Selenium-Catalyzed Regioselective Intermolecular Diamination of Dienes and Dienolate Derivatives.

We report a selenium-catalyzed diamination of dienes using sulfamates as a convenient nitrogen source. This reaction proceeds regioselectively for 1,2-addition at the less substituted alkene, without the need for a tethered diamine. We also report the first diamination of dienyl phosphates and tosylates, affording synthetically useful α,β-diaminoketone derivatives with high diastereoselectivity.

α'-Selective Selenium-catalyzed Allylic C-H Amination of Enol Derivatives.

A transition metal-free Se-catalyzed C-H amination protocol for α'-amination of enol derivatives has been developed. This reaction can be used to functionalize a wide variety of oxygen- and halogen-substituted alkenes spanning a vast range of nucleophilicities, giving α'-aminated enol derivatives with high regioselectivity. Amination of E/Z mixtures of alkenes proceeds stereoconvergently to give the (Z)-enol derivatives exclusively.

C-H Functionalization and Allylic Amination for Post-Polymerization Modification of Polynorbornenes.

Post-polymerization modification (PPM) via direct C-H functionalization is a powerful synthetic strategy to convert polymer feed-stocks into value-added products. We found that a metal-free, Se-catalyzed allylic C-H amination provided an efficient method for PPM of polynorbornenes (PNBs) produced via ring-opening metathesis polymerization. Inherent to the mechanism of the allylic amination, PPM on PNBs preserved the alkene functional groups along the polymer backbone, while also avoiding transposition of the double bonds.

Upcycling of Polybutadiene Facilitated by Selenium-Mediated Allylic Amination.

Accumulation of end-of-life plastics presents ongoing environmental concerns. One strategy to solve this grand challenge is to invent new techniques that modify post-consumer waste and impart new functionality. While promising approaches for the chemical upcycling of commodity polyolefins and polyaromatics exist, analogous approaches to repurpose unsaturated polymers (e.

Metal-Free Allylic C-H Amination of Vinylsilanes and Vinylboronates using Silicon or Boron as a Regioselectivity Switch.

Vinylsilanes and vinylboronates are common building blocks for organic synthesis, but direct functionalization of these species without the participation of either the C=C or C-Si/B bonds is rare. Herein, we report a metal-free allylic C-H amination reaction of these vinylmetalloid species that installs a new C-N bond without competing transmetallation or alkene addition. In this transformation, the silicon or boron substituent inverts the usual regioselectivity, directing amination to the site distal to that group.

Diastereoconvergent synthesis of -1,2-amino alcohols with N-containing quaternary stereocenters selenium-catalyzed intermolecular C-H amination.

We report a diastereoconvergent synthesis of -1,2-amino alcohols bearing N-containing quaternary stereocenters using an intermolecular direct C-H amination of homoallylic alcohol derivatives catalyzed by a phosphine selenide. Destruction of the allylic stereocenter during the selenium-catalyzed process allows selective formation of a single diastereomer of the product starting from any diastereomeric mixture of the starting homoallylic alcohol derivatives, eliminating the need for the often-challenging diastereoselective preparation of starting materials. Mechanistic studies show that the diastereoselectivity is controlled by a stereoelectronic effect (inside alkoxy effect) on the transition state of the final [2,3]-sigmatropic rearrangement, leading to the observed selectivity.

Stereoretentive and regioselective selenium-catalyzed intermolecular propargylic C-H amination of alkynes.

Herein we report an intermolecular propargylic C-H amination of alkynes. This reaction is operationally convenient and requires no transition metal catalysts or additives. Terminal, silyl, and internal alkynes bearing a wide range of functional groups can be aminated in high yields.

Catalytic Metal-free Allylic C-H Amination of Terpenoids.

The selective replacement of C-H bonds in complex molecules, especially natural products like terpenoids, is a highly efficient way to introduce new functionality and/or couple fragments. Here, we report the development of a new metal-free allylic amination of alkenes that allows the introduction of a wide range of nitrogen functionality at the allylic position of alkenes with unique regioselectivity and no allylic transposition. This reaction employs catalytic amounts of selenium in the form of phosphine selenides or selenoureas.

Selenophosphoramide-catalyzed diamination and oxyamination of alkenes.

A new selenophosphoramide-catalyzed diamination of terminal- and -1,2-disubstituted olefins is presented. Key to the success of this transformation was the introduction of a fluoride scavenger, trimethylsilyl trifluoromethanesulfonate (TMSOTf), to prevent a competitive -elimination pathway, as was the use of a phosphoramide ligand on selenium to promote the desired substitution reaction. A screen of catalysts revealed that more electron-rich phosphine ligands resulted in higher yields of the desired product, with selenophosphoramides giving the optimal results.

Regioselective Metal-Free Aza-Heck Reactions of Terminal Alkenes Catalyzed by Phosphine Selenides.

Phosphine selenides are introduced as an alternate class of selenium-based catalysts for the aza-Heck reaction of alkenes. Using these catalysts, a range of terminal alkenes react with NFBS to give oxidative amination products. Judicious choice of phosphine ligand gives greater regio- and stereoselectivity than with diphenyl diselenide, enabling the selective formation of E terminal enimides in high yields.

Palladium-Catalyzed Cross-Coupling of N-Sulfonylaziridines and Alkenylboronic Acids: Stereospecific Synthesis of Homoallylic Amines with Di- and Trisubstituted Alkenes.

A palladium-catalyzed cross-coupling of 2-alkylaziridines with alkenylboronic acids to give homoallylamines is presented. The reaction is highly regioselective and stereospecific and provides convenient access to enantioenriched amines with 1,1-disubstituted, 1,2-disubstituted, and trisubstituted alkenes. The modular synthesis of a 2,5-disubstituted pyrrolidine natural product was completed in three steps and 67% overall yield.

Chelation-driven rearrangement of primary alkyl aminopalladation products to stable trisubstituted alkyl-palladium complexes.

The formation of highly substituted carbon centers using catalysis has been a widely sought after goal, but complexes of highly substituted carbon atoms with transition metals are rare, and the factors that affect the relative stability of complexes with differentially substituted carbon atoms are poorly understood. In this study, a set of equilibrating alkyl-palladium complexes were subtly tuned to form either a primary or trisubstituted alkyl complex as the more thermodynamically favored state, depending on either the substrate or reaction conditions. An X-ray crystal structure of the trisubstituted alkyl-palladium complex is presented and compared with the corresponding primary alkyl complex.

Palladium-catalyzed cross-coupling of N-sulfonylaziridines with boronic acids.

A mild palladium-catalyzed cross-coupling of unsubstituted and 2-alkyl-substituted aziridines with arylboronic acid nucleophiles is presented. The reaction is highly regioselective and compatible with diverse functionality. A catalytic amount of base, a sterically demanding triarylphosphine ligand, and a phenol additive are critical to the success of the reaction.

Stereoselective synthesis of 2,5-disubstituted morpholines using a palladium-catalyzed hydroamination reaction.

A palladium-catalyzed hydroamination reaction is the key step in a stereoselective synthesis of 2,5-disubstituted and 2,3,5-trisubsituted morpholines from carbamate-protected aziridines. Aziridines are selectively attacked at the more substituted position by unsaturated alcohol nucleophiles using Lewis acid catalysts. Palladium-catalyzed hydroamination of the resulting aminoalkenes gives morpholines as a single diastereomer in excellent yield.

Enantioselective palladium-catalyzed diamination of alkenes using N-fluorobenzenesulfonimide.

An enantioselective Pd-catalyzed vicinal diamination of unactivated alkenes using N-fluorobenzenesulfonimide as both an oxidant and a source of nitrogen is reported. The use of Ph-pybox and Ph-quinox ligands afforded differentially protected vicinal diamines in good yields with high enantioselectivities. Mechanistic experiments revealed that the high enantioselectivity arises from selective formation of only one of four possible diastereomeric aminopalladation products of the chiral Pd complex.

Computational design of enone-binding proteins with catalytic activity for the Morita-Baylis-Hillman reaction.

The Morita-Baylis-Hillman reaction forms a carbon-carbon bond between the α-carbon of a conjugated carbonyl compound and a carbon electrophile. The reaction mechanism involves Michael addition of a nucleophile catalyst at the carbonyl β-carbon, followed by bond formation with the electrophile and catalyst disassociation to release the product. We used Rosetta to design 48 proteins containing active sites predicted to carry out this mechanism, of which two show catalytic activity by mass spectrometry (MS).

Palladium-catalyzed alkoxyamination of alkenes with use of N-fluorobenzenesulfonimide as oxidant.

A Pd-catalyzed alkoxyamination of protected aminoalkenes promoted by N-fluorobenzenesulfonimide is described. This mild transformation allows the direct formation of ethers from carbon-carbon double bonds. An unusual switch from exo to endo selectivity in polar solvents was discovered, allowing the selective formation of either regioisomer by careful choice of reaction conditions.

Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction.

The Diels-Alder reaction is a cornerstone in organic synthesis, forming two carbon-carbon bonds and up to four new stereogenic centers in one step. No naturally occurring enzymes have been shown to catalyze bimolecular Diels-Alder reactions. We describe the de novo computational design and experimental characterization of enzymes catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity.

Platinum-catalyzed intramolecular hydrohydrazination: evidence for alkene insertion into a Pt-N bond.

Dicationic (bpy)Pt(II) complexes were found to catalyze the intramolecular hydrohydrazination of alkenes. Reaction optimization revealed Pt(bpy)Cl(2) (10 mol %) and AgOTf (20 mol %) in DMF-d(7) to be an effective catalyst system for the conversion of substituted hydrazides to five- and six-membered N-amino lactams (N-amino = N-acetamido at 120 degrees C, N-phthalimido at 80 degrees C, (-)OTf = trifluoromethanesulfonate). Of the four possible regioisomeric products, only the product of 5-exo cyclization at the proximal nitrogen is formed, without reaction at the distal nitrogen or 6-endo cyclization.

Metal-free highly regioselective aminotrifluoroacetoxylation of alkenes.

We report a highly regioselective metal-free oxidative cyclization of sulfonamides onto tethered, unactivated alkenes using hypervalent iodine and Brønsted acids. Under these conditions the acid counterion is incorporated into the cyclized products providing an overall aminotrifluoroacetoxylation of the alkene. An unusual preference for endo ring closure is exhibited in contrast to existing exo selective methods.

Mechanism of N-fluorobenzenesulfonimide promoted diamination and carboamination reactions: divergent reactivity of a Pd(IV) species.

The mechanism of the Pd-catalyzed diamination and carboamination of alkenes promoted by N-fluorobenzenesulfonimide (NFBS) was investigated. Stereochemical labeling experiments established that the diamination reaction proceeds via overall syn addition of the two nitrogen groups, whereas carboamination is the result of an anti addition of arene and nitrogen to the alkene. The intermediate Pd-alkyl complex arising from aminopalladation was observed, and an X-ray crystal structure of its 2,2'-bipyridine (bipy) complex was obtained, revealing strong chelation of the amide protecting group to palladium.

Palladium-catalyzed carboamination of alkenes promoted by N-fluorobenzenesulfonimide via C-H activation of arenes.

This report describes a unique Pd-catalyzed oxidative carboamination of protected aminoalkenes in which inexpensive unactivated nucleophilic arenes are incorporated to give carboamination products in good yields. A variety of protected amide and carbamate groups are tolerated, and various five-, six-, and seven-membered rings are formed in good yields. Under these conditions, halobenzenes are activated at the C-H bond rather than the C-X bond, and very high regioselectivity for the para substitution product is observed in all cases.

Palladium-catalyzed diamination of unactivated alkenes using N-fluorobenzenesulfonimide as source of electrophilic nitrogen.

A remarkable Pd-catalyzed diamination of unactivated alkenes using N-fluorobenzenesulfonimide (NFBS) as an aminating reagent is described. The reaction occurs in an intra/intermolecular fashion, incorporating one nitrogen donor from the substrate and the other from the NFBS, thereby generating cyclic diamine derivatives in a single step. The products are differentially protected at both nitrogens, allowing for maximal synthetic flexibility.

Metal-free oxidative cyclization of urea-tethered alkenes with hypervalent iodine.

A metal-free oxidative cyclization of ureas onto unactivated alkenes using iodosylbenzene and an acid promoter is described. The products isolated are predominantly bicyclic isoureas resulting from an intramolecular oxyamination reaction. The acid type and urea substitution have a strong effect on the product formed.