Cycloaddition Of Azomethine Ylides Research Articles

Synthesis of Complex Tetracyclic Fused Scaffolds Enabled by (3 + 2) Cycloaddition.

We describe the single-step formation of complex tetracyclic fused scaffolds enabled by (3 + 2) cycloaddition of azomethine ylides. Various indoles, N-protecting groups, and amino acids are well tolerated. The products are obtained in a catalyst-free manner with moderate to excellent yield and high diastereoselectivity. Representing a new scaffold that is not yet found in nature, the construction of pyrrolidine-fused cyclohepta-, azepino-, or oxepinoindoles could be found valuable in the synthesis of new pseudo-natural products.

Modular Access to Tetrasubstituted N−H Pyrroles by Catalytic 1,3‐Dipolar Cycloaddition of Azomethine Ylides and α,β‐Ynones

AbstractThe development of efficient synthetic strategies for the preparation of tetrasubstituted N−H pyrrole derivatives, especially in an environmentally benign fashion is important yet challenging. Herein, we report a copper(II)‐catalyzed tandem reaction involving 1,3‐dipolar cycloaddition of α,β‐ynones and glycine iminoesters, followed by copper(II)‐promoted oxidative (air) dehydrogenative aromatization, allowing de novo access to tetrasubstituted N−H pyrroles in up to 81 % yield under green reaction conditions. A possible reaction pathway is tentatively proposed. Finally, fully substituted pyrroles are available by N‐alkylation, and a preliminary phase‐transfer catalytic asymmetric N‐alkylation was also studied to give an axially chiral pyrrole.

1,3‐Dipolar Cycloaddition of Polycyclic Aromatic Azomethine Ylides and Alkynylbenziodoxoles for Synthesis of Functional Dibenzoullazines†

Comprehensive SummaryA new family of dibenzoullazine derivatives was synthesized through 1,3‐dipolar cycloaddition of polycyclic aromatic azomethine ylides with alkynylbenziodoxoles followed by oxidation. The benziodoxole moiety in the resulting products was used as a versatile linchpin for the synthesis of structurally diverse functional dibenzoullazines that are difficult to access by other synthetic methods.

Synthesis and Properties of Azahomocorannulenyl Cations and Radicals

AbstractCycloheptatrienyl (tropyl) molecules are representative non‐alternant hydrocarbons that offer interesting chemistry because of their unique structures and properties. However, there have been a limited number of polycyclic aromatic tropyl cations and radicals reported in the literature. Herein, we report the synthesis of a series of azahomocorannulene derivatives, where the key reactions are a 1,3‐dipolar cycloaddition of polycyclic aromatic azomethine ylides with dibenzotropone and a subsequent palladium‐catalyzed cyclization. X‐ray diffraction analysis revealed that the obtained azahomocorannulenyl cation and radical adopt planar structures and exhibit unique packing structures. Their electronic and optical properties were investigated experimentally and theoretically to reveal their aromatic character.

Synthesis and Properties of Azahomocorannulenyl Cations and Radicals.

Cycloheptatrienyl (tropyl) molecules are representative non-alternant hydrocarbons that offer interesting chemistry because of their unique structures and properties. However, there have been a limited number of polycyclic aromatic tropyl cations and radicals reported in the literature. Herein, we report the synthesis of a series of azahomocorannulene derivatives, where the key reactions are a 1,3-dipolar cycloaddition of polycyclic aromatic azomethine ylides with dibenzotropone and a subsequent palladium-catalyzed cyclization. X-ray diffraction analysis revealed that the obtained azahomocorannulenyl cation and radical adopt planar structures and exhibit unique packing structures. Their electronic and optical properties were investigated experimentally and theoretically to reveal their aromatic character.

Synthesis of polysubstituted fused pyrrolidines via [2 + 2]/[2 + 3] cycloaddition of azomethine ylides

A general approach via [2 + 2]/[2 + 3] cycloaddition is elaborated for the preparation of densely substituted 3-azabicyclo[3.2.0]heptanes in good yields with excellent diastereoselectivities.

Well-defined Cu(I) complexes based on [N,P]-pyrrole ligands catalyzed a highly endoselective 1,3-dipolar cycloaddition.

We herein report the synthesis and catalytic application of a new family of dinuclear Cu(I) complexes based on [N,P]-pyrrole ligands. The Cu(I) complexes (4a-d) were obtained in good yields and their catalytic properties were evaluated in the1,3-dipolar cycloaddition of azomethine ylides and electron-deficient alkenes. The air-stable complexes 4a-d exhibited high endo-diasteroselectivity to obtain substituted pyrrolidines, and the catalytic system showed excellent reactivity and wide substitution tolerance.

Intramolecular hydrogen bond activation for kinetic resolution of furanone derivatives by an organocatalyzed [3 + 2] asymmetric cycloaddition

A formal highly enantioselective organocatalyzed [3 + 2] cycloaddition of furanones and azomethine ylides paired to a highly efficient kinetic resolution is presented.

Diastereoselective 1,3-dipolar cycloaddition of cyclopropenes to acenaphthenequinone azomethine ylides

A diastereoselective 1,3-dipolar cycloaddition of azomethine ylides generated from acenaphthylene-1,2-dione (or aceantrylene-1,2-dione) and amino acids with 1,2-diphenylcyclopropenes has been developed. As a result, cyclopropa[a]pyrrolizidines and 3-azabicyclo[3.1.0]hexanes spiro-fused to acenaphthylen-1(2H)-one and aceanthrylen-1(2H)-one fragments were obtained for the first time. Based on DFT calculations at M11/cc-pVDZ level of theory, a concerted mechanism of cycloaddition was proposed to explain the observed diastereoselectivity. The cytotoxic activity of newly synthesized compounds against human erythroleukemia (K562) and human cervical carcinoma (HeLa) cell lines was evaluated in vitro by MTS-assay.

Visible‐Light‐Mediated Cycloaddition of Azobenzenes and Nonstabilized Azomethine Ylides to Access 1,2,4‐Triazolidines

AbstractA visible‐light‐mediated cycloaddition of azobenzenes and nonstabilized azomethine ylides has been developed to access 1,2,4‐triazolidines. With readily available organic dye rose bengal as a photocatalyst and alkyl tertiary amines as precursors for azomethine ylides, the reaction proceeded smoothly under visible light irradiation at room temperature, affording various 4‐alkyl‐1,2‐diaryl‐1,2,4‐triazolidines with yields of up to 96%. Preliminarily mechanistic studies suggest that the nonstabilized azomethine ylides are formed in situ through photoredox catalysis.

Semisynthesis of Novel Dispiro-pyrrolizidino/thiopyrrolizidino-oxindolo/indanedione Natural Product Hybrids of Parthenin Followed by Their Cytotoxicity Evaluation.

Natural products possess unique and broader intricacies in the chemical space and have been essential for drug discovery. The crucial factor for drug discovery success is not the size of the library but rather its structural diversity. Although reports on the number of new structurally diverse natural products (NPs) have declined recently, researchers follow the next logical step: synthesizing natural product hybrids and their analogues using the most potent tool, diversity-oriented synthesis (DOS). Here, we use weed Parthenium hysterophorus as a source of parthenin for synthesis of novel dispiro-pyrrolizidino/thiopyrrolizidino-oxindolo/indanedione natural product hybrids of parthenin via chemo-, regio-, and stereoselective azomethine ylide cycloaddition. All synthesized compounds were characterized through a detailed analysis of one-dimensional (1D) and two-dimensional (2D) NMR and HRMS data, and the stereochemistries of the compounds were confirmed by X-ray diffraction analysis. All compounds were evaluated for their cytotoxicity against four cell lines (HCT-116, A549, Mia-Paca-2, and MCF-7), and compound 6 inhibited the HCT-116 cells with an IC50 of 5.0 ± 0.08 μM.

Copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with β-trifluoromethyl-substituted alkenyl heteroarenes

Copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with β-trifluoromethyl-substituted alkenyl heteroarenes

Reaction-Environment-Dependent Photoaddition Reactions of N-Phenyl Amino Acid Esters Possessing a Silyl Group with Fullerene C60: Selective Formation of Aminomethyl-1,2-dihydrofullerenes vs Fulleropyrrolidines.

The current study investigates SET-promoted photoaddition reactions of the silyl-group-containing N-phenylglycinates and N-phenylalaninates, N-((trimethylsilyl)methyl)-N-phenyl-substituted glycinates and alaninates, respectively, with fullerene C60 to explore how the types of amino acid esters (AAEs) and molecular oxygen affect the photoaddition reaction efficiencies and chemoselectivity of in situ formed radical cations of AAEs. The results showed that under deoxygenated (N2-purged) conditions, photoreactions of N-phenylglycinates with C60 produced aminomethyl-1,2-dihydrofullerenes through the addition of α-amino radicals arising by sequential SET and desilylation processes from initially formed secondary anilines to C60. In oxygenated conditions, photoreactions of N-phenylglycinates with C60, albeit less efficient, took place to form fulleropyrrolidines through a pathway involving 1,3-dipolar cycloaddition of azomethine ylides to C60 assisted by in situ formed 1O2. The same types of photoproducts were observed with N-phenylalaninates, though the reactions were less efficient. The use of methylene blue (MB) as a photosensitizer in the photoreactions under oxygenated conditions was especially effective in enhancing the efficiency of fulleropyrrolidine formation. These results demonstrate that photoaddition reactions of silyl-tether-containing N-phenyl AAEs with C60 can be governed by the reaction conditions and the presence or absence of a photosensitizer employed.

Copper(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of 1,3-enynes and azomethine ylides

Herein, we report a copper(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides and 1,3-enynes, which provides a series of chiral poly-substituted pyrrolidines in high regio-, diastereo-, and enantioselectivities. Both 4-aryl-1,3-enynes and 4-silyl-1,3-enynes serve as suitable dipolarophiles while 4-alkyl-1,3-enynes are inert. Moreover, the method is successfully applied in the construction of both tetrasubstituted stereogenic carbon centers and chiral spiro pyrrolidines. The DFT calculations are also conducted, which imply a concerted mechanism rather than a stepwise mechanism. Finally, various transformations started from the pyrrolidine bearing a triethylsilylethynyl group and centered on the alkyne group are achieved, which compensates for the inertness of 4-alkyl-1,3-enynes in the present reaction.

A 1,3-dipolar cycloaddition of azomethine ylides to imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine oxindolylidene derivatives in the synthesis of novel spirooxindole derivatives

A 1,3-dipolar cycloaddition of azomethine ylides to imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine oxindolylidene derivatives in the synthesis of novel spirooxindole derivatives

1,3-dipolar cycloaddition of stable azomethine ylide based on ninhydrin and l-proline to phosphorylated acetylenes

The reaction of 1,3-dipolar cycloaddition of a stable azomethine ylide formed from ninhydrin and L-proline to activated acetylenic phosphonates was studied. It was found that the reactions proceed under mild conditions with high regioselectivity with the formation of cycloadducts with a spiro[inden-2,3’-pyrrolysine]-1,3-dione backbone.

Spiroindole-containing compounds bearing phosphonate group of potential Mpro-SARS-CoV-2 inhibitory properties

Microwave-assisted reaction of 3,5-bis((E)-ylidene)-1-phosphonate-4-piperidones 3a‒g with azomethine ylide (produced through interaction of isatins 4 and sarcosine 5) cycloaddition afforded the corresponding (dispiro[indoline-3,2′-pyrrolidine-3′,3″-piperidin]-1″-yl)phosphonates 6a‒l in excellent yields (80–95%). Structure of the synthesized agents was evidenced by single crystal X-ray studies of 6d, 6i and 6l. Some of the synthesized agents revealed promising anti-SARS-CoV-2 properties in the viral infected Vero-E6 cell technique with noticeable selectivity indices. Compounds 6g and 6b are the most promising agents synthesized (R = 4-BrC6H4, Ph; R' = H, Cl, respectively) with considerable selectivity index values. Mpro-SARS-CoV-2 inhibitory properties supported the anti-SARS-CoV-2 observations of the potent analogs synthesized. Molecular docking studies (PDB ID: 7C8U) are consistent with the Mpro inhibitory properties. The presumed mode of action was supported by both experimentally investigated Mpro-SARS-CoV-2 inhibitory properties and explained by docking observations.

Catalytic Enantioselective [3+2] Cycloaddition of N-Metalated Azomethine Ylides.

Asymmetric [3+2] cycloaddition reactions are fascinating and powerful methods for the synthesis of enantioenriched pyrrolidines up to four stereocentres. Pyrrolidines are important compounds for both biology and organocatalytic applications. This review summarizes the most recent advances in the enantioselective synthesis of pyrrolidines by [3+2] cycloadditions of azomethine ylides using metal catalysis. It has been organized by the type of metal catalysis used and further arranged by the complexity nature of dipolarophile. The presentation of each reaction type highlights their advantages and limitations.

Dipolarophile-Controlled Regioselective 1,3-Dipolar Cycloaddition: A Switchable Divergent Access to Functionalized N-Fused Pyrrolidinyl Spirooxindoles

N-fused pyrrolidinyl spirooxindole belongs to a class of privileged heterocyclic scaffolds and is prevalent in natural alkaloids and synthetic pharmaceutical molecules. To realize the switchable synthesis of divergent N-fused pyrrolidinyl spirooxindoles for further biological activity evaluation via a substrate-controlled strategy, a chemically sustainable, catalysis-free, and dipolarophile-controlled three-component 1,3-dipolar cycloaddition of isatin-derived azomethine ylides with diverse dipolarophiles is described in this work. A total of 40 functionalized N-fused pyrrolidinyl spirooxindoles were synthesized in 76-95% yields with excellent diastereoselectivities (up to >99:1 dr). The scaffolds of these products can be well-controlled by employing different 1,4-enedione derivatives as dipolarophiles in EtOH at room temperature. This study provides an efficient strategy to afford a spectrum of natural-like and potentially bioactive N-fused pyrrolidinyl spirooxindoles.

Deterministic organic functionalization of monolayer graphene via high resolution surface engineering

Spatially selective functionalization of monolayer graphene is achieved by combining electron beam irradiation patterning with 1,3-dipolar cycloaddition of azomethine ylide and shown to be reversible via focused laser irradiation-induced desorption.