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The nuclear receptor retinoic acid receptor-related orphan receptor gamma-t (RORγt) is a transcription factor regulating Th17 cell differentiation and proliferation from naive CD4 + T cells. Since Th17 cells have demonstrated the antitumor efficacy by eliciting remarkable activation of CD8 + T cells, RORγt agonists could be applied as potential small molecule therapeutics for cancer immunotherapy. Based on the previously reported RORγt agonist 1 and its resolved co-crystal structure, a series of new tertiary amines were designed, synthesized and biologically evaluated, yielding optimal moieties with improved chemical properties and biological responses. The combination of these optimal moieties resulted in identification of novel RORγt agonists such as 8b with further elevated RORγt agonism responses at a target-based level as well as in cell-based assays, which provided some structural knowledge for further optimization of RORγt agonists as small molecule therapeutics for cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Tertiary amines are one kind of identified amines in the atmosphere. Here, the atmospheric oxidation mechanism and kinetics of tertiary amines were investigated by using computational methods. As proxies of these amines, trimethylamine (TMA) and triethylamine (TEA) have been selected. Results indicate that N-containing peroxy radicals (NRO 2 ⋅), which are key intermediates in ⋅OH initiated oxidation of TMA and TEA, can follow a so-called autoxidation mechanism (a chain reaction of H-shift followed by O 2 addition) even on the condition of high NO/HO 2 ⋅ concentration. Such unique mechanism can be ascribed to the ability of N-atom in facilitating the unimolecular H-shift of NRO 2 ⋅ and the absence of H-atoms on N-atom. However, different from TMA reaction system, the pathway dissociating into fragmental products can compete with the autoxidation pathway for TEA system. More importantly, TEA reaction system cannot lead to the formation of products with high O/C ratio due to the autoxidation pathway terminated by the release of fragmental molecules. Such difference can be corroborated by previously observing lower secondary organic aerosol yield of TEA oxidation than that of TMA oxidation. The unveiled mechanism enhances current understanding on atmospheric fate of amines and autoxidation mechanism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Studies of catalytic CO₂ absorption and desorption were completed in two well-performed tertiary amines: diethylmonoethanolamine (DEEA) and 1-dimethylamino-2-propanol (1DMA-2P), with the aid of CaCO₃ and MgCO₃ in the absorption process, and with the aid of γ-Al₂O₃ and H-ZSM-5 in the desorption process. The batch process was used for CO₂ absorption with solid alkalis, and the recirculation process was used for CO₂ desorption with solid acid catalysts. The CO₂ equilibrium solubility and pKa were also measured at 293 K with results comparable to the literature. The catalytic tests discovered that the heterogeneous catalysis of tertiary amines on both absorption and desorption sides were quite different from monoethanolamine (MEA) and diethanolamine (DEA). These results were illustrative as a start-up to further study of the kinetics of heterogeneous catalysis of CO₂ to tertiary amines based on their special reaction schemes and base-catalyzed hydration mechanism.

This study examined the potential of using a novel bulk amine assay as an approximation for the tertiary and quaternary amine load in wastewaters and surface water samples, and this approximation was compared to N-nitrosodimethylamine (NDMA) formation potential using chloramines. An existing colorimetric method was examined and optimized for the detection of amines in environmental water samples. The method consists of liquid-liquid extraction followed by a catalyzed reaction to form a yet-undefined product that is known to be both a strong chromophore and fluorophore. Previous work verified that this reaction was effectively catalyzed by a number of compounds containing tertiary and quaternary amine moieties. Many tertiary and quaternary compounds are also efficient producers of NDMA under chloramination conditions, and a linear correlation was consequently derived from the bulk amine signals vs. NDMA formation potential in various wastewater samples (R 2  = 0.74; n = 24; p-value < 0.05). The results provide evidence that approximately 2% of the tertiary and quaternary amines measured can form NDMA and an estimated 0.01-1.3% of nitrogen in dissolved organic nitrogen originates from these bulk amines. The normalization of NDMA concentration by the amine measurement revealed that ozone effectively destroyed those tertiary and quaternary amine structures more likely to form NDMA in treated wastewater samples. This bulk amine assay illustrates that proxy measurements of tertiary and quaternary amines can be linked to the NDMA formation potential of a given sample, and this approach may prove useful as a characterizing tool for NDMA precursors in wastewater., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

CXCR4 inhibitors are promising agents for the treatment of cancer metastasis and inflammation. A series of novel tertiary amine derivatives targeting CXCR4 were designed, synthesized, and evaluated. The central benzene ring linker and side chains were modified and optimized to study the structure-activity relationship. Seven compounds displayed much more potent activity than the reference drug, AMD3100, in both the binding affinity assay and the blocking of Matrigel invasion functional assay. These compounds exhibited effective concentration ranging from 1 to 100 nM in the binding affinity assay and inhibited invasion from 65.3% to 100% compared to AMD3100 at 100 nM. Compound IIn showed a 50% suppressive effect against carrageenan-induced paw inflammation in a mouse model, which was as effective as the peptidic antagonist, TN14003 (48%). These data demonstrate that symmetrical bis-tertiary amines are unique CXCR4 inhibitors with high potency., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

An unprecedented eco-friendly multi-component domino reaction for the synthesis of novel N,O-acetals is reported. The protocol involves sequential coupling, [1,5]-hydride transfer and hetero-Diels–Alder cyclization. This new strategy enables direct α,β-difunctionalization of cyclic amines utilizing enamines generated in situ. The methodology features high atom and step economy, excellent regioselectivity, a simple work-up procedure and molecular diversity. [ABSTRACT FROM AUTHOR]

Earth abundant metal‐based heterogeneous catalysts with highly active and at the same time stable isolated metal sites constitute a key factor for the advancement of sustainable and cost‐effective chemical synthesis. In particular, the development of more practical, and durable iron‐based materials is of central interest for organic synthesis, especially for the preparation of chemical products related to life science applications. Here, we report the preparation of Fe‐single atom catalysts (Fe‐SACs) entrapped in N‐doped mesoporous carbon support with unprecedented potential in the preparation of different kinds of amines, which represent privileged class of organic compounds and find increasing application in daily life. The optimal Fe‐SACs allow for the reductive amination of a broad range of aldehydes and ketones with ammonia and amines to produce diverse primary, secondary, and tertiary amines including N‐methylated products as well as drugs, agrochemicals, and other biomolecules (amino acid esters and amides) utilizing green hydrogen. [ABSTRACT FROM AUTHOR]

The CO2 absorption–desorption performances of nonaqueous trisolvent blended amines, monoethanolamine (MEA), 2‐amino‐2‐methyl‐1‐propanol (AMP), methyl diethanol amine (MDEA), 1‐dimethyl amino‐2‐propanol (1DMA2P), diethyl ethanol amine (DEEA), and piperazine (PZ), are investigated in terms of desorption parameters. Two trisolvent amine combinations, primary amine (MEA)/sterically hindered amine (AMP) and tertiary amine (MDEA/1DMA2P/DEEA)‐polyamine (PZ), are prepared at 5 m total amine concentrations with different molarities. Response surface methodology based on a central composite design is used to obtain the optimal condition. This study aims to determine the molarity ratios of solvent systems and investigate their effects on objective functions: heat duty, desorption rate, and desorption factor. Surface analysis suggests optimum conditions as 3 m MEA–1.375 m MDEA–0.625 m PZ for the lowest energy consumption. The experimental results of the proposed system are compared with the 5 m MEA solution. The extensive energy penalty of the CO2 desorption of amine absorbents is reduced with the newly developed solution. [ABSTRACT FROM AUTHOR]

This study explores the stability of electrodeposited copper catalysts utilized in electrochemical CO2 reduction (ECR) across various amine media. The focus is on understanding the influence of different amine types, corrosion ramifications, and the efficacy of pulse ECR methodologies. Employing a suite of electrochemical techniques including potentiodynamic polarization, linear resistance polarization, cyclic voltammetry, and chronopotentiometry, the investigation reveals useful insights. The findings show that among the tested amines, CO2-rich monoethanolamine (MEA) exhibits the highest corrosion rate. However, in most cases, the rates remain within tolerable limits for ECR operations. Primary amines, notably monoethanolamine (MEA), show enhanced compatibility with ECR processes, attributable to their resistance against carbonate salt precipitation and sustained stability over extended durations. Conversely, tertiary amines such as methyldiethanolamine (MDEA) present challenges due to the formation of carbonate salts during ECR, impeding their effective utilization. This study highlights the effectiveness of pulse ECR strategies in stabilizing ECR. A noticeable shift in cathodic potential and reduced deposit formation on the catalyst surface through periodic oxidation underscores the efficacy of such strategies. These findings offer insights for optimizing ECR in amine media, thereby providing promising pathways for advancements in CO2 emission reduction technologies. [ABSTRACT FROM AUTHOR]

Nucleophilic substitution of α‐bromocarboxamide with amines have been demonstrated to synthesize sterically congested C−N bonds. Electrochemical reductive coupling is an efficient route to access hindered amino acid derivatives possessing a quaternary carbon center with excellent yields under mild reaction conditions. Cyclic voltammetry analyses indicated the cathodic reduction of α‐bromocarboxamides in the presence of amines as nucleophiles. The control experiment using the N‐methyl derivative of α‐bromocarboxamide suggested that the aziridinone is the most probable intermediate in this method. [ABSTRACT FROM AUTHOR]

A novel method to prepare asymmetric amine ethers is reported. Tertiary amine alcohol hydrogen sulfate intermediates are prepared through a reactive distillation process, followed by the transesterification process to afford eventually asymmetric amine ethers. Experiments and DFT calculations revealed the essential roles the sulfate group plays in the highly selective monoesterification process. This clean method is tolerant towards various functional groups with good yields under mild condition, which is obviously superior compared to the conventional processes. [ABSTRACT FROM AUTHOR]

A method to identify and quantify amines in polymers by X-ray photoelectron spectroscopy using the energetic distribution of N1s atomic orbitals is presented in this work. The N orbital energetic states were obtained and associated with the atomic chemical states of amines through their formation energy. Pyrrole and allylamine plasma polymers were used as test polymers of this method because they potentially have primary, secondary and tertiary amines in their structure; although, additional unsaturated and oxidized amines were also found in the test polymers as a function of the synthesis power. The participation percentages of amines obtained with this method indicated that secondary amines had the greatest participation in the polymers followed by unsaturated and tertiary amines. The lowest participation belonged to primary amines or to the oxidized amines found during the analyses. This method is new and can be applied to other materials in solid state, not only to polymers, with enough stability to resist the X-ray beams of the XPS spectrometers. [ABSTRACT FROM AUTHOR]

Covering: 2013 to 2023 The α-tertiary amine moiety is a common structural motif in natural alkaloids and is frequently associated with intriguing biological activities and inherent synthetic challenges. A major hurdle in the total synthesis of these alkaloids is the asymmetric construction of the α-tertiary amine moiety. Temporary chirality inductions have been effective strategies employed to address this issue, particularly in natural product synthesis. The temporary chirality induction strategies in α-tertiary amine synthesis can be broadly classified into three categories based on the types of temporary chirality involved: Seebach's self-regeneration of stereocenters (SRS), C-to-N-to-C chirality transfer, and memory of chirality (MOC). This review highlights the recent advancements in temporary chirality induction strategies for the total synthesis of α-tertiary amine-containing natural products between 2013 and 2023. [ABSTRACT FROM AUTHOR]

The effective synthesis of N-benzyl cyclo-tertiary amines using imine reductase, key components in natural products and pharmaceutical synthesis, is a green approach. Traditional methods faced challenges with enzyme activity and selectivity. This study focused on enhancing Mesorhizobium imine reductase (MesIRED) for better N-benzyl cyclo-tertiary amine production. Through alanine scanning and consensus mutation, 12 single-site MesIRED mutants were identified from 23 candidates, showing improved conversion of N-benzylpyrrolidine and N-benzylpiperidine. Notably, mutants from I177, V212, I213, and A241 significantly boosted conversions. The best-performing mutant for N-benzylpyrrolidine, MesIREDV212A/I213V (M1), increased conversion from 23.7% to 74.3%. For N-benzylpiperidine, MesIREDV212A/I177A/A241I (M2) enhanced conversion from 22.8% to 66.8%. Tunnel analysis revealed M1 and M2 have more efficient tunnels for larger product movement compared to wild-type MesIRED. Using recombinant E. coli coexpressing MesIRED and glucose dehydrogenase (GDH), high conversions were achieved: 75.1% for N-benzylpyrrolidine (M1) and 88.8% for N-benzylpiperidine (M2). A preparative experiment resulted in 86.2% conversion and 60.2% yield for N-benzylpiperidine. This research offers an efficient method for engineering IRED, significantly improving conversion and selectivity for N-benzyl cyclo-tertiary amines, aiding drug synthesis and providing insights into rational design of other enzymes. [ABSTRACT FROM AUTHOR]

Amines are a very important class of compounds and the selective synthesis of differently substituted primary, secondary and tertiary alkyl amines is challenging. Here we present the synthesis of primary, secondary, and tertiary alkyl amines from ammonia and alcohols, aldehydes, ketones and hydrogen by combining borrowing hydrogen or hydrogen autotransfer and reductive amination with hydrogen. The key is a nanostructured, bimetallic Co/Sc catalyst able to mediate both reactions or concepts efficiently. We observe a broad product scope, a very good functional group tolerance, upscaling is easily accomplished and our catalyst is reusable. [ABSTRACT FROM AUTHOR]

N -Nitrosamines are a class of indirect acting mutagens, as their metabolic degradation leads to the formation of the DNA-alkylating diazonium ion. Following up on the in-silico identification of thousands of nitrosamines that can potentially be derived from small molecule drugs and their known impurities described in a previous publication, we have now re-analyzed this dataset to apply EMA's Carcinogenic Potency Categorization Approach (CPCA) introduced with the 16th revision of their Q&A document for Marketing Authorization Holders. We find that the majority of potential nitrosamines from secondary amine precursors belongs to potency categories 4 and 5, corresponding to an acceptable daily intake of 1500 ng, whereas nitrosamines from tertiary amine precursors distribute more evenly among all categories, resulting in a substantial number of structures that are assigned the more challenging acceptable intakes of 18 ng/day and 100 ng/day for potency categories 1 and 2, respectively. However, the nitrosative dealkylation pathway for tertiary amine is generally far slower than the direct nitrosation on secondary amines, with a direct nitrosation mechanism suspected only for structures featuring electron-rich (hetero)aromatic substituents. This allows for greater focus towards those structures that require further review, and we demonstrate that their number is not substantial. In addition, we reflect on the nitrosamine risk posed by secondary amine API impurities and demonstrate that based on the ICH Q3A/B identification threshold unknown impurities may exist that could be transformed to relevant amounts of NA. We also demonstrate that the analytical sensitivity required for the quantification of high potency nitrosamines can be problematic especially for high dose APIs. In summary, the regulatory framework rolled out with the latest Q&A document represents a substantial improvement compared with the previous situation, but further refinement through interaction between manufacturers, regulators, not-for-profit and academic institutions will be required to ensure patient access to vital medicines without compromising safety. [Display omitted] [ABSTRACT FROM AUTHOR]

The sulfatobetaine formation from epoxides and tertiary amine‐sulfur trioxide complexes was studied. It was revealed that heterocyclic tertiary amine‐sulfur trioxide complexes being the most electrophilic and reactive complexes produce sulfatobetaines in 15.5–62.6 % isolation yields, the aliphatic tertiary amine sulfur‐trioxide complexes failed to form the expected products. The presence of the amine taken in 5‐fold excess improves the isolation yields of the sulfatobetaines (52–100 %). [ABSTRACT FROM AUTHOR]

The catalytic C(sp3)−C(sp3) coupling of alkyl halides and tertiary amines offers a promising tool for the rapid decoration of amine skeletons. However, this approach has not been well established, partially due to the challenges in precisely distinguishing and controlling the reactivity of amine‐coupling partners and their product homologues. Herein, we developed a metal‐free photocatalytic system for the aminomethylation of alkyl halides through radical‐involved C(sp3)−C(sp3) bond formation, allowing for the synthesis of sterically congested tertiary amines that are of interest in organic synthesis but not easily prepared by other methods. Mechanistic studies disclosed that sterically hindered N‐substituents are key to activate the amine coupling partners by tuning their redox potentials to drive the reaction forward. [ABSTRACT FROM AUTHOR]

Herein, we report a green and sustainable electrochemical strategy for α-alkylation of tertiary amines with halogenated alkanes under undivided electrolytic conditions. A Barbier–Grignard-type reaction at the cathode produces an organozinc reagent that reacts with an iminium ion produced at the anode to provide the α-alkylated amine. The reaction proceeds under mild reaction conditions with wide-ranging functional-group and substrate compatibilities, affording the products in good yields. More importantly, convergent pair electrolysis, an ideal but challenging electrochemical technique, is effectively utilized in this reaction system. Detailed mechanistic study indicated that an imine ion intermediate is involved in the reaction process. [ABSTRACT FROM AUTHOR]

The value of Matteson‐type reactions has been increasingly recognized for developing automated organic synthesis. However, the typical Matteson reactions almost exclusively focus on homologation of carbon units. Here, we report the detailed development of sequential insertion of nitrogen and carbon atoms into boronate C−B bonds, which provides a modular and iterative approach to access functionalized tertiary amines. A new class of nitrenoid reagents is uncovered to allow direct formation of aminoboranes from aryl or alkyl boronates via N‐insertion. The one‐pot N‐insertion followed by controlled mono‐ or double‐carbenoid insertion has been realized with widely available aryl boronates. The resulting aminoalkyl boronate products can undergo further homologation and various other transformations. Preliminary success on homologation of N,N‐dialkylaminoboranes and sequential N‐ and C‐insertions with alkyl boronates have also been achieved. To broaden the synthetic utility, selective removal of a benzyl or aryl substituent permits access to secondary or primary amine products. The application of this method has been demonstrated in the modular synthesis of bioactive compounds and the programmable construction of diamines and aminoethers. A plausible reaction mechanism, supported by preliminary NMR (nuclear magnetic resonance) and computational studies, is also proposed. [ABSTRACT FROM AUTHOR]

We reported a new electrophilic amination of various primary, secondary and tertiary alkyl, benzylic, allylic zinc and magnesium organometallics with O‐2,4,6‐trimethylbenzoyl hydroxylamines (O‐TBHAs) in 52–99 % yield. These O‐TBHAs displayed an excellent long‐term stability and were readily prepared from various highly functionalized secondary amines via a convenient 3 step procedure. The amination reactions showed remarkable chemoselectivity proceeding without any transition‐metal catalyst and were usually complete after 1–3 h reaction time at 25 °C. Furthermore, this electrophilic amination also provided access to enantioenriched tertiary amines (up to 88 % ee) by using optically enriched secondary alkylmagnesium reagents of the type s‐AlkylMgCH2SiMe3. [ABSTRACT FROM AUTHOR]

The deoxygenation of secondary and tertiary amides to the corresponding amines catalyzed by simple Mn(CO)5Br using Ph2SiH2 or PMHS as the reductant was established. This transformation could proceed under mild conditions without sensitive and specialized external ligands. [Display omitted] • Mn(CO) 5 Br-catalyzed deoxygenation of the secondary and tertiary amides with Ph 2 SiH 2 or PMHS under ligands-free conditions. • (a) using commercial manganese catalyst Mn(CO) 5 Br, (b) no external ligand, (c) mild conditions, and (d) broad substrate scope. Herein, we report the deoxygenation of secondary and tertiary amides enabled by [Mn(CO) 5 Br] with Ph 2 SiH 2 or inexpensive polymethylhydrosiloxane (PMHS) as the reducing agents, which provides expedient access to the corresponding secondary and tertiary amines. The operationally simple transformation proceeds under mild conditions without external ligands and features high catalytic efficacy and good functional-group tolerance. Furthermore, the generality of this developed catalytic system was further demonstrated by the late-stage modification of bioactive molecules. [ABSTRACT FROM AUTHOR]

A nine-step synthetic route to access the tricyclic core of FR901483 is reported, featuring a key aza-Wacker cyclization step to construct an α-tertiary amine (ATA) in the bridged structure. The aza-Wacker protocol can tolerate both exocyclic and endocyclic double bonds, providing viable access to various bridged bicyclic rings bearing an ATA (e.g., 6-azabicyclo[3.2.1]octane, 7-azabicyclo[3.3.1]nonane, and 7-azabicyclo[4.2.1]nonane) in good to excellent yields. The synthetic studies presented herein enable structural derivatization of FR901483 to further exploit its compelling biological activities. [ABSTRACT FROM AUTHOR]

This study used monoethanolamine (MEA) as an amine-based solvent, which was blended with secondary amines (DIPA), tertiary amines, stereo amines, and piperazine (PZ) to prepare mixed amines at the required concentrations, which were used as the test solvents. To search for the best-mixed amines, a continuous bubble-column scrubber was adopted to explore the performance of mixed solvents presented in this study. The solvent regeneration test was also carried out at different temperatures. The selected factors included the type of mixed amine (A), the ratio of mixed amines (B), the liquid feed flow (C), the gas flow rate (D), the concentration of mixed amines (E), and the liquid temperature (F), each having five levels. Using the Taguchi experimental design, the conventional experimental number could be reduced from 15,625 to 25, saving much time and cost. The absorption efficiency (EF), absorption rate (RA), overall mass-transfer coefficient (KGa), and absorption factor (ϕ) were estimated as the indicators. After the Taguchi analysis, E, D, and C were found to play important roles in the capture of CO2 gas. Verifications of optimum conditions were found to be 100%, 19.96 × 10−4 mole/s·L, 1.2312 1/s, and 0.6891 mol-CO2/L·mol-solvent for EF, RA, KGa, and ϕ, respectively. The evaluated indexes suggested that MEA + PZ was the best-mixed amine, followed by MEA and MEA + DIPA. The solvent regeneration tests for the scrubbed solutions performed at different optimum conditions showed that the heat of the regeneration sequence was in the order of MEA > MEA + PZ > MEA + DIPA with minimum energy required at 110 °C. The individual energy required was also analyzed here. [ABSTRACT FROM AUTHOR]

Secondary and tertiary amine derivatives are very important in chemical and pharmaceutical industries. The N‐alkylation of amines with aldehydes is a proper way to form secondary and tertiary amines. However, the traditional catalyst systems for this transformation bring a series of problems such as narrow substrate scope, challenges of difficult catalyst preparation and metal residues and toxicity. Herein an efficient way to perform N‐alkylation of amines with aldehydes was described which used a molecular Mo oxide catalyst. In this pathway, various aldehyde and amine derivatives were successfully converted to the corresponding secondary and tertiary amines with high selectivity and efficiency. In addition, the catalyst was easy to prepare, and could be recycled six times without appreciable loss of conversion. Finally, the reaction mechanism was presented based on the observation of the possible intermediates and control experiments. [ABSTRACT FROM AUTHOR]

Organic molecules, containing one or more amine chiral centers, are very common to see in natural products and medicines. Although a large number of methods have been developed to afford enantiopure amines, most of the known approaches are limited with various reasons. For example, many methodologies start from nitrogen protected and activated substrates, which usually need multistep operations and seriously decrease the atom economy. Here we disclose a new catalytic strategy from commercial nitriles to high enantioselective α‐tertiary primary amines in up to 90 % yield and 95 % enantiomeric excess. This transformation firstly undergoes an addition process of organolithium reagents to nitriles to generate the imine intermediates in situ. Subsequently, the most challenging step is by employing copper catalytic enantioselective addition of AllylBpin to the imine intermediates to form the final amines in one pot. [ABSTRACT FROM AUTHOR]

Aqueous hydroaminomethylation (HAM) is an atom economical route for the efficient production of amines in one reaction step, starting from basic chemicals like alkenes. Herein we present the first successful establishment of a continuous process for HAM in an aqueous multiphase system. The green mass transfer agents randomly methylated-β-cyclodextrins (CD) enabled the catalytic system consisting of rhodium/sulfoXantphos to achieve high yields of up to 70% with selectivities of up to 80% in several continuous experiments with a total run time of more than 220 h. The key here is that water and products have large polarity differences, but the reaction still proceeds effectively due to the addition of cyclodextrin, which made the application of solvents obsolete. The main achievements in this way were the investigation of the influence of the randomly methylated-β-cyclodextrin concentration on the reaction rate and the selectivity in batch studies and finding promising operating points in the first continuous experiments. In a final experiment, the separation temperature was investigated. It was shown that the catalyst loss in the product phase is enormously small at 0.003% h−1 of the initial mass (0.24% in total), which is the lowest ever reported value for the HAM on this scale. Within a run time of 78 hours, 2.87 kg of tertiary amine were produced using only 0.2 g (>14 000 : 1) of transition metal, while the loss of rhodium per kg of product produced was mostly around 0.15 mg kg−1, suggesting possible economical applicability. [ABSTRACT FROM AUTHOR]

This article reports the outcome of an in silico analysis of more than 12,000 small molecule drugs and drug impurities, identifying the nitrosatable structures, assessing their potential to form nitrosamines under relevant conditions and the challenges to determine compound-specific AIs based on data available or read-across approaches for these nitrosamines and their acceptance by health authorities. Our data indicate that the presence of nitrosamines in pharmaceuticals is likely more prevalent than originally expected. In total, 40.4 % of the analyzed APIs and 29.6 % of the API impurities are potential nitrosamine precursors. Most structures identified through our workflow could form complex API-related nitrosamines, so-called nitrosamine drug substance related impurities (NDSRIs), although we also found structures that could release the well-known small and potent nitrosamines NDMA, NDEA, and others. Due to common structural motifs including secondary or tertiary amine moieties, whole essential drug classes such as beta blockers and ACE inhibitors are at risk. To avoid the risk of drug shortages or even the complete loss of therapeutic options, it will be essential that the well-established ICH M7 principles remain applicable for nitrosamines and that that the industry and regulatory authorities keep an open communication not only about the science but also to make sure there is a good balance between risk and benefit to patients. [Display omitted] [ABSTRACT FROM AUTHOR]

The asymmetric synthesis of highly sterically congested α-tertiary amines was achieved by an organocatalyzed kinetic resolution (KR) protocol, which were otherwise difficult to access. A variety of substituted N-aryl α-tertiary amines bearing 2-substitued phenyl groups were kinetically resolved through the asymmetric C–H amination reaction, affording good to high KR performances. [ABSTRACT FROM AUTHOR]

The significance of chiral α-tertiary amines in medicinal chemistry and drug development has been unquestionably established in the last few decades. α-Tertiary amines are attractive structural motifs for natural products, bioactive molecules and pharmaceuticals and are preclinical candidates. Their syntheses have been the focus of intensive research, and the development of new methods has continued to attract more and more attention. In this review, we present the progress in the last decade in the development of synthetic methods for the assembly of chiral ATAs via transition-metal catalysis. To date, the effective approaches in this area could be categorized into three strategies: enantioselective direct and indirect Mannich addition to ketimines; umpolung asymmetric alkylation of imine derivatives; and asymmetric C–N cross-coupling of tertiary alkyl electrophiles. Several related developing strategies for the synthesis of ATAs, such as hydroamination of alkenes, HAT amination approaches and the C–C coupling of α-aminoalkyl fragments, are also described in this article. These strategies have emerged as attractive C–C and C–N bond-forming protocols for enantioselective construction of chiral α-tertiary amines, and to some extent are complementary to each other, showing the prospect of application in medicinal chemistry and chemical biology. [ABSTRACT FROM AUTHOR]

Chiral primary amines widely exist in drugs and are exceptionally important subunits or synthons in the syntheses of chiral secondary and tertiary amines of medicinal interest. Metal-catalyzed enantioselective reductive amination (ERA) of ketones with ammonium salts or ammonia provides a direct method for their synthesis. Although very useful, progress in this field has been very slow and important advances have only been achieved in the last few years. Several major challenges exist in this reaction, including (1) the reversible formation of unstable NH-imine intermediates; (2) the strong coordination property of N-containing reagents toward metal species; and (3) the lack of efficient catalytic systems that enable high enantiocontrol. Generally, the efficiency and enantiocontrol of this reaction is dependent on the substrate type, for instance, the use of α-keto esters/amides or aryl alkyl ketones is well established and they have even been used in the industrial production of chiral amine drugs. However, highly enantioselective control in dialkyl ketones, cyclic ketones, and α-keto acids remains unsolved. Herein, the historical development of ERA reactions with ammonium salts or ammonia gas is summarized, and novel synthetic applications toward useful synthons or drugs are presented. In addition, the factors restricting the growth of this method are also discussed. 1 Introduction 2 Enantioselective Reductive Amination via Hydrogenation 2.1 Enantioselective Reductive Amination of β-Keto Esters/Amides 2.2 Enantioselective Reductive Amination of Simple Ketones 2.3 Enantioselective Reductive Amination of α-Functionalized Ketones 2.4 Enantioselective Reductive Amination/Cyclization Cascade Reactions 2.5 Others 3 Enantioselective Reductive Amination via Transfer Hydrogenation 4 Synthetic Applications 5 Conclusions and Outlook [ABSTRACT FROM AUTHOR]

C–N bond cross-couplings are fundamental in the field of organic chemistry. Herein, silylboronate-mediated selective defluorinative cross-coupling of organic fluorides with secondary amines via a transition-metal-free strategy is disclosed. The cooperation of silylboronate and potassium tert-butoxide enables the room-temperature cross-coupling of C–F and N–H bonds, effectively avoiding the high barriers associated with thermally induced SN2 or SN1 amination. The significant advantage of this transformation is the selective activation of the C–F bond of the organic fluoride by silylboronate without affecting potentially cleavable C–O, C–Cl, heteroaryl C–H, or C–N bonds and CF3 groups. Tertiary amines with aromatic, heteroaromatic, and/or aliphatic groups were efficiently synthesized in a single step using electronically and sterically varying organic fluorides and N-alkylanilines or secondary amines. The protocol is extended to the late-stage syntheses of drug candidates, including their deuterium-labeled analogs. C–N bond cross-coupling is fundamental in organic chemistry, but the readily available organic fluorides are unsuitable as coupling substrates. Here, we realize defluorinative cross-coupling with amines via a silylboronate-mediated strategy. [ABSTRACT FROM AUTHOR]

The selective synthesis of monomethylated amines with CO2 is particularly challenging because the formation of tertiary amines is thermodynamically more favorable. Herein, a new strategy for the controllable synthesis of N‐monomethylated amines from primary amines and CO2/H2 is explored. First‐principle calculations reveal that the dissociation of H2 via an heterolytic route reduces the reactivity of methylated amines and thus inhibit successive methylation. In situ DRIFTS proves the process of formation and decomposition of ammonium salt by secondary amine reversible binding with H+ on the Ag/Al2O3 catalyst, thereby reducing its reactivity. Meanwhile, the energy barrier for the rate‐determining step of monomethylation was much lower than that of overmethylation (0.34 eV vs. 0.58 eV) means amines monomethylation in preference to successive methylation. Under optimal reaction conditions, a variety of amines were converted to the corresponding monomethylated amines in good to excellent yields, and more than 90 % yield of product was obtained. [ABSTRACT FROM AUTHOR]

Opening the ring of cyclic amines by regioselective fission of one of the carbon–nitrogen bonds greatly expands the repertoire of available nitrogen‐containing skeletons. Unlike approaches starting from cyclic tertiary amines, methods that can directly open secondary amines are still scarce. The present work discloses an efficient reductive ring opening of either of these cyclic amines using PhSiH3 under B(C6F5)3 catalysis. By this, the direct transformation of unstrained cyclic amines into the corresponding acyclic amines is achieved in a simple one‐pot operation. A stepwise mechanism proceeding through the intermediacy of silylammonium ions followed by reductive cleavage of a carbon–nitrogen bond was experimentally verified. [ABSTRACT FROM AUTHOR]

[Fe(TPA)(N3)2](ClO4) and [Fe(TPA)Br2](ClO4), where TPA is tris-(2-pyridylmethyl)amine, crystallize in the monoclinic space group P21/c with a = 8.7029(5) Å, b = 19.168(1) Å, c = 13.5728(7) Å, β = 101.472(3)°, and a = 8.944(3) Å, b = 16.578(6) Å, c = 15.108(6) Å, β = 103.18(2)°, respectively. The structures were determined at 150 K from 3397 reflections (1426 observed) with R = 0.063 (Rw = 0.097), and at 115 K from 5617 reflections (2261 observed) with R = 0.057 (Rw = 0.065), respectively. In both cases, the iron is pseudo-octahedral with the two halide/pseudohalide ions cis. The Fe–X bond trans to the tertiary amine is shorter. The structures of [{Fe(TPA)X}2O](ClO4)2 where X = N3, Br, NCO, and two polymorphic forms of NCS, are also reported. The azide derivative [CH3CN solvate, monoclinic P21/n, a = 11.8038(11) Å, b = 22.547(2) Å, c = 17.344(2) Å, β = 106.972(4)°, determined at 100 K from 8972 reflections (4404 observed) with R = 0.087 (Rw = 0.145)] has two distinct Fe environments—the tertiary amine is cis to the oxido bridge at one site and is trans to the oxido bridge at the other site; the trans Fe–N3° distance is longer. Both the Br and NCO derivatives are monoclinic, C2/c [with a = 16.1480(17), b = 17.2036(13), c = 16.8521(12), β = 111.204(10), data collected at 293 K, 3753 reflections (2404 observed), R = 0.069 (Rw = 0.151), and a = 15.7470(9), b = 18.2270(11), c = 16.8950(8), β = 110.666(3), data collected at 90 K, 5392 reflections (3028 observed), R = 0.064 (Rw = 0.091), respectively]. Both polymorphs of the NCS derivative are monoclinic—one is P21/c and the other P21/n [a = 11.075(2), b = 15.436(2), c = 12.351(2), β = 95.528(7), data collected at 90 K, 5378 reflections (4345 observed), R = 0.068 (Rw = 0.198), and a = 12.396(2), b = 15.428(3), c = 44.505(8), β = 95.211(7), data collected at 110 K, 16,527 reflections (6540 observed), R = 0.069 (Rw = 0.105), respectively]. For the Br, NCO and NCS dimers, each iron of the [{Fe(TPA)X}2O]2+ unit is pseudo-octahedral with the halide/pseudohalide and oxide ions cis. The oxide bridge is linear, and the two halides/pseudohalides are anti. The ranking of trans influence of the ligands is O2− ≫ Br− > Cl− > N3− > NCO− ≥ NCS− > pyridyl > tertiary amine and the ranking of cis influence of the ligands is O2− ≫ N3− > NCO− > Cl− ≥ Br− > NCS−. The X-ray structures of two monomeric [Fe(TPA)(X)2](ClO4), where TPA is tris-(2-pyridylmethyl)amine and X = N3, and Br, and four dimeric [{Fe(TPA)Y}2O](ClO4)2, where Y =N3, Br, NCO, and NCS are presented and discussed. [ABSTRACT FROM AUTHOR]

Direct C−H bond functionalization is a useful strategy for the straightforward formation of C−C and C−Heteroatom bonds. In the present work, a unique approach for the challenging electrophilic Au‐catalyzed α‐C−H bond functionalization of tertiary amines is presented. Electronic, steric and conformational synergistic effects exerted by the use of a malonate unit in the substrate were key to the success of this transformation. This new reactivity was applied to the synthesis of tetrahydro‐γ‐carboline products which, under oxidative conditions, could be converted into valuable structural motifs found in bioactive alkaloid natural products. [ABSTRACT FROM AUTHOR]

An operationally simple process has been developed for the synthesis of unsymmetrical amines and α‐amino carbonyl derivatives in the absence of a catalyst, ligand, oxidant, or any additives. Contrary to known reductive amination methods, this protocol is amenable to substrates containing other reducible groups. This process effectively results in consecutive cleavage and formation of C−N bonds. DFT studies and Hammett analysis provide useful insight into the mechanism. The role of noncovalent interactions as a stabilizing factor have been examined in the protocol. A wide range of alkyl‐bromides have been coupled efficiently with a variety of dimethyl anilines to get unsymmetric tertiary amines with yields up to 90%. This methodology was further extended to the synthesis of α‐amino carbonyl derivatives with yields up to 93%. [ABSTRACT FROM AUTHOR]

Accurate and efficient molecular dynamic simulation of amine functional group is crucial for designing improved carbon dioxide absorption processes, as thermodynamic and transport properties can be concurrently calculated with molecular-level insight. The exploration of these properties has been limited, and all-atom force fields have struggled to cope with the dynamic and equilibrium characteristics of amines, especially monoethanolamine, which possess and exceptionally low self-diffusivity. In response to this situation, we propose using an anisotropic united atom (AUA4) force field, which strikes a balance between precision and performance allowing to predict the key transport and equilibrium properties involved in mass transfer units. A total of 7 amines were included in this study. Among the main results observed in this work, there was excellent recreation of density. The surface tension evidenced performance similar to other transferable force fields with a general positive deviation of 20%. Regarding transport properties, methylamine and linear alkylamines shows moderate uniform deviations. Trimethylamne, being the only one tertiary amine, exhibited higher deviations than the other amines. In contrast, excellent results were obtained for ET-DI, while significant deviations were found for MEA. Nevertheless, in light of previous studies on this alkanolamine, these deviations appear promising. Finally, we were able to achieve the best predictions of the currently available force fields for ethanolamine by increasing its torsional barriers. This allowed us to accurately reproduce its low self-diffusion and viscosity while maintaining its main structural features. • MD computation of density, surface tension, viscosity and self-diffusion of amines. • Anisotropic united atom (AUA4) force field is compared to all-atoms force fields. • Exceptional recreation of the thermodynamic and transport properties for ET-DI. • Modifications to AUA4 energy barriers obtained the best force field available for MEA. [ABSTRACT FROM AUTHOR]

Two bi‐functional ionic liquid extractants (Bif‐ILs) comprising tertiary amine and carboxylic acids, namely [TOAH]+[OHex]− (Tri‐n‐octylaminehexanoate) and [TOAH]+[ODec]− (Tri‐n‐octylaminedecanoate) in kerosene have been used for extraction of Nd(III), Sm(III) and Eu(III) from aqueous phase with EDTA as a complexing agent. The extraction ability of both the extracting agents has been analyzed with respect to variations in shaking time, concentration of extractant, aqueous phase pH, molarity of EDTA, diluents and phase volume ratio. Using 0.08 mol/L EDTA,extraction of Nd(III) was maximum with both the extractants followed by Sm(III) and Eu(III).At 4 : 1 (O/A) phase volume ratio, the extraction percentages using [TOAH]+[OHex]− were 93.42 % (Nd), 89.83 % (Sm), 84.14 % (Eu) and with [TOAH]+[ODec]− the values were 90.42 % (Nd), 89.37 % (Sm), 83.65 % (Eu), respectively.Extraction efficiency of both Bif‐ILs is maximum for Nd(III). Stripping was quantitative with HNO3 and HCl.Speciation studies and FTIR spectra provide valuable information regarding the stoichiometry of the extracted species. [ABSTRACT FROM AUTHOR]

Self‐assembled peptides are an emerging family of biomaterials that show great promise for a range of biomedical and biotechnological applications. Introducing and tuning the pH‐responsiveness of the assembly is highly desirable for improving their biological activities. Inspired by proteins with internal ionizable residues, we report a simple but effective approach to constructing pH‐responsive peptide assembly containing unnatural ionic amino acids with an aliphatic tertiary amine side chain. Through a combined experimental and computational investigation, we demonstrate that these residues can be accommodated and stabilized within the internal hydrophobic compartment of the peptide assembly. The hydrophobic microenvironment shifts their pKa significantly from a basic pH typically found for free amines to a more biologically relevant pH in the weakly acidic range. The pH‐induced ionization and ionization‐dependent self‐assembly and disassembly are thoroughly investigated and correlated with the biological activity of the assembly. This new approach has unique advantages in tuning the pH‐responsiveness of self‐assembled peptides across a large pH range in a complex biological environment. We anticipate the ionizable amino acids developed here can be widely applicable to the synthesis and self‐assembly of many amphiphilic peptides with endowed pH‐responsive properties to enhance their biological activities toward applications ranging from targeted therapeutic delivery to proton transport. [ABSTRACT FROM AUTHOR]

The N -oxidation of tertiary amines was achieved by using electrochemically generated peroxodicarbonate solutions as sustainable oxidizers. The presence of EDTA and 2,2,2-trifluoroacetophenone as a mediator was found to be crucial for converting water-insoluble substrates. Various tertiary amines were converted into their corresponding N -oxides in yields of up to 98%. The scope includes economically important surfactants and potential platform oxidizers. [ABSTRACT FROM AUTHOR]

An Ir-catalyzed tandem synthesis of various N-methylated tertiary amines from three-component coupling of carbonyl compounds, amines, and methanol following reductive amination/N-methylation is reported for the first time. A wide array of substrates with tolerance of different functional groups was demonstrated. The protocol was extended to the synthesis of N-methyl containing pharmaceutically important drug molecules. A probable catalytic cycle was proposed based on various control experiments and different analytical techniques such as NMR, IR and ESI-MS. [ABSTRACT FROM AUTHOR]

We designed a borane/gold(I) co‐catalytic system and used it for C−H functionalization reactions and cycloaddition reactions between tertiary amines and α‐alkynylenones. Both reactions effectively incorporated a furan ring into the amine. [ABSTRACT FROM AUTHOR]

Direct reductive amination (DRA) is a ubiquitous reaction in organic chemistry. This transformation between a carbonyl group and an amine is most often achieved by using a super stoichiometric amount of hazardous hydride reagents, thus being incompatible with many sensitive functional groups. DRA could also be achieved by means of chemo‐ or biocatalysis, thereby attracting the interest of industry as well as academic laboratories due to the virtually perfect atom economy. Although DRAs are well‐established for substrate pairs such as aldehydes with either 1° or 2° amines as well as ketones with 1° amines, the current methodologies are limited in the case of ketones with 2° amines. Herein, we present a general DRA protocol that overcomes this major limitation by means of iridium catalysis. The applicability of the methodology is demonstrated by accessing an unprecedented range of biologically relevant tertiary amines starting from both aliphatic ketones and aliphatic amines. The choice of a disphosphane ligand (Josiphos A or Xantphos) is essential for the success of the transformation. [ABSTRACT FROM AUTHOR]

Ni‐Mo/ZrO2 catalysts with Ni‐Mo loadings of 10 wt % were prepared by a sol‐gel method on a ZrO2 support and subsequently applied in the simple reductive amination of heterocyclic aldehydes. Among the various catalysts prepared, Ni‐Mo/ZrO2 catalysts with Ni:Mo = 2:1 exhibited the highest metal dispersion and the smallest Ni particle size. The results showed that the catalyst has good catalytic performance, in which the yield of furfurylamine can reach 96.6 %. Initially, oximes were synthesized from the corresponding aldehydes and hydroxylamine hydrochloride, and then heterocyclic primary amines were synthesized by simple hydroreductive amination of the oximes with a 12 % methanolic solution of NH3 in the presence of an Ni‐Mo/ZrO2 catalyst. The methanolic solution of NH3 was found to be more effective in inhibiting the formation of secondary and tertiary amines. [ABSTRACT FROM AUTHOR]

Ni‐Mo/ZrO2 catalysts with Ni‐Mo loadings of 10 wt % were prepared by a sol‐gel method on a ZrO2 support and subsequently applied in the simple reductive amination of heterocyclic aldehydes. Among the various catalysts prepared, Ni‐Mo/ZrO2 catalysts with Ni:Mo = 2:1 exhibited the highest metal dispersion and the smallest Ni particle size. The results showed that the catalyst has good catalytic performance, in which the yield of furfurylamine can reach 96.6 %. Initially, oximes were synthesized from the corresponding aldehydes and hydroxylamine hydrochloride, and then heterocyclic primary amines were synthesized by simple hydroreductive amination of the oximes with a 12 % methanolic solution of NH3 in the presence of an Ni‐Mo/ZrO2 catalyst. The methanolic solution of NH3 was found to be more effective in inhibiting the formation of secondary and tertiary amines. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel tri-solvent amine absorbent was synthesized for efficient CO 2 capture. • The absorbent exhibited a high CO 2 loading and cyclic capacity. • The absorbent exhibited a reduced regeneration heat duty of 2.14 GJ/t CO2. • The reaction products of the absorbent mainly included bicarbonates and unstable carbamates. Blended amine scrubbing is considered as a promising alternative to the monoamine scrubbing process due to the potential for enhanced CO 2 capture efficiency and reduced energy consumption. However, striking a balance between absorption rate and regeneration energy consumption in blended amine systems by establishing suitable interactions between activated amines and proton-acceptor amines remains a significant challenge. In this study, a novel blended amine system, involving tertiary amine diethanolamine (DEEA) as the main agent and several monoamines as promoters, was first proposed to achieve highly effective CO 2 capture. The designed tri-solvent amine system of DEEA combined with piperazine (PZ) and 4-amino-1-methylpiperidine (PD) (denoted as DEEA + PZ + PD) exhibited exceptional CO 2 loading (0.988 mol CO 2 /mol amine), superior cyclic capacity (0.788 mol CO 2 /mol amine), and reduced regeneration heat duty (2.14 GJ/t), surpassing monoethanolamine (MEA) by 79.6 %, 277 %, and decreasing by 43.7 %, respectively. Furthermore, the performance improvement mechanism of DEEA + PZ + PD was systematically elucidated, showcasing the swift CO 2 absorption facilitated by PD or PZ in the initial reaction phase, and the subsequent formation of bicarbonate from PDCOO− and DEEA in the later stage, enhancing CO 2 absorption capacity. The predominant reaction products, bicarbonate and unstable carbamate (PZ(COO−) 2 , PDCOO−), contribute to the high regeneration efficiency and minimal energy consumption during regeneration for DEEA + PZ + PD. Consequently, this facilely prepared tri-solvent amine system, characterized by high capture efficiency and low energy consumption, holds promise for achieving carbon–neutral operations in coal-fired power plants. [ABSTRACT FROM AUTHOR]

[Display omitted] • Suitable modification of tertiary amines alkyl chain structures enhances uranium extraction by 2 orders of magnitude. • Intermediate branching, as one or two short branched alkyl chains, yields optimal uranium extraction and limits third-phase formation. • Effect of branching on third phase formation and uranium extraction can be rationalized by considering that tertiary amines form reverse micelle-type aggregates. • The Gibbs free energy of transfer is monitored by the film term which is impacted by the packing parameter of the molecules and by the penetration of the diluent into the apolar shell of the aggregates. In uranium production, liquid–liquid extraction using the AMEX (AMine EXtraction) process employs tertiary amines solubilized in an aliphatic diluent. Practical constraints as phase stability problems and co-extraction of competitive elements highlight the need for in-depth investigation and optimization. Modifying gradually the alkyl chain structure of tertiary amines, we investigate here the large variation in extraction performance in terms of Gibbs free energy of transfer using the ienaic decomposition taking into account long-range interactions. We show hereby that structuration of the solvent phase can change uranium distribution by 2 orders of magnitude, which is incompatible with standard complexation theory of liquid–liquid extraction. We observe that co-extraction of water and aggregation number higher than four are required to obtain uranium extraction. We conclude that the film term in the ienaic decomposition of the Gibbs energy of transfer, is the one that governs extraction performance. It shows that metal transfer is beyond complexation, and that organization of the solvent phase must be considered to quantitatively interpret the distribution coefficients. [ABSTRACT FROM AUTHOR]

Chiral α-tertiary amines, a motif present in α,α-disubstituted α-amino acids, in a wide range of natural products, and many drugs and drug candidates, are important targets in organic chemistry. Among the possible strategies, 1,2-addition to chiral N -sulfinyl-ketimines is one of the best routes to form chiral α-tertiary amines with a high level of stereoselectivity. In this review, we focus first on the addition of organometallic reagents or other nucleophiles as enols or ylides to chiral N -sulfinylketimines. Then secondly we cover a selection of applications of these additions in the synthesis of valuable biologically active compounds. 1 Introduction 2 1,2-Addition Reaction Methodologies 2.1 Organolithium Reagent Additions 2.2 Grignard Additions 2.3 Organozinc Reagent Additions 2.4 Organoindium Reagent Additions 2.5 Organoboron Reagent Additions 2.6 Strecker Reactions 2.7 Palladium-Catalyzed Reactions 2.8 Enols, Enolates, and Other Deprotonated Reagent Additions 2.9 Ylide Additions 2.10 Heteroatom Nucleophiles 2.11 Miscellaneous Reactions 3 Applications to the Synthesis of Biologically Active Molecules 4 Conclusions [ABSTRACT FROM AUTHOR]

A tetrasubstituted carbon atom connected by three sp3 or sp2-carbons with single nitrogen, i.e., the α-tertiary amine (ATA) functional group, is an essential structure of diverse naturally occurring alkaloids and pharmaceuticals. The synthetic approach toward ATA structures is intricate, therefore, a straightforward catalytic method has remained a substantial challenge. Here we show an efficient water-accelerated organocatalytic method to directly access ATA incorporating homoallylic amine structures by exploiting readily accessible general ketones as useful starting material. The synergistic action of a hydrophobic Brønsted acid in combination with a squaramide hydrogen-bonding donor under aqueous condition enabled the facile formation of the desired moiety. The developed exceptionally mild but powerful system facilitated a broad substrate scope, and enabled efficient multi-gram scalability. The α-tertiary amine functional group is an essential structure of diverse naturally occurring alkaloids and pharmaceuticals. Here the authors show an efficient water-accelerated organocatalytic method to access α-tertiary amines incorporating homoallylic amine structures by exploiting ketones as useful starting material. [ABSTRACT FROM AUTHOR]