Amine-Functionalized Polybutadiene Synthesis by Tunable Postpolymerization Hydroaminoalkylation.

Early transition metal-catalyzed hydroaminoalkylation is a powerful single-step method to selectively add amines to polybutadienes, offering an efficient strategy to access amine-functionalized polyolefins. Aryl and alkyl secondary amines were used with a tantalum catalyst to functionalize both 28 wt% (PBD13) and 70 wt% (PBD50) 1,2-polybutadiene polymers. The degree of amination was controlled by modifying amine and catalyst loading in both small- and multigram-scale reactions. The vinyl groups of 1,2-polybutadiene were aminated with ease, and unexpectedly the hydroaminoalkylation of challenging internal alkenes of the 1,4-polybutadiene unit was observed. This unanticipated reactivity was proposed to be due to a directing group effect. This hypothesis was supported with small-molecule model substrates, which also showed directed internal alkene amination. Increasing degrees of amination resulted in materials with dramatically higher and tunable glass transition temperature (Tg) values, due to the dynamic cross-linking accessible to hydrogen-bonding, amine-containing materials. Primary amine-functionalized polybutadiene was also prepared, demonstrating that a broad new class of amine-containing polyolefins can be accessed by postpolymerization hydroaminoalkylation.

Tantalum ureate complexes for photocatalytic hydroaminoalkylation.

Using a tantalum ureate pre-catalyst, photocatalytic hydroaminoalkylation of unactivated alkenes with unprotected amines at room temperature is demonstrated. The combination of Ta(CH2SiMe3)3Cl2 and a ureate ligand with a saturated cyclic backbone resulted in this unique reactivity. Preliminary investigations of the reaction mechanism suggest that both the thermal and photocatalytic hydroaminoalkylation reactions begin with N-H bond activation and subsequent metallaaziridine formation. However, a select tantalum ureate complex, through ligand to metal charge transfer (LMCT), results in photocatalyzed homolytic metal-carbon bond cleavage and subsequent addition to unactivated alkene to afford the desired carbon-carbon bond formation. Origins of ligand effects on promoting homolytic metal-carbon bond cleavage are explored computationally to support enhanced ligand design efforts.

One-Pot Sequential Hydroamination Protocol for N-Heterocycle Synthesis: One Method To Access Five Different Classes of Tri-Substituted Pyridines.

Tri-substituted pyridines are important scaffolds that can be found in a plethora of commercially available drugs. A one-pot general method for the selective synthesis of less explored/challenging patterns of tri-substituted pyridines is described. Hydroamination of alkynes with commercially available N-triphenylsilylamine generates N-silylenamines. These in situ generated N-silylenamines, upon reaction with α,ß-unsaturated carbonyl compounds and subsequent oxidation, furnish 25 examples of selectively substituted 2,4,5-, 2,3,4-, 3,4,5-, 2,3,5-, and 2,3,6-trisubstituted pyridines in up to 78% yield. The reaction features high functional group compatibility providing an expeditious and general approach for the assembly of selectively substituted tri-substituted pyridine derivatives. The robustness and practicality of the reaction have been demonstrated in a gram-scale reaction.

Vanadium pyridonates: dimerization, redox behaviour, and metal-ligand cooperativity.

The synthesis, structure, and reactivity of vanadium pyridonate complexes are described. Vanadium(III) pyridonate complexes were accessed through protonolysis and reduction of a tetrakis(amido)vanadium(IV) starting material. Bis(pyridonate) vanadium(IV) precursors could be isolated depending on the amount of proteoligand added. The targeted vanadium(III) species tend to form dimers, but monomeric complexes can be achieved in the presence of neutral donors such as amines or pyridine derivatives or through the use of sterically demanding proligands. The reduction process is proposed to involve dimeric intermediates and be mediated by the amine released from protonolysis, thereby forming the corresponding imine as a byproduct. Isolated amine complexes of vanadium(III) are presented. In contrast, bis(amidate)vanadium(IV) complexes were not found to undergo a similar reduction. This work informs on design principles for the synthesis and application of new vanadium pyridonate catalysts for transformations involving dimerization and PCET for changes in oxidation state.

The Catalytic Synthesis of N-Aryl Indoles Featuring an Alternative Disconnection. Hydroaminoalkylation for a Telescoped Reaction Sequence.

A tricatalytic telescoped synthesis toward C3-methyl-N-aryl indoline and indole products is reported. An in situ generated tantalum(V) ureate catalyst is used for the hydroaminoalkylation of o-chlorostyrene with N-methylaniline to first make a Csp3─Csp3 bond. Subsequent nickel-catalyzed C-N coupling forms N-aryl indolines, and if desired, subsequent oxidation to N-aryl indoles can be achieved using catalytic [Cu(MeCN)4]BF4 and tert-butylperoxy-2-ethylhexyl carbonate as the terminal oxidant. This strategy highlights an alternative C-C bond disconnection for the synthesis of indoles, which is enabled by the atom-economic hydroaminoalkylation reaction. The method was streamlined using a three-step, two-pot approach to afford up to 73% overall isolated yield of variously substituted C3-methyl-N-aryl indoles.

N-Silylamines in catalysis: synthesis and reactivity.

A summary of the catalytic synthesis and reactivity of N-silylated amines is presented. Dehydrocoupling of amines with silanes, hydrosilylation of imines and dealkenylative coupling of amines with vinylsilanes are three ways to achieve their catalytic syntheses. The resultant N-silylamines serve as substrates in a variety of reactions, including C-N and C-C bond forming reactions, and are preferred in transformations because of the facile Si-N hydrolytic cleavage to reveal free amine products upon reaction completion. This review highlights the distinct electronic properties of N-silyl amines, N-silyl imines and N-silyl enamines that result in complementary reactivity to that of parent non-silyl variants.

Hydroaminoalkylation for the Catalytic Addition of Amines to Alkenes or Alkynes: Diverse Mechanisms Enable Diverse Substrate Scope.

Hydroaminoalkylation is a powerful, atom-economic catalytic reaction for the reaction of amines with alkenes and alkynes. This C-H functionalization reaction allows for the atom-economic alkylation of amines using simple alkenes or alkynes as the alkylating agents. This transformation has significant potential for transformative approaches in the pharmaceutical, agrochemical, and fine chemical industries in the preparation of selectively substituted amines and N-heterocycles and shows promise in materials science for the synthesis of functional and responsive aminated materials. Different early transition-metal, late transition-metal, and photoredox catalysts mediate hydroaminoalkylation by distinct mechanistic pathways. These mechanistic insights have resulted in the development of new catalysts and reaction conditions to realize hydroaminoalkylation with a broad range of substrates: activated and unactivated, terminal and internal, C-C double and triple bonds with aryl or alkyl primary, secondary, or tertiary amines, including N-heterocyclic amines. By deploying select catalysts with specific substrate combinations, control over regioselectivity, diastereoselectivity, and enantioselectivity has been realized. Key barriers to widespread adoption of this reaction include air and moisture sensitivity for early transition-metal catalysts as well as a heavy dependence on amine protecting or directing groups for late transition-metal or photocatalytic routes. Advances in improved catalyst robustness, substrate scope, and regio-/stereoselective reactions with early- and late transition-metal catalysts, as well as photoredox catalysis, are highlighted, and opportunities for further catalyst and reaction development are included. This perspective shows that hydroaminoalkylation has the potential to be a disruptive and transformative strategy for the synthesis of selectively substituted amines and N-heterocycles from simple amines and alkenes.

Direct, Catalytic α-Alkylation of N-Heterocycles by Hydroaminoalkylation: Substrate Effects for Regiodivergent Product Formation.

Saturated N-heterocycles are prevalent in pharmaceutical and agrochemical industries, yet remain challenging to catalytically alkylate. Most strategies for C-H activation of these challenging substrates use protected amines or high loadings of precious metal catalysts. We report an early transition-metal system for the broad, robust, and direct alkylation of unprotected amine heterocycles with simple alkenes. Short reaction times are achieved using an in situ generated tantalum catalyst that avoids the use of bases, excess substrate, or additives. In most cases, this catalyst system is selective for the branched reaction product, including examples of products that are generated with excellent diastereoselectivity. Alkene electronic properties can be exploited for substrate-modified regioselectivity to access the alternative linear amine alkylation product with a group 5 catalyst. This method allows for the facile isolation of unprotected N-heterocyclic products, as useful substrates for further reactivity.

Using Catalysts To Make Catalysts: Titanium-Catalyzed Hydroamination To Access P,N-Ligands for Assembling Catalysts in One Pot.

Using a diamido-bis(amidate) titanium precatalyst, the hydroamination of alkynylphosphines afforded phosphinoenamine products. After reduction, 2-aminophosphines are prepared in excellent yield and on gram scale. A broad variety of alkynylphosphines and primary amines with different electronic and steric features are tolerated in this sequential transformation, enabling the rapid assembly of a collection of ligands. Additionally, intermediate phosphinoenamines can be used directly as proligands for coordination to transition metals using protonolysis or salt metathesis reactions. These transformations result in easy-to-use one pot protocols to prepare metal P,N-complexes for catalysis or small molecule activation.

Zirconium Catalyzed Hydroaminoalkylation for the Synthesis of α-Arylated Amines and N-Heterocycles.

The zirconium catalyzed hydroaminoalkylation of alkenes with N-aryl- and sterically demanding N-alkyl-α-arylated secondary amines by using commercially available Zr(NMe2 )4 is reported. N-phenyl- and N-isopropylbenzylamine are used as amine substrates to establish the alkene substrate scope. Exclusively linear products are obtained in the presence of bulky vinylsilanes. Challenging α-heteroarylated amines and functionalized alkene substrates are compatible with this easy to use catalyst, affording a new disconnection strategy for the atom- and step-economic preparation of selectively substituted saturated α-arylated heterocycles.

Commodity Polymers to Functional Aminated Materials: Single-Step and Atom-Economic Synthesis by Hydroaminoalkylation.

Hydroaminoalkylation (HAA) is demonstrated to be a promising postpolymerization route to catalytically prepare amine-functionalized atactic polypropylene. Using a recently reported tantalum catalyst supported by a N,O-chelating cyclic ureate ligand, vinyl-terminated polypropylene (VTPP) is transformed into both aryl and alkyl secondary amine-terminated polyolefins. Early transition-metal-catalyzed hydroaminoalkylation avoids protection/deprotection protocols typically required for secondary amine synthesis. This single-step reaction can be performed at multigram scale with minimal solvent and is atom economic, thereby allowing for optimized product isolation. Materials are characterized by multinuclear NMR spectroscopy, IR spectroscopy, DSC, and TGA. The utility of the reactive and unprotected amine terminus is highlighted by the installation of a fluorescent end group and the assembly of a graft copolymer by condensation of the secondary amine terminus with carboxylic acid moieties.

Direct metal-carbon bonding in symmetric bis(C-H) agostic nickel(i) complexes.

Agostic interactions are examples of σ-type interactions, typically resulting from interactions between C-H σ-bonds with empty transition metal d orbitals. Such interactions often reflect the first step in transition metal-catalysed C-H activation processes and thus are of critical importance in understanding and controlling σ bond activation chemistries. Herein, we report on the unusual electronic structure of linear electron-rich d9 Ni(i) complexes with symmetric bis(C-H) agostic interactions. A combination of Ni K edge and L edge XAS with supporting TD-DFT/DFT calculations reveals an unconventional covalent agostic interaction with limited contributions from the valence Ni 3d orbitals. The agostic interaction is driven via the empty Ni 4p orbitals. The surprisingly strong Ni 4p-derived agostic interaction is dominated by σ contributions with minor π contributions. The resulting ligand-metal donation occurs directly along the C-Ni bond axis, reflecting a novel mode of bis-agostic bonding.

Zirconium-Catalyzed Hydroaminoalkylation of Alkynes for the Synthesis of Allylic Amines.

A zirconium-catalyzed hydroaminoalkylation of alkynes to access α,ß,γ-substituted allylic amines in an atom-economic fashion is reported. The reaction is compatible with N-(trimethylsilyl)benzylamine and a variety of N-benzylaniline substrates, with the latter giving the allylic amine as the sole organic product. Various internal alkynes with electron-withdrawing and electron-donating substituents were tolerated. Model intermediates of the reaction were synthesized and structurally characterized. Stoichiometric studies on key intermediates revealed that the open coordination sphere at zirconium, imparted by the tethered bis(ureate) ligand, is crucial for the coordination of neutral donors. These complexes may serve as models for the inner-sphere protonolysis reactions required for catalytic turnover.

Cyclic Ureate Tantalum Catalyst for Preferential Hydroaminoalkylation with Aliphatic Amines: Mechanistic Insights into Substrate Controlled Reactivity.

The efficient and catalytic amination of unactivated alkenes with simple secondary alkyl amines is preferentially achieved. A sterically accessible, N,O-chelated cyclic ureate tantalum catalyst was prepared and characterized by X-ray crystallography. This optimized catalyst can be used for the hydroaminoalkylation of 1-octene with a variety of aryl and alkyl amines, but notably enhanced catalytic activity can be realized with challenging N-alkyl secondary amine substrates. This catalyst offers turnover frequencies of up to 60 h-1, affording full conversion at 5 mol% catalyst loading in approximately 20 min with these nucleophilic amines. Mechanistic investigations, including kinetic isotope effect (KIE) studies, reveal that catalytic turnover is limited by protonolysis of the intermediate 5-membered azametallacycle. A Hammett kinetic analysis shows that catalytic turnover is promoted by electron rich amine substrates that enable catalytic turnover. This more active catalyst is shown to be effective for late stage drug modification.

Titanium catalysis for the synthesis of fine chemicals - development and trends.

Titanium is the second most abundant transition metal and is already a key player in important industrial processes (e.g. polyethylene). Titanium is an attractive metal to use for catalytic transformations as it is a versatile and inexpensive metal of low-toxicity and of established biocompatibility. However, its potential use as a catalyst for the synthesis of fine chemicals, pharmaceuticals and agrochemicals is often overlooked due to its oxophilic, Lewis acidic character, which renders complexes of titanium less functional group tolerant than their late transition metal counterparts. Nevertheless, three different fields of research in titanium catalysis have drawn attention in recent years: formal redox catalysis, hydroamination and hydroaminoalkylation. For these reactions, titanium offers new approaches and alternative pathways/mechanisms that are complementary to late transition metal-based catalysis. This review focuses on advances in fine chemical synthesis by titanium-catalyzed reactions featuring redox transformations and two important hydrofunctionalization reactions, hydroamination and hydroaminoalkylation. Starting from the late 90s, we provide an overview of historic inspirational contributions, both catalytic and stoichiometric, and the latest insights in catalyst design efforts, mechanistic details and utility of the three different classes of transformations. Insights to enhance catalyst activity as well as catalyst controlled regio- and stereoselectivities are presented. Illustrative examples that highlight substrate scope and the application of titanium catalysis to the synthesis of complex organic small molecules, natural products and materials are shown. Finally, opportunities and strategies for on-going research and development activities in titanium catalysis are highlighted.

Vanadium Pyridonate Catalysts: Isolation of Intermediates in the Reductive Coupling of Alcohols.

The reductive coupling of alcohols using vanadium pyridonate catalysts is reported. This attractive approach for C(sp3)-C(sp3) bond formation uses an oxophilic, earth-abundant metal for a catalytic deoxygenation reaction. Several pyridonate complexes of vanadium were synthesized, giving insight into the coordination chemistry of this understudied class of compounds. Isolated intermediates provide experimental mechanistic evidence that complements reported computational mechanistic proposals for the reductive coupling of alcohols. In contrast to previous mononuclear vanadium(V)/vanadium(III)/vanadium(IV) cycles, this pyridonate catalyst system is proposed to proceed by a vanadium(III)/vanadium(IV) cycle involving bimetallic intermediates.

Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary Amines.

Primary amine products have been prepared using zirconium-catalyzed hydroaminoalkylation of alkenes with N-silylated benzylamine substrates. Catalysis using commercially available Zr(NMe2)4 affords an alternative disconnection to access α-arylated primary amines upon aqueous workup. Substrate-dependent regio- and diastereoselectivity of the reaction is observed. Bulky substituents on the terminal alkene exclusively generate the linear regioisomer. This atom-economic catalytic strategy for the synthesis of building blocks that can undergo further synthetic elaboration is highlighted in the preparation of trifluoroethylated α-arylated amines.