Azomethine Imines Research Articles

Solvent‐ and Temperature‐Switched Chemoselectivity: Controlled Synthesis of Diverse Pyrazolo[5,1‐a]isoquinolines

AbstractDivergent synthesis of two types of functionalized pyrazolo[5,1‐a]isoquinolines was established via a one‐pot two‐step protocol involving a tunable dehydrogenation process and deacylative oxidation accompanied by elimination of the HNO2 pathway. Key attributes of the procedure included the initial formation of C,N‐cyclic‐N’‐acyl azomethine imines and subsequent switchable chemoseletivity that either led to aroyl‐ and nitro‐substituted pyrazolo[5,1‐a]isoquinolines or proceeded via deacylative oxidation and elimination of HNO2 pathway to afford the aromatized pyrazolo[5,1‐a]isoquinolines. The present approach features the use of readily available amines and aldehydes as raw materials, switchable chemoselectivity, wide functional group tolerance such as nitro, halide, aryl, aroyl and sulfonyl group, and easy separation and purification. A combination of control experiments and density functional theory (DFT) calculations provided important insights into the possible mechanism.

Quinazoline-Derived Azomethine Imines as Substrates To Access Polycyclic Compounds.

Quinazolines are essential structural constituents of many pharmaceuticals and bioactive natural products. Quinazoline-derived azomethine imines (QAIs) have emerged recently as valuable building blocks for the synthesis of various quinazoline derivatives. This Synopsis presents recent advances in (formal) cycloaddition reactions of QAIs for the synthesis of quinazoline-fused 5- to 8-membered heterocycles as well as three-dimensional compounds.

Palladium‐Catalyzed Umpolung Allylation of Isatin‐Derived Azomethine Imines with Vinylcyclopropanes

AbstractA Pd‐catalyzed umpolung allylation of isatin‐derived azomethine imines with vinyl cyclopropanes was disclosed. This protocol provides an efficient and atom‐economic approach to access an array of structurally interesting allylic aminooxindole derivatives in good yields and linear‐selectivities (up to 95 % yield). Further product derivatization and asymmetric catalytic studies proved the practicability of reaction and potential application.

Visible light-driven decarboxylative alkylation of azomethine imines with carboxylic acids

The alkylation of cyclic five-membered azomethine imines with carboxylic acids proceeds under irradiation with 400 nm light using a dual catalytic system consisting of 9-arylacridine and tetrabutylammonium decatungstate. Azomethine imines containing aromatic, heterocyclic and aliphatic groups are suitable for the process providing pyrazolidin-3-ones in 42–98% yields.

Synthesis of Angular Polycyclic Aromatic Molecules Via Pd‐Catalyzed Decarboxylative Cycloaddition of 2‐Alkylidenetrimethylene Carbonates with Quinazoline‐Derived Azomethine Imines

AbstractA formal [4+3] cycloaddition of 2‐alkylidenetrimethylene carbonates with quinazoline‐derived azomethine imines is described. Under Pd catalysis, the reaction works efficiently under room temperature to afford angular quinazoline‐fused seven‐membered N,N,O‐heterocycles. A variety of cyclic carbonates and azomethine imines were well tolerated under mild reaction conditions. This work demonstrates the synthetic utility of decarboxylative cycloadditions of 2‐alkylidenetrimethylene carbonates for the synthesis of angular polycyclic aromatic molecules.

1,3-Hydro-di/monofluoromethylation of N,N'-Cyclic Azomethine Imines with HCF2SO2Na/H2CFSO2Na via Photocatalytic Radical Addition.

The radical 1,3-hydro-di/monofluoromethylation of N,N'-cyclic azomethine imines with HCF2SO2Na/H2CFSO2Na via photoredox catalysis is described. This reaction exhibits broad functional group compatibility, providing the desired products in good yields. However, CF3SO2Na failed to produce the trifluoromethyl product. DFT calculations revealed that the transition state activation energy for radical trifluoromethylation was significantly higher and the isotropic charge repulsion makes it difficult for the CF3 radical to transfer electrons.

R‐BINOL‐Chiral Phosphoric Acid Catalyzed Regioselective Synthesis of 7‐Oxo‐Pyrazolo[1,2‐a]Pyrazoles via [3+2] Cycloaddition Reaction of Morita Baylis Hillman Adducts with N, N’‐Cyclic Azomethine Imines

AbstractWe report an efficient [3+2] cycloaddition protocol for the synthesis of pyrazolo[1,2‐a]pyrazolones from Morita‐Baylis‐Hillman adducts and N,N’‐cyclic azomethine imines. The R‐BINOL chiral phosphoric acid was identified as the suitable catalyst for the reported cycloaddition protocol. Almost all MBH adducts regioselectively delivered 7‐oxo‐pyrazolo[1,2‐a]pyrazoles at an efficient yield of 69–91 %. With exception, the MBH adducts derived from acrylonitrile deliver 5‐oxo‐pyrazolo[1,2‐a]pyrazoles comparatively at a higher yield than the 7‐oxo‐pyrazolo[1,2‐a]pyrazoles. The density functional theory (DFT) studies demonstrate that the reaction is thermodynamically more feasible in the presence of R‐BINOL chiral phosphoric acid.

Iridium-catalysed synthesis of C,N,N-cyclic azomethine imines enables entry to unexplored nitrogen-rich 3D chemical space

Three-dimensional nitrogen-rich bridged ring systems are of great interest in drug discovery owing to their distinctive physicochemical and structural properties. However, synthetic approaches towards N–N-bond-containing bridged heterocycles are often inefficient and require tedious synthetic strategies. Here we delineate an iridium-catalysed reductive approach to such architectures from C,N,N-cyclic hydrazide substrates using IrCl(CO)[P(OPh)3]2 and 1,1,3,3-tetramethyldisiloxane (TMDS), which provided efficient access to the unstabilized and highly reactive C,N,N-cyclic azomethine imine dipoles. These species were stable and isolable in their dimeric form, but, upon dissociation in solution, reacted with a broad range of dipolarophiles in [3 + 2] cycloaddition reactions with high yields and good diastereoselectivities, enabling the direct synthesis of nitrogen-rich sp3-hybridized pyrazoline polycyclic ring systems. Density functional theory calculations were performed to elucidate the origin of the diastereoselectivity of the cycloaddition reaction, and principal moment of inertia (PMI) analysis was conducted to enable visualization of the topological information of the dipolar cycloadducts.

Polycyclic Pyrazolidines by Tandem Diazomalonate Dipolar Cycloadditions and CpRu-Catalyzed Carbene Additions.

Thanks to the ability of diazo derivatives to react either as 1,3-dipoles and as carbenes after dinitrogen extrusion, combinations of oxa or aza benzonorbornadienes and diazomalonates afford polycyclic pyrazolidines via a three-step sequence of (i) a highly diastereoselective [3+2]-cycloaddition, (ii) a CpRu-catalyzed carbene addition, and (iii) a second dipolar cycloaddition. Of importance, step (II) represents a unique access to novel bench-stable N,N-cyclic azomethine imines, which behave as effective 1,3-dipoles in combination with electron-poor dipolarophiles. Each step proceeds efficiently and the 3-step process can be performed in one-pot to yield a polycyclic pyrazolidine in excellent overall yield (90 %).

Synthesis of 2-(Trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline via Cycloaddition of C,N-Cyclic Azomethine Imine with CF3CN.

A [3 + 2] cycloaddition of C,N-cyclic azomethine imine with in situ-generated CF3CN for the construction of 2-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline is reported. Remarkably, this process shows a broad substrate scope with excellent functional group tolerance, which is scalable and enables a practical route to a library of 2-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline derivatives in moderate to good yields.

Sequential Dearomatization/Rearrangement of Quinazoline-Derived Azomethine Imines for the Synthesis of Nitrogen-Rich Three-Dimensional Cage-Like Molecules.

A sequential dearomatization/rearrangement reaction between quinazoline-derived azomethine imines and crotonate sulfonium salts has been developed to provide a series of three-dimensional cage-like molecules. The reaction involves two dearomatizations, two cyclizations, and two C-C bond and three C-N bond formations in one step. The new transformation has a broad substrate scope, does not require any added reagents, and proceeds under room temperature in a short time. A mechanistic rationale for the sequential dearomatization/rearrangement is also presented. Furthermore, the synthetic compounds are evaluated for their glucose control effect. Compounds 3aa and 3aj were found to be hyperglycemic, which might be lead compounds for treating hypoglycemia.

DFT study on the Stereoselectivity of Asymmetric Synthesis of C, N‐Cyclic Azomethine Imines with Allyl Alkyl Ketones

AbstractBased on the density functional theory, the stereoselectivity of the asymmetric synthesis of tetrahydroisoquinolinopyrazole derivatives by the cycloaddition reaction of C, N‐cyclic azomethine imines with allyl alkyl ketones which was catalyzed using a chiral primary amine is studied theoretically. The results demonstrate that the four chiral transition states (TS‐1R2R, TS‐1R2S, TS‐1S2R and TS‐1S2S) are formed by the reaction of dienamine intermediate with C, N‐cyclic azomethine imine, and the reaction barrier of TS‐1R2S is in the lowest level (ΔG=6.98 kcal/mol). The consequence reveal that the 1R2S configuration product is formed by TS‐1R2S transition state. Non‐covalent interaction and electron density topology analysis show that the stereoselectivity of the chiral product is determined through van der Waals forces and hydrogen bond interaction of the transition state molecules.

Asymmetric (3+2) Cycloaddition Employing β‐Fluoroalkylated α,β‐Unsaturated 2‐Acyl Imidazole Catalyzed by a Chiral‐at‐Metal Rhodium Complex

AbstractAn asymmetric 1,3‐dipolar cycloaddition of β‐fluoroalkylated α,β‐unsaturated 2‐acyl imidazole with nitrones or N,N’‐cyclic azomethine imines to construct chiral α‐fluoroalkylated γ‐amino alcohols or chiral α‐fluoroalkylated 1,3‐diamino compounds has catalyzed by chiral‐at‐metal rhodium complexes is reported. The corresponding products with three contiguous tertiary stereocenters were obtained in 62%–98% yields with stereoselectivities up to >20:1 dr and 99% ee. Remarkably, as low as 0.06 mol% of chiral‐at‐metal rhodium complex can promote a gram‐scale reaction with nitrones or N,N’‐cyclic azomethine imines.

Novel green protocols for the synthesis of tetrahydropyrazolopyrazolones

1,3 – Dipolar cycloadditions represent an important method for obtaining novel bicyclic heterocycles which is of great importance due to their medicinal application and diverse bioactivity such as antitumor, antibacterial and etc. The most suitable way for the synthesis of bicyclic heterocycles such as pyrazolopyrazolones is based on dipolar cycloaddition of azomethine imines and enones. This reaction was explored to develop more sustainable protocols by using less toxic chemicals and different sources of energy. Herein novel green protocols for the synthesis of tetrahydropyrazolopyrazolones are presented. These green protocols avoid hazardous AlCl3 and CH2Cl2 which were used until now, and implement green sources of irradiation. In this research, acetic acid has proved itself as a great catalyst for this type of reaction. Different azomethine imines and enones were submitted to the reaction in the presence of acetic acid for 12 h. A series of ten tetrahydropyrazolopyrazolones is successfully synthesized. The impact of ultrasound and microwave irradiation was also investigated. Three novel protocols for the synthesis of tetrahydropyrazolopyrazolones were established. The best results with significant improvement in yield, reaction time, and cleaner reaction conditions were observed when acetic acid and microwave irradiation were used. These novel protocols for the synthesis of pyrazolopyrazolones based on the usage of acetic acid as a catalyst and ultrasound and microwave irradiation represent a noteworthy advancement in research of sustainable methods for obtaining heterocycles.

Inside Back Cover: Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation (Angew. Chem. Int. Ed. 5/2024)

Inside Back Cover: Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation (Angew. Chem. Int. Ed. 5/2024)

Innenrücktitelbild: Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation (Angew. Chem. 5/2024)

Innenrücktitelbild: Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation (Angew. Chem. 5/2024)

Chiral phosphoric acid-catalyzed enantioselective [5+1] cycloaddition reaction of C,N-cyclic azomethine imines with isocyanides.

The first catalytic enantioselective [5+1] cycloaddition reactions of C,N-cyclic azomethine imines with isocyanides are reported herein. The method displays a broad substrate scope and atom-economy. A series of chiral tetrahydroisoquinoline containing indole skeletons were obtained in up to 90% yield with 95% ee under mild reaction conditions. A possible catalytic model was also proposed.

Visible-light-induced [1,3]-brook rearrangements of α-ketoacylsilanes and their subsequent trapping in a tandem annulation with 1,3,5-triazinanes and azomethine imines

An unusual visible-light-induced [1,3]-brook rearrangement of α-ketoacylsilanes for cascade cyclization with 1,3,5-triazinanes and C,N-cyclic azomethine imines has been realized to assemble various β-lactams and pyrazolidinone scaffolds.

Pd-catalyzed sequential intramolecular annulation/intermolecular [3+2] cycloaddition of 5-allenyloxazolidine-2,4-diones with dipoles: synthesis of spiroheterocycles.

Pd-catalyzed sequential intramolecular annulation/intermolecular [3+2] cycloaddition of 5-allenyloxazolidine-2,4-diones with dipoles was achieved. Under palladium catalysis, various 5-allenyloxazolidine-2,4-diones reacted with 1,3-dipoles such as nitrile N-oxides, azomethine imines or nitrilimines to give a series of functionalized spiroheterocycles in high yields. The scale-up reaction and further derivation of products were successful. A plausible mechanism was also proposed based on the control experiments.

4-Vinylbenzodioxinones as a new type of precursor for palladium-catalyzed (4+3) cycloaddition of azomethine imines.

In this paper, benzo-fused cyclic carbonates were designed and synthesized as a new type of precursor of π-allylpalladium zwitterionic intermediates, and were applied in Pd-catalyzed diastereo- and enantioselective (4+3) cycloaddition with C,N-cyclic azomethine imines, leading to various biologically important 1,3,4-benzoxadiazepine derivatives in 43-99% yields with 6 : 1 to >20 : 1 dr and up to 95% ee.