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.

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.

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.

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.

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.

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.

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.

Regio- and Stereoselective Hydroamination of Alkynes Using an Ammonia Surrogate: Synthesis of N-Silylenamines as Reactive Synthons.

An anti-Markovnikov selective hydroamination of alkynes with N-silylamines to afford N-silylenamines is reported. The reaction is catalyzed by a bis(amidate)bis(amido)Ti(IV) catalyst and is compatible with a variety of terminal and internal alkynes. Stoichiometric mechanistic studies were also performed. This method easily affords interesting N-silylenamine synthons in good to excellent yields and the easily removable silyl protecting group enables the catalytic synthesis of primary amines.

Understanding Ni(II)-Mediated C(sp3)-H Activation: Tertiary Ureas as Model Substrates.

We report a mechanistic study of C(sp3)-H bond activation mediated by nickel. Cyclometalated Ni(II) ureate [(PEt3)Ni(κ3- C,N,N-(CH2)N(Cy)(CO)N((N)-quinolin-8-yl))] was synthesized and isolated from the urea precursor, (Me)(Cy)N(CO)N(H)(quinolin-8-yl), via C(sp3)-H activation. We investigated the effects of solvents and base additives on the rate of C-H activation. Kinetic isotope effect experiments showed that C-H activation is rate determining. Through deuterium labeling and protonation studies, we also showed that C-H activation can be reversible. We extended this reaction to a range of ureas with primary and secondary C(sp3)-H bonds, which activate readily to form analogous nickelated products. Finally, we showed that carboxylate additives assist with both ligand dissociation and initial N-H bond activation, consistent with a concerted metalation-deprotonation mechanism.

Ti-Catalyzed Hydroamination for the Synthesis of Amine-Containing π-Conjugated Materials.

A series of conjugated enamines were prepared by Ti catalyzed anti-Markovnikov hydroamination. The synthetic route is efficient with yields of up to 94 % and the 100 % atom efficiency of the reaction means that these products are easily isolated and purified. Due to the extended conjugated system, the enamine tautomers were observed exclusively in both solid and solution phases, as determined by X-ray crystallography and NMR spectroscopy. These new conjugated molecules, with N incorporated into the backbone, show interesting photophysical properties including photo-luminescent quantum yields of up to 0.26. Notably, through the incorporation of B to give a donor-acceptor π-conjugated system, a redshift of approximately 100 nm is observed for the emission maximum along with the anticipated solvatochromic shifts.

1,3-N,O-Complexes of late transition metals. Ligands with flexible bonding modes and reaction profiles.

1,3-N,O-Chelating ligands are ubiquitous in nature owing to their occurrence as α-chiral amino acids in metalloproteins. These structural units also display diverse coordination modes, which lend themselves to applications in catalysis as well as novel fundamental stoichiometric reactivity, including the activation of inert bonds. This review comments on recent developments in N,O-ligated late transition metal complexes with an emphasis on preparation, characterization, and reactivity.

Catalytic and Atom-Economic Csp3 -Csp3 Bond Formation: Alkyl Tantalum Ureates for Hydroaminoalkylation.

Atom-economic and regioselective Csp3 -Csp3 bond formation has been achieved by rapid C-H alkylation of unprotected secondary arylamines with unactivated alkenes. The combination of Ta(CH2 SiMe3 )3 Cl2 , and a ureate N,O-chelating-ligand salt gives catalytic systems prepared in situ that can realize high yields of ß-alkylated aniline derivatives from either terminal or internal alkene substrates. These new catalyst systems realize C-H alkylation in as little as one hour and for the first time a 1:1 stoichiometry of alkene and amine substrates results in high yielding syntheses of isolated amine products by simple filtration and concentration.

Bis(tert-butylimido)bis(N,O-chelate)tungsten(VI) Complexes: Probing Amidate and Pyridonate Hemilability.

Four new bis(tert-butylimido)bis(N,O-chelate)tungsten(VI) complexes (3-6), in which the N,O-chelate is an amidate or pyridonate ligand, have been synthesized and characterized. Computational analysis has been used to calculate the relative energies of different stereoisomers and shown how the steric demand of each ligand influences coordination and bonding modes. The electronically saturated complexes have been employed to evaluate 1,3-N,O-chelated metal-ligand interactions. Complexes 3-6 were treated with electrophilic reagents, which resulted in strikingly different reactivity patterns between the amidate and the pyridonate ligated complexes. The observed reactivity differences are accompanied by direct observation of different trends in the hemilability of these two different classes of 1,3-N,O-chelates.

Toward anti-Markovnikov 1-Alkyne O-Phosphoramidation: Exploiting Metal-Ligand Cooperativity in a 1,3-N,O-Chelated Cp*Ir(III) Complex.

Metal-ligand cooperation between iridium(III) and a 1,3-N,O-chelating phosphoramidate ligand has been used to develop a protocol for the intermolecular O-phosphoramidation of 1-alkynes. This selective C-O bond-forming reaction differs from that of standard amidation reactions, highlighting the ability to control N- or O-functionalization based on judicious choice of N,O-chelating ligand and metal center. Advances toward the development of catalytic anti-Markovnikov O-phosphoramidation using iridium(III), including characterization of rare reactive intermediates that invoke 1,3-bidentate donor ligand hemilability, are disclosed.

N,O-Chelating Four-Membered Metallacyclic Titanium(IV) Complexes for Atom-Economic Catalytic Reactions.

Titanium, as the second most abundant transition metal in the earth's crust, lends itself as a sustainable and inexpensive resource in catalysis. Its nontoxicity and biocompatibility are also attractive features for handling and disposal. Titanium has excelled as a catalyst for a broad range of transformations, including ethylene and α-olefin polymerizations. However, many reactions relevant to fine chemical synthesis have preferrentially employed late transition metals, and reactive, inexpensive early transition metals have been largely overlooked. In addition to promising reactivity, titanium complexes feature more robust character compared with some other highly Lewis-acidic metals such as those found in the lanthanide series. Since the advent of modulating ligand scaffolds, titanium has found use in a growing variety of reactions as a versatile homogeneous catalyst. These catalytic transformations include hydrofunctionalization reactions (adding an element-hydrogen (E-H) bond across a C-C multiple bond), as well as the ring-opening polymerization of cyclic esters, all of which are atom-economic transformations. Our investigations have focused on tight bite angle monoanionic N,O-chelating ligands, forming four-membered metallacycles. These ligand sets, including amidates, ureates, pyridonates, and sulfonamidates, have flexible binding modes offering a range of stable and reactive intermediates necessary for catalytic activity. Additionally, the simple form of these ligands leads to easily prepared proligands, along with facile tuning of steric and electronic factors. A sterically bulky titanium amidate complex has proven to be a leading catalyst for the selective formation of anti-Markovnikov addition products via intermolecular hydroamination of terminal alkynes, while sterically less demanding titanium pyridonates have opened the path to the selective formation of amine substituted cycloalkanes via the intramolecular hydroaminoalkylation of aminoalkenes over the competing hydroamination pathway. Sulfonamidates have boosted reactivity for hydrofunctionalization and polymerization reactions compared with amide ligands not bearing a sulfonyl group. N,O-Chelated titanium complexes have been used to synthesize ultrahigh molecular weight polyethylene and have been utilized in the challenging task of realizing equal incorporation of two different cyclic esters in a random ring-opening copolymerization. These discrete complexes have allowed for careful study of fundamental coordination chemistry and stoichiometric organometallic investigations. With inexpensive starting materials and modular ligands, titanium N,O-chelated complexes are well-suited to address the challenges of achieving greener chemical processes while accessing useful reaction manifolds for sustainable synthesis.

Phosphoramidate-Supported Cp*Ir(III) Aminoborane H2 B=NR2 Complexes: Synthesis, Structure, and Solution Dynamics.

Reaction of aminoboranes H2 B=NR2 (R=iPr or Cy) with the cationic Cp*Ir(III) phosphoramidate complex [IrCp*{κ(2) -N,O-Xyl(N)P(O)(OEt)2 }][BAr(F) 4 ] generates the aminoborane complexes [IrCp*(H){κ(1) -N-η(2) -HB-Xyl(N)P(OBHNR2 )(OEt)2 }][BAr(F) 4 ] (R=iPr or Cy) in which coordination of a P=O bond with boron weakens the B=N multiple bond. For these complexes, solution- and solid-state, as well as DFT computational techniques, have been employed to substantiate B-N bond rotation of the coordinated aminoborane.

Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights To Realize the Enantioselective Synthesis of Piperazines.

An efficient and practical catalytic approach for the enantioselective synthesis of 3-substituted morpholines through a tandem sequential one-pot reaction employing both hydroamination and asymmetric transfer hydrogenation reactions is described. Starting from ether-containing aminoalkyne substrates, a commercially available bis(amidate)bis(amido)Ti catalyst is utilized to yield a cyclic imine that is subsequently reduced using the Noyori-Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η6-p-cymene), to afford chiral 3-substituted morpholines in good yield and enantiomeric excesses of >95%. A wide range of functional groups is tolerated. Substrate scope investigations suggest that hydrogen-bonding interactions between the oxygen in the backbone of the ether-containing substrate and the [(S,S)-Ts-DPEN] ligand of the Ru catalyst are crucial for obtaining high ee's. This insight led to a mechanistic proposal that predicts the observed absolute stereochemistry. Most importantly, this mechanistic insight allowed for the extension of this strategy to include N as an alternative hydrogen bond acceptor that could be incorporated into the substrate. Thus, the catalytic, enantioselective synthesis of 3-substituted piperazines is also demonstrated.