Allylamine Research Articles

Palladium-Catalyzed Oxidative Amination of Unactivated Olefins with Primary Aliphatic Amines

Direct coupling of unactivated olefins with primary alkylamines is considered to be an efficient but unknown method for the construction of complex amines. Herein we report a catalytic intermolecular oxidative amination of unactivated olefins with primary aliphatic amines based on the combination of a palladium catalyst, a bidentate phosphine ligand, and duroquinone. A range of secondary allylic amines were obtained in good yields with excellent regio- and stereoselectivity. Mechanistic control experiments revealed that the reaction proceeds by allylic C(sp3)-H activation and nucleophilic amination. The utility of the protocol is further demonstrated with the late-stage modification and streamlined synthesis of drug molecules.

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.g., polybutadiene) are scarce. In this work, we propose a method to upcycle polybutadiene, one of the most widely used commercial rubbers, via a mild, metal-free allylic amination reaction. The resulting materials have tunable thermal and surface wetting properties as a function of both sulfonamide identity and grafting density. Importantly, this approach maintains the parent alkene microstructure without evidence of olefin reduction, olefin transposition, and/or chain scission. Based on these findings, we anticipate future applications in the remediation of complex elastomers and vulcanized rubbers.

Regioselective anti-Silyllithiation of Propargylic Amines

AbstractThe regioselective anti-silyllithiation of propargylic amines is developed to facilitate the efficient synthesis of alkenylsilanes. This reaction generates an alkenyllithium intermediate that is stabilized by the formation of a five-membered cyclic structure through intramolecular coordination of the nitrogen functional group. Upon subsequent treatment with an electrophile, the alkenyllithium intermediate is further functionalized to afford tetrasubstituted allylic amines bearing a β-silicon substituent.

Modular Access tometa-Substituted Benzenes via Mo-Catalyzed Intermolecular Deoxygenative Benzene Formation

The substituted benzene derivatives are essential to organic synthesis, medicinal chemistry, and material science. However, the 1,3-di- and 1,3,5-trisubstituted benzenes are far less prevalent in small-molecule drugs than other substitution patterns, likely due to the lack of robust, efficient, and convenient synthetic methods. Here, we report a Mo-catalyzed intermolecular deoxygenative benzene-forming reaction of readily available ynones and allylic amines. A wide range of unsymmetric and unfunctionalized 1,3-di- and 1,3,5-trisubstituted benzenes were obtained in up to 88% yield by using a commercially available molybdenum catalyst. The synthetic potential of the method was further illustrated by synthetic transformations, a scale-up synthesis, and derivatization of bioactive molecules. Preliminary mechanistic studies suggested that this benzene-forming process might proceed through a Mo-catalyzed aza-Michael addition/[1,5]-hydride shift/cyclization/aromatization cascade. This strategy not only provided a facile, robust, and modular approach to various meta-substituted benzene derivatives but also demonstrated the potential of molybdenum catalysis in the challenging intermolecular deoxygenative cross-coupling reactions.

Mechanistic Investigation of Zirconium-Catalyzed Hydroaminoalkylation of Alkynes: Substrate and Ligand Effects

The mechanism of zirconium-catalyzed hydroaminoalkylation of diphenylacetylene, and the origin of the contrasting reactivity with N-benzylaniline or N-(trimethylsilyl)benzylamine substrates, have been investigated. Isolated intermediates have revealed that the nature of the C–H activation and C–C bond-forming steps in alkyne hydroaminoalkylation are analogous to those of the alkene variant, regardless of the amine substrate. In the zirconium-catalyzed hydroaminoalkylation of alkynes, the open coordination sphere at the zirconium center, supported by the bis(ureate) ligand, enables the coordination of neutral protic donors. This is essential for promoting catalytic turnover in these reactions. Under catalytic conditions, dimethylamine acts as a proton source for releasing the allylic amine products while minimizing the formation of side products. Additionally, we identified the formation of a homoleptic tetra(ureate) zirconium complex as the main catalyst decomposition pathway in catalytic alkyne hydroaminoalkylation. The formation of similar homoleptic structures is further favored when employing smaller bis(urea) proligands, thus explaining the poor performance of some ligands in catalysis. However, further increasing the bis(urea) proligand size to minimize such catalyst decomposition favors isomerization side-products resulting in reduced yields of the desired product. This study provides ligand design principles that guide the development of coordinatively flexible catalysts to achieve catalytic turnover in systems that rely upon protonolysis steps, as in hydroaminoalkylation.

Metal-Free Allylic C-H Amination

Allylic amination reactions of alkenes are useful tools to construct N-functionalized molecules and now one of the main research targets in the field of allylic oxidation reaction. Although many reactions using transition metal catalysts have been developed, the examples of metal-free systems are relatively limited. This short review focuses on recent reports about metal-free allylic C-H amination, and three types of the reactions, (1) enantioselective reactions using organobase catalysts, (2) iodine-mediated reaction systems, and (3) selenium-catalyzed reactions will be described.

One-Pot Chemoenzymatic Cascade for the Enantioselective C(1)-Allylation of Tetrahydroisoquinolines.

Herein, we report a one-pot, chemoenzymatic process for the synthesis of enantioenriched C(1)-allylated tetrahydroisoquinolines. This transformation couples a monoamine oxidase (MAO-N)-catalyzed oxidation with a metal catalyzed allylboration, followed by a biocatalytic deracemization to afford allylic amine derivatives in both high yields and good to high enantiomeric excess. The cascade is operationally simple, with all components added at the start of the reaction and can be used to generate key building blocks for further elaboration.

Merging Alkene Isomerization Enables Difunctionalization of Cyclic Enamines toward Ring-Fused Aminal Synthesis.

Here we report a Pd-catalyzed isomerization of alicyclic allyl amine to achieve the unprecedented α,β-difunctionalization of synthetically inaccessible trisubstituted cyclic enamine. The dual role of in situ formed enamine intermediate allows for the intermolecular formal [4 + 2] reaction with acrylamide or isatoic anhydride to simultaneously construct the C-C bond and C-N bond, thus realizing the expedient construction of [4.3.0]-aminal with excellent diastereoselectivity and high atom economy.

O- and N-Selective Electrophilic Activation of Allylic Alcohols and Amines in Pd-Catalyzed Direct Alkylation.

Catalytic control of chemoselectivity is crucial in the synthesis of highly functionalized compounds. Although there are reports of efficient chemoselective reactions of alcohols and amines as nucleophiles, there are no reports of the chemoselective activation of alcohols and amines as electrophiles. In this study, highly O- and N-selective electrophilic activation of allylic alcohols and amines was achieved in Pd-catalyzed direct allylic alkylation. Allylamines were inherently more reactive than allylic alcohols (N-selectivity). On the other hand, the addition of catalytic amounts of 9-phenanthreneboronic acid preferentially activated allylic alcohols over allylamines (O-selectivity). Density functional theory (DFT) calculations suggested that the N-selectivity is due to the selective activation of allylic amines with ammonium cations, and boronate formation accelerates the activation of allylic alcohols.

Development of Immobilized Carreira (Phosphoramidite, Olefin) Ligands and Application in Iridium-Catalyzed Asymmetric Allylic Amination

A family of polystyrene-supported (phosphoramidite, olefin) ligands L1-L4, based on the original design by Defieber and Carreira, has been developed and applied in iridium-catalyzed asymmetric allylic amination of unmasked allylic alcohols (27 examples, up to 99% ee). Among them, functional resins L1 and L4 exhibit important advantages such as easy preparation, ligand recyclability, and easy handling for sequential use. As a distinctive advantage, the catalytic use of the iridium complexes of L1 and L4 allows the straightforward reuse of a high percentage of the expensive iridium metal involved in the complexes, which is not achievable under homogeneous conditions with the corresponding monomeric complexes.

Indication of Pd-C or Cu-C Intermediate in Respective Bimetallic Nanoclusters Pd/Au-PVP or Cu/Au-PVP Catalyzed Oxidations of endo-4-Oxatricyclo[5.2.1.02,6]-8-decene and Tetrahydro-γ-carbolines.

Catalytic oxidations of tricyclic endo-norbornene-fused tetrahydrofuran with bimetallic nanoclusters Cu/Au-PVP and H2O2 or t-BuOOH as an oxidant provided C-H bond oxidation adjacent to the ether function and 4-oxa-tricyclo[5.2.1.0]-8,9-exo-epoxydecane (4), however, oxidation with Pd/Au-PVP took place at the C=C function giving epoxide 4 and oxidative three-bond forming dimeric product, dodecahydro-1,4:6,9-dimethanodibenzofurano[2,3-b:7,8-b']bisoxolane (5). Formation of the latter suggests the involvement of a reactive Pd-C intermediate. Similarly, oxidative C-C bond forming reactions were found in cycloaddition reactions of N2-Boc-1,2,3,4-tetrahydro-γ-carbolines and 2,3-dihydroxybenzoic acid with 2 - 5 mol% Cu/Au-PVP and H2O2 at 25 °C, providing two-bond-forming [4+2] cycloadducts. Under similar reaction conditions, Pd/Au-PVP did not produce the cycloadduct, indicating a need of complexation between Cu with the carboxylic acid group of 2,3-dihydroxybenzoic acid and allylic amine function of γ-carbolines in the cyclization reaction. The reported intermolecular coupling reactions using Pd/Au-PVP or Cu/Au-PVP nanocluster catalysts under oxidative conditions at 25 °C are unprecedented.

Practical synthesis of allylic amines via nickel-catalysed multicomponent coupling of alkenes, aldehydes, and amides.

Molecules with an allylic amine motif provide access to important building blocks and versatile applications of biologically relevant chemical space. The need for diverse allylic amines requires the development of increasingly general and modular multicomponent reactions for allylic amine synthesis. Herein, we report an efficient catalytic multicomponent coupling reaction of simple alkenes, aldehydes, and amides by combining nickel catalysis and Lewis acid catalysis, thus providing a practical, environmentally friendly, and modular protocol to build architecturally complex and functionally diverse allylic amines in a single step. The method is remarkably simple, shows broad functional-group tolerance, and facilitates the synthesis of drug-like allylic amines that are not readily accessible by other methods. The utilization of accessible starting materials and inexpensive Ni(ii) salt as the alternative precatalyst offers a significant practical advantage. In addition, the practicality of the process was also demonstrated in an efficient, gram-scale preparation of the prostaglandin agonist.

Palladium-catalyzed decarboxylative allylation of vinyloxazolidin-2-ones with sodium sulfinates: stereoselective assembly of highly functionalized (Z)-allylic amines.

We report a general approach to highly functionalized (Z)-allylic amines by decarboxylative allylation of vinyloxazolidin-2-ones. This process engages sodium sulfinates as nucleophiles to form a new carbon-sulfur bond, utilizing a palladium catalyst generated from Pd(OAc)2 and diphosphine ligand dpppe. The scope of the protocol is illustrated by the synthesis of 30 representative allylic amines with high regio- and stereoselectivity. Mechanistic studies show that the Z-selectivity of the reaction stems from the formation of a palladacycle intermediate through Pd-N chelation. The synthetic utility of this method was further exemplified by the gram-scale synthesis and subsequent transformations to various compounds.

A highly efficient method to access unprotected C-3 bifunctional quaternary 3-allyl-3-(amino)oxindoles.

A highly efficient Rh(II) catalyzed non-radical protocol to access NH-free C-3 bifunctional oxindoles, which possess 3-allyl and 3-amino simultaneously, was first achieved by employing an intermolecular [2,3]-sigmatropic rearrangement reaction between diazooxindoles and tertiary allylic amines. Utilizing readily available allylamines as the nitrogen and allyl source concurrently, a wide range of bio-active 3-allyl-3-(amino)oxindoles were obtained in excellent yields under very mild reaction conditions; meanwhile, the TON can be up to 90 000. Our study addresses a gap in the literature by investigating intermolecular rearrangements of ammonium ylides with diazoamides, which have been relatively understudied.

Stereoselective two-carbon ring expansion of allylic amines via electronic control of palladium-promoted equilibria.

General methodologies enabling the two-carbon homologation of pyrrolidine and piperidine systems have yet to be developed. Herein we report that palladium-catalysed allylic amine rearrangements enable efficient two-carbon ring expansion of 2-alkenyl pyrrolidine and piperidines to their azepane and azocane counterparts. Conditions are mild, tolerant of a range of functional groups and the process can occur with high enantioretention. The products formed undergo a range of orthogonal transformations, making them ideal scaffolds for the creation of compound libraries.

Surface Preparation and Cytocompatibility of Three-Dimensional Printed Fully Degraded Coronary Stents Using the Plasma Polymerization Technology

Vascular stents made based on three-dimensional (3D) printing technology for interventional therapy have become one of the more common clinical means to treat patients with severe coronary heart disease (CHD). However, the biocompatibility of stent surface needs to be further improved. Over the past years, many researchers have adopted surface modification technology to improve the cytocompatibility of vascular stents. In this work, plasma polymerization (PP) technology was employed to introduce the allylamine (AA) and nitrogen with different concentrations as auxiliary gases. After ionization, fragmentation, and recombination, the surface of the stent was deposited to form amine-rich coatings (AMMak membrane and AMMak-N membrane). The composition and surface morphology of the coating were analyzed by physical characterization (infrared, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), atomic force microscopy (AFM), contact angle (CA), etc.). In addition, the cytocompatibility of the coating before and after modification was evaluated by using the endothelial cells (EC) implantation test. The biodegradable substrate (MgZnMn, Fe) was employed to deposit the amine-rich coatings and evaluate their cytocompatibility. The results told that the polymeric coating had a higher concentration of amine group when the nitrogen flow rate was at 5 sccm, and the coating was conductive to the adhesion and proliferation of ECs by adsorbing proteins. After the introduction of biodegradable substrate, the amino group on the coating surface further improved the cytocompatibility of the material. The PP technology can be applied to prepare a relatively dense PP coating, which can be further precipitated and solvent-free deposition. Therefore, it is very suitable for modifying the surface of degradable vascular stent materials.

Direct and modular access to allylic amines via nickel-catalyzed three-component coupling

We herein report direct and modular access to allylic amines via Ni(0)-catalyzed three-component coupling of commercially available and inexpensive aldehydes, amines, and alkenes, without the additional steps for isolation of unstable imines.

Fragile intermediate identification and reactivity elucidation in electrochemical oxidative α-C(sp3)-H functionalization of tertiary amines.

The direct α-C(sp3)-H functionalization of widely available tertiary amines holds promise for the rapid construction of complex amine architectures. The activation of C(sp3)-H bonds through electron transfer and proton transfer by oxidants, photoredox catalysis and electrochemical oxidation have received wide attention recently. In these reactions, the direct capture and identification of the key reactive radical intermediates are technically difficult due to their short life-time. Herein, an online electrochemical mass spectrometry (MS) methodology was utilized to probe the short-lived intermediates in the electrochemical oxidative α-C(sp3)-H functionalization of tertiary amines. The resulting electrochemical oxidation intermediates, α-amino radical cation and iminium cation were successfully detected. Further, the α-amino C(sp3) radical added to the double bond of a phenyl trans-styryl sulfone, yielding another C(sp3) radical that leads to the final vinylation. Based on the mass spectrometric elucidation of the reactivity of the α-amino radical, a scale-up electrochemical radical vinylation methodology was established, with which a large variety of allylic amines with broad functional group tolerance were synthesized.

Insight into Stereocontrol in the Asymmetric Intramolecular Allylation with a tert-Butylsulfinamide Nucleophile: Application in the Synthesis of Chiral Isoindoline-1-Carboxylic Acid Esters.

The asymmetric induction afforded by a chiral sulfinyl group in a palladium/Brønsted-acid-catalyzed intramolecular allylic amination was investigated. Predictions of the diastereoselectivity for various substrates under assumed total thermodynamic control were obtained from density functional theory (DFT), and the correlation with experimental data demonstrates abrupt changes to kinetic control across the substrate scope. The resulting heterocyclic product was readily converted to valuable isoindoline-1-carboxylic acid esters by a two-step oxidation sequence, providing asymmetric access to a key unnatural α-amino acid scaffold.

Palladium-Catalyzed Branch- and Z-Selective Allylic C-H Amination with Aromatic Amines.

Allylamines are important building blocks in the synthesis of bioactive compounds. The direct coupling of allylic C-H bonds and commonly available amines is a major synthetic challenge. An allylic C-H amination of 1,4-dienes has been accomplished by palladium catalysis. With aromatic amines, branch-selective allylic aminations are favored to generate thermodynamically unstable Z-allylamines. In addition, more basic aliphatic cyclic amines can also engage in the reaction, but linear dienyl allylic amines are the major products.