N−H Imine as a Powerful Directing Group for Cobalt‐Catalyzed Olefin Hydroarylation

N‐alkyl and N‐aryl imines have been frequently used as directing groups in rhodium‐ and cobalt‐catalyzed hydroarylation reactions of olefins and alkynes. However, the scope of such hydroarylation reactions has been limited by the difficulty of preparation of sterically hindered imines by condensation, and also by the steric bulkiness of the imine group itself. Reported herein is that an N?H imine serves as an alternative and highly effective directing group for cobalt‐catalyzed hydroarylation of olefins, and unlocks many of the limitations associated with the previously employed N‐aryl imine directing group. The power of this minimal nitrogen directing group is manifested in a fourfold ortho alkylation of benzophenone imine, and it occurs rapidly at ambient temperature.     

Dynamic covalent polypeptides showing tunable secondary structures and thermoresponsiveness

Lysine‐based polypeptides can be afforded with steerable secondary structures and tunable thermoresponsiveness through dynamic covalent OEGylation. These polypeptides were formed through dynamic imine linkage via reactions of amino moieties from poly(l ‐lysine)s with aldehydes from oligoethylene glycol (OEG)‐based dendrons. In addition to solution concentrations and pH values, macromolecular effect was found to play an important role on the imine formation. OEGylated polypeptides showed characteristic thermoresponsive properties, and their phase transition temperatures were governed predominately by terminal groups and the coverage of OEG dendrons. Notably, thermally induced aggregation would enhance the imine formation even at elevated temperature. In contrast to the covalent polypeptide representatives, the dynamic covalent polypeptides conveyed different thermoresponsiveness due to imine linkages, and their phase transition temperatures could be tuned simply by varying ratios of OEG dendrons with different hydrophilicity. Furthermore, helical conformation of these polypeptides was enhanced with attachment of OEG dendrons, and could be reversibly switched through thermally induced aggregation. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 33–41     

Continuous‐Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet Oxygen

Primary and secondary amines can be rapidly and quantitatively oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable‐temperature continuous‐flow LED‐photoreactor with a catalytic amount of tetraphenylporphyrin as the sensitizer. α‐Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an in situ imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addition and yielded secondary α‐aminonitriles. Primary α‐aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at –50 °C. This atom‐economic and protecting‐group‐free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert‐leucine hydrochloride from neopentylamine.     

Quantification and Prediction of Imine Formation Kinetics in Aqueous Solution by Microfluidic NMR Spectroscopy

Quantitatively predicting the reactivity of dynamic covalent reaction is essential to understand and rationally design complex structures and reaction networks. Herein, the reactivity of aldehydes and amines in various rapid imine formation in aqueous solution by microfluidic NMR spectroscopy was quantified. Investigation of reaction kinetics allowed to quantify the forward rate constants k₊ by an empirical equation, of which three independent parameters were introduced as reactivity parameters of aldehydes (S_E, E) and amines (N). Furthermore, these reactivity parameters were successfully used to predict the unknown forward rate constants of imine formation. Finally, two competitive reaction networks were rationally designed based on the proposed reactivity parameters. Our work has demonstrated the capability of microfluidic NMR spectroscopy in quantifying the kinetics of label-free chemical reactions, especially rapid reactions that are complete in minutes.     

Pt-Sn/γ-Al2O3-catalyzed highly efficient direct synthesis of secondary and tertiary amines and imines

Versatile syntheses of secondary and tertiary amines by highly efficient direct N‐alkylation of primary and secondary amines with alcohols or by deaminative self‐coupling of primary amines have been successfully realized by means of a heterogeneous bimetallic Pt–Sn/γ‐Al₂O₃ catalyst (0.5 wt % Pt, Pt/Sn molar ratio=1:3) through a borrowing‐hydrogen strategy. In the presence of oxygen, imines were also efficiently prepared from the tandem reactions of amines with alcohols or between two primary amines. The proposed mechanism reveals that an alcohol or amine substrate is initially dehydrogenated to an aldehyde/ketone or NH‐imine with concomitant formation of a [PtSn] hydride. Condensation of the aldehyde/ketone species or deamination of the NH‐imine intermediate with another molecule of amine forms an N‐substituted imine which is then reduced to a new amine product by the in‐situ generated [PtSn] hydride under a nitrogen atmosphere or remains unchanged as the final product under an oxygen atmosphere. The Pt–Sn/γ‐Al₂O₃ catalyst can be easily recycled without Pt metal leaching and has exhibited very high catalytic activity toward a wide range of amine and alcohol substrates, which suggests potential for application in the direct production of secondary and tertiary amines and N‐substituted imines.     

Reactive interaction of aromatic amines with dialdehyde cellulose gel

A new chromatographic method was developed for separation of amines based on their interaction with aldehyde groups in stationary phase. Expecting specific interaction with aldehyde groups through imine formation (Schiff base), we introduced dialdehyde groups to a commercial cellulose packing by periodate oxidation and examined eluting behavior of various aromatic amines. Primary amines with acid dissociation constants (pKa) greater than 6 showed no delay at pHs of 4.0–5.5, indicating the lack of interaction because of complete protonation. Primary amines with pKa less than 6 showed remarkable delays according to the amount of aldehyde groups on cellulose. The delay was dependent on the pH of eluent. The amines with pKa of 4–5.3 eluted faster at lower pH, apparently because of the change in proportion of free and protonated species. Amines with pKa less than 3.4 also showed delays but they eluted slower at lower pH. The latter behavior can be ascribed to the change in the ratio of free/protonated species of imines formed. Certain degree of steric effect was also noted, that is, compounds with a primary amino group adjacent to bulky substituents (ortho compounds) showed weaker interaction with aldehyde groups than meta- and para-isomers.     

Mechanistic investigation of imine formation in ruthenium‐catalyzed N‐alkylation of amines with alcohols

Imines are observed frequently in ruthenium‐catalyzed N‐alkylation of amines with alcohols. Herein, nitrogen–phosphine functionalized carbene ligands were developed and used in ruthenium‐catalyzed N‐alkylation to explore the mechanism of imine formation. The results showed that strongly electron‐donating ligands were beneficial for imine formation and alcohol dehydrogenation to generate acid. In addition, with an increase of electron density of nitrogen atom in substituted amines, the yield of imines in N‐alkylation was improved. At the same time, with electron‐rich imines as substrates, the transfer hydrogenation of imines became difficult. It is suggested that strongly electron‐donating ligands and substrates caused an increase of electron density on the ruthenium center, which resulted in the elimination of hydrogen atoms in active species [LRuH₂] as hydrogen gas rather than transfer onto the imine coordinated with the ruthenium center.     

Dynamic Covalent Organocatalysts Discovered from Catalytic Systems through Rapid Deconvolution Screening

The first example of a bifunctional organocatalyst assembled through dynamic covalent chemistry (DCC) is described. The catalyst is based on reversible imine chemistry and can catalyze the Morita–Baylis–Hillman (MBH) reaction of enones with aldehydes or N‐tosyl imines. Furthermore, these dynamic catalysts were shown to be optimizable through a systemic screening approach, in which large mixtures of catalyst structures were generated, and the optimal catalyst could be directly identified by using dynamic deconvolution. This strategy allowed one‐pot synthesis and in situ evaluation of several potential catalysts without the need to separate, characterize, and purify each individual structure. The systems were furthermore shown to catalyze and re‐equilibrate their own formation through a previously unknown thiourea‐catalyzed transimination process.     

Organocatalysis of CN/CN and CC/CN Exchange in Dynamic Covalent Chemistry

The reversibly formed C?N bond plays a very important role in dynamic covalent chemistry and the C?N/C?N exchange of components between different imine constituents to create dynamic covalent libraries has been extensively used. To facilitate diversity generation, we have investigated an organocatalyzed approach, using L ‐proline as catalyst, to accelerate the formation of dynamic libraries of [n×n] imine components. The organocatalysis methodology has also been extended, under somewhat modified conditions, to reversible C?C/C?N exchange processes between Knoevenagel derivatives of barbituric acid and imines, allowing for the generation of increased diversity.     

Visible‐Light‐Induced Selective Photocatalytic Aerobic Oxidation of Amines into Imines on TiO2

Imines are important intermediates for the synthesis of fine chemicals, pharmaceuticals, and agricultural chemicals. Selective oxidation of amines into their corresponding imines with dioxygen is one of the most‐fundamental chemical transformations. Herein, we report the oxidation of a series of benzylic amines into their corresponding imines with atmospheric dioxygen as the oxidant on a surface of anatase TiO₂ under visible‐light irradiation (λ>420 nm). The visible‐light response of this system was caused by the formation of a surface complex through the adsorption of a benzylic amine onto the surface of TiO₂. From the analysis of products of specially designed benzylic amines, we demonstrated that a highly selective oxygenation reaction proceeds via an oxygen‐transfer mechanism to afford the corresponding carbonyl compound, whose further condensation with an amine would generate the final imine product. We found that when primary benzylic amines (13 examples), were chosen as the substrates, moderate to excellent selectivities for the imine products were achieved (ca. 38–94 %) in moderate to excellent conversion rates (ca. 44–95 %). When secondary benzylic amines (15 examples) were chosen as the substrates, both the corresponding imines and aldehydes were detected as the main products with moderate to high conversion rates (ca. 18–100 %) and lower selectivities for the imine products (ca. 14–69 %). When tribenzylamine was chosen as the substrate, imine (27 %), dibenzylamine (24 %), and benzaldehyde products (39 %) were obtained in a conversion of 50 %. This report can be viewed as a prototypical system for the activation of C? H bonds adjacent to heteroatoms such as N, O, and S atoms, and oxofuctionalization with air or dioxygen as the terminal oxidant under visible‐light irradiation using TiO₂ as the photocatalyst.     

Intramolecular Aza‐Diels–Alder Reactions of ortho‐Quinone Methide Imines: Rapid,Catalytic, and Enantioselective Assembly of Benzannulated Quinolizidines

Aza‐Diels–Alder reactions (ADARs) are powerful processes that furnish N‐heterocycles in a straightforward fashion. Intramolecular variants offer the additional possibility of generating bi‐ and polycyclic systems with high stereoselectivity. We report herein a novel Brønsted acid catalyzed process in which ortho‐quinone methide imines tethered to the dienophile via the N substituent react in an intramolecular ADAR to form complex quinolizidines and oxazinoquinolines in a one‐step process. The reactions proceed under very mild conditions, with very good yields and good to very good diastereo‐ and enantioselectivities. Furthermore, the process was extended to a domino reaction that efficiently combines substrate synthesis, ortho‐quinone methide imine formation, and ADAR.     

Lewis Acid Mediated Vinyl‐Transfer Reaction of Alkynes to N‐Alkylimines by Using the N‐Alkyl Residue as a Sacrificial Hydrogen Donor

A variety of N‐alkyl‐α,α‐dichloroaldimines were vinylated by terminal acetylenes in the presence of Lewis acids such as In(OTf)₃ or BF₃ ? OEt₂ and hexafluoroisopropanol (HFIP) as an additive. The reaction proceeds at ambient temperature and leads to geometrically pure allylic β,β‐dichloroamines. This approach is complementary to previously reported transition‐metal‐catalyzed vinyl‐transfer methods, which are not applicable to aliphatic imines and are restricted to imines that contain an electron‐withdrawing nitrogen substituent. In the present approach, terminal alkynes were used as a source of the vinyl residue, and the N‐alkyl moiety of the imine acts as a sacrificial hydrogen donor. The additional advantage of this methodology is the fact that no external toxic or hazardous reducing agents or molecular hydrogen has to be used. This new methodology nicely combines a C(sp²)? C(sp) bond formation, hydride transfer, and an unusual cleavage of an unactivated C? N bond, thereby giving rise to functionalized primary allylic amines. A detailed experimental study supported by DFT calculations of the mechanism has been done.     

Catalytic Asymmetric Synthesis of 3‐Indolyl Methanamines Using Unprotected Indoles and N‐Boc Imines under Basic Conditions

A chiral imidazolidine‐containing NCN/Pd‐OTf catalyst ( C4 ) promoted the nucleophilic addition of unprotected indoles to N‐Boc imines. Using sulfinyl amines as the N‐Boc imine precursors, the combined use of C4 with K₂CO₃ activated the NH indoles to give chiral 3‐indolyl methanamines with up to 98 % ee. Compared with conventional acid‐catalyzed Friedel–Crafts reactions, this reaction proceeds under mildly basic conditions and is advantageous for the use of acid‐sensitive substrates.     

Dynamic Covalent Chemistry within Biphenyl Scaffolds: Reversible Covalent Bonding,Control of Selectivity,and Chirality Sensing with a Single System

Axial chirality is a prevalent and important phenomenon in chemistry. Herein we report a combination of dynamic covalent chemistry and axial chirality for the development of a versatile platform for the binding and chirality sensing of multiple classes of mononucleophiles. An equilibrium between an open aldehyde and its cyclic hemiaminal within biphenyl derivatives enabled the dynamic incorporation of a broad range of alcohols, thiols, primary amines, and secondary amines with high efficiency. Selectivity toward different classes of nucleophiles was also achieved by regulating the distinct reactivity of the system with external stimuli. Through induced helicity as a result of central‐to‐axial chirality transfer, the handedness and ee values of chiral monoalcohol and monoamine analytes were reported by circular dichroism. The strategies introduced herein should find application in many contexts, including assembly, sensing, and labeling.     

Metal‐Ion‐Induced Switch of Liquid‐Crystalline Orientation of Metallomacrocycles

A new series of shape‐persistent imine‐bridged macrocycles were synthesized based on dynamic covalent chemistry. The macrocycles had an alternating sequence of dibenzothiophene and N,N′‐bis(salicylidene)‐ethylenediamine (salen) tethering branched alkyl chains. The macrocycles and tetranuclear metallomacrocycles bearing long and branched alkyl chains exhibited thermotropic columnar liquid‐crystalline phases over a wide temperature range and the metallomacrocycles greatly depended on the characteristics of the coordinated metal ions. The metal‐free macrocycle showed a liquid‐crystalline phase with a lamellar structure and poor birefringence. In sharp contrast, the macrocyclic Ni complex showed a columnar oblique liquid‐crystalline phase, whereas the Pd and Cu complexes showed columnar liquid‐crystalline phases with a lamellar structure. The macroscopic organization and thermal properties of the corresponding liquid‐crystalline metallomacrocycles were significantly dependent on the subtle structural differences among the planar macrocycles, which were revealed by single‐crystal X‐ray crystallographic analysis of the macrocycles with shorter alkyl chains.     

Control of Imine Exchange Kinetics with Photoswitches to Modulate Self‐Healing in Polysiloxane Networks by Light Illumination

Various aldehyde‐containing photoswitches have been developed whose reactivity toward amines can be controlled externally. A thermally stable bifunctional diarylethene, which in its ring‐closed form exhibits imine formation accelerated by one order of magnitude, was used as a photoswitchable crosslinker and mixed with a commercially available amino‐functionalized polysiloxane to yield a rubbery material with viscoelastic and self‐healing properties that can be reversibly tuned by irradiation.     

Visible-light-induced selective photocatalytic aerobic oxidation of amines into imines on TiO2

Imines are important intermediates for the synthesis of fine chemicals, pharmaceuticals, and agricultural chemicals. Selective oxidation of amines into their corresponding imines with dioxygen is one of the most-fundamental chemical transformations. Herein, we report the oxidation of a series of benzylic amines into their corresponding imines with atmospheric dioxygen as the oxidant on a surface of anatase TiO(2) under visible-light irradiation (λ>420 nm). The visible-light response of this system was caused by the formation of a surface complex through the adsorption of a benzylic amine onto the surface of TiO(2). From the analysis of products of specially designed benzylic amines, we demonstrated that a highly selective oxygenation reaction proceeds via an oxygen-transfer mechanism to afford the corresponding carbonyl compound, whose further condensation with an amine would generate the final imine product. We found that when primary benzylic amines (13 examples), were chosen as the substrates, moderate to excellent selectivities for the imine products were achieved (ca. 38-94%) in moderate to excellent conversion rates (ca. 44-95%). When secondary benzylic amines (15 examples) were chosen as the substrates, both the corresponding imines and aldehydes were detected as the main products with moderate to high conversion rates (ca. 18-100%) and lower selectivities for the imine products (ca. 14-69%). When tribenzylamine was chosen as the substrate, imine (27%), dibenzylamine (24%), and benzaldehyde products (39%) were obtained in a conversion of 50%. This report can be viewed as a prototypical system for the activation of C-H bonds adjacent to heteroatoms such as N, O, and S atoms, and oxofuctionalization with air or dioxygen as the terminal oxidant under visible-light irradiation using TiO(2) as the photocatalyst.     

Asymmetric Mannich Reaction of Aryl Methyl Ketones with Cyclic Imines Benzo[e][1,2,3]oxathiazine 2,2‐Dioxides Catalyzed by Cinchona Alkaloid‐based Primary Amines

Aryl ketones represent problematic substrates for asymmetric Mannich reactions due to a large steric hindrance exhibited by such compound species. A highly enantioselective direct Mannich reaction of aryl methyl ketones with cyclic imine benzo[e][1,2,3]oxathiazine 2,2‐dioxides could be successfully carried out utilizing a combination of cinchona alkaloid‐derived primary amines with trifluoroacetic acid (TFA); the primary amines feature a superior catalytic efficacy over secondary amines with a variety of sterically hindered carbonyl compounds as substrates. The reaction proceeded well with various cyclic imines in 89–97 % ee and with various aryl methyl ketones in 85–98 % ee. Moreover, the aryl carbonyl of a Mannich product could be transformed to ketoxime, which further undergoes a Beckmann rearrangement to produce an amide compound while maintaining enantioselectivity.     

Comb‐like polymers pendanted with elastin‐like peptides showing sharp and tunable thermoresponsiveness through dynamic covalent chemistry

Comb‐like polymers carrying two elastin‐like polypeptide (ELP) pendants in each repeat unit were synthesized. The densely attached peptide chains afford these polymers with sharp thermally induced phase transitions, and their lower critical solution temperature (LCST) can be varied with molecular weights, solution pH and salt concentrations. Through amino terminals in ELP pendants, oligoethylene glycol (OEG)‐based dendrons cored with aldehyde were attached to the polymers through dynamic covalent imines. By virtue of dynamic characteristics of these novel dendronized polymers, their LCSTs can be tuned significantly by dendron coverage to shift from that dominated by ELPs to that dominated by OEG dendrons. Furthermore, dendron coverage can be enhanced obviously by the thermally induced phase transitions or greatly by freezing the polymer aqueous solutions. The work provides a convenient methodology to improve thermoresponsiveness of ELPs through polymer topology and to switch their properties through dynamic covalent chemistry. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3379–3387     

Metal Ion-Driven Constitutional Adaptation in Dynamic Covalent C=C/C=N Organo-Metathesis

Knoevenagel barbiturate derivatives and imines are able to undergo efficient component recombination through dynamic covalent C=C/C=N organo-metathesis in absence of a catalyst. A [2×2] dynamic covalent library (DCL) containing two Knoevenagel derivatives Kn1 and Kn2 and two imines A1 and A2 has been established and its adaptive features in response to the addition of metal cations have been investigated. Addition of Cu(I) triflate as an effector, induces fast and remarkable constitutional selection of the DCL towards amplification of the Cu(I)- A2 complex and its agonist Kn1 . This adaptation process could be reversed by addition of neocuproine as a competitive Cu(I) ligand. Furthermore, separate addition of five other metal cations as input agents, i. e. Ag(I), Fe(II), Zn(II), Cu(II) and Li(I), led to the generation of cation-specific distribution patterns as outputs, showing the ability of the present DCL to recognize different effectors.