic amino acid derivatives, thus enabling the simultaneous functionalization of two vicinal C(sp3 )-H bonds.

Micelle Formation of Morpholinium Bromide Surfactants in Aqueous Solution

Abstract The micelle formation of N-alkyl-N-methylmorpholinium bromide (CnMMB, n = 12, 14, 16) surfactants in aqueous solution has been investigated. Their critical micelle concentration (CMC), effectiveness and efficiency of the surface tension reduction, and the maximum surface excess concentration were derived from the surface tension curves. Thermodynamic parameters were then evaluated in the temperature range of 25 °C ∼ 45 °C. The results showed that with increasing the alkyl chain length, the CMC values were decreased gradually, which is consistent with the enhancement of hydrophobic effect. Due to the existence of an oxygen atom in the headgroup, an unusual surface activity of CnMMB surfactants was obtained. The obtained results should help to better understand the effect of the hydrophilic headgroup on the micelle behavior of cationic surfactants containing saturated nitrogen-containing heterocycles.

Adamantylation of saturated nitrogen-containing heterocycles

Adamantylation of saturated nitrogen-containing heterocycles

Transformation of saturated nitrogen-containing heterocyclic compounds by microorganisms

The saturated nitrogen-containing heterocyclic compounds include many drugs and compounds that may be used as synthons for the synthesis of other pharmacologically active substances. The need for new derivatives of saturated nitrogen-containing heterocycles for organic synthesis, biotechnology and the pharmaceutical industry, including optically active derivatives, has increased interest in microbial synthesis. This review provides an overview of microbial technologies that can be valuable to produce new derivatives of saturated nitrogen-containing heterocycles, including hydroxylated derivatives. The chemo-, regio- and enantioselectivity of microbial processes can be indispensable for the synthesis of new compounds. Microbial processes carried out with fungi, including Beauveria bassiana, Cunninghamella verticillata, Penicillium simplicissimum, Aspergillus niger and Saccharomyces cerevisiae, and bacteria, including Pseudomonas sp., Sphingomonas sp. and Rhodococcus erythropolis, biotransform many substrates efficiently. Among the biological activities of saturated nitrogen-containing heterocyclic compounds are antimicrobial, antitumor, antihypertensive and anti-HIV activities; some derivatives are effective for the treatment and prevention of malaria and trypanosomiasis, and others are potent glycosidase inhibitors.

Alkylation of saturated nitrogen-containing heterocycles with 1-bromo-4-oxoadamantane

A synthetic route toward 1-N-heteryl-4-oxoadamantanes, intermediates in the synthesis of 1-heteryl-4-(R)-amino(acylamino)adamantanes used for treating type II diabetes and other diseases, was developed. Synthesis of 1-N-heteryl-4-oxoadamantanes was carried out by alkylation of saturated nitrogen-containing heterocycles with 1-bromo-4-oxoadamantane.

Ruthenium-Catalyzed Intramolecular Hydrocarbamoylation of Allylic Formamides: Convenient Access to Chiral Pyrrolidones

An attractive strategy for the synthesis of saturated nitrogen-containing heterocycles is described herein, involving the implementation of ruthenium-catalyzed intramolecular hydrocarbamoylation of olefins. The process proceeds by formal C-H bond cleavage of an allylic formamide followed by construction of a new C-C bond in a reaction that is characterized by complete atom-economy. The method is particularly valuable in conjunction with the numerous efficient strategies available for the preparation of optically active allylic formamides.

Recent advancements in the homoallylamine chemistry

AbstractNew advances in preparation of homoallylamines are discussed. Novel syntheses of saturated nitrogen‐containing heterocycles from N‐substituted homoallylic amines are reviewed.

6-(6-Substituted amino-2-hydroxypropyl)-5,6,7,8-tetrahydrodibenz[c, e]azocines

Nucleophilic addition of alkyl-, cycloalkylamines, or saturated nitrogen-containing heterocycles to isolated or in situ generated 6-(2,3-epoxypropyl)-5,6,7,8-tetrahydrodibenz[c,e]azocine (III) afforded 6-(3-substituted amino-2-hydroxypropyl)-5,6,7,8-tetrahydrodibenz[c,e]azocines IV and their hydrochlorides. The starting 5,6,7,8-tetrahydrodibenz[c,e]azocine (I) reacted with 1-chloro-2,3-epoxypropane to yield 6-(3-chloro-2-hydroxypropyl)-5,6,7,8-tetrahydrodibenz[c,e]azocine (II), which, on treatment with sodium ethoxide or an excess of an amine eliminated hydrogen chloride to give the intermediate III.

Sulphonamidomercuriation of olefins and subsequent reductive demercuriation or bromodemercuriation

The addition of toluene-p-sulphonamide to olefins in the presence of anhydrous mercury(II) nitrate and subsequent sodium borohydride reduction leads to the corresponding N-alkylsulphonamides. The sulphonamidomercuriation–demercuriation of 1,4- and 1,5-dienes yields saturated nitrogen-containing heterocycles. A possible mechanism for the stereoselective synthesis of cis-2,5-dimethyl-N-tosylpyrrolidine is proposed. The treatment of the intermediate organomercurials, isolated as the sodium salts of their bromomercurio derivatives, with bromine gives the corresponding 2-bromoalkyl-sulphonamides through a regiospecific bromodemercuriation process.

Sulphonamidomercuration; a new method for amination of olefins

The addition of toluene-p-sulphonamide to olefins in the presence of anhydrous mercury(II) nitrate and subsequent sodium borohydride reduction leads to the corresponding N-alkyl-sulphonamides; the use of 1, 4- and 1,5-dienes yields saturated nitrogen-containing heterocycles, the synthesis of tosylated pyrrolidine being a stereoselective reaction.