Heterocyclic Intermediates Research Articles

Understanding the Molecular Mechanism of Thermal and LA-Catalysed Diels-Alder Reactions between Cyclopentadiene and Isopropyl 3-Nitroprop-2-Enate.

The molecular mechanism of the Diels-Alder reaction with the participation of cyclopentadiene and isopropyl 3-nitroprop-2-enate was examined based on wb97xd/6-311+G(d) (PCM) quantum chemical calculations. It was found that the type of mechanism for the conversion of addends depends significantly on the reaction conditions. In less-polar environments, a one-step polar mechanism is realised. In more polar solvents, the formation of "extended"-type zwitterionic intermediates is possible. In contrast, in the presence of an LA-type catalyst, the one-step mechanisms are replaced by respective stepwise mechanisms with zwitterionic or heterocyclic intermediates.

Stereoselective synthesis of trans-benzo[d]oxazolyl)phenyl substituted β-lactams decorated with C-3 thio/seleno rich motifs: synthetic intermediates for diverse heterocycles

Herein, we reported an effectual protocol for the stereoselective synthesis of novel C-3 thio/seleno substituted ortho-, meta- and para-(2-benzo[d]oxazolyl)phenyl-β-lactams 7a-i. The reaction was performed by utilizing different S/Se-alkyl/aryl substituted acids 6a-d and isomeric ortho-, meta- and para-(2-benzo[d]oxazolyl)phenyl Schiff’s bases 3a-c and afforded exclusive formation of trans-β-lactams. The trans configuration was assigned with respect to coupling constant values of C3-H and C4-H (J = 1.4 to 2.6; C3-H and C4-H). The structure elucidation of all the thio/seleno anchored β-lactams 7a-i was performed using various spectroscopic techniques viz. FT-IR, NMR (1H, 13C, and 13C DEPT–135), 2D-NMR (1H–1H COSY and 1H–13C HSQC), elemental analysis (CHN), and mass spectrometry (ESI-MS). Further, divergent substrate scope accompanied by plausible mechanistic investigation have been also described. Stereoselectivity, good functional group tolerance and excellent yield along with wider synthetic utility bestows advantages to the present protocol.

Synthesis of Complex Ureas with Brominated Heterocyclic Intermediates

AbstractHerein we present an efficient method to synthesize novel complex ureas from simple ureas, with potential pharmacological activity. First, 3‐methylindole ketones are protected via a two‐phase N‐tosylation reaction catalyzed by NBu4HSO4 as the PTC. Second, an NBS bromination of the terminal methyl group is performed with high selectivity and very good yields. Finally, complex novel and promising ureas are synthesized in 46 %–92 % yields using non‐base‐catalyzed substitution reactions with simple monosubstituted and disubstituted ureas. All products were easily purified through column chromatography and/or crystallization. The overall procedure produces very high yields and selectivity for bromination.

Flow synthesis of n-substituted 5-benzylidinethiazolidine-2,4-dione

Process intensification based on micro reactor technology allows safe manner and a new pathway to run organic synthesis due to its intrinsic characteristics, and can reduce time-to-market of new drugs. The main objective of this work was to study the batch and flow reaction of five n-substituted 5-benzylidenethiazolidine-2,4-dione heterocyclic intermediates present in the synthesis of glitazone class drugs, in capillary micro reactor. Batch process was conducted with ethanol as solvent at the boiling point and pyrrolidine as promoting base of the reaction. Higher yields were obtained in shorter reaction times in temperatures above solvent boiling point. Also, we evaluated that 3.8 micro reactors in parallel would be necessary to reach the same mean molar flow rate of a 60 mL batch reactor. Kinetic and thermodynamic study indicated that the reaction followed the second-order model and allowed estimating its main thermodynamic parameters. The continuous flow micro reactor proved to be an efficient alternative to the batch process in scaling up the production of Active Pharmaceutical Ingredient intermediates (APIs).

Intramolecular Diels–Alder Reactions of Oxazoles, Imidazoles, and Thiazoles

AbstractThe development of the intramolecular Diels–Alder cycloaddition­ of azole heterocycles, i.e. oxazoles (IMDAO), imidazoles (IMDAI), and thiazoles (IMDAT), has had a significant impact on the efficient preparation of heterocyclic intermediates and natural products. In particular, highly efficient and versatile IMDAO reactions have been utilized as a key step in several synthetic schemes to provide alkaloids and terpenoid target molecules. More limited studies have been performed on IMDAI and IMDAT cycloadditions. Some drawbacks, such as the occasionally­ challenging preparation of IMDA precursors, are also highlighted in this review. Perspectives are provided on how IMDAI and IMDAT­ transformations can be further expanded for target-directed syntheses.1 Introduction2 Oxazoles2.1 IMDAO Approaches to Furanosesquiterpenes and Furanosteroids2.1.1 Syntheses of Highly Oxygenated Sesquiterpenes2.1.2 Syntheses of (±)-Gnididione and (±)-Isognididione2.1.3 Synthesis of (±)-Stemoamide2.1.4 Synthesis of (±)-Paniculide A2.1.5 Syntheses of (+)- and (–)-Norsecurinine2.1.6 Synthesis of Evodone2.1.7 Syntheses of (±)-Ligularone and (±)-Petasalbine2.1.8 Syntheses of Imerubrine, Isoimerubrine, and Grandirubrine2.1.9 Syntheses of Furanosteroids2.1.10 Syntheses of Substituted Indolines and Tetrahydroquinolines2.2 IMDAO Approaches to Pyridines: the Kondrat’eva Reaction2.2.1 Syntheses of Suaveoline and Norsuaveoline2.2.2 Synthesis of Eupolauramine2.2.3 Syntheses of (–)-Plectrodorine and (+)-Oxerine2.2.4 Synthesis of Amphimedine2.2.5 Synthetic Approach to the Western Segment of Haplophytine2.2.6 Synthesis of Marinoquinoline A2.2.6.1 IMDAO Approach to Marinoquinoline A2.2.6.2 Scope of Allenyl IMDAO Cycloaddition2.3 Lewis Acid Catalysis in IMDAO Reactions2.3.1 Effects of Europium Catalysts on IMDAO Reactions2.3.2 Effects of Copper Catalysts on IMDAO Reactions3 Imidazoles4 Thiazoles4.1 Syntheses of Menthane and Eremophilane4.2 Further Comments on the Intramolecular Cycloadditions of Thiocarbonyl Ylides5 Conclusions and Outlook

Riley Oxidation of Heterocyclic Intermediates on Paths to Hydroporphyrins-A Review.

Riley oxidation of advanced heterocyclic intermediates (dihydrodipyrrins and tetrahydrodipyrrins) is pivotal in routes to synthetic hydroporphyrins including chlorins, bacteriochlorins, and model (bacterio)chlorophylls. Such macrocycles find wide use in studies ranging from energy sciences to photomedicine. The key transformation (–CH3 → –CHO) is often inefficient, however, thereby crimping the synthesis of hydroporphyrins. The first part of the review summarizes 12 representative conditions for Riley oxidation across diverse (non-hydrodipyrrin) substrates. An interlude summarizes the proposed mechanisms and provides context concerning the nature of various selenium species other than SeO2. The second part of the review comprehensively reports the conditions and results upon Riley oxidation of 45 1-methyltetrahydrodipyrrins and 1-methyldihydrodipyrrins. A comparison of the results provides insights into the tolerable structural features for Riley oxidation of hydrodipyrrins. In general, Riley oxidation of dihydrodipyrrins has a broad scope toward substituents, but proceeds in only modest yield. Too few tetrahydrodipyrrins have been examined to draw conclusions concerning scope. New reaction conditions or approaches will be required to achieve high yields for this critical transformation in the synthesis of hydroporphyrins.

A green and facile synthesis of an industrially important quaternary heterocyclic intermediates for baricitinib

BackgroundBaricitinib, with a 2-(1-(ethylsulfonyl)azetidin-3-yl)acetonitrile moiety at N-2 position of the pyrazol skeleton, is an oral and selective reversible inhibitor of the JAK1 and JAK2 and displays potent anti-inflammatory activity. Several research-scale synthetic methods have been reported for the preparation of key quaternary heterocyclic intermediates of baricitinib. However, they were all associated with several drawbacks, such as the expensive materials, usage of pollutional reagents, and poor yields.ResultsIn this manuscript, we established a green and cost-effective synthesis of 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate for further scale-up production of baricitinib. This synthetic method employs commercially available and low-cost starting material benzylamine and an industry-oriented reaction of green oxidation reaction in microchannel reactor to yield important quaternary heterocyclic intermediates.ConclusionGenerally, this procedure is reasonable, green and suitable for industrial production.

Heterogeneous Nucleation of Trichloroethylene Ozonation Products in the Formation of New Fine Particles

Free radicals in atmosphere have played an important role in the atmospheric chemistry. The chloro-Criegee free radicals are produced easily in the decomposition of primary ozonide (POZ) of the trichloroethylene, and can react with O2, NO, NO2, SO2 and H2O subsequently. Then the inorganic salts, polar organic nitrogen and organic sulfur compounds, oxygen-containing heterocyclic intermediates and polyhydroxy compounds can be obtained. The heterogeneous nucleation of oxidation intermediates in the formation of fine particles is investigated using molecular dynamics simulation. The detailed nucleation processes are reported. According to molecular dynamics simulation, the nucleation with a diameter of 2 nm is formed in the Organic Compounds-(NH4)2SO4-H2O system. The spontaneous nucleation is an important process in the formation of fine particles in atmosphere. The model study gives a good example from volatile organic compounds to new fine particles.

Single‐Step Modular Synthesis of Unsaturated Morpholine N‐Oxides and Their Cycloaddition Reactions

A single-flask procedure for the generation of α-keto-N-alkenylnitrones through a Chan-Lam coupling and subsequent spontaneous 6π electrocyclization of these intermediates for the synthesis of 2H-1,4-oxazine N-oxides has been developed for a variety of α-ketooximes and alkenylboronic acids. This transformation provides a new approach to C-substituted unsaturated morpholine derivatives that are poised to undergo further functionalization for the preparation of a diverse array of novel heterocyclic structures. The scope of the new method for the synthesis of 2H-1,4-oxazine N-oxides is discussed, in addition to initial studies describing the cycloaddition reactivity of these new heterocyclic intermediates.

Single‐Step Modular Synthesis of Unsaturated Morpholine N‐Oxides and Their Cycloaddition Reactions

AbstractA single‐flask procedure for the generation of α‐keto‐N‐alkenylnitrones through a Chan–Lam coupling and subsequent spontaneous 6π electrocyclization of these intermediates for the synthesis of 2H‐1,4‐oxazine N‐oxides has been developed for a variety of α‐ketooximes and alkenylboronic acids. This transformation provides a new approach to C‐substituted unsaturated morpholine derivatives that are poised to undergo further functionalization for the preparation of a diverse array of novel heterocyclic structures. The scope of the new method for the synthesis of 2H‐1,4‐oxazine N‐oxides is discussed, in addition to initial studies describing the cycloaddition reactivity of these new heterocyclic intermediates.

Development of Gold‐catalyzed [4+1] and [2+2+1]/[4+2] Annulations between Propiolate Derivatives and Isoxazoles

AbstractTwo new gold‐catalyzed annulations of isoxazoles with propiolates have been developed. Most isoxazoles follow an initial O attack on the alkyne to afford a [4+1] annulation product. This process results in a remarkable alkyne cleavage of initial propiolates. Unsubstituted isoxazoles proceed through an N attack step to yield formal [2+2+1]/[4+2] annulation products. These two annulation products arise initially from two seven‐membered heterocyclic intermediates, which then lead to products.

Development of Gold-catalyzed [4+1] and [2+2+1]/[4+2] Annulations between Propiolate Derivatives and Isoxazoles.

Two new gold-catalyzed annulations of isoxazoles with propiolates have been developed. Most isoxazoles follow an initial O attack on the alkyne to afford a [4+1] annulation product. This process results in a remarkable alkyne cleavage of initial propiolates. Unsubstituted isoxazoles proceed through an N attack step to yield formal [2+2+1]/[4+2] annulation products. These two annulation products arise initially from two seven-membered heterocyclic intermediates, which then lead to products.

Antioxidant Properties of Heterocyclic Intermediates of the Maillard Reaction and Structurally Related Compounds.

It is well established that a wide range of reductones is formed in the course of the Maillard reaction and that these substances contribute to the oxidative stability of food. The aim of this study was to analyze 12 important heterocyclic intermediates with and without reductone structure as well as structurally related substances under equal conditions to compare their antioxidant properties in detail. For this purpose, five methods were selected including photometrical methods such as the trolox equivalent antioxidant capacity assay and an electron paramagnetic resonance spectroscopic method. Reductones with furan-3-one structure and 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one were reducing in all assays, whereas isomaltol and maltol did not react in assays based on the reduction of metal ions because of their complexing abilities. The introduction of protecting groups to the free hydroxyl functions of selected reductones could nearly eliminate their reducing abilities. In addition, the oxidation products of the different reductive heterocycles were compared after treatment with iodine. Mainly short-chained organic acids such as lactic, glycolic, and glyceric acid are formed as result of the degradation, which indicates 1,3-dicarbonyl cleavage reactions of corresponding tricarbonyl compounds as intermediates of the oxidation.

ChemInform Abstract: Expanding the Strained Alkyne Toolbox: Generation and Utility of Oxygen‐Containing Strained Alkynes.

We report synthetic methodology that permits access to two oxacyclic strained intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these intermediates affords an array of heterocyclic scaffolds by the formation of one or more new C–C or C–heteroatom bonds. Experimentally determined regioselectivities were consistent with predictions made using the distortion/interaction model and were also found to be greater compared to selectivities seen in the case of trapping experiments of the corresponding N-containing intermediates. These studies demonstrate the synthetic versatility of oxacyclic arynes and alkynes for the synthesis of functionalized heterocycles, while further expanding the scope of the distortion/interaction model. Moreover, these efforts underscore the value of harnessing strained heterocyclic intermediates as a unique approach to building polycyclic heteroatom-containing frameworks.

Expanding the Strained Alkyne Toolbox: Generation and Utility of Oxygen-Containing Strained Alkynes.

We report synthetic methodology that permits access to two oxacyclic strained intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these intermediates affords an array of heterocyclic scaffolds by the formation of one or more new C-C or C-heteroatom bonds. Experimentally determined regioselectivities were consistent with predictions made using the distortion/interaction model and were also found to be greater compared to selectivities seen in the case of trapping experiments of the corresponding N-containing intermediates. These studies demonstrate the synthetic versatility of oxacyclic arynes and alkynes for the synthesis of functionalized heterocycles, while further expanding the scope of the distortion/interaction model. Moreover, these efforts underscore the value of harnessing strained heterocyclic intermediates as a unique approach to building polycyclic heteroatom-containing frameworks.

Synthesis of 2‐Phosphaindolizine and [1,3]Azaphospholo[1,5‐a]quin­oline

AbstractThe reaction of (chloromethyl)dichlorophosphine (1) with 2‐[(trimethylsilyl)methyl]pyridine (6) and 2‐[(trimethylsilyl)methyl]quinoline (12) in THF affords unsubstituted parent 2‐phosphaindolizine (5) and [1,3]azaphospholo[1,5‐a]quinoline (7). Multinuclear low‐temperature NMR spectroscopy was used to investigate the reaction mechanism; a cascade of substitution and cyclization steps involving transient picolylphosphines and phosphorus heterocycles was identified. The molecular and crystal structures of two heterocyclic intermediates and of 7 were determined by single‐crystal X‐ray diffraction. Moreover, all intermediates and products were characterized by multinuclear 1H, 13C and 31P NMR spectroscopy.

Novel Heterocyclic Intermediates for Cross-Coupling Reactions

Novel Heterocyclic Intermediates for Cross-Coupling Reactions

Novel Heterocyclic Intermediates for Cross-coupling Reactions

Novel Heterocyclic Intermediates for Cross-coupling Reactions

Novel Heterocyclic Intermediates for Cross-coupling Reactions

Novel Heterocyclic Intermediates for Cross-coupling Reactions

Novel Heterocyclic Intermediates for Cross-coupling Reactions

Novel Heterocyclic Intermediates for Cross-coupling Reactions