Complex Substitution Patterns Research Articles

Electrochemical Synthesis of C(sp3)‐Rich Amines by Aminative Carbofunctionalization of Carbonyl Compounds

AbstractAlkylamines form the backbone of countless nitrogen‐containing small molecules possessing desirable biological properties. Despite advances in amine synthesis through transition metal catalysis and photoredox chemistry, multicomponent reactions that leverage inexpensive materials to transform abundant chemical feedstocks into three‐dimensional α‐substituted alkylamines bearing complex substitution patterns remain scarce. Here, we report the design of a catalyst‐free electroreductive manifold that merges amines, carbonyl compounds and carbon‐based radical acceptors under ambient conditions without rigorous exclusion of air and moisture. Key to this aminative carbofunctionalization process is the chemoselective generation of nucleophilic α‐amino radical intermediates that readily couple with electrophilic partners, providing straightforward access to architecturally intricate alkylamines and drug‐like scaffolds which are inaccessible by conventional means.

Electrochemical Synthesis of C(sp3)-Rich Amines by Aminative Carbofunctionalization of Carbonyl Compounds.

Alkylamines form the backbone of countless nitrogen-containing small molecules possessing desirable biological properties. Despite advances in amine synthesis through transition metal catalysis and photoredox chemistry, multicomponent reactions that leverage inexpensive materials to transform abundant chemical feedstocks into three-dimensional α-substituted alkylamines bearing complex substitution patterns remain scarce. Here, we report the design of a catalyst-free electroreductive manifold that merges amines, carbonyl compounds and carbon-based radical acceptors under ambient conditions without rigorous exclusion of air and moisture. Key to this aminative carbofunctionalization process is the chemoselective generation of nucleophilic α-amino radical intermediates that readily couple with electrophilic partners, providing straightforward access to architecturally intricate alkylamines and drug-like scaffolds which are inaccessible by conventional means.

Pyrroloindoles as Therapeutically Invaluable Agents: A Review on their Diverse Synthetic Methodologies

AbstractIn the realm of medicinal chemistry, heterocyclic compounds play a vital role due to their diverse pharmacological properties, especially, pyrroloindoles standing out as crucial motifs in drug development. Pyrroloindoles, which are formed by combining indole and pyrrole rings, exhibit unique characteristics and serve as integral components in numerous drugs and natural compounds. The synthesis of pyrroloindoles is challenging due to their complex ring structures and diverse substitution patterns. This comprehensive review compiles various synthetic strategies for obtaining pyrroloindole derivatives via metal‐catalyzed reactions; cyclopropanation/ ring opening/ iminium cyclization (CRI reaction); organocatalytic cascade addition‐cyclization; 1,3‐dipolar cycloaddition; Brønsted acid‐catalyzed [3+2] cyclodimerization; ring closure mechanisms; thermally‐induced ring‐opening and cyclization reactions; condensation reactions; and visible‐light photocatalytic asymmetric reactions providing a valuable resource for synthetic organic chemists and researchers interested in the synthesis of pyrroloindoles and their derivatives. These compounds play a pivotal role in drug discovery thus, making this review an indispensable reference.

2,5-[C4+C2] Ringtransformation of Pyrylium Salts with α-Sulfinylacetaldehydes.

A rapid synthesis of chiral sulfoxide-functionalized meta-terphenyl derivatives by a 2,5-[C4+C2] ring transformation reaction of pyrylium salts with in situ generated enantiomerically pure α-sulfinylacetaldehydes is described in this paper. This synthetic method demonstrates, for the first time, the use of α-sulfinylacetaldehydes in a reaction sequence initiated by the nucleophilic attack of pyrylium salts by α-sulfinylcarbanions to generate chiral aromatic systems. The method presented shows a broad applicability starting with various methyl sulfoxides and a number of functionalized pyrylium salts, furnishing meta-terphenyls with complex substitution patterns from readily accessible starting compounds.

Exploring Cuneanes as Potential Benzene Isosteres and Energetic Materials: Scope and Mechanistic Investigations into Regioselective Rearrangements from Cubanes.

Cuneane is a strained hydrocarbon that can be accessed via metal-catalyzed isomerization of cubane. The carbon atoms of cuneane define a polyhedron of the C2v point group with six faces─two triangular, two quadrilateral, and two pentagonal. The rigidity, strain, and unique exit vectors of the cuneane skeleton make it a potential scaffold of interest for the synthesis of functional small molecules and materials. However, the limited previous synthetic efforts toward cuneanes have focused on monosubstituted or redundantly substituted systems such as permethylated, perfluorinated, and bis(hydroxymethylated) cuneanes. Such compounds, particularly rotationally symmetric redundantly substituted cuneanes, have limited potential as building blocks for the synthesis of complex molecules. Reliable, predictable, and selective syntheses of polysubstituted cuneanes bearing more complex substitution patterns would facilitate the study of this ring system in myriad applications. Herein, we report the regioselective, AgI-catalyzed isomerization of asymmetrically 1,4-disubstituted cubanes to cuneanes. In-depth DFT calculations provide a charge-controlled regioselectivity model, and direct dynamics simulations indicate that the nonclassical carbocation invoked is short-lived and dynamic effects augment the charge model.

A GC-MS Protocol for the Identification of Polycyclic Aromatic Alkaloids from Annonaceae.

The Annonaceae are an old family of flowering plants belonging to the order Magnoliales, distributed mainly in tropical regions. Numerous Annonaceae species find ethnobotanical use for curing a broad range of diseases, among them cancer and infections by diverse pathogens. Hence, bioactive natural products from Annonaceae have received considerable interest in drug development. Beyond cytotoxic acetogenins, unique aporphine-derived polycyclic aromatic alkaloids are characteristic constituents of Annonaceae. Among them are unique tri- and tetracyclic aromatic alkaloids like azafluorenones, diazafluoranthenes, azaanthracenes, and azaoxoaporphines. The complex substitution pattern of these alkaloids represents a major challenge in structure elucidation of isolated natural products. Based on a broad spectrum of alkaloids available from our previous work, we present a GC-MS protocol for the identification of over 20 polycyclic aromatic alkaloids from Annonaceae. This collection of data will contribute to the future identification of the metabolite patterns of extracts from Annonaceae as an important source of novel bioactive secondary metabolites.

New York, Abu Dhabi, London or Stay at Home? Using a Cross-Nested Logit Model to Identify Complex Substitution Patterns in Migration

The question of how people revise their decisions about whether to emigrate, and where to, when facing changes in the global environment is of critical importance in migration literature. We propose a cross-nested logit (CNL) approach to generalize the way deviations from the IIA (independence from irrelevant alternatives)) hypothesis can be tested and exploited in migration studies. Compared with the widely used logit model, the structure of a CNL model allows for more sophisticated substitution patterns between destinations. To illustrate the relevance of our approach, we provide a case study using migration aspiration data from India. We demonstrate that the CNL approach outperforms standard competing approaches in terms of quality of fit, has stronger predictive power, implies stronger heterogeneity in responses to shocks, and highlights complex and intuitive substitution patterns between all possible alternatives. In particular, we shed light on the low degree of substitutability between the home and foreign alternatives as well as on the subgroups of countries that are considered by potential Indian movers as highly or poorly substitutable.

Iron-catalyzed arene C-H hydroxylation.

The sustainable, undirected, and selective catalytic hydroxylation of arenes remains an ongoing research challenge because of the relative inertness of aryl carbon-hydrogen bonds, the higher reactivity of the phenolic products leading to over-oxidized by-products, and the frequently insufficient regioselectivity. We report that iron coordinated by a bioinspired -cystine–derived ligand can catalyze undirected arene carbon-hydrogen hydroxylation with hydrogen peroxide as the terminal oxidant. The reaction is distinguished by its broad substrate scope, excellent selectivity, and good yields, and it showcases compatibility with oxidation-sensitive functional groups, such as alcohols, polyphenols, aldehydes, and even a boronic acid. This method is well suited for the synthesis of polyphenols through multiple carbon-hydrogen hydroxylations, as well as the late-stage functionalization of natural products and drug molecules.

N‐Heterocyclic Carbene Catalyzed Benzannulations: Mechanism and Synthetic Utility

AbstractAromatic compounds are ubiquitous in pharmaceutical agents and other functional materials. Therefore, synthetic methods to construct highly functionalized aromatic frameworks have attracted considerable attention, especially when utilizing acyclic precursors instead of pre‐existing benzenoid cores. A plethora of methods exist in the literature for the construction of substituted aromatic products by using transition metal catalysis and base‐promoted benzannulation reactions starting from acyclic precursors. In recent years, organocatalytic approaches such as N‐heterocyclic carbene catalysis have emerged as effective tools for the efficient and regioselective construction of highly functionalized aryl rings under metal‐free and mild reaction conditions. The fundamental objective of this minireview is to highlight the synthetic potential of NHC‐catalyzed benzannulations for the generation of aromatic rings with complex substitution patterns and to discuss these reactions from the perspective of their mechanistic design.

Regioselective Synthesis of Benzofuranones and Benzofurans.

Reaction of 3-hydroxy-2-pyrones with nitroalkenes bearing ester groups gives benzofuranones. The reaction allows regioselective preparation of the benzofuranones with programmable substitution at any position. Complex substitution patterns are readily created. The substituted benzofuranones can be converted to substituted benzofurans.

New York, Abu Dhabi, London or Stay at Home? Using a Cross-Nested Logit Model to Identify Complex

The question of how people revise their decisions about whether to emigrate, and where to, when facing changes in the global environment is of critical importance in migration literature. We propose a cross-nested logit (CNL) approach to generalize the way deviations from the IIA (independence from irrelevant alternatives)) hypothesis can be tested and exploited in migration studies. Compared with the widely used logit model, the structure of a CNL model allows for more sophisticated substitution patterns between destinations. To illustrate the relevance of our approach, we provide a case study using migration aspiration data from India. We demonstrate that the CNL approach outperforms standard competing approaches in terms of quality of fit, has stronger predictive power, implies stronger heterogeneity in responses to shocks, and highlights complex and intuitive substitution patterns between all possible alternatives. In particular, we shed light on the low degree of substitutability between the home and foreign alternatives as well as on the subgroups of countries that are considered by potential Indian movers as highly or poorly substitutable.

New York, Abu Dhabi, London or Stay at Home? Using a Cross-Nested Logit Model to Identify Complex Substitution Patterns in Migration

The question of how people revise their decisions about whether to emigrate, and where to, when facing changes in the global environment is of critical importance in migration literature. We propose a cross-nested logit (CNL) approach to generalize the way deviations from the IIA (independence from irrelevant alternatives)) hypothesis can be tested and exploited in migration studies. Compared with the widely used logit model, the structure of a CNL model allows for more sophisticated substitution patterns between destinations. To illustrate the relevance of our approach, we provide a case study using migration aspiration data from India. We demonstrate that the CNL approach outperforms standard competing approaches in terms of quality of fit, has stronger predictive power, implies stronger heterogeneity in responses to shocks, and highlights complex and intuitive substitution patterns between all possible alternatives. In particular, we shed light on the low degree of substitutability between the home and foreign alternatives as well as on the subgroups of countries that are considered by potential Indian movers as highly or poorly substitutable.

Assembly of Complex 1,4‐Cycloheptadienes by (4+3) Cycloaddition of Rhodium(II) and Gold(I) Non‐Acceptor Carbenes

AbstractThe formal (4+3) cycloaddition of 1,3‐dienes with Rh(II) and Au(I) non‐acceptor vinyl carbenes, generated from vinylcycloheptatrienes or alkoxyenynes, respectively, leads to 1,4‐cycloheptadienes featuring complex and diverse substitution patterns, including natural dyctiopterene C′ and a hydroxylated derivative of carota‐1,4‐diene. A complete mechanistic picture is presented, in which Au(I) and Rh(II) non‐acceptor vinyl carbenes were shown to undergo a vinylcyclopropanation/Cope rearrangement or a direct (4+3) cycloaddition that takes place in a non‐concerted manner.

Assembly of Complex 1,4-Cycloheptadienes by (4+3) Cycloaddition of Rhodium(II) and Gold(I) Non-Acceptor Carbenes.

The formal (4+3) cycloaddition of 1,3‐dienes with Rh(II) and Au(I) non‐acceptor vinyl carbenes, generated from vinylcycloheptatrienes or alkoxyenynes, respectively, leads to 1,4‐cycloheptadienes featuring complex and diverse substitution patterns, including natural dyctiopterene C′ and a hydroxylated derivative of carota‐1,4‐diene. A complete mechanistic picture is presented, in which Au(I) and Rh(II) non‐acceptor vinyl carbenes were shown to undergo a vinylcyclopropanation/Cope rearrangement or a direct (4+3) cycloaddition that takes place in a non‐concerted manner.

A biorefinery strategy for the manufacture and characterization of oligosaccharides and antioxidants from poplar hemicelluloses

A combination of biorefinery processes (hydrothermal and membrane processing) was performed for the manufacture of oligosaccharides and natural phenolic compounds from poplar hemicelluloses. Both, oligosaccharides and phenolics have multiple potential applications related to their bioactive properties. Firstly, non-isothermal autohydrolysis of poplar was performed to obtain oligosaccharides from the hemicellulosic fraction, while cellulose and lignin remained almost unaltered in the spent solid allowing their valorization in further processing stages. Operating at 210 ºC and liquid to solid ratio of 6 kg/kg, solutions containing 28.71 g oligosaccharides/L were obtained. Secondly, membrane refining of the resulting solution and further freeze-drying resulted in a product with high purity (90 kg of substituted oligosaccharides/100 kg of non-volatile compounds). The yield of substituted oligosaccharides in the target product accounted 16.6 kg/100 kg of poplar wood. Product characterization was accomplished by HPLC, HPSEC, HPAEC-PAD and MALDI TOF-MS. The data confirmed the presence of backbones containing up to DP13 pentose units, with a complex substitution pattern by acetyl groups and O-methyl-uronic moieties. Additionally, the presence of natural phenolic compounds bounded to oligosaccharides conferred antioxidant properties to the target product. Substituted oligosaccharides and phenolics are postulated as valuable products with interest in food and pharmaceutical industries.

Asymmetric Reductive Dicarbofunctionalization of Alkenes via Nickel Catalysis.

Alkenes are an appealing functional group that can be transformed into a variety of structures. Transition-metal catalyzed dicarbofunctionalization of alkenes can efficiently afford products with complex substitution patterns from simple substrates. Under reductive conditions, this transformation can be achieved while avoiding stoichiometric organometallic reagents. Asymmetric difunctionalization of alkenes has been underdeveloped, in spite of its potential synthetic utility. Herein, we present a summary of our efforts to control enantioselectivity for alkene diarylation with a nickel catalyst. This reaction is useful for preparing triarylethanes. The selectivity is enhanced by an N-oxyl radical additive.

Site-selective electrooxidation of methylarenes to aromatic acetals

Aldehyde is one of most synthetically versatile functional groups and can participate in numerous chemical transformations. While a variety of simple aromatic aldehydes are commercially available, those with a more complex substitution pattern are often difficult to obtain. Benzylic oxygenation of methylarenes is a highly attractive method for aldehyde synthesis as the starting materials are easy to obtain and handle. However, regioselective oxidation of functionalized methylarenes, especially those that contain heterocyclic moieties, to aromatic aldehydes remains a significant challenge. Here we show an efficient electrochemical method that achieves site-selective electrooxidation of methyl benzoheterocycles to aromatic acetals without using chemical oxidants or transition-metal catalysts. The acetals can be converted to the corresponding aldehydes through hydrolysis in one-pot or in a separate step. The synthetic utility of our method is highlighted by its application to the efficient preparation of the antihypertensive drug telmisartan.

Interpretable machine learning for demand modeling with high-dimensional data using Gradient Boosting Machines and Shapley values

Forecasting demand and understanding sales drivers are one of the most important tasks in retail analytics. However, traditionally, linear models and/or models with a small number of predictors have been predominantly used in sales modeling. Taking into account that real-world demand is naturally determined by complex substitution and complementation patterns among a large number of interrelated SKUs, nonlinear effects of prices, promotions, seasonality, as well as many other factors, their lagged values, and interactions, a realistic model has to be able to account for all that. We propose a conceptual model for sales modeling based on standard POS data available to any retailer and generate almost 500 potentially useful predictors of a focal SKU’s sales accordingly. In our comparison of three classes of models, Gradient Boosting Machines outperformed Random Forests and Elastic nets. By using interpretable machine learning methods, we came up with actionable insights related to the importance of various groups of predictors from the conceptual model, as well as demonstrated how helpful it can be for marketing managers to decompose predictions into the effects of individual regressors by using an approximation of Shapley values for feature attribution.

Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones.

We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.

Access to the meta position of arenes through transition metal catalysed C-H bond functionalisation: a focus on metals other than palladium.

The elaboration of simple arenes in order to access more complex substitution patterns is a crucial endeavor for synthetic chemists, given the central role that aromatic rings play in all manner of important molecules. Classical methods are now routinely used alongside stoichiometric organometallic approaches and, most recently, transition metal catalysis in the range of methodologies that are available to elaborate arene C-H bonds. Regioselectivity is an important consideration when selecting a method and, of all those available, it is arguably those that target the meta position that are fewest in number. The rapid development of transition metal-catalysed C-H bond functionalisation over the last few decades has opened new possibilities for meta-selective C-H functionalisation through the diverse reactivity of transition metals and their compatibility with a wide range of directing groups. The pace of discovery of such processes has grown rapidly in the last five years in particular and it is the purpose of this review to examine these but in doing so to place the focus on metals other than palladium, the specific contributions of which have been very recently reviewed elsewhere. It is hoped this will serve to highlight to the reader the breadth of current strategies and mechanisms that have been used to tackle this challenge, which may inspire further progress in the field.