Cyclization Pathway Research Articles

Gold(I)‐Catalyzed Conia‐ene Cyclization of Internal ϵ‐Acetylenic β‐Ketoesters under High Pressure.

AbstractThe influence of pressure on the gold(I)‐catalyzed Conia‐ene cyclization of ϵ‐acetylenic‐β‐ketoesters bearing an internal alkyne moiety was investigated for the first time. The reaction catalyzed by commercially available PPh3AuNTf2 complex, which is sluggish at ambient pressure owing to steric reasons, proceeds smoothly under high‐pressure conditions (6 kbar). Mechanistic aspects of the reaction proceeding via 5‐exo‐dig and 6‐endo‐dig cyclization pathways were also studied employing DFT methods. Differences in the reactivity of substrates containing terminal and internal alkynes is discussed.

Pd/C: An efficient and reusable catalyst for the synthesis of flavones via carbonylation of aryl halides

This work describes an efficient and mild approach for the synthesis of flavones via catalytic carbonylation of aryl halides with 2‐hydroxyacetophenone using the commercial Pd/C as an efficient, heterogeneous and recyclable catalyst. Under balloon pressure of CO, 0.6 mol% Pd/C is sufficient for moderate yields of flavones for the carbonylation of aryl iodides under phosphine‐free conditions and aryl bromides in the presence of phosphine ligand. The catalyst is easily separable and shows significant recyclability. Moreover, the reaction mechanism was discussed, and a possible mechanism that contains two different cyclisation pathways was proposed.

Gold Catalysis for Heterocyclic Chemistry: A Representative Case Study on Pyrone Natural Products.

2-Pyrones and 4-pyrones are common structural motifs in bioactive natural products. However, traditional methods for their synthesis, which try to emulate the biosynthetic pathway of cyclization of a 1,3,5-tricarbonyl precursor, are often harsh and, therefore, not particularly suitable for applications to polyfunctionalized and/or sensitive target compounds. π-Acid catalysis, in contrast, has proved to be better for a systematic exploration of the pyrone estate. To this end, alkynes are used as stable ketone surrogates, which can be activated under exceedingly mild conditions due to the pronounced carbophilicity of [LAu]+ fragments (L=two electron donor ligand); attack of a tethered ester carbonyl group onto the transient alkyne-gold complex then forges the pyrone ring in a fully regiocontrolled manner.

Molecular Basis of Gut Microbiome-Associated Colorectal Cancer: ASynthetic Perspective.

A significant challenge toward studies of the human microbiota involves establishing causal links between bacterial metabolites and human health and disease states. Certain strains of commensal Escherichia coli harbor the 54-kb clb gene cluster which codes for small molecules named precolibactins and colibactins. Several studies suggest colibactins are genotoxins and support a role for clb metabolites in colorectal cancer formation. Significant advances toward elucidating the structures and biosynthesis of the precolibactins and colibactins have been made using genetic approaches, but their full structures remain unknown. In this Perspective we describe recent synthetic efforts that have leveraged biosynthetic advances and shed light on the mechanism of action of clb metabolites. These studies indicate that deletion of the colibactin peptidase ClbP, a modification introduced to promote accumulation of precolibactins, leads to the production of non-genotoxic pyridone-based isolates derived from the diversion of linear biosynthetic intermediates toward alternative cyclization pathways. Furthermore, these studies suggest the active genotoxins (colibactins) are unsaturated imines that are potent DNA damaging agents, thereby confirming an earlier mechanism of action hypothesis. Although these imines have very recently been detected in bacterial extracts, they have to date confounded isolation. As the power of "meta-omics" approaches to natural products discovery further advance, we anticipate that chemical synthetic and biosynthetic studies will become increasingly interdependent.

Cycloaromatization of Enediyne Compounds under the Action of Bromide Ions: Diradical/Zwitterionic/Anionic Pathways

AbstractCycloaromatization reactions of enediynes are renowned for their widespread applications and interesting reactivity characteristics. In the presence of a lithium halide and a weak acid, the cycloaromatization of cyclodeca‐1,5‐diyn‐3‐ene can be redirected away from the usual formation of a phenyl diradical towards a zwitterionic pathway. We extended this zwitterionic reaction system to other enediyne compounds and found that it offered good applicability to all‐carbon systems. However, in the case of maleimide‐based enediynes, only diradical (phenyl‐substituted) or anionic (butyl‐substituted) cyclization pathways were observed. Notably, the nucleophilic cyclization of maleimide‐based enediynes that was initiated by bromide ions exhibited a previously unreported C2−C7 cyclization pattern.

Convergent Synthesis of α-Branched Amines by Transition-Metal-Catalyzed C-H Bond Additions to Imines.

α-Branched amines are ubiquitous in drugs and natural products, and consequently, synthetic methods that provide convergent and efficient entry to these structures are of considerable value. Transition-metal-catalyzed C-H bond additions to imines have the potential to be highly practical and atom-economic approaches for the synthesis of a diverse and complex array of α-branched amine products. These strategies typically employ readily available starting inputs, display high functional group compatibility, and often avoid the production of stoichiometric waste byproducts. A number of C-H functionalization methods have also been developed that incorporate cascade cyclization pathways to give amine-substituted carbocycles, and in many cases, proceed with the formation of multiple stereogenic centers. Advances in the area of asymmetric C-H bond additions to imines have also been achieved through the use of chiral imine N-substituents as well as by enantioselective catalysis.

Mechanistic Study of SmI2/H2O and SmI2/Amine/H2O-Promoted Chemoselective Reduction of Aromatic Amides (Primary, Secondary, Tertiary) to Alcohols via Aminoketyl Radicals.

Samarium(II) iodide-water and samarium(II) iodide-water-amine complexes have been recognized as valuable reagents for the selective generation of aminoketyl radicals from amides and derivatives. The resulting aminoketyl radicals can undergo reduction or reductive cyclization pathways, providing a powerful method for (i) direct synthesis of alcohols from amides by the challenging N-C bond scission and (ii) synthesis of nitrogen-containing heterocycles via polarity reversal of the amide bond. This report describes mechanistic investigation into samarium(II) iodide-water and samarium(II) iodide-water-amine-mediated generation of benzylic aminoketyl radicals from aromatic primary, secondary, and tertiary amides (benzamides). The mechanistic experiments suggest that the rate and selectivity of the reduction is closely dependent on the water concentration and the type of amide undergoing the reduction. The data also suggest that benzylic aminoketyl radicals generated in the reduction of benzamides are significantly more dependent on the electronic effects of α-substitution than the corresponding aminoketyl radicals generated by single-electron transfer to unactivated aliphatic amides; however, little variation in terms of steric influence of N-substituents is observed. These observations will have implications for the design of reductive processes involving Sm(II)-mediated reduction of amides and reductive umpolung cyclizations via aminoketyl radicals as a key step.

Fabrication of Core-Shell-Structured Organic-Inorganic Hybrid Nanocatalyst for the Expedient Synthesis of Polysubstituted Oxazoles via Tandem Oxidative Cyclization Pathway.

The quest for designing efficient heterogeneous catalytic systems for tandem oxidative cyclization reactions has provided a great impetus to research efforts, as it enables the step-economic construction of complex heterocyclic molecules as well as confers the benefits of a facile catalytic recovery. In the present study, we disclose a new core–shell-structured organic–inorganic hybrid copper nanocatalyst fabricated via the covalent grafting of 2,2′-dipyridyl ketone ligand on amine-functionalized silica-encapsulated magnetite nanoparticles, followed by its metallation with cupric acetate for the tandem oxidative cyclization of amines and β-ketoesters, leading to the production of biologically active polysubstituted oxazole moieties. This programmed catalytic protocol proceeds via the formation of intermolecular C–C and C–N bonds by single-step synthesis and accommodates a broad combination of reaction coupling partners.

Halogen-Mediated Cascade Cyclization Reaction of Aryldiynes to Indeno[1,2-c]chromene Derivatives.

The halogen-mediated cyclization reaction of aryldiynes to produce halogenated indeno[1,2-c]chromene derivatives is described. Treatment of aryldiynes 1 with one equivalent of iodine gave iodinated indeno[1,2-c]chromenes 3 in good chemical yields. When two equivalents of iodine were employed into the reaction mixture, dimer 9 was obtained as the major products. On the other hand, reaction of two equivalents of CuBr2 with compounds 1 gave the brominated indeno[1,2-c]chromenes 4. The DFT calculation of the iodine-mediated cyclization reactions for molecules containing methoxy, carboxy, amino, and sulfide substituents were carried out in order to understand how the substituent affects the cyclization pathway.

Degradation of Hole Transport Materials via Exciton-Driven Cyclization

Organic light-emitting diode (OLED) displays have been an active and intense area of research for well over a decade and have now reached commercial success for displays from cell phones to large format televisions. A more thorough understanding of the many different potential degradation modes which cause OLED device failure will be necessary to develop the next generation of OLED materials, improve device lifetime, and to ultimately improve the cost vs performance ratio. Each of the different organic layers in an OLED device can be susceptible to unique decomposition pathways, however stability toward excitons is critical for emissive layer (EML) materials as well as any layer near the recombination zone. This study will specifically focus on degradation modes within the hole transport layer (HTL) with the goal being to identify the general decomposition paths occurring in an operating device and use this information to design new derivatives which can block these pathways. Through post-mortem analyses of several aged OLED devices, an apparently common intramolecular cyclization pathway has been identified that was not previously reported for arylamine-containing HTL materials and that operates parallel to but faster than the previously described fragmentation pathways.

Pathways of cycloaddition of carbodiimides to N-alkenylidenetriflamides: A theoretical study

Possible cyclization pathways for the reaction of (1E,2E)-N-(but-2-en-1-ylidene)triflamide with N,N'-dimethylcarbodiimide have been investigated by DFT and MP2 calculations. The [4+2] route is shown to be thermodynamically unfavorable due to a small content of the reactive s-cis conformer of the azadiene. The [2CN+2CN] route has ΔGº>0 and therefore is thermodynamically forbidden. The only allowed route is the [2CN+2CC] cycloaddition, which has ΔGº < 0 and leads to 2-methylimino-3-(2-trifliminomethyl)-1,4-dimethylazetidine with further isomerization to 3-(triflamidomethylidene)-2-methylimino-1,4-dimethylazetidine in full agreement with the experimental results. These results indicate the necessity of considering free energy changes rather than only enthalpy changes for accurate prediction of the course of cyclization reactions.

Accessing pyrrolones and pyridinones: controlling 5-exo and 6-endo ring closures in heterocyclic alkynylamides

Competitive 5-exo and 6-endo anionic intramolecular cyclization reactions in heterocyclic alkynylamides were explored via experimental and computational analysis. The 5-exo-dig cyclization pathway is usually disfavoured in heterocyclic systems, and 6-endo products are often both the kinetic and thermodynamic products. However, we’ve found that it is possible to shift selectivity toward the 5-exo-dig pyrrolone products away from the less strained pyridinone products that are produced via the 6-endo-dig cyclization. Parameters such as identity of heteroatom, heteroatom positioning within the heterocycle, and functionality on the alkyne were investigated and, in many cases, were found to strongly influence product ratios. A series of computational studies was performed to provide further insight into the 5-exo-dig and 6-endo-dig pathways in these heterocyclic systems. Theoretical predictions were found to reproduce experimental results, highlighting the predictive capabilities of the computations in determining preferred products.

Alternate Cyclization Cascade Initiated by Substrate Isomer in Multiproduct Terpene Synthase from Medicago truncatula

Promiscuity of terpene synthases results in the enormous diversity of terpenes found in nature. Multiproduct sesquiterpene synthase MtTPS5 isolated from Medicago truncatula generates 27 optically pure products from its natural substrate (2E,6E)-farnesyl diphosphate (FDP). In order to study the promiscuity of MtTPS5, (2Z,6E)-FDP, an analogue of presumptive reaction intermediates from natural reaction cascade, was utilized as a substrate. This stereoisomer induced a novel cyclization pathway leading to sesquiterpenes based on humulane, amorphene, and himachalane skeletons. Interestingly, none of these products matched those observed on incubation of MtTPS5 with natural (2E,6E)-FDP. Further determination of the absolute configuration of each product helped rebuild the stereochemical route of the reaction cascade. Interestingly, the presence of only one enantiomer of each product was observed, indicating the highly stereospecific nature of the enzymatic reaction. Substrate promiscuity of terpene synthases provides organism access to novel chemical bouquets of high optical purity by utilizing existing enzymes. The presence of this mechanism was indicated by the presence of these alternate products in natural herbivore-induced volatiles of M. truncatula.

Novel pyrrolobenzodiazepine and pyrroloquinazoline scaffolds synthesized by a simple and highly selective Ugi/cyclization sequence.

Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) and other benzo-fused N-heterocycles constitute privileged structures found in numerous bioactive compounds. Thus, developing simple and selective syntheses to furnish these derivatives from easily accessible starting materials is an important and challenging goal. In this work, novel pyrrolobenzodiazepine and pyrroloquinazoline derivatives have been synthesized following a common two step synthetic strategy. This strategy involves a one-pot Ugi/cyclization sequence followed by a reduction with spontaneous thermocontrolled cyclization. The control of the temperature in this second step allows fully selective access to either pyrrolo[2,1-c][1,4]benzodiazepine-3-ones 6 or pyrrolo[2,1-b]quinazolines 7. Density functional theory (DFT) calculations have been carried out to rationalize this reactivity, identifying the kinetic and thermodynamic reaction products and offering insights into the cyclization pathways. These synthetic methodologies show the versatility of the Ugi reaction as a tool in the synthesis of heterocyclic compounds with a pseudopeptidic skeleton.

Highly efficient and versatile synthesis of α,α-difluoro-γ-lactams via aminodifluoroalkylation of alkenes

An efficient approach to α,α-difluoro-γ-lactam derivatives was developed using a copper/amine catalyst via a tandem radical cyclization pathway.

Unified Approach to (Thio)chromenones via One-Pot Friedel-Crafts Acylation/Cyclization: Distinctive Mechanistic Pathways of β-Chlorovinyl Ketones.

A facile synthetic method to chromenones and thiochromenones has been developed using a one-pot Friedel-Crafts acylation of alkynes with suitably substituted benzoyl chlorides. This unified approach to (thio)chromenones is readily applicable to aryl- and alkylalkynes where the stereochemically well-defined β-chlorovinyl ketone intermediates undergo distinctively different cyclization pathways. The ready availability of both starting materials, alkynes and benzoyl chlorides, coupled with the experimental simplicity makes the current synthetic method to (thio)chromenones fast, efficient, and practical.

Copper-Catalyzed Radical-Promoted Aminocyclization of Acrylamides with N-Fluorobenzenesulfonimide.

A facile copper-catalyzed radical aminoarylation of acrylamide with N-fluorobenzenesulfonimide (NFSI) is described. In the presence of copper acetate and 1,10-phenanthroline, a range of isoquinoline-1,3-diones can be constructed in moderate to good yields using NFSI as the amination reagent. Mechanistic studies demonstrated the reaction went through a sequential radical addition and cyclization pathway, which was supported by DFT calculations.

ChemInform Abstract: One‐Pot Cascade Reactions Leading to Pyrido[2′,1′:2,3]imidazo[4,5‐c][1,2,3]triazolo[1,5‐a]quinolines under Bimetallic Relay Catalysis with Air as the Oxidant.

AbstractThe title compounds are prepared from 2‐(o‐bromophenyl)imidazo[1,2‐a]pyridines, terminal alkynes, and sodium azide via a click reaction/substitution/oxidative cyclization pathway.

Regioselective synthesis of functionalized [1,6]-naphthyridines by KF/basic alumina as a recyclable catalyst and a brief study of their photophysical properties

ABSTRACTAn efficient, one-pot, solvent-free, regioselective synthesis of functionalized [1,6]-naphthyridines was explored by a heterogeneous catalyst via a three-component multicomponent reaction (MCR). KF/basic alumina–catalyzed double heteroannulation of aryl alkyl ketones, malononitrile, and alkyl amines generates the compounds with high appendage diversity combinatorially via Knoevenagel condensation followed by Michael addition and cyclization pathway. Short reaction time, high yield, simple reaction technique, and recoverability and reusability of the catalyst without compromising the yield and purity of the compounds are the salient features of this methodology. Additionally, these compounds exhibit promising photophysical properties.

Noncovalent Dimerization after Enediyne Cyclization on Au(111)

We investigate the thermally induced cyclization of 1,2-bis(2-phenylethynyl)benzene on Au(111) using scanning tunneling microscopy and computer simulations. Cyclization of sterically hindered enediynes is known to proceed via two competing mechanisms in solution: a classic C(1)-C(6) (Bergman) or a C(1)-C(5) cyclization pathway. On Au(111), we find that the C(1)-C(5) cyclization is suppressed and that the C(1)-C(6) cyclization yields a highly strained bicyclic olefin whose surface chemistry was hitherto unknown. The C(1)-C(6) product self-assembles into discrete noncovalently bound dimers on the surface. The reaction mechanism and driving forces behind noncovalent association are discussed in light of density functional theory calculations.