Cycloaddition Cascade Research Articles

Dearomative Functionalization of Activated Quinolines: Transfer Hydrogenation/Cycloaddition Cascade to Construct α‐Tertiary Amines

AbstractCascade dearomative functionalization is a robust protocol to convert flat arenes into medicinally relevant three‐dimensional architectures with added new functionality. Herein, a dearomative cycloaddition protocol for synthesizing tetrahydroquinoline‐embedded α‐tertiary amine scaffolds has been developed employing quinolinium salts and sulfonyl azides under metal‐free conditions. An underexplored and mechanistically distinct pathway is unveiled, creating quaternary‐center‐bearing amine skeletons by an amine group migration during the transfer hydrogenation and cycloaddition cascade reaction. This approach provided a broad substrate scope of α‐tertiary amine scaffolds from a plethora of C3‐substituted quinolinium and sulfonyl azides. The post‐synthetic modifications have further diversified the α‐tertiary amine core into interesting scaffolds. Preliminary mechanistic studies suggested the involvement of aziridine ring formation for the amine migration to the C‐3 position of quinoline to generate the α‐tertiary amine core.

Synthesis of 6/5/3-Fused Tricyclic Scaffolds via Multistep Cascade Cyclization of α-Aryl Vinylsulfoniums with para-Quinamines and para-Quinols.

Herein, we present a straightforward approach to access hydroindoline-5-one-based 6/5/3-fused polycyclic ring structures through multistep cascade reactions involving α-aryl vinylsulfoniums and para-quinamines. The reactions proceed smoothly under mild conditions to deliver the desired products in generally good isolated yields. This protocol is also applicable to the cascade cycloaddition reactions of α-aryl vinylsulfoniums and para-quinols, effectively generating complex tricyclic scaffolds. In addition, the scale-up synthesis and further derivatizations demonstrate the potential synthetic application of the protocol.

Theoretical investigation on diastereoselective [2+2] cycloaddition and Pd-catalyzed enantioselective [3+2] cycloaddition for synthesis of cis-β-lactam and exo-furobenzopyranone

The mechanism is investigated for Wolff rearrangement/Staudinger [2+2] cycloaddition cascade and Pd-catalyzed, decarboxylative, formal [3+2] cycloaddition. Wolff rearrangement of 3-diazotetramic acid is determined to be rate-limiting step generates cyclic acyl ketene. The interaction of ketene with imine firstly results in zwitterion followed by conrotatory cyclization giving major cis-β-lactam. For synthesis of s-VECs, the epoxidation−cyclization cascade and hydrolysis give precursor of better performing exocyclic derivative. The reaction with 3-cyanochromone includes decarboxylation, nucleophilic attack and subsequent ring closure yielding 5-exo-trig furobenzopyranone. Based on the comparison between possible paths, the diastereoselectivity of cis over trans and regio-divergence of 5-exo-trig over 7-endo-trig are both kinetically controlled for [2+2] and [3+2] cycloaddition in common. The positive solvation effect is suggested by decreased absolute and activation energies in chlorobenzene and chloroform solution compared with in gas. These results are supported by Multiwfn analysis on FMO composition of specific TSs, and MBO value of vital bonding, breaking.

Rh(II)‐Catalyzed Homocoupling/[4+1] Cycloaddition Cascade of Diazobarbiturates with Diazopyrazolones to Prepare Spirobarbiturates

AbstractUnder the catalysis of Rh2(OAc)4 (10 mol%) and (±)‐Me‐Pybox (20 mol%) in 1,2‐DCE at 80 °C, the homocoupling/[4+1] cycloaddition cascade of diazobarbiturates with diazopyrazolones proceeded readily and provided spirobarbiturates in 32–88% chemical yields. The chemical structure of the obtained spirobarbiturates was identified by X‐ray diffraction analysis.

Substituent-dependent [4+2] or [2+2] cycloadditions of phenylallenyl phosphine oxides with arynes.

A [4+2] cycloaddition strategy to assemble phenanthren-9-yldiphenylphosphine oxides is reported. This reaction relies on the strategic use of readily available phenylallenyl phosphine oxides as dienes to participate in [4+2] cycloaddition with arynes. Notably, benzo[b][1,4]oxaphosphinin-4-iums can be controllably synthesized by simply tuning the substituents in the phosphine oxide unit through a [2+2] cycloaddition cascade.

Synthesis of 3-sulfonylisoindolin-1-ones from olefinic amides and sodium sulfinates via electrooxidative tandem cyclization.

Sulfonyl groups are motifs that are widely found in biologically active compounds and drug molecules, many isolated natural products as well as pharmaceuticals contain sulfonyl groups. Herein, we present the synthesis of sulfonyl-substituted isoindolones by a electrochemical oxidative radical cascade cycloaddition reaction of olefinic amides with sodium sulfite under oxidant- and catalyst-free conditions. Various olefinic amides and sodium sulfinates were compatible and gave the desired products in yields up to 99%.

Synthesis of Bridged Cycloisoxazoline Scaffolds via Rhodium-Catalyzed Coupling of Nitrones with Cyclic Carbonate.

Bridged isoxazolidines were synthesized via Rh(III)-catalyzed C-H allylation of α-aryl nitrones with 5-methylene-1,3-dioxan-2-one. The nitrone group serves as a directing group and 1,3-dipole in the C-H activation/[3 + 2] cycloaddition cascade, exhibiting excellent chemo- and stereoselectivity along with good functional group compatibility. The resulting skeletal structure was conveniently modified to produce a range of important chemical frameworks, and the protocol was applied to biologically active molecules.

Synthesis, structural determination, in vitro antioxidant and antibacterial efficacy of dispirooxindolopyrrolidine embedded indole heterocycle

Synthesis of dispirooxindolopyrrolidine embedded indole hybrid heterocycle was achieved in excellent yield employing intermolecular 1,3-dipolar cycloaddition cascade reaction sequence. The non-stabilized 1,3-dipole component was derived from isatin and l-tryptophan under decarboxylative condensation methodology, was reacts with 3-(4-fluorobenzylidene)indolin-2-one to form 5-benzyl-spiro[2.3′]oxindolo-spiro[3.3′′]-oxindolo-4-[4-fluorophenyl-pyrrolidinewith four stereogenic center via two CC and one CN bonds in single synthetic operation. The structure of compound was undoubtably determined by 1D and 2D NMR spectroscopic analysis. The stereo and regiochemistry of cycloadduct was confirmed through single crystal X-ray diffraction studies. The packing aspects of compound 4 were analyzed using Hirshfeld calculations. It is found that the O…H, N…H, C…H and H…H interactions have major role in the crystal stability. Their percentages are estimated to be 10.1, 3.4, 25.0 and 51.0%, respectively indicating that the H…H contacts are the most dominant. Different electronic parameters such as charge population, dipole moment, molecular electrostatic potential map and frontier molecular orbitals as well as their derived reactivity descriptors were presented. Compound 4 showed potent antibacterial efficacy against E. coli with MIC value of >7.8 µg/mL, besides, compound 4 displayed significant antioxidant activity (84.05%) at the concentration of 500 µg/mL.

Stereo and regioselective synthesis, structural elucidation and antibacterial activity of novel spiropyrrolidine embedded with two units of oxindoles

An excellent yield of spiropyrrolidine grafted with two units of oxindole moieties was obtained employing a one-pot three component 1,3-dipolar cycloaddition cascade reaction strategy. In this cascade reaction, the key intermediate 1,3-dipole compound is formed in situ from isatin and l-phenylalanine, which was further reacted with highly functionalized 3-benzylideneindolin-2-one to form structurally complex heterocycles viz. 5-benzyl-2-spiro[2.3′]-3-spiro[3.3′′]-4-chlorophenylpyrrolidine with broad substrate diversity. The formation of a stereoselective spirocycloadduct with four contiguous stereogenic centers, two of which are spirocarbons. The structure of compound 4 was assigned through one-, two-dimensional NMR and mass spectroscopic analyses. The structure of the spiroadduct was undoubtable determined through single crystal analysis. The supramolecular structure aspects of 4 was found to depend on the O…H, N…H, C…O, and H…H interactions. Their percentages are 49.4, 24.4, 1.0 and 11.1%, respectively based on Hirshfeld analysis. The DFT/B3LYP optimized structure is found to agree well with the experimental one. Compound 4 has significant polarity where the calculated dipole moment is 4.2147 Debye. The antibacterial efficacy of the compound 4 showed more sensitive results against Shigella sp. (19.00±0.30 mm) followed by Acinetobacter sp. (17.00±0.15 mm), besides, the compound 4 showed notable antioxidant properties.

Environmentally-friendly synthesis, structural determination and antimicrobial activity of new class of spiropyrrolidine embedded with indenoquinoxaline and chromanone heterocyclic units

A regio- and stereoselective synthesis of hitherto unexplored novel class of dispiropyrrolidine embedded with indenoquinoxaline and chromanone hybrid heterocycle has been achieved employing an eco-friendly ionic liquid assisted multicomponent 1,3-dipolar cycloaddition cascade protocol. The dipolarophile, 3-(4-methoxybenzylidene)chroman-4-one reacts with non-stabilized 1,3-dipole component derived from indenoquinoxalinone and l-phenylalanine through decarboxylative cascade reaction pathway affording (2′S,4′S)-5′-benzyl-4′-(4-methoxyphenyl)dispiro[chromane-3,3′-pyrrolidine-2′,11′'-indeno[1,2-b]quinoxalin]-4-one (6) as the final product. The structure of 6 was confirmed through NMR and mass spectroscopic analyses. Further, stereochemistry of the spirocompound was undoubtedly determined through single crystal XRD analysis. In the crystal structure, the O…H and N…H interactions are the most common contacts and also have great importance in molecular packing. In addition, the C…H contacts are also important in the studied crystal structure. DFT and NBO calculations were performed on this system in order to discuss its electronic and reactivity parameters. The calculated dipole moment value is 2.9238 Debye indicating a polar compound. Compound 6 was assayed for antimicrobial efficacy and found to have potential activity against eight tested microbial pathogens. Among them, E. coli ML_KSUB22 and C. albicans ML_KSUF05 were found to be highly susceptible than the other pathogens.

Inside Back Cover

This cover picture shows a ligand‐controlled, palladium‐catalyzed migration reaction of [60]fullerene with allyloxy‐tethered aryl iodides. Using 1,2‐bis(diphenylphosphino)benzene (DPPBz) as a ligand, the chemoselectivity is switched to synthesize [60]fullerene‐fused allylbenzofurans instead of previous spirocyclic derivatives through a sequential C—O bond cleavage/allyl‐migration/intermolecular cycloaddition cascade process. Such transformation provides a unique and efficient route to rare [60]fullerene‐fused benzofurans. More details are discussed in the article by Liu et al. on page 1733—1739.image

Synthesis of [60]Fullerene‐Fused Allylbenzofurans via Palladium‐Catalyzed Migration Reaction†

Comprehensive SummaryChemical functionalization of fullerenes has been an important topic in fullerene chemistry. Herein, an unprecedented Pd‐catalyzed migration reaction of [60]fullerene with allyloxy‐tethered aryl iodides is present for the preparation of novel [60]fullerene‐fused allylbenzofurans. The use of 1,2‐bis(diphenylphosphino)benzene (DPPBz) as a ligand is crucial for the success of the transformation. The reaction shows high chemo‐ and regioselectivity, and is flexible with regard to allyl‐migration site, providing a new and efficient approach to rare [60]fullerene‐fused benzofurans. Control experiments disclose that the reaction most probably undergoes a sequential C—O bond cleavage/allyl‐migration/intermolecular cycloaddition cascade process.

Design, synthesis, structural characterization and computational studies of new class of dispirooxindolopyrrolidine embedded chromanone hybrid heterocycles

Synthesis of a new class of heterocyclic hybrid embedding spirooxindole, pyrrolidine and chromanone structural moieties was achieved in excellent yield using an intermolecular [3+2]-cycloaddition cascade reaction protocol. The synthesized spiropyrrolidines were unambiguously determined by spectroscopic analysis and the stereo- and regiochemistry of the cycloadducts were undoubtably assigned by single crystal X-ray diffraction analysis. Structural features of the compounds were examined by using X-ray crystallographic studies. The molecular packing was defined by Hirshfeld surface analysis. Furthermore, the structure and reactivity of the synthesized dispiropyrrolidines were investigated by density functional theory (DFT) calculations.

Rh(I)-Catalyzed [5 + 2]/[2 + 2] Cycloaddition Cascade to Access a Cyclobutane-Fused [4–5–6–7] Tetracyclic Framework

A Rh(I)-catalyzed [5 + 2]/[2 + 2] cycloaddition cascade has been developed to afford a complex and highly strained [4-5-6-7] tetracyclic framework in good yields and excellent diastereoselectivities. During this transformation, three rings, three C-C bonds, and four contiguous stereocenters were formed efficiently. Mechanistically, the rare sterically congested multisubstituted cyclobutanes are constructed readily through Michael addition and a Mannich reaction cascade.

Rapid access to molecular complexity from bioderived 5-HMF derivativesviacascade cycloadditions

Dimeric 5-HMF derivatives have been used in a cascade 2 × [4 + 2] cycloaddition reaction with alkynes leading to a drastic increase in molecular complexity. The reaction proceeds under thermodynamic control, diastereoselectively and regioselectively.

Gram-Scale Enantioselective Synthesis of (+)-Lucidumone.

The first enantioselective total synthesis of (+)-lucidumone is described through a 13-step synthetic pathway (longest linear sequence). The key steps involve the formation of a bridged bicyclic lactone by an enantioselective inverse-electron-demand Diels-Alder cycloaddition, C-O bond formation to assemble two fragments, and a one-pot retro-[4 + 2]/[4 + 2] cycloaddition cascade. The synthesis is scalable, and more than one gram of natural product was synthesized in one batch.

Palladium-Catalyzed Intramolecular Heck Dearomative Alkenylation of Indoles with N-Tosylhydrazones.

An elegant Pd-catalyzed intramolecular Heck dearomative alkenylation of aryl iodides with functionalized N-tosylhydrazones proceeded through a sequential dearomative carbopalladation, migratory insertion, and β-hydride elimination in the presence of Pd(CF3COO)2 (10 mol %), PPh3 (30 mol %), and Cs2CO3 (2.0 equiv) in 1,4-dioxane (2.0 mL) at 120 °C for 14 h under an argon atmosphere. This cascade cycloaddition protocol provided a reliable and versatile approach to a sequence of structurally diverse indolines in moderate to good yields with good functional group compatibility. In addition, the synthetic robustness of the methodology is highlighted by a scaled-up experiment and derivatization of products via epoxidation and reduction reactions.

Stereoselective Addition of Alkynes to Ketenimines: Copper/Amine Catalyzed Sulfonyl Azide–Alkyne Cycloaddition Reactions for the Synthesis of (Z)-1,3-Enynes

Herein, we report a copper/amine catalyzed stereoselective addition of alkynes to ketenimine intermediates generated in situ from the sulfonyl azide-alkyne cycloaddition cascade for the stereoselective synthesis of (Z)-1,3-enynes. Significantly, for the first-time, enamine intermediates generated in the copper-catalyzed sulfonyl azide-alkyne cycloaddition reactions have been successfully trapped and isolated as the products. Density functional theory computations have also been performed and found to be consistent with the observed experimental stereoselectivity.

Pd-Catalyzed Asymmetric Three-Component Allenol Carbopalladation and Allylic Cycloaddition Cascade: A Route to Functionalized Tetrahydrofurans

The first Pd-catalyzed asymmetric three-component reaction of 2,3-allenol, aryl iodides, and 2-arylmethylenemolononitriles has been developed via an allenol carbopalladation and an allylic cycloaddition cascade. This process allows rapid access to substituted tetrahydrofurans bearing diverse functional groups in good yields with high diastereoselectivities and excellent enantioselectivities. The concise total synthesis of a lignan, (-)-2-episesaminone, has been achieved by the elaboration of a functionalized tetrahydrofuran obtained from this reaction.

Mechanism of the Stereoselective Catalysis of Diels-Alderase PyrE3 Involved in Pyrroindomycin Biosynthesis.

The biosynthesis of pyrroindomycins A and B features a complexity-building [4 + 2] cycloaddition cascade, which generates the spirotetramate core under the catalytic effects of monofunctional Diels-Alderases PyrE3 and PyrI4. We recently showed that the main functions of PyrI4 include acid catalysis and induced-fit/conformational selection. We now present quantum mechanical and molecular dynamics studies implicating a different mode of action by PyrE3, which prearranges an anionic polyene substrate into a high-energy reactive conformation at which an inverse-electron-demand Diels-Alder reaction can occur with a low barrier. Stereoselection is realized by strong binding interactions at the endo stereochemical relationship and a local steric constraint on the endo-1,3-diene unit. These findings, illustrating distinct mechanisms for PyrE3 and PyrI4, highlight how nature has evolved multiple ways to catalyze Diels-Alder reactions.