Cyclization Reactions of In Situ-Generated Acyl Ketene with Ynones to Form Oxacycles.

Acyl ketenes react with polar unsaturated functional groups to give unique heterocyclic rings, yet reactions with unpolarized unsaturated functional groups have not been reported. Herein, we describe two effective ring-forming reactions between acetyl ketene and electron-deficient alkynes. The first reaction involves in situ tethering between acetyl ketene and nucleophile-containing 1,3-diynones, which promotes sequential intramolecular 1,6/1,4-additions to generate 2-methylene-2H-pyrans in various yields (24-91%). The other involves a zwitterionic intermediate generated from acetyl ketene and DABCO, which undergoes a Michael addition with terminal alkynyl ketones to generate 3-acyl-4-pyrones (11-79%).

Intramolecular Carboxyamidation of Alkyne-Tethered O-Acylhydroxamates through Formation of Fe(III)-Nitrenoids.

We developed intramolecular carboxyamidations of alkyne-tethered O-acylhydroxamates followed by either thermally induced spontaneous or 4-(dimethylamino)pyridine-catalyzed O→O or O→N acyl group migration. Under iron-catalyzed conditions, the carboxyamidation products were generated in high yield from both Z-alkene and arene-tethered substrates. DFT calculations indicate that the iron-catalyzed carboxyamidation proceeds via a stepwise mechanism involving iron-imidyl radical cyclization followed by intramolecular acyloxy transfer from the iron center to the alkenyl radical center to furnish the cis-carboxyamidation product. Upon treatment with 4-(dimethylamino)pyridine, the Z-alkene-tethered carboxyamidation products underwent selective O→O acyl migration to generate 2-acyloxy-5-acyl pyrroles. Thermal O→N acyl migration occurs during carboxyamidation if the Z-alkene linker contains an alkyl or an aryl substituent at the ß-position of the carbonyl group. On the other hand, the arene linker-containing compounds selectively undergo O→N acyl migration to generate N-acyl-3-acylisoindolinones, and the corresponding O→O acyl migration forming isoindole derivatives was not observed.

Categorizing Student Learning about Research, Nature of Science, and Poster Presentation in a Workshop-Based Undergraduate Research Experience.

This article examines student experiences in a workshop-based undergraduate research experience studying the activity and inhibition of salivary amylase that provides students with the chance to participate in authentic scientific research prior to the start of their undergraduate studies, following the structure of a course-based undergraduate research experience (CURE). Understanding student experiences at this point in their studies is important because research experiences at the beginning of university studies have been shown to increase retention in STEM. This study utilizes meaningful learning and situated cognition as theoretical frameworks and phenomenography as a methodological framework, applied to data from semi-structured interviews with six students. The student experiences were characterized as an outcome space detailing the degree of their meaningful learning with respect to their understanding of the research process, nature of science, and the poster creation and presentation process. The findings highlight that meaningful learning is achieved when research is connected to students' personal lives and/or future job interests. The research process and nature of science must also be made explicit to students by emphasizing the iterative nature of research and highlighting distinctions between science and non-science fields. All participating students displayed an understanding that anyone can partake in science anywhere. Implications for building on this work to develop an understanding of students' sense of belonging and self-identity are also discussed.

Substituent and Solvent Effect Studies of N-Alkenylnitrone 4π Electrocyclizations.

The roles of substituent and solvent effects in promoting the 4π electrocyclization of N-alkenylnitrones to give azetidine nitrones have been investigated by experimental examination of relative rates, activation energies, and linear free energy relationships. These transformations are synthetically important because they favor the formation of a strained heterocyclic ring with imbedded functionality and stereochemical information for versatile derivatization. Mechanistic investigations, including Hammett studies, solvent-dependent Eyring studies, and solvent isotope effects, provide insight into the steric and electronic factors that control these electrocyclizations and identify trends that can be used to advance this approach towards the rapid synthesis of complex azetidines.

Cycloisomerization of Alkyne-Tethered N-Acyloxycarbamates to 2-(3H)Oxazolones through Nitrenoid-Mediated Carboxyamidation.

The cycloisomerization of alkyne-tethered N-benzoyloxycarbamates to 2-(3H)oxazolones is described. Two catalytic systems are tailored for intramolecular 5-exo-alkyne carboxyamidation and concomitant alkene isomerization. PtCl2 /CO (5 mol%, toluene, 100 °C) promotes both carboxyamidation and alkene isomerization but has a limited substrate scope. On the other hand, FeCl3 (5 mol%, CH3 CN, 100 °C) promotes carboxyamidation effectively but a cocatalyst is required for the exocyclic alkene isomerization. Thus, a two-step one-pot protocol has been developed for a broader reaction scope, which involves FeCl3 -catalyzed carboxyamidation and base-induced alkene isomerization. Crossover experiments suggest that these reactions proceed mainly through a mechanism involving acylnitrenoid intermediates rather than carbenoid intermediates.

Synthesis, Characterization, and X-ray Crystallography, of the First Cyclohexadienyl Trifluoromethyl Metal Complex (η5-C6H7)Fe(CO)2CF3.

Fluorochemistry is a field of tremendous developments and advances in several areas of science including materials, pharmaceuticals and agriculture. This makes the design and synthesis of fluorine-containing substances highly desirable research targets. The sub-area of synthetic perfluorinated chemistry proportionately attracts widespread interest by applying to all areas of chemistry including organic and inorganic. Particularly, the latter is much underdeveloped as metal complexes with perfluoroalkyl moieties are scarce, with the vast majority of perfluorinated analogs, of long known, halo and alkylated derivatives never having been synthesized. Focusing on the chemistry of trifluoromethyl group, which is the most important in the class of perfluoroalkyls, we set out to explore the possibility of synthesizing and completely characterizing a cyclohexadienyl metal complex. Upon utilizing a number of trifluorometylating reagents, we only arrived at an efficient preparation by the use of Morrison's trifluormethylating reagent. As a result, the new, air- and moisture-sensitive complex (η5-C6H7)Fe(CO)2CF3, was prepared in 71% yield, using a nucleophilic iodo-for-trifluoromethyl substitution, and was completely characterized including by X-ray crystallography.

CoLab: A workshop-based undergraduate research experience for entering college students.

The goal of undergraduate chemistry laboratories is to allow students to learn about chemical systems and key laboratory skills. They should then apply this knowledge to solve problems and connect macroscopic observations in the laboratory with those occurring at the submicroscopic level. Unfortunately, these needs are not met through traditional confirmation labs. Therefore, many chemistry instructors are turning towards research-based labs course-based undergraduate research experiences (CUREs). There are also many cases where summer workshops, often with non-traditional pedagogy, are used for students. This article describes the STEM CoLab Program, a novel type of summer workshop that seeks to build student chemistry knowledge and skills in research and presentation at the beginning of their college work. This program uses the principles of CUREs for students who are just entering the university, mostly as freshmen. Several different phenomena have been investigated during the program. In this paper, we report the overall work of the program from 2016 through 2021 and provide additional details on the program's implementation in 2020 and 2021 when students conducted their work from home, using a combination of a take home research kit for studying salivary amylase "in vitro" and computer-based visualizations of amylase-inhibitor interactions "in silico" using PyMOL and online docking tools.

Rh2(II)-Catalyzed Intermolecular N-Aryl Aziridination of Olefins Using Nonactivated N Atom Precursors.

The development of the first intermolecular Rh2(II)-catalyzed aziridination of olefins using anilines as nonactivated N atom precursors and an iodine(III) reagent as the stoichiometric oxidant is reported. This reaction requires the transfer of an N-aryl nitrene fragment from the iminoiodinane intermediate to a Rh2(II) carboxylate catalyst; in the absence of a catalyst only diaryldiazene formation was observed. This N-aryl aziridination is general and can be successfully realized by using as little as 1 equiv of the olefin. Di-, tri-, and tetrasubstituted cyclic or acylic olefins can be employed as substrates, and a range of aniline and heteroarylamine N atom precursors are tolerated. The Rh2(II)-catalyzed N atom transfer to the olefin is stereospecific as well as chemo- and diastereoselective to produce the N-aryl aziridine as the only amination product. Because the chemistry of nonactivated N-aryl aziridines is underexplored, the reactivity of N-aryl aziridines was explored toward a range of nucleophiles to stereoselectively access privileged 1,2-stereodiads unavailable from epoxides, and removal of the N-2,4-dinitrophenyl group was demonstrated to show that functionalized primary amines can be constructed.

Counterion Control of t-BuO-Mediated Single Electron Transfer to Nitrostilbenes to Construct N-Hydroxyindoles or Oxindoles.

tert-Butoxide unlocks new reactivity patterns embedded in nitroarenes. Exposure of nitrostilbenes to sodium tert-butoxide was found to produce N-hydroxyindoles at room temperature without an additive. Changing the counterion to potassium changed the reaction outcome to yield solely oxindoles through an unprecedented dioxygen-transfer reaction followed by a 1,2-phenyl migration. Mechanistic experiments established that these reactions proceed via radical intermediates and suggest that counterion coordination controls whether an oxindole or N-hydroxyindole product is formed.

Ruthenabenzene: A Robust Precatalyst.

Metallaaromatics constitute a unique class of aromatic compounds where one or more transition metal elements are incorporated into the aromatic system, the parent of which is metallabenzene. One of the main concerns about metallabenzenes generally deals with the structural characterization related to their relative aromaticity compared to the carbon archetype. Transition metal-containing metallabenzenes are also implicated in certain catalytic processes such as alkyne metathesis polymerization; however, these transition metal-based metallaaromatic compounds have not been developed as a catalyst. Herein, we describe an effective strategy to generate diverse arrays of ruthenabenzenes and demonstrated them as an aromatic equivalent of the Grubbs-type ruthenium alkylidene catalysts. These ruthenabenzenes can be prepared via an enyne metathesis and metallotropic [1,3]-shift cascade process to form alkyne-chelated ruthenium alkylidene intermediates followed by spontaneous cycloaromatization. The aromatic nature of these complexes was confirmed by spectroscopic and X-ray crystallographic data, and the mechanistic pathways for the cycloaromatization process were studied by DFT calculations. These ruthenabenzenes display robust catalytic activity for metathesis and other transformations, which illustrates that metallabenzenes are not only compounds of structural and theoretical interests but also are a novel platform for new catalyst development.

Synthesis of Spirocyclic 1-Pyrrolines from Nitrones and Arynes through a Dearomative [3,3']-Sigmatropic Rearrangement.

A dearomative [3,3']-sigmatropic rearrangement that converts N-alkenylbenzisoxazolines into spirocyclic pyrroline cyclohexadienones has been developed by using the dipolar cycloaddition of an N-alkenylnitrone and an aryne to access these unusual transient rearrangement precursors. This cascade reaction affords spirocyclic pyrrolines that are inaccessible through dipolar cycloadditions of exocyclic cyclohexenones and provides a fundamentally new approach to novel spirocyclic pyrroline and pyrrolidine motifs that are common scaffolds in biologically-active molecules. Diastereoselective functionalization processes have also been explored to demonstrate the divergent synthetic utility of the unsaturated spirocyclic products.

Oxidation of Nonactivated Anilines to Generate N-Aryl Nitrenoids.

A low-temperature, protecting-group-free oxidation of 2-substituted anilines has been developed to generate an electrophilic N-aryl nitrenoid intermediate that can engage in C-NAr bond formation to construct functionalized N-heterocycles. The exposure of 2-substituted anilines to PIFA and trifluoroacetic acid or 10 mol % Sc(OTf)3 triggers nitrenoid formation, followed by productive and selective C-NAr and C-C bond formation to yield spirocyclic- or bicyclic 3H-indoles or benzazepinones. Our experiments demonstrate the breadth of these oxidative processes, uncover underlying fundamental elements that control selectivity, and demonstrate how the distinct reactivity patterns embedded in N-aryl nitrenoid reactive intermediates can enable access to functionalized 3H-indoles or benzazepinones.

C-H Insertion by Alkylidene Carbenes To Form 1,2,3-Triazines and Anionic [3 + 2] Dipolar Cycloadditions To Form Tetrazoles: Crucial Roles of Stereoelectronic and Steric Effects.

The synthesis of 1,2,3-triazines and bicyclic tetrazoles from α-azido ketones is described. The common intermediate generated from lithiated trimethylsilyldiazomethane and α-azido ketones diverges depending on the steric bulk of the substituents. The formation of 1,2,3-triazines via a C-H insertion of alkylidene carbene to form 3-azidocyclopropene, followed by its rearrangement, is supported by density functional theory calculations. Tetrazole formation proceeds via a facile anionic [3 + 2] dipolar cycloaddition between a lithiated diazo moiety and an azido group facilitated by the chelation of a lithium ion.

Silver-Catalyzed Selective Multicomponent Coupling Reactions of Arynes with Nitriles and Isonitriles.

Pathway selective aryne-based novel multicomponent coupling reactions with isonitriles and nitriles are described. Crucial to these reactions is the formation of a silver-aryne complex, which shows differential reactivity toward isonitriles and nitriles to form two different forms of ortho-nitrilium organosilver arene species. Interception of the nitrilium of an aryne-isonitrile adduct with another isonitrile leads to the formation of benzocyclobutene-1,2-diimines, whereas the nitrilium of an aryne-nitrile adduct renders selective formation of 3H-indol-3-imines or 3-iminoindolin-2-ol depending on the structure of the nitrile employed.

Silver-Catalyzed Annulation of Arynes with Nitriles for Synthesis of Structurally Diverse Quinazolines.

An efficient silver catalyzed annulation reaction of aryne with nitriles to generate quinazolines is described. Arynes generated from triynes or tetraynes through a hexadehydro Diels-Alder reaction readily participated in an [A + 2B] mode of annulation with nitriles in the presence of AgSbF6 catalyst. The mechanism was explored by DFT calculations, which supports the silver-catalyzed formation of nitrilium ion as a key intermediate. This annulation generates an array of polysubstituted novel quinazoline derivatives with excellent regioselectivity.

Alder-ene reactions driven by high steric strain and bond angle distortion to form benzocyclobutenes.

A unique aryne-based Alder-ene reaction to form benzocyclobutene is described. In this process, the thermodynamic barrier to form a four-membered ring is compensated by the relief of the strain energy of an aryne intermediate. On the other hand, the driving force to overcome the high kinetic barrier is provided by the gearing effect of the bulky substituent at the ortho-position of the ene-donor alkene. To maximize the steric strain by the ortho-substituent, a structural element for internal hydrogen bonding is installed, which plays a crucial role for both the hexadehydro Diels-Alder and the Alder-ene reactions. DFT calculations show that the bulky hydrogen bonding element lowers the activation barrier for the Alder-ene reaction by destabilizing the intermediate, which is due to the severe bond angle distortion. The preferred formation of cis-isomers can also be explained by the extent of bond angle distortion.

Controlling the Selectivity Patterns of Au-Catalyzed Cyclization-Migration Reactions.

As little as 2 mol % of (XPhos)AuNTf2 catalyzes the transformation of a broad range of o-acetylene-substituted styrenes into 1,2-dihydronaphthalenes. Our data suggests that this transformation occurs via a gold-stabilized cyclopropyl carbinyl cation, which triggers either a [1,2] carboxylate shift or a less favorable [1,2] aryl shift. The relative rates of these migrations can be controlled by the identity of the ligand or by stabilizing the mesomeric cation.

Catalyst-controlled cascade synthesis of bridged bicyclic tetrahydrobenz[b]azepine-4-ones.

A catalyst-controlled cascade reaction has been developed for the synthesis of bridged bicyclic tetrahydrobenz[b]azepin-4-ones from N-arylnitrones and allenes. This method expands the accessible structural diversity of a synthetically challenging heterocyclic scaffold and tunes a catalyst-sensitive process in a new direction.

Generation and Rearrangement of N,O-Dialkenylhydroxylamines for the Synthesis of 2-Aminotetrahydrofurans.

A new diastereoselective route to 2-aminotetrahydrofurans has been developed from N,O-dialkenylhydroxylamines. These intermediates undergo a spontaneous C-C bond-forming [3,3]-sigmatropic rearrangement followed by a C-O bond-forming cyclization. A copper-catalyzed N-alkenylation of an N-Boc-hydroxylamine with alkenyl iodides, and a base-promoted addition of the resulting N-hydroxyenamines to an electron-deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base-promoted ring-opening and Mannich reaction has been discovered to covert 2-aminotetrahydrofurans to cyclopentyl ß-aminoacid derivatives or cyclopentenones.

Cascade Synthesis of 3-Functionalized Indoles from Nitrones and Their Conversion to Cycloheptanone-Fused Indoles.

A cascade reaction of N-aryl-α,ß-unsaturated nitrones and electron-deficient allenes has been discovered that allows single-step access to 3-functionalized indoles that usually require preformation and alkylation of an indole precursor. The heterocycles prepared through the hydrogen bond donor catalyzed cascade reaction are poised to undergo a McMurry coupling to form previously synthetically elusive cycloheptanone-fused indoles. The scope of these transformations is discussed as well as mechanistic experiments describing proposed intermediates of the cascade reaction and an initial catalytic asymmetric example that generates a carbon stereocenter during the cascade process.