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

A series of structurally diverse α-heteroatom substituted methyl azides (XCH2N3, where X = phthalimidoyl, benzotriazolyl, arylsulfanyl, aryloxy, alkoxy) have been prepared and evaluated for the in situ generation of imines via the Staudinger/aza-Wittig tandem reaction with aldehydes and triphenylphosphine. The obtained imines were successfully introduced into four types of multicomponent reactions: the Staudinger ß-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. Moreover, it was demonstrated that phthalimide derivatives can be deprotected to afford medicinally relevant N-aminomethyl lactams.

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. Such binding reasonably restricts mutual diffusion of cations and anions, leading to modification of nano-ordering and character of structural anomalies in these glassy nanomaterials, as has been investigated using Electron Paramagnetic Resonance (EPR) spectroscopy. In particular, the occurrence of structural anomalies in ZIL glasses was revealed, and their characteristic temperatures were found to be higher compared to common ILs of a similar structure. Altogether, this work broadens the scope of structural anomalies in ionic liquid glasses and indicates new routes to tune their properties.

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 present review focuses on the notable synthetic routes to such drugs invented in industry and academia, and is intended to serve as a useful reference source of synthetic as well as general drug information for researchers engaging in the design of new spirocyclic scaffolds for medicinal use or embarking upon analog syntheses inspired by the existing approved drugs.

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. These further unravel the potential of the Castagnoli-Cushman reaction in generating polyheterocyclic molecular scaffolds.

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.

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

A new efficient protocol for diastereoselective three-component one-pot lactam synthesis involving the in situ generation of imines via 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 ß-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 1st step provided facile access to seven-membered cyclic imines, which allowed further preparation of a series of rare tricyclic ß-lactams. For the intermolecular version of the 1st step (acyclic imine generation), it was shown that the outcome of the synthesis is different from that using pre-synthesized and isolated imines. Additionally, this is the first example of the implementation of the Staudinger/aza-Wittig tandem reaction for the preparation of four-membered heterocycles.

Extending the Scope of the New Variant of the Castagnoli-Cushman Cyclocondensation onto o-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 o-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. Homophthalic acid monoamides either gave low yields or failed to react with imines. Sulfonyl-substituted substrates gave the desired (and hitherto unknown) type of tetrahydroisoquinolines. Despite the low yields, this approach to sulfonyl-substituted tetrahydroisoquinolines appears practical as alternative syntheses based on the traditional, carboxylic acid CCR adducts would presumably be cumbersome and multistep. The azido- and nitro-substituted o-methyl benzoic acids failed to react with imines.

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, ß,γ-unsaturated N-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. The products were shown to be easily amenable to post-condensational double-bond transposition or reduction. As expected from cyclic hydroxamic acids, the reaction products were shown to bind Fe(III) and Cu(II) ions (selectively out of a panel of 16 metal cations) and potentially serve as fluorescent metal sensors.

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. With the activity spectrum of the new derivatives being substantially narrower than that of ciprofloxacin, compounds were distinctly active against two of the five strains: gram-negative Acinetobacter baumannii 987® and gram-positive Bacillus cereus 138®. Towards these two strains, a large group of compounds displayed equal or higher potency than ciprofloxacin.

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: [Cnmim][Ibu], [Cnmim][Gly], and [Cnmim][Sal] with n = 2, 4, and 6, respectively. We reveal similar trends for API-ILs and common ILs, as well as peculiarities inherent to the studied API-ILs. Unusual behavior observed for [Cnmim][Ibu] has been assigned to the presence of a non-polar fragment in the [Ibu]- anion, which leads to the formation of more complex nanostructures around the radical compared to common ILs. Understanding general trends in the formation of such self-organized molecular structures is of fundamental interest and importance for applying API-ILs.

Conjugates of Iron-Transporting N-Hydroxylactams with Ciprofloxacin.

Screening of a library of novel N-hydroxylactams amenable by the Castagnoli-Cushman reaction identified four lead compounds that facilitated 55Fe transport into P. aeruginosa 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 P. aeruginosa POA1 (wild type) and the ∆pvdF∆pchA mutant strain. The antibacterial activity was found to be pronounced against the ∆pvdF∆pchA mutant strain grown in CAA medium but not for the POA1 strain. This may be indicative of these compounds being 'Trojan horse' antibiotics. Further scrutiny of the mechanism of the antibacterial action of the newly developed conjugates is warranted.

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 N-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.

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

A N-(2-methoxy-2-oxoethyl)-N-(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 NH-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. Although such behavior has been proven to originate from dynamics of alkyl chains of IL cations, the role of electron spin relaxation induced by surrounding protons still remains unclear. In this work we synthesized two deuterated imidazolium-based ILs to reduce electron-nuclear couplings between radical probe and alkyl chains of IL, and investigated molecular mobility in these glasses. The obtained trends were found closely similar for deuterated and protonated analogs, thus excluding the relaxation-induced artifacts and reliably demonstrating structural grounds of the observed anomalies in heterogeneous IL glasses.

Unexpected formal [4 + 2]-cycloaddition of chalcone imines and homophthalic anhydrides: preparation of dihydropyridin-2(1H)-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). The developed atom-economical, stereoselective and catalyst- and chromatography-free protocol provided facile access to 28 structurally diverse heterocyclic products (in up to 88% yield) including synthetically challenging annelated tricyclic and previously unreported pentaaryl-substituted dihydropyridin-2(1H)-ones.

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. A series of phthalates clearly demonstrates very similar behavior to imidazolium-based ILs with the same length of alkyl chain. Glasses of alkyl alcohols and alkyl benzenes show only some similarities to the corresponding ILs, mainly due to a lower glass transition temperature hindering the development of the anomaly. Therefore, we demonstrate the general nature and broad scope of nanoscale structural anomalies in organic glasses based on alkyl-chain compounds. The 'roadmap' for their occurrence is provided, which aids in understanding and future applications of these anomalous nanoheterogeneities.

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 via 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 via the Stevens type rearrangement leading to an [n + 1] ring expansion of the tetrahydrofuran moiety, which results in the formation of a medicinally relevant 6-oxa-2-azaspiro[4.5]decane scaffold. The spirocyclization process was often observed in competition with mechanistically distinct C-H insertion into a tetrahydrofuran molecule. This competing process gave compounds based on the 3-(tetrahydrofur-2-yl)pyrrolidine scaffold, which are also relevant from the medicinal chemistry standpoint. These findings enrich the available arsenal of metal-catalyzed spirocyclization methods based on the use of cyclic diazo compounds.