Pd-Catalyzed Alkene Diamination Reactions with O-Benzoylhydroxylamine Electrophiles: Evidence Supporting a Pd(II/IV) Catalytic Cycle, the Role of 2,4-Pentanedione Derivatives as Ligands, and Expanded Substrate Scope.

This article describes continued studies on Pd-catalyzed alkene diamination reactions between N-allylguanidines or ureas and O-benzoylhydroxylamine derivatives, which serve as N-centered electrophiles. The transformations generate cyclic guanidines and ureas bearing dialkylaminomethyl groups in moderate to good yield. We describe new mechanistic experiments that have led to a revised mechanistic hypothesis that involves a key oxidative addition of the electrophile to a PdII complex, followed by reductive elimination from PdIV to form the alkyl carbon-nitrogen bond. In addition, we demonstrate that acac, not phosphine, serves as a key ligand for palladium. Moreover, simple acac derivatives bearing substituted aryl groups outperform acac in the catalytic reactions, and phosphines inhibit catalysis in many cases. These discoveries have led to a significant expansion in the scope of this chemistry, which now allows for the coupling of a variety of cyclic amines, acyclic secondary amines, and primary amines. In addition, we also demonstrate that these new conditions allow for the use of amide nucleophiles, in addition to guanidines and ureas.

Pd-Catalyzed C-C, C-N, and C-O Bond-Forming Difunctionalization Reactions of Alkenes Bearing Tethered Aryl/Alkenyl Triflates.

Over the past few years our group has described a new type of alkene difunctionalization reaction in which aryl or alkenyl triflates bearing tethered alkenes are coupled with various nucleophiles to afford carbocyclic products. The products are formed in moderate to good chemical yield, with generally high levels of stereoselectivity. Our progress to date in this area, which includes reactions of amine, alcohol, enolate, and indole nucleophiles, is described in this review.

Stereocontrolled synthesis of bicyclic ureas and sulfamides via Pd-catalyzed alkene carboamination reactions.

The synthesis of bicyclic ureas and sulfamides via palladium-catalyzed alkene carboamination reactions between aryl/alkenyl halides/triflates and alkenes bearing pendant cyclic sulfamides and ureas is described. The substrates for these reactions are generated in 3-5 steps from commercially available materials, and products are obtained in good yield with up to >20:1 diastereoselectivity. The stereochemical outcome of the sulfamide alkene addition is consistent with a mechanism involving anti-aminopalladation of the alkene, whereas the stereochemical outcome of the urea alkene addition is consistent with a syn-aminopalladation mechanism.

A Cross-Metathesis/Aza-Michael Reaction Strategy for the Synthesis of Cyclic and Bicyclic Ureas.

The synthesis of cyclic and bicyclic ureas via a ruthenium-catalyzed cross-metathesis / aza-Michael reaction strategy between protected alkenyl ureas and Michael acceptors is described. The substrates for these reactions are generated in 1-3 steps from commercially available materials, and products are formed in moderate yield with up to >20:1 diastereoselectivity.

Pd-Catalyzed Alkene Carboheteroarylation Reactions for the Synthesis of 3-Cyclopentylindole Derivatives.

The Pd-catalyzed alkene carboheteroarylation of aryl and alkenyl triflate electrophiles bearing pendant alkenes with heteroaromatic nucleophiles affords substituted carbocycles with 3-indolyl or 3-pyrrolyl groups. The products are obtained in moderate to good yields, and the use of alkenyl triflate substrates produces products with high diastereoselectivities. The transformation is believed to proceed via a Friedel-Crafts-like reaction between the heteroaromatic nucleophile and an intermediate electrophilic palladium complex.

Stereocontrolled Synthesis of Amino-Substituted Carbocycles by Pd-Catalyzed Alkene Carboamination Reactions.

Amino-substituted alkylidenecyclopentanes were synthesized through a stereoselective intermolecular Pd-catalyzed alkene carboamination reaction between alkenyl triflates bearing a pendant alkene and exogenous amine nucleophiles. The reactions are effective with a range of different substrate combinations, and proceed with generally high diastereoselectivity. Use of (S)-tBuPhox as the ligand in reactions of achiral substrates provides enantioenriched products with up to 98.5:1.5 e.r.

Synthesis of Substituted γ- and δ-Lactams via Pd-Catalyzed Alkene Carboamination Reactions.

The synthesis of substituted γ- and δ-lactams via palladium-catalyzed alkene carboamination reactions between aryl halides and alkenes bearing pendant amides is described. The substrates for these reactions are generated in 1-3 steps from commercially available materials, and products are obtained in good yield with up to >20:1 diastereoselectivity. The stereochemical outcome of the alkene addition is consistent with a mechanism involving anti-aminopalladation of the alkene.

Asymmetric Palladium-Catalyzed Alkene Carboamination Reactions for the Synthesis of Cyclic Sulfamides.

The synthesis of cyclic sulfamides by enantioselective Pd-catalyzed alkene carboamination reactions between N-allylsulfamides and aryl or alkenyl bromides is described. High levels of asymmetric induction (up to 95:5 e.r.) are achieved using a catalyst composed of [Pd2 (dba)3 ] and (S)-Siphos-PE. Deuterium-labelling studies indicate the reactions proceed through syn-aminopalladation of the alkene and suggest that the control of syn- versus anti-aminopalladation pathways is important for asymmetric induction.

Asymmetric Pd-Catalyzed Alkene Carboamination Reactions for the Synthesis of 2-Aminoindane Derivatives.

A new type of Pd-catalyzed alkene carboamination reaction that provides direct access to enantioenriched 2-aminoindanes from 2-allylphenyltriflate derivatives and aliphatic amines is described. A catalyst generated in situ from Pd(OAc)2 and (S)-tert-butylPHOX provides the functionalized carbocycles in good yield with up to >99:1 er. The transformations occur via a key anti-aminopalladation that involves intermolecular attack of an amine nucleophile on an arylpalladium alkene complex.

Palladium-Catalyzed Alkene Carboamination Reactions of Electron-Poor Nitrogen Nucleophiles.

Modified reaction conditions that facilitate Pd-catalyzed alkene carboamination reactions of electron-deficient nitrogen nucleophiles are reported. Pent-4-enylamine derivatives bearing N-tosyl or N-trifluoroacetyl groups are coupled with aryl triflates to afford substituted pyrrolidines in good yield. These reactions proceed via a mechanism involving anti-aminopalladation of the alkene, which differs from previously reported analogous reactions of N-aryl and N-boc pentenylamines. The application of these conditions to a formal synthesis of (±)-aphanorphine is also described.

Aza-Wittig Rearrangements of N-Benzyl and N-Allyl Glycine Methyl Esters. Discovery of a Surprising Cascade Aza-Wittig Rearrangement/Hydroboration Reaction.

Treatment of N-(arylmethyl)-N-aryl or N-allyl-N-aryl glycine methyl ester derivatives with (n)Bu2BOTf and (i)Pr2NEt effects an aza-Wittig rearrangement that provides N-aryl phenylalanine methyl ester derivatives and N-aryl allylglycine methyl ester derivatives, respectively, in good yield with moderate to good diastereoselectivity. Under similar conditions, analogous substrates bearing N-carbonyl groups are converted to 1,4,2-oxazaborole derivatives. Additionally, N-allyl-N-aryl glycine methyl ester derivatives subjected to similar conditions at elevated temperatures undergo an aza-[2,3]-Wittig rearrangement, followed by a subsequent hydroboration oxidation reaction, to afford substituted amino alcohol products.

Development of Enantioselective Palladium-Catalyzed Alkene Carboalkoxylation Reactions for the Synthesis of Tetrahydrofurans.

The Pd-catalyzed coupling of γ-hydroxyalkenes with aryl bromides affords enantiomerically enriched 2-(arylmethyl)tetrahydrofuran derivatives in good yield and up to 96:4 e.r. This transformation was achieved through the development of a new TADDOL/2-arylcyclohexanol-derived chiral phosphite ligand. The transformations are effective with an array of different aryl bromides, and can be used for the preparation of products bearing quaternary stereocenters.

Influence of catalyst structure and reaction conditions on anti- versus syn-aminopalladation pathways in Pd-catalyzed alkene carboamination reactions of N-allylsulfamides.

The Pd-catalyzed coupling of N-allylsulfamides with aryl and alkenyl triflates to afford cyclic sulfamide products is described. In contrast to other known Pd-catalyzed alkene carboamination reactions, these transformations may be selectively induced to occur by way of either anti- or syn-aminopalladation mechanistic pathways by modifying the catalyst structure and reaction conditions.

Synthesis of substituted tetrahydroindoloisoquinoline derivatives via intramolecular Pd-catalyzed alkene carboamination reactions.

Intramolecular Pd-catalyzed alkene carboamination reactions of substituted 2-allyl-N-(2-bromobenzyl)anilines are described. The substrates for these reactions are generated in two steps from readily available 2-allylanilines and 2-bromobenzaldehyde derivatives. The transformations afford substituted tetrahydroindoloisoquinolines, an uncommon class of fused bicyclic heterocycles, in good yield. The mechanism of these transformations is described, and a model that accounts for the observed product stereochemistry is proposed.

Synthesis of Biindene Derivatives via Pd-Catalyzed Alkene Difunctionalization Reactions.

The palladium-catalyzed cross-coupling of 2-allylphenyl triflate and related electrophiles with substituted indenes affords biindene derivatives in moderate to good yields with high selectivity for thermodynamically preferred alkene isomers. The transformations involve alkene nucleopalladation with indenyl anions, and we also demonstrate that 2-allylphenyl triflates can be transformed to indenes under similar conditions. The scope of this transformation, along with the mechanism of formation of both indene and biindene products, is described.

Synthesis of 2-Cyanomethyl Indane Derivatives via Pd-Catalyzed Alkene Difunctionalization Reactions of Alkyl Nitriles.

The synthesis of indanes bearing substituted cyanomethyl groups at C2 is achieved through Pd-catalyzed coupling reactions between 2-allylphenyl triflate derivatives and alkyl nitriles. Related partially saturated analogues were generated from analogous transformations of alkenyl triflates. The use of a preformed BrettPhosPd(allyl)(Cl) complex as a precatalyst was essential for the success of these reactions.

Palladium-Catalyzed Synthesis of 1-Alkylidene-2-dialkylaminomethyl Cyclobutane Derivatives via Pd-Catalyzed Alkene Difunctionalization Reactions: Influence of Nucleophile and Water on the Reaction Mechanism.

The Pd-catalyzed coupling of 1,5-diene-2-yl triflates with amine nucleophiles affords exomethylenecyclobutanes bearing dialkylaminomethyl groups at C2. The strained carbocyclic products are obtained in moderate to excellent yields, with regioselectivities of up to >95:5 for four-membered ring formation. The mechanism of these reactions, which provides products resulting from anti-addition to alkenes, differs from related reactions involving malonate nucleophiles that provide syn-addition products.

Influence of CUREs on STEM retention depends on demographic identities.

Research has shown that undergraduate research experiences can have substantive effects on retaining students in science, technology, engineering and mathematics (STEM). However, it is impossible to provide individual research experiences for every undergraduate student, especially at large universities. Course-based undergraduate research experiences (CUREs) have become a common approach to introduce large numbers of students to research. We investigated whether a one-semester CURE that replaced a traditional introductory biology laboratory course could increase retention in STEM as well as intention to remain in STEM, if the results differed according to demography, and investigated the possible motivational factors that might mediate such an effect. Under the umbrella of the Authentic Research Connection (ARC) program, we used institutional and survey data from nine semesters and compared ARC participants to non-participants, who applied to ARC but either were not randomly selected or were selected but chose not to enroll in an ARC section. We found that ARC had significant effects on demographic groups historically less likely to be retained in STEM: ARC participation resulted in narrowing the gaps in graduation rates in STEM (first vs continuing-generation college students) and in intention to major in STEM [females vs males, Persons Excluded because of Ethnicity or Race (PEERs) vs non-PEERs]. These disproportionate boosts in intending STEM majors among ARC students coincide with their reporting a greater sense of student cohesiveness, retaining more interest in biology, and commenting more frequently that the course provided a useful/valuable learning experience. Our results indicate that CUREs can be a valuable tool for eliminating inequities in STEM participation, and we make several recommendations for further research.

Synthesis of enantiomerically enriched imidazolidin-2-ones through asymmetric palladium-catalyzed alkene carboamination reactions.

Positive water effect: A catalyst composed of [Pd(2)(dba)(3)] (dba=dibenzylideneacetone) and (S)-Siphos-PE is effective for the enantioselective coupling of N-allyl ureas with aryl bromides to afford 4-substituted imidazolidin-2-ones. Added water leads to significantly improved enantioselectivities with electron-poor aryl halide substrates. It is suggested that the C-C bond-forming reductive elimination is the enantiodetermining step in these reactions.