Aromatization Step Research Articles

One-pot synthesis of benzofluorene fused aromatic hydrocarbons

A new and efficient synthetic approach for the one-pot construction of benzofluorene fused aromatic hydrocarbons was developed via a transient-directing group strategy. The palladium-catalyzed cascade reaction proceeded via consecutive arylation, cyclization and aromatization steps. Moderate to good yields along with broad functional group tolerance were achieved under mild reaction conditions.

Photoredox catalytic cascade radical addition/aromatization of methylene-2-oxazolines: Mild access to C(sp3)-difluoro-oxazole derivatives

Difluoroalkylated oxazoles were prepared from methylene-2-oxazolines (MOs) and difluoroalkylating reagents via a photoredox strategy. This reaction includes tandem radical addition and subsequent aromatization steps, resulting in 19 difluorinated oxazole derivatives with diverse functionalities and excellent reaction selectivity in the presence of multiple reactivity pathways.

Lignin-Biosynthetic Study: Reactivity of Quinone Methides in the Diastereopreferential Formation of p-Hydroxyphenyl- and Guaiacyl-Type β- O-4 Structures.

p-Quinone methides are involved in lignin biosynthesis as transient intermediates, and the aromatization step has a great impact on the chemical structure of the resulting lignin. A series of quinone methides (QMs) were synthesized and allowed to react with water in pH 3-7 buffers at 25 °C to mimic the formation of p-hydroxyphenyl- and guaiacyl-type (H- and G-type, respectively) β- O-4 structures in gymnosperm-plant cell walls. Water addition occurred in 3-methoxy-substituted QMs (G-type QMs) with half-lives of 1.4-15 min. In contrast, nonsubstituted QMs (H-type QMs) were very labile; they were aromatized to β- O-4 products with half-lives of only 10-40 s. The rapid aromatization in H-type QMs may provide an advantage over G-type species for efficiently driving the lignin-polymerization cycle, which possibly contributes to the development of highly lignified compression wood. In the water-addition reaction, the threo isomers of the β- O-4 products were stereopreferentially formed more than the erythro isomers from both G- and H-type QMs ( erythro/ threo ratios of 24:76 and 50:50, respectively). The proportion of erythro isomers was higher at lower-pH conditions. This pH-dependent trend agrees with findings from a previous study on 3,5-dimethoxy-substituted (syringyl-type, S-type) QMs; thus, this pH-dependent trend is common in H-, G-, and S-type lignin-related QMs. Higher threo-selectivity was obtained by changing the β-etherified aromatic rings from G- to H-type. A similar but weaker effect was also observed by changing the QM moiety from G- to H-type.

Oxidant-free, three-component synthesis of 7-amino-6H-benzo[c]chromen-6-ones under green conditions.

An oxidant-free three-component synthesis of biologically significant 7-amino-6H-benzo[c]chromen-6-ones was established involving a Sc(OTf)3 catalyzed three-component reaction between primary amines, β-ketoesters and 2-hydroxychalcones under green conditions. In this strategy, both the B and C rings of 6H-benzo[c]chromen-6-ones were constructed simultaneously starting from acyclic precursors by generating four new bonds including two C–C, one C–N and one C–O in a single synthetic operation. The mechanism of this sequential cascade process involves the initial formation of a β-enaminone intermediate followed by Michael addition with 2-hydroxychalcone, intramolecular cyclization, dehydration, lactonization and aromatization steps. Unlike the related literature approaches, this reaction delivered the products without the addition of any external oxidants to achieve the key aromatization step.

Formal [4 + 2] benzannulation of 2-alkenyl indoles with aldehydes: a route to structurally diverse carbazoles and bis-carbazoles.

Construction of structurally diverse carbazoles and bis-carbazoles by protecting-group-free formal [4 + 2]-benzannulation of 2-alkenyl indoles and aldehydes is demonstrated. The sequence of four different reactions is executed in one-pot using readily available and cheap bottle reagents as catalysts rendering this method attractive. The incorporation of inexpensive and environmentally benign molecular oxygen as the oxidant into the final aromatization step enables tolerance of several functional groups.

A Dehydrogenase Dual Hydrogen Abstraction Mechanism Promotes Estrogen Biosynthesis: Can We Expand the Functional Annotation of the Aromatase Enzyme?

Cytochrome P450 (CYP450) enzymes are involved in the metabolism of exogenous compounds and in the synthesis of signaling molecules. Among the latter, human aromatase (HA) promotes estrogen biosynthesis, which is a key pharmacological target against breast cancers. After decades of debate, interest in gaining a comprehensive picture of HA catalysis has been renewed by the recent discovery that compound I (Cpd I) is the reactive species of the peculiar aromatization step. Herein, for the first time, a complete atomic-level picture of all controversial steps of estrogen biosynthesis is presented. By performing cumulative quantum-classical molecular dynamics and metadynamics simulations of about 180 ps, it is revealed that the most likely enzymatic path relies on three factors: 1) androstenedione enolization and compound 0 (Cpd 0) formation through a proton network mediated by Asp309; 2) subsequent formation of Cpd I, upon rearrangement of the Asp309 side chain and the establishment of a proton network involving Asp309 and Thr310; and 3) after two hydroxylation reactions, 19,19-gem-diol is converted into estrone by Cpd I, through an uncommon dehydrogenase-like dual hydrogen abstraction mechanism. As a result, HA performs estrogen biosynthesis by merging hydroxylase with dehydrogenase activity, which suggests that the need to perform complex chemical transformations led nature to engineer HA, and possibly other steroidogenic CYP450s, by expanding its range of functions to achieve an optimal catalytic efficiency.

Merging Visible‐Light Photoredox and Lewis Acid Catalysis for the Intramolecular Aza‐Diels–Alder Reaction: Synthesis of Substituted Chromeno[4,3‐b]quinolines and [1,6]Naphthyridines

AbstractSubstituted chromeno[4,3‐b]quinolines and [1,6]naphthyridines were achieved by tandem intramolecular aza‐Diels–Alder reaction using a strategy of combination of visible‐light photoredox and Lewis‐acid‐catalysis. This intramolecular aza‐Diels–Alder cycloaddition took place between the in situ generated benzylidene anilines derived from arylamines and salicylaldehyde or 2‐aminoaryl aldehydes bearing a tethered alkene partner, followed by oxidative aromatization to give the target products. The study on the oxidative aromatization step revealed that it is much faster than the cyclization step; both the combination of imine and Lewis acid, and the combination of photocatalyst and Lewis acid under aerobic condition with the irradiation of visible light are efficient to achieve the transformation. This method provided a new access to the synthesis of important heterocycles under mild reaction conditions.

Theoretical insight into phosphoric acid-catalyzed asymmetric conjugate addition of indolizines to α,β-unsaturated ketones

Phosphoric acid catalysis is a powerful tool for the construction of new CC bonds because of its unique LUMO-lowering activity. Theoretical calculations were employed to investigate phosphoric acid-catalyzed asymmetric conjugate addition of indolizines to α,β-unsaturated ketones. The calculation results showed that this transformation proceeds via a reaction pathway involving nucleophilic addition, deprotonation–aromatization, and tautomerization. The computational results showed that deprotonation–aromatization is the rate-determining step and the enantioselectivity-determining step. The S-configured product was preferentially generated via a pathway starting from the s-cis conjugated ketone, whereas the s-trans isomer led to a side product with the R configuration. Non-covalent interaction analysis showed that the enantioselectivity is mainly caused by bond-rotation strain in the transition states of the deprotonation–aromatization step.

Efficient and selective conversion of methanol to para-xylene over stable H[Zn,Al]ZSM-5/SiO2 composite catalyst

A highly shape-selective H[Zn,Al]ZSM-5/SiO2 composite catalyst was prepared by direct incorporating Zn species via isomorphous substitution into the zeolite framework and subsequent SiO2 deposition on zeolite surface. Its catalytic performance in methanol to aromatics (MTA) was compared with Zn/HZSM-5/SiO2 prepared by impregnation of Zn species and subsequent SiO2 deposition. The textural properties and acidic properties as well as the subsequent catalytic performances of the resultant catalysts in MTA reaction were obviously influenced by the introduction method of Zn species. H[Zn,Al]ZSM-5/SiO2 prepared by isomorphous substitution contained more inter-crystalline voids, which provided much space to resist deposition of coke and avoided quick blockage of micropore entrances. In contrast, Zn/HZSM-5/SiO2 prepared by impregnation contained sub-nanometric ZnO clusters at the pore entrances, which might restrict large molecule products diffusion and deteriorated the catalyst deactivation. Moreover, the sum of strong and medium acid sites in H[Zn,Al]ZSM-5/SiO2 was more than that in Zn/HZSM-5/SiO2, which meant there were more active sites for cyclization and aromatization steps in MTA reaction in the former. As a result, the lifetime of H[Zn,Al]ZSM-5/SiO2 was almost twice that of Zn/HZSM-5/SiO2. In addition, the enhancement in catalytic activity by Zn introduction and the improvement in para-selectivity in xylene by SiO2 deposition were also studied. Finally, nearly 100% methanol conversion, 95.6% para-selectivity in xylene and 18.2% para-xylene yield were simultaneously obtained over the stable H[Zn,Al]ZSM-5/SiO2 (with 24 h lifetime) in MTA reaction.

Use of a Traceless Activating and Directing Group for the Construction of Trifluoromethylpyrazoles: One-Pot Transformation of Nitroolefins and Trifluorodiazoethane.

We disclose an efficient one-pot transformation of trifluorodiazoethane and higher perfluorinated homologues with various nitroolefins. This method takes advantage of the nitro group as a traceless activating and directing group (TADG) that is released in the aromatization step to produce 4-substituted 3-perfluoroalkyl pyrazoles with complete regioselectivity. The potential of this method is further demonstrated by the synthesis of penthiopyrad.

Use of a Traceless Activating and Directing Group for the Construction of Trifluoromethylpyrazoles: One‐Pot Transformation of Nitroolefins and Trifluorodiazoethane

AbstractWe disclose an efficient one‐pot transformation of trifluorodiazoethane and higher perfluorinated homologues with various nitroolefins. This method takes advantage of the nitro group as a traceless activating and directing group (TADG) that is released in the aromatization step to produce 4‐substituted 3‐perfluoroalkyl pyrazoles with complete regioselectivity. The potential of this method is further demonstrated by the synthesis of penthiopyrad.

Conversion of Glycerol to Hydrocarbon Fuels via Bifunctional Catalysts

Utilization of byproduct glycerol improves biodiesel production in terms of both economics and sustainability. Conversion of glycerol to hydrocarbon (GTH) fuels is among the promising options, which provides additional renewable energy besides biodiesel and contributes further to independence from fossil fuels. In the present work, bifunctional catalysts (Pt/H-ZSM-5 and Pd/H-ZSM-5) were selected, prepared, characterized, and tested for GTH conversion. The addition of noble metals enhances aromatics’ yield, and both catalysts convert GTH fuels effectively. On the basis of the experimental observations and prior literature, it is proposed that GTH conversion follows sequential hydrodeoxygenation and aromatization steps. Under optimized conditions, ∼90% glycerol conversion and ∼60% yield of aromatic hydrocarbons were achieved over the Pd/H-ZSM-5 catalyst.

Application of the ring-closing metathesis to the formation of 2-aryl-1H-pyrrole-3-carboxylates as building blocks for biologically active compounds

Ring-closing metathesis (RCM) is a powerful tool for the preparation of cyclic organic compounds. Yet, one of the major limitations of this method is the difficulty to prepare large quantities of target molecules. Herein we describe a comprehensive study regarding the gram-scale synthesis of 2-aryl-1H-pyrrole-3-carboxylates based on the ring-closing metathesis of the corresponding β-amino esters as a key step. This study includes evaluation of solvent and catalyst as well as reaction kinetics on the RCM. After an aromatization step, this methodology allowed for an efficient generation of variously substituted and unprecedented 2-aryl-1H-pyrrole-3-carboxylates in good yields and cost-effectiveness. The resulting molecules might serve as key building blocks for the generation of CNS-oriented compound libraries.

Enzymatic and Inhibition Mechanism of Human Aromatase (CYP19A1) Enzyme. A Computational Perspective from QM/MM and Classical Molecular Dynamics Simulations.

The enzyme human aromatase (HA), a member of the cytochrome P450 family, catalyses in a highly specific and peculiar manner the conversion of estrogens to androgens. Thus, this enzyme is a relevant target for inhibitor design for the treatment of breast cancer and currently there are several HA inhibitors employed in clinical practice. The HA crystal structure was solved only in 2009 and, since then, several studies have been done to characterize a variety of its structural, dynamical and mechanistic properties. In the last decade, the predictive power and the accuracy of computer simulations techniques, either relying on force field or on "ab initio" description of the system, has enormously increased. This was mainly due to the development of more accurate algorithms, which allow accelerating the time-scale accessible by simulations techniques, and to the increase of computer power. Hence, computer simulations can now accurately paint an atomistic picture to the molecular mechanism of biomolecules providing also an estimate of the kinetic and thermodynamic properties of the enzyme at increasingly quantitative level. In this review, on the basis of selected examples taken from our work, we summarize current active research topics concerning HA enzyme, with a focus on computational studies. In particular, we will illustrate current results and novel hypothesis concerning the final (rate-determining) aromatization step promoted by this enzyme, on how the structural/dynamics/functional properties of HA are modulated in a membrane lipophilic environment, and finally on novel possible (allosteric) inhibition mechanisms which may modulate estrogen production in HA.

Pericyclic Cascade toward Isochromenes: Application to the Synthesis of Alkaloid Benzosimuline

The synthesis of biologically active alkaloid benzosimuline, isolated from the shrub Zanthoxylum simulans, is reported. Key transformation involves an oxa-6π electrocyclic ring-opening/hetero-Diels-Alder pericyclic cascade. Although the last aromatization step proved to be cumbersome, this work unfolds a unique route to access interesting molecules from simple precursors.

Impact of Microwave Assisted Infusion on the Quality and Volatile Composition of Olive Oil Aromatized with Rosemary Leaves

AbstractOlive oil with rosemary leaves by microwave assisted infusion (MAI) as an alternative to conventional infusion (CI) was evaluated. Microwave heating was applied to the mixture in order to accelerate diffusion of the rosemary volatile compounds into the olive oil. The volatile components of the aromatized oils were quantified by HS‐SPME/GC–MS, as well as several quality indexes such as free fatty acids (FFA), peroxide value (PV), specific coefficients of extinction, chlorophyll and carotenoid content, and color assessment. Fatty acid profiles of the oils aromatized by MAI were compared to those produced by CI. Results showed that the infusion time is reduced from 12 h to 10 min when utilizing MAI in place of CI. MAI treatment caused a slight increase in FFA levels, and specific extinction coefficient indices (K232 and K270). PV during MAI remained unchanged for the first 3 min, after which there was an observable increase. All physico‐chemical values were found to be well below the maximum permitted limits. The MAI treatment reduced chlorophyll and carotenoid levels during the final step of aromatization, thus affecting final color. The MAI aromatized oil was characterized by its clear green color (L*, a*, b* parameters). Fatty acid analysis showed that MAI slightly changed the fatty acid composition of the olive oil. This study indicates that MAI appears to be a viable and rapid method to flavor olive oil with rosemary leaves.

ChemInform Abstract: Microwave‐Assisted Organocatalyzed Rearrangement of Propargyl Vinyl Ethers to Salicylaldehyde Derivatives: An Experimental and Theoretical Study.

AbstractAccording to a DFT study on a simplified model, the reaction proceeds via a domino process comprising a [3,3]‐propargyl Claisen rearrangement, a [1,3]—H shift, a [1,7]—H shift (enolization), a 6π electrocyclization, and an aromatization step.

Enantioselective Synthesis of Four Stereoisomers of Sulfinyl Ferrocenyl Quinones with Central, Planar, and Helical Chirality.

Four stereoisomers of sulfinyl ferrocenyl-substituted helicenequinones having central, planar, and helical elements of chirality were stereoselectively formed, in one step, from reaction between enantiopure sulfinyl ferrocenyl dienes and a sulfinyl quinone. Asymmetric synthesis, kinetic resolution, or chemical resolution processes occurred in sequential cycloaddition, sulfoxide elimination, and partial aromatization steps.

Role of Water in the Puzzling Mechanism of the Final Aromatization Step Promoted by the Human Aromatase Enzyme. Insights from QM/MM MD Simulations.

The enzyme human aromatase (HA) catalyzes the conversion of androgens to estrogens via two hydroxylation reactions and a final unique aromatization step. Despite the great interest of HA as a drug target against breast cancer detailed structural and spectroscopic information on this enzyme became available only in the past few years. As such, the enigmatic mechanism of the final aromatization step is still a matter of debate. Here, we investigated the final step of the HA enzymatic cycle via hybrid quantum-classical (QM/MM) metadynamics and blue-moon ensemble simulations. Our results show that the rate-determining step of the aromatization process is the nucleophilic attack of the distal oxygen of a peroxo-ferric species on the formyl carbon of the enol-19-oxo-androstenedione, which occurs with a free energy barrier (ΔF(#)) of ∼ 16.7 ± 1.9 kcal/mol, in good agreement with experimental data. This reaction is followed by a water mediated 1β-hydrogen abstraction (ΔF(#) = 7.9 ± 0.8 kcal/mol) and by the formation of a hydroxo-ferric moiety. This latter may be finally protonated by a hydrogen delivery channel involving Asp309 and Thr310, both residues pointed out as crucial for HA activity. In the absence of the catalytic water in the active site the substrate does not assume a position suitable to undergo the nucleophilic attack. Our data not only reveal a novel possible mechanism for the aromatization process consistent with some of the spectroscopic and kinetic data available in the literature, complementing current knowledge on the mechanism of this enzyme, but also point out a remarkable influence of the level of theory used on the calculated free energy barriers. The structural information obtained in this study may be used for the rational structure-based drug design of HA inhibitors to be employed in breast cancer therapy.

ChemInform Abstract: Iron‐Catalyzed Tandem Carbon—Carbon/Carbon—Oxygen Bond Formation/Aromatization of 2′‐Alkynyl‐biphenyl‐2‐carbinols: A New Approach to the Synthesis of Substituted Phenanthrenes.

An iron-catalyzed efficient synthesis of substituted phenanthrenes through tandem intramolecular C–C/C–O bond formations/aromatization of 2′-alkynyl-biphenyl-2-carbinols is reported. This method provides a novel, highly efficient, and straightforward route to 9,10-substituted phenanthrene in good to excellent yields. The present strategy involves tandem Fe(OTf)3-catalyzed generation of benzylic carbocation, 6-exo-dig cyclization of alkyne, carbon–oxygen bond formation, and aromatization steps in one pot.