Regioselective Dearomative Amidoximation of Nonactivated Arenes Enabled by Photohomolytic Cleavage of N-nitrosamides.

Dearomative spirocyclization reactions represent a promising means to convert arenes into three-dimensional architectures; however, controlling the regioselectivity of radical dearomatization with nonactivated arenes to afford the spirocyclizative 1,2-difunctionalization other than its kinetically preferred 1,4-difunctionalization is exceptionally challenging. Here we disclose a novel strategy for dearomative 1,2- or 1,4-amidoximation of (hetero)arenes enabled by direct visible-light-induced homolysis of N-NO bonds of nitrosamides, giving rise to various highly regioselective amidoximated spirocycles that previously have been inaccessible or required elaborate synthetic efforts. The mechanism and origins of the observed regioselectivities were investigated by control experiments and density functional theory calculations.

Regioselective Cycloaddition of Nitrile Imines to 5-Methylidene-3-phenyl-hydantoin: Synthesis and DFT Calculations.

Nitrile imine cycloaddition to hydantoins containing an exocyclic C=C double bond has been previously described in a very limited number of examples. In this work, regioselective synthesis of spiro-pyrazoline-imidazolidine-2,4-diones based on a 1,3-dipolar cycloaddition reaction of nitrile imines to 5-methylidene-3-phenyl-hydantoin have been proposed. It was found that, regardless of the nature of the aryl substituents at the terminal C and N atoms of the C-N-N fragment of nitrile imine (electron donor or electron acceptor), cycloaddition to the 5-methylidenhydantoin exocyclic C=C bond proceeds regioselectively, and the terminal nitrogen atom of the nitrile imine connects to the more sterically hindered carbon atom of the double bond, which leads to the formation of a 5-disubstituted pyrazoline ring. The observed cycloaddition regioselectivity was rationalized using DFT calculations of frontier molecular orbital interactions, global CDFT reactivity indices, and minimum energy paths.

[3+2]-Cycloaddition of Nitrile Imines to Parabanic Acid Derivatives-An Approach to Novel Spiroimidazolidinediones.

Approximately 1,3-Dipolar cycloaddition of imidazolidine derivatives containing exocyclic double bonds is a convenient method of creating spiro-conjugated molecules with promising anticancer activity. In this work, the derivatives of parabanic acid (2-thioxoimidazolidine-4,5-diones and 5-aryliminoimidazolidine-2,4-diones) were first investigated as dipolarophiles in the reactions with nitrile imines. The generation of nitrile imines was carried out either by the addition of tertiary amine to hydrazonoyl chlorides «drop by drop¼ or using the recently proposed diffusion mixing technique, which led to ~5-15% increases in target compound yields. It was found that the addition of nitrile imines to C=S or C=N exocyclic double bonds led to 1,2,4-thiazolines or triazolines and occurred regioselectively in accordance with the ratio of FMO coefficients of reactants. The yield of the resulting spiro-compound depended on the presence of alkyl substituents in the nitrile imine structure and was significantly decreased in reactions with imines with strong electron donor or electron-withdrawing groups. Some of the obtained compounds showed reasonable in vitro cytotoxicity. IC50 values were calculated for HCT116 (colon cancer) cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test.

[4+2]-Cycloaddition to 5-Methylidene-Hydantoins and 5-Methylidene-2-Thiohydantoins in the Synthesis of Spiro-2-Chalcogenimidazolones.

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels-Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids. It was demonstrated that ZnI2 is an effective catalyst in the Diels-Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH2Cl or Boc2O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH2Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H2O2 or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2.

3-[N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses.

Spirocyclic compounds containing heterocyclic moieties represent promising 3D scaffolds for modern drug design. In the search for novel anti-flaviviral agents, we have obtained a series of 3-[N,N-bis(sulfonyl)amino]isoxazolines containing spiro-annulated cyclooctane rings and assessed their antiviral activity against tick-borne encephalitis (TBEV), yellow fever (YFV), and West Nile (WNV) viruses. The structural analogs of spirocyclic compounds with a single sulfonyl group or 1,2-annulated cyclooctane ring were also investigated. Almost all the studied 3-[N,N-bis(sulfonyl)amino]isoxazolines revealed antiviral activity against TBEV and WNV. The most active against TBEV was spiro-isoxazoline derivative containing p-nitrophenyl groups in the sulfonyl part (EC50 2.0 ± 0.5 µM), while the highest potency against WNV was found for the compounds with lipophilic substituents in sulfonyl moiety, naphtyl being the most favorable one (EC50 1.3 ± 0.5 µM). In summary, two novel scaffolds of anti-flaviviral agents based on N,N-bis(sulfonyl)amino]isoxazoline were proposed, and the compounds of this type demonstrated activity against TBEV and WNV.

Toward a Formyl-to-Phenyl Conversion: An Unexpected Photochemical Fulvene Rearrangement.

Toward a conversion of aldehydes into arenes, we designed a sequence involving the initial reaction of an aldehyde to give a fulvene, followed by photochemical and platinum-catalyzed rearrangements into a Dewar benzene derivative, which finally isomerizes into the targeted arene. While computational studies support the plausibility of this route, we found that fulvene irradiation resulted in an unexpected isomerization into a spiro[2.4]heptadiene. This unusual photorearrangement has been investigated mechanistically and provides access to a variety of spiro[2.4]heptadienes with different substituents.

Cation-Promoted Strain-Release-Driven Access to Functionalized Azetidines from Azabicyclo[1.1.0]butanes.

Access to 1,3-functionalized azetidines through a diversity-oriented approach is highly sought-after for finding new applications in drug-discovery. To this goal, strain-release-driven functionalization of azabicyclo[1.1.0]-butane (ABB) has generated significant interest. Through appropriate N-activation, C3-substituted ABBs are shown to render tandem N/C3-fucntionalization/rearrangement, furnishing azetidines; although, modalities of such N-activation vis-à-vis N-functionalization remain limited to selected electrophiles. This work showcases a versatile cation-driven activation strategy of ABBs. And capitalizes on the use of Csp3 precursors amenable to forming reactive (aza)oxyallyl cations in situ. Herein, N-activation leads to formation of a congested C-N bond, and effective C3 activation. The concept was extended to formal [3+2] annulations involving (aza)oxyallyl cations and ABBs, leading to bridged bicyclic azetidines. Besides the fundamental appeal of this new activation paradigm, operational simplicity and remarkable diversity should engender its prompt use in synthetic and medicinal chemistry.

A Concise Total Synthesis of (-)-Berkelic Acid.

Reported here is a concise total synthesis of (-)-berkelic acid in eight linear steps. This synthesis features a Catellani reaction/oxa-Michael cascade for the construction of the isochroman scaffold, a one-pot deprotection/spiroacetalization operation for the formation of the tetracyclic core structure, and a late-stage Ni-catalyzed reductive coupling for the introduction of the lateral chain. Notably, four stereocenters are established from a single existing chiral center with excellent stereocontrol during the deprotection/spiroacetalization process. Stereocontrol of the intriguing deprotection/spiroacetalization process is supported by DFT calculations.

Dearomatizing [4+1] Spiroannulation of Naphthols: Discovery of Thermally Activated Delayed Fluorescent Materials.

Disclosed here is a palladium-catalyzed direct [4+1] spiroannulation of ortho-C-H bonds of naphthols with cyclic diaryliodonium salts to construct spirofluorenyl naphthalenones (SFNP) under mild reaction conditions. This spiroannulation directly transforms the hydroxy group into a carbonyl group, and also tolerates reactive functional groups such as the halo groups, which provide an opportunity to rapidly assemble structurally new thermally activated delayed fluorescent (TADF) materials that feature a carbonyl group with an adjacent spirofluorenyl unit as the acceptor. As an illustrated example, the OLED device utilizing the assembled DMAC-SFNP as the host material exhibits a low turn-on voltage of 2.5 V and an ultra-high external quantum efficiency of 32.2 %. This work provides inspiration for structurally new TADF materials, and also displays the potential of C-H activation as a synthetic strategy for the innovation of optoelectronic materials.

Kinetic Resolution of Aziridines Enabled by N-Heterocyclic Carbene/Copper Cooperative Catalysis: Carbene Dose-Controlled Chemo-Switchability.

Catalytic kinetic resolution (KR) and dynamic kinetic asymmetric transformation (DyKAT) are alternative and complementary avenues to access chiral stereoisomers of both starting materials and reaction products. The development of highly efficient chiral catalytic systems for kinetically controlled processes has therefore been one of the linchpins in asymmetric synthesis. N-heterocyclic carbene (NHC)/copper cooperative catalysis has enabled highly efficient KR and DyKAT of racemic N-tosylaziridines by [3+3] annulation with isatin-derived enals, leading to highly enantioenriched N-tosylaziridine derivatives (up to >99 % ee) and a large library of spirooxindole derivatives with high structural diversity and stereoselectivity (up to >95:5 d.r., >99 % ee). Mechanistic studies suggest that the NHC can bind reversibly to the copper catalyst without compromising its catalytic activity and regulate the catalytic activity of the copper complex to switch the chemoselection between KR and DyKAT.

Ultrasound-assisted synthesis of heterocyclic compounds.

In this review, we tried to underscore the synthesis of the heterocyclic compounds under assisted ultrasonic irradiation. The ultrasonic irradiation has been applied for medicinal chemistry and drug discovery process since it dramatically reduces reaction times, from days or hours to minutes. Also, ultrasonic irradiation provides lower cost, excellent yields, greater purity, and simple workups as compared to lower yields, longer reaction times, lesser purity and in the conventional methods. In this review, we have compared synthesis of the heterocyclic compounds under ultrasonic irradiation with other methods.

Asymmetric Synthesis and Application of Chiral Spirosilabiindanes.

Reported here is the development of a class of chiral spirosilabiindane scaffolds by Rh-catalyzed asymmetric double hydrosilation, for the first time. Enantiopure SPSiOL (spirosilabiindane diol), a new type of chiral building block for the preparation of various chiral ligands and catalysts, was readily prepared on greater than 10 gram scale using this protocol. The potential of this new spirosilabiindane scaffold in asymmetric catalysis was preliminarily demonstrated by development of the corresponding monodentate phosphoramidite ligands (SPSiPhos), which were used in both a Rh-catalyzed hydrogenation and a Pd-catalyzed intramolecular carboamination.

Enantioselective Synthesis of 2-Oxindole Spirofused Lactones and Lactams by Heck/Carbonylative Cylization Sequences: Method Development and Applications.

An efficient one-pot assembly of all-carbon spiro-oxindole compounds from non-oxindole-based materials has been developed through a palladium-catalyzed asymmetric Heck/carbonylative lactonization and lactamization sequence. Diversified spirooxindole γ-and δ-lactones/lactams were accessed in high yields with good to excellent enantioselectivities (up to 99 % ee) under mild reaction conditions. The natural product coixspirolactam A was conveniently synthesized by applying the current methodology, and thus its absolute configuration was elucidated for the first time. Asymmetric synthesis of an effective CRTH2 receptor antagonist has also been demonstrated utilizing this method in the key step.

C1-Linked Spirobifluorene Dimers: Pure Hydrocarbon Hosts for High-Performance Blue Phosphorescent OLEDs.

Reported here are C1-linked spiro-bifluorene dimers. A comprehensive study is carried out to analyze the electronic properties of these highly twisted structures. This work shows that the C1-position enables the design of pure hydrocarbon materials, with a high triplet energy, for hosting blue phosphors in efficient phosphorescent OLEDs (PhOLEDs). To date, this work describes the highest performance of blue PhOLEDs ever reported for pure hydrocarbons (external quantum efficiency of ca. 23 %), thus highlighting the potential of the C1-spirobifluorene scaffold in organic electronics.

Insight into 6π Electrocyclic Reactions of 1,8-Dioxatetraene.

A variety of benzofuranone-based spiroisochromenes were originally designed and synthesized to gain insight into the oxa-6π electrocyclic reaction of cis,cis-1,8-dioxatetraene for the first time. The stability of the 1,8-dioxatetraene intermediate is governed by its steric congestion and can be fine-tuned through modification of the backbone structure, leading to the reactivity differences in the 6π electrocyclic reaction and the emergence of photochromic properties.

Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of α-Haloaldehydes.

Asymmetric construction of halogenated quaternary carbon centers under mild reaction conditions remains challenging. Reported here is an unprecedented and highly stereoselective Brønsted base catalyzed [4+2] cycloaddition between either α-chloro- or α-bromoaldehydes and cyclic enones. The key intermediate, an α-halogenated enolate, is susceptible to dehalogenation and can be stabilized and stereochemically controlled using bifunctional tertiary amines. This method provides facile access to a collection of optically pure bicyclic dihydropyrans having three contiguous stereocenters, including a halogen-bearing quaternary carbon center. Of note, the product can be transformed in situ into densely functionalized spirocyclopropanes in a highly efficient and stereoselective manner.

Synthesis of Spirocyclic Ethers by Enantioselective Copper-Catalyzed Carboetherification of Alkenols.

Spirocyclic ethers can be found in bioactive compounds. This copper-catalyzed enantioselective alkene carboetherification provides 5,5-, 5,6- and 6,6-spirocyclic products containing fully substituted chiral carbon centers with up to 99 % enantiomeric excess. This reaction features the formation of two rings from acyclic substrates, 1,1-disubstituted alkenols functionalized with either arenes, alkenes, or alkynes, and clearly constitutes a powerful way to synthesize chiral spirocyclic ethers.

Revisiting Arene C(sp2 )-H Amidation by Intramolecular Transfer of Iridium Nitrenoids: Evidence for a Spirocyclization Pathway.

Two mechanistic pathways, that is, electrocyclization and electrophilic aromatic substitution, are operative in most intramolecular C-H amination reactions proceeding by metal nitrenoid catalysis. Reported here is an alternative mechanistic scaffold leading to benzofused δ-lactams selectively. Integrated experimental and computational analysis revealed that the reaction proceeds by a key spirocyclization step followed by a skeletal rearrangement. Based on this mechanistic insight, a new synthetic route to spirolactams has been developed.

A Tunable and Enantioselective Hetero-Diels-Alder Reaction Provides Access to Distinct Piperidinoyl Spirooxindoles.

The active complexes of chiral N,N'-dioxide ligands with dysprosium and magnesium salts catalyze the hetero-Diels-Alder reaction between 2-aza-3-silyloxy-butadienes and alkylidene oxindoles to selectively form 3,3'- and 3,4'-piperidinoyl spirooxindoles, respectively, in very high yields and with excellent enantioselectivities. The exo-selective asymmetric cycloaddition successfully regaled the construction of sp3 -rich and highly substituted natural-product-based spirooxindoles supporting many chiral centers, including contiguous all-carbon quaternary centers.

Switchable Access to Different Spirocyclopentane Oxindoles by N-Heterocyclic Carbene Catalyzed Reactions of Isatin-Derived Enals and N-Sulfonyl Ketimines.

A novel NHC-catalyzed annulation protocol for the asymmetric synthesis of biologically important ß-lactam fused spirocyclopentane oxindoles with four contiguous stereocenters, including two quaternary carbon centers, was developed. Alternatively, spirocyclopentane oxindoles containing an enaminone moiety can be achieved using the same starting materials, isatin-derived enals, and N-sulfonyl ketimines, in the presence of a slightly different NHC catalytic system. This switchable annulation strategy enables the selective assembly of both heterocyclic scaffolds with good yields and excellent enantioselectivities for a broad range of substrates.