Azide-based preparation of fused heterocyclic imines and their multicomponent reactions.

Structurally diverse pyrroles, indoles and imidazoles bearing an -ω-azidoalkyl moiety and an aldehyde or ketone function were prepared and successfully introduced into imine generation the intramolecular Staudinger/aza-Wittig tandem reaction. Reduction of the generated imines led to medicinally relevant nitrogen-containing fused heterocycles such as tetrahydropyrrolo[1,2-]pyrazines and diazepines. Rare 8-membered hexahydropyrrolo[1,2-][1,4]diazocine and 9-membered dihydro-4,8-(metheno)pyrrolo[1,2-][1,4]diazacycloundecine were also synthesized.

Imines with rare α-heteroatom substituted amine components generated the Staudinger/aza-Wittig tandem reaction and their application in multicomponent reactions.

A series of structurally diverse α-heteroatom substituted methyl azides (XCHN, where X = phthalimidoyl, benzotriazolyl, arylsulfanyl, aryloxy, alkoxy) have been prepared and evaluated for the generation of imines the Staudinger/aza-Wittig tandem reaction with aldehydes and triphenylphosphine. The obtained imines were successfully introduced into four types of multicomponent reactions: the Staudinger β-lactam synthesis with diazo carbonyl compounds, the Castagnoli-Cushman reaction with cyclic anhydrides, and the Ugi and azido-Ugi reactions with isocyanides and carboxylic acids or TMS-azides. These transformations allowed the preparation of four-to-seven-membered lactams, acyclic bisamides and 5-(aminomethyl)-1-alkyltetrazoles with a complex and previously poorly accessible periphery.

Effects of Zwitterions on Structural Anomalies in Ionic Liquid Glasses Studied by EPR.

Ionic liquids (ILs) form a variety of nanostructures due to their amphiphilic nature. Recently, unusual structural phenomena have been found in glassy ILs near their glass transition temperatures; however, in all studied cases, IL cations and anions were in the form of separate moieties. In this work, we investigate for the first time such structural anomalies in zwitterionic IL glasses (ZILs), where the cation and anion are bound in a single molecule.

Synthetic Routes to Approved Drugs Containing a Spirocycle.

The use of spirocycles in drug discovery and medicinal chemistry has been booming in the last two decades. This has clearly translated into the landscape of approved drugs. Among two dozen clinically used medicines containing a spirocycle, 50% have been approved in the 21st century.

The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli-Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center.

Novel aryl-substituted homophthalic acids were cyclodehydrated to the respective homophthalic anhydrides for use in the Castagnoli-Cushman reaction. With a range of imines, this reaction proceeded smoothly and delivered hitherto undescribed 4-aryl-substituted tetrahydroisoquinolonic acids with remarkable diastereoselectivity, good yields and no need for chromatographic purification. These findings significantly extend the range of cyclic anhydrides employable in the Castagnoli-Cushman reaction and signify access to a novel substitution pattern around the medicinally relevant tetrahydroisoquinolonic acid scaffold.

One-Pot Sequence of Staudinger/aza-Wittig/Castagnoli-Cushman Reactions Provides Facile Access to Novel Natural-like Polycyclic Ring Systems.

Realization of the one-pot Staudinger/aza-Wittig/Castagnoli-Cushman reaction sequence for a series of azido aldehydes and homophthalic anhydrides is described. The reaction proceeded at room temperature and delivered novel polyheterocycles related to the natural product realm in high yields and high diastereoselectivity. The methodology has been extended to three other cyclic anhydrides.

generation of imines by the Staudinger/aza-Wittig tandem reaction combined with thermally induced Wolff rearrangement for one-pot three-component β-lactam synthesis.

A new efficient protocol for diastereoselective three-component one-pot lactam synthesis involving the generation of imines the Staudinger/aza-Wittig tandem reaction combined with the Wolff-rearrangement and ketene-imine cycloaddition was developed to produce a series of 24 novel structurally diverse β-lactam- or 1,3-oxazine-products. It was shown that this synthesis can be performed both as a two step-procedure and true MCR with simultaneous loading of all reactants. The intramolecular version of the 1 step provided facile access to seven-membered cyclic imines, which allowed further preparation of a series of rare tricyclic β-lactams.

Extending the Scope of the New Variant of the Castagnoli-Cushman Cyclocondensation onto -Methyl Benzoic Acids Bearing Various Electron-Withdrawing Groups in the α-Position.

Based on the previously reported involvement of homophthalic acid monoesters in the Castagnoli-Cushman reaction-type cyclocondensation with imines, we tested a number of other -methyl benzoic acids bearing various electron-withdrawing groups in the α-position. The majority of these substrates delivered the expected tetrahydroisoquinolone adducts on activation with CDI or acetic anhydride. Homophthalic acid mononitriles displayed the highest promise as substrates for the new reaction, both in terms of scope and product yields.

New reagent space and new scope for the Castagnoli-Cushman reaction of oximes and 3-arylglutaconic anhydrides.

The Castagnoli-Cushman reaction of oximes, discovered originally for homophthalic anhydride, stimulated the search for other cyclic anhydrides that would be workable in that reaction. Finally, 3-arylglutaconic acid anhydrides were identified as displaying the right reactivity towards a wide range of oximes (including those which did not react with homophthalic anhydride, such as derivatives of aliphatic aldehydes or ketones and substrates with nucleophilic side groups) and delivering, after 18 h at 110 °C in DMSO, β,γ-unsaturated -hydroxylactam products lacking the carboxylic acid functionality as the result of decarboxylation accompanying the cyclocondensation process. The reaction was found to be scalable to gram quantities of the starting anhydrides.

Active Pharmaceutical Ingredient-Ionic Liquids (API-ILs): Nanostructure of the Glassy State Studied by Electron Paramagnetic Resonance Spectroscopy.

Active Pharmaceutical Ingredient-Ionic Liquids (API-ILs) draw increasing interest as a particular class of ILs that possess unusual physicochemical properties along with simultaneous potentials for pharmaceutical applications. Although nanostructuring phenomena were actively investigated in common ILs, their studies in API-ILs are scarce so far. In this work, using the complex methodology of Electron Paramagnetic Resonance (EPR) and dissolved spin probes, we investigate nanostructuring phenomena in a series of API-ILs: [Cmim][Ibu], [Cmim][Gly], and [Cmim][Sal] with = 2, 4, and 6, respectively.

Exploration of Spirocyclic Derivatives of Ciprofloxacin as Antibacterial Agents.

The previously reported as well as newly synthesized derivatives of the 1-oxa-9-azaspiro[5.5]undecane were employed in the synthesis of thirty-six derivatives of ciprofloxacin using commercially available 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and the literature protocol involving the preparation of boron chelate complex to facilitate nucleophilic aromatic substitution. All new fluoroquinolone derivatives were tested against two gram-positive as well as three gram-negative strains of bacteria.

Unexpected Ring Contraction of Homophthalic Anhydrides under Diazo Transfer Conditions.

An attempted Regitz diazo transfer onto homophthalic anhydride led to the discovery of an unexpected ring contraction, which gave -sulfonyl phthalide-3-carboxamide derivatives. The reaction is thought to proceed via a [3 + 2] cycloaddition of the substrate's enol form and the azide followed by a two-step fragmentation of the intermediate 1,2,3-triazoline with a loss of the nitrogen molecule.

Conjugates of Iron-Transporting -Hydroxylactams with Ciprofloxacin.

Screening of a library of novel -hydroxylactams amenable by the Castagnoli-Cushman reaction identified four lead compounds that facilitated Fe transport into cells (one of these synthetic siderophores was found to be as efficient at promoting iron uptake as the natural siderophores pyoverdine, pyochelin or enterobactin). Conjugates of the four lead siderophores with ciprofloxacin were tested for antibacterial activity against POA1 (wild type) and the mutant strain. The antibacterial activity was found to be pronounced against the mutant strain grown in CAA medium but not for the POA1 strain.

Dicarboxylic Acid Monoesters in β- and δ-Lactam Synthesis.

A -(2-methoxy-2-oxoethyl)--(phenylsulfonyl)glycine monomethyl ester of the respective dicarboxylic acid was involved in a reaction with imines promoted by acetic anhydride at an elevated temperature. Instead of the initially expected δ-lactam products of the Castagnoli-Cushman-type reaction, medicinally important 3-amino-2-azetidinones were obtained as the result of cyclization, involving a methylene group adjacent to an acid moiety. In contrast, replacing alcohol residue with hexafluoroisopropyl in the same substrate made another methylene group (adjacent to the ester moiety) more reactive to furnishing the desired δ-lactam in the Castagnoli-Cushman fashion.

Preparation and Synthetic Applications of Five-to-Seven-Membered Cyclic α-Diazo Monocarbonyl Compounds.

The reactivity of cyclic α-diazo monocarbonyl compounds differs from that of their acyclic counterparts. In this review, we summarize the current literature available on the synthesis and synthetic applications of three major classes of cyclic α-diazo monocarbonyl compounds: α-diazo ketones, α-diazo lactones and α-diazo lactams.

Synthesis of γ-Sultam-Annelated δ-Lactams via the Castagnoli-Cushman Reaction of Sultam-Based Dicarboxylic Acids.

An unusual type of highly reactive sultam-based dicarboxylic acids and correscponding anhydrides was employed in the Castagnoli-Cushman reaction delivering diastereomerically pure adducts at room temperature. Due to steric congestion, the initial adducts were prone to decarboxylation affording diastereomeric mixtures of bicyclic sultam lactams, separable by HPLC. The choice of a protecting group on the sultam nitrogen atom allows liberation of the -sultam, which is not only suitable for further modification but represents a known pharmacophore for carbonic anhydrase inhibition.

Multicomponent Reactions Involving Diazo Reagents: A 5-Year Update.

This review summarizes recent developments in multicomponent reactions of diazo compounds. The role of diazo reagent and the type of interaction between components was analyzed to structure the discussion. In contrast to previous reviews on related topics mostly focused on metal catalyzed transformations, a substantial amount of organocatalytic or catalyst-free methodologies is covered in this work.

Validation of Structural Grounds for Anomalous Molecular Mobility in Ionic Liquid Glasses.

Ionic liquid (IL) glasses have recently drawn much interest as unusual media with unique physicochemical properties. In particular, anomalous suppression of molecular mobility in imidazolium IL glasses vs. increasing temperature was evidenced by pulse Electron Paramagnetic Resonance (EPR) spectroscopy.

Inherent heterogeneities and nanostructural anomalies in organic glasses revealed by EPR.

Intriguing heterogeneities and nanostructural reorganizations of glassy ionic liquids (ILs) have recently been found using electron paramagnetic resonance (EPR) spectroscopy. Alkyl chains of IL cations play the key role in such phenomena and govern the anomalous temperature dependence of local density and molecular mobility. In this paper we evidence and study similar manifestations in a variety of common non-IL glasses, which also contain molecules with alkyl chains.

Unexpected formal [4 + 2]-cycloaddition of chalcone imines and homophthalic anhydrides: preparation of dihydropyridin-2(1)-ones.

A series of medicinally important dihydropyridin-2(1H)-ones have been prepared via a novel [4 + 2]-formal cycloaddition reaction of chalcone imines and homophthalic anhydrides, which is a rare example of lactam construction from an imine acting as a four-atom building block. In contrast to previous studies on the reactivity of homophthalic anhydrides towards similar substrates, N-tosyl chalcone imines, we found the possibility of switching chemoselectivity by changing substituents at the nitrogen atom, which leads to the formation of heterocycles instead of the expected carbocycles. This reaction is very similar in appearance to the classic 1,2-addition of cyclic anhydrides to imines, often referred to as the Castagnoli-Cushman reaction, but differs in mechanistic details (representing a 1,4-reaction of imine).

Spirocyclizations Involving Oxonium Ylides Derived from Cyclic α-Diazocarbonyl Compounds: An Entry into 6-Oxa-2-azaspiro[4.5]decane Scaffold.

New types of cyclic diazo compounds capable of Rh(II)-catalyzed spirocyclizations with tetrahydrofuran have been discovered. The formation of the spirocyclic framework is thought to proceed the formation of Rh(II) carbene species followed by interaction with the Lewis basic oxygen atom of tetrahydrofuran to give oxonium ylide species. The latter evolves predominantly the Stevens type rearrangement leading to an [ + 1] ring expansion of the tetrahydrofuran moiety, which results in the formation of a medicinally relevant 6-oxa-2-azaspiro[4.

Mutually Isomeric 2- and 4-(3-nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens.

Starting from the structure of antimycobacterial screening hit OTB-021 which was devoid of activity against ESKAPE pathogens, we designed, synthesized and tested two mutually isomeric series of novel simplified analogs, 2- and 4-(3-nitro-1,2,4-triazol-1-yl)pyrimidines, bearing various amino side chains. These compounds demonstrated a reverse bioactivity profile being inactive against while inhibiting the growth of all ESKAPE pathogens (with variable potency patterns) except for Gram-negative . Reduction potentials (E, V) measured for selected compounds by cyclic voltammetry were tightly grouped in the -1.

Nanocage formation and structural anomalies in imidazolium ionic liquid glasses governed by alkyl chains of cations.

Intriguing nanostructuring anomalies have been recently observed in imidazolium ionic liquids (ILs) near their glass transition points, where local density around a nanocaged solute progressively grows up with temperature. Herewith, we for the first time demonstrate experimentally and theoretically, that these anomalies are governed by alkyl chains of cations and crucially depend on their length. Electron Paramagnetic Resonance (EPR) spectroscopy on a series of ILs [Cmim]BF (n = 0-12) shows that only the chains with n = 3-10 favor anomaly.

Two Annulated Azaheterocyclic Cores Readily Available from a Single Tetrahydroisoquinolonic Castagnoli-Cushman Precursor.

A novel approach to indolo[3,2-]isoquinoline and dibenzo[,][1,6]naphthyridine tetracyclic systems was discovered based on switchable reduction of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid prepared via Castagnoli-Cushman reaction. Reduction with ammonium formate resulted in the expected selective transformation of the nitro group (thus providing access to substituted dibenzo[,][1,6]naphthyridine via cyclization and dehydrogenation). However, attempted reduction with sodium sulfide initiated a previously unknown reaction cascade including double reduction, cyclization, and decarboxylation, leading to formation of indolo[3,2-]isoquinoline polyheterocycle in one synthetic step.