Tertiary Amine Function Research Articles

Ortho-quinone methide driven synthesis of kynurenic acid lactams.

Lactam formation of different KYNA amides and Mannich bases mediated by ortho-quinone methide has been investigated. The efficiency of the two routes of the cyclization process was revealed and the influence of diverse amide side chains was explored. In this regard compounds bearing a tertiary amine function in the amide side chain resulted in the formation of the lactam product, while the formation of dimer derivatives was observed in the case of other KYNA amides. Furthermore, derivatives bearing different substituents on the KYNA B ring were synthesized and their effects on the ring-closure reaction were investigated.

Bifunctional Ligand Enables Gold-Catalyzed Propargyl C-H Functionalization via Reactive Gold Allenylidene Intermediate.

Gold allenylidene species have been seldom exploited as reactive intermediates in synthetically versatile catalytic reactions. By employing alkynylbenziodoxoles as the substrates and bifunctional WangPhos as the metal ligand, this work demonstrated ready catalytic access to these intermediates of general substitution patterns and their electrophilic reactivities at the γ-carbon center with a diverse range of nucleophiles. The reaction is driven by the reductive decomposition of the benziodoxole moiety and achieves the replacement of a propargylic proton with an N/O/C-based nucleophile, hence realizing reactivity umpolung. Corroborated by Density Functional Theory (DFT) calculations, the reaction mechanism involves a mild propargylic deprotonation. In contrast to prior works employing a tertiary amine functionality, a weakly BrØnsted-basic amide group in WangPhos is surprisingly effective in deprotonation at the propargylic position under a gold-ligand cooperation regime.

Bifunctional Ligand Enables Gold‐Catalyzed Propargyl C−H Functionalization via Reactive Gold Allenylidene Intermediate

AbstractGold allenylidene species have been seldom exploited as reactive intermediates in synthetically versatile catalytic reactions. By employing alkynylbenziodoxoles as the substrates and bifunctional WangPhos as the metal ligand, this work demonstrated ready catalytic access to these intermediates of general substitution patterns and their electrophilic reactivities at the γ‐carbon center with a diverse range of nucleophiles. The reaction is driven by the reductive decomposition of the benziodoxole moiety and achieves the replacement of a propargylic proton with an N/O/C‐based nucleophile, hence realizing reactivity umpolung. Corroborated by Density Functional Theory (DFT) calculations, the reaction mechanism involves a mild propargylic deprotonation. In contrast to prior works employing a tertiary amine functionality, a weakly BrØnsted‐basic amide group in WangPhos is surprisingly effective in deprotonation at the propargylic position under a gold‐ligand cooperation regime.

Transition Metal-free α-C-H Functionalization of Tertiary Amines Catalysed/ Promoted by Acids: A Brief Review

Abstract: C-H Functionalization of α-carbon of tertiary amines has been of great importance for the past two decades as N-heterocycles can be synthesized by this approach and these heterocycles are highly useful as drugs or drug precursors in the pharmaceutical industry. In this review article, we have summarized only the α-C-H functionalization reactions of tertiary amines that are catalysed or promoted by acids. These C-H functionalization reactions are usually catalysed by transition metal salts, although metal-free catalysts are also used. However, several such reactions have been reported that are efficiently catalysed by acids. They are cost-effective, have a simple purification process, less sensitive to air/moisture, and are relatively environmentally benign. However, this area has not received enough focus due to the lack of review articles, which encouraged us to write this review.

Tertiary Amines as Temporary Masked Secondary Amines: A Direct Access to 5-Dialkylamino-1,2,4-oxadiazoles from 1,2,4-Oxadiazol-5(4H)-ones

AbstractA novel strategy utilizing tertiary amines as temporary masked secondary amines to synthesize 5-dialkylamino 1,2,4-oxadiazoles via Ph3P-I2 mediated amination of 1,2,4-oxadiazol-5(4H)-ones was developed. A one-step N-dealkylative functionalization of tertiary amines with the 1,2,4-oxadiazole ring enables a convenient access to diverse 5-amino-1,2,4-oxadiazoles. Additionally, orthogonally functionalized piperazine derivatives can be effectively constructed through site-selective reaction of 1,4-dialkylpiperazines or via a sequential N-functionalization of 1-methylpiperazine obviating laborious protection/deprotection steps.

Polyurethane based thin hydrogels for sustained protein delivery

The development of materials that allow the sustained release of therapeutic proteins is the key feature for improving their pharmacokinetics, bioavailability, and dose reduction. In this context, hydrogels are attracting interest, but their design to provide a sustained release profile is still a challenge. Usually, a large mass of polymer is required to prolong the release of the therapeutic agent, involving hydrogels with high thicknesses, which limits their use in some applications. Here, the synthesis of thin thermoresponsive and functionalized hydrogels (tHGs) for sustained protein release is reported to tackle this problem. tHGs were obtained by photo-crosslinking of linear thermoresponsive polyurethanes (PU) based on polyethilenglycol and a functional diol (methyldiethanolamine) that contribute to tertiary amine functionality. These biocompatible tHGs conserved the thermosensitive property of PU, exhibiting a reversible volume change between the swollen and the collapsed state, as a function of temperature. tHGs were able to load the model protein ovalbumin homogenously in their matrix, and sustainably release it during 25 days with a tuneable profile, by changing the PU composition. Finally, this proposal, which combined a very thin delivery film with a sustained protein release, could be a good candidate for its application in ocular therapy.

Electron transport chain-inspired coordination polymers for macroscopic spatiotemporal scales of charge separation and transport in photocatalysis.

Classic homogeneous photocatalysis is limited by the temporal transience and the spatial proximity of photoinduced charge separation and transport. The electron transfer chain (ETC) in cellular respiration can mediate unidirectional and long-range electron transfer to isolate the oxidation and reduction centres. Inspired by this, we modified electron-accepting (A) viologen with π-extending thiazolothiazole and electron-donating (D) phenyl carboxylate into a D-A-π-A-D-type ligand and assembled segregated dye stacking in coordination polymer Cd-TzBDP for breaking the spatiotemporal limitation of single-molecule photocatalysis. The offset characteristics of D-A segregated stacking not only allowed the photoinduced-2e- transfer from the D-type carboxylate terminal to the spatially adjacent A-type viologen motif within 1 ps but also permitted the following delocalization of e- and h+ along stacked columns. These advantages endowed Cd-TzBDP with long-lived photochromic visualization of intermittent aerobic photooxidation steps, which enabled the bioinspired ETC-mediated aerobic respiration of mitochondria, achieving the continuous photocatalytic α-C(sp3)-H functionalization of tertiary amines with pharmaceutical interest. Enlightened by ETC-mediated electron leak in hypoxia, the coordination polymer was further employed in a photocatalytic membrane reactor, which visually illustrated the photo-driven cross-membrane long-range transfers of multiple electrons and protons from the hypoxic compartment to normoxic one, benefiting the distal photooxidation and photoreduction with biomimetic compartment selectivity.

Expedient deaminative phosphorylation and sulfonylation of benzylic tertiary amines enabled by difluorocarbene

A deaminative functionalization of aliphatic tertiary amines via the cleavage of C(sp3)–N bonds under transition metal-free conditions was disclosed, which goes through SN2 reaction with various phosphorus and sulfur nucleophiles.

Hydrogenation of CO2 by a Bifunctional PC(sp3 )P Iridium(III) Pincer Complex Equipped with Tertiary Amine as a Functional Group.

Reversible hydrogen storage in the form of stable and mostly harmless chemical substances such as formic acid (FA) is a cornerstone of a fossil fuels-free economy. In the past, we have reported a primary amine-functionalized bifunctional iridium(III)-PC(sp3 )P pincer complex as a mild and chemoselective catalyst for the additive-free decomposition of neat formic acid. In this manuscript, we report on the successful application of a redesigned complex bearing tertiary amine functionality as a catalyst for mild hydrogenation of CO2 to formic acid. The catalyst demonstrates TON up to 6×104 and TOF up to 1.7×104 h-1 . In addition to the practical value of the catalyst, experimental and computational mechanistic studies provide the rationale for the design of improved next-generation catalysts.

CO2-switchable thermoresponsiveness of poly(N,N-(diethylamino)ethyl acrylamide)-based homo- and copolymers in water

The properties of thermo-sensitive polymers can be easily and reversibly switched using addition/removal of carbon dioxide (CO2) as an innovative and ecological trigger. N,N-(diethylamino)ethyl acrylamide (DEAEAM) was copolymerized with N-isopropylacrylamide (NIPAM) by Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization to obtain copolymers with various compositions and architectures. The properties (solubility, aggregation behavior…) of these polymers in aqueous solution in the presence of CO2 was studied via scattering, microscopy and turbidimetry measurements. The copolymerization of DEAEAM monomer with NIPAM enables to produce either statistical or diblock copolymers and to tune the cloud point temperature of obtained copolymers either by changing the composition or the architecture (statistical, block) or by CO2 addition/removal. Whereas, for a given composition, statistical copolymer does not display thermoresponsive behavior, block copolymers present a thermoresponsiveness which depends on the protonation degree of tertiary amine functions. Additionally, CO2 can be used to reversibly modulate the properties of these materials in aqueous media.

Strategies Toward the Catalyst-Free α-C–H Functionalizations of Tertiary Amines

α-C-H functionalization of tertiary amines has been a highly studied field for the past two decades because several important nitrogen containing heterocycles or compounds can be synthesized through this strategy. Though transition metal catalysts and some metal-free catalysts are mainly used for these reactions, a few catalyst-free reactions have recently been efficiently performed. Catalyst-free reactions are cost-effective, less sensitive to air/moisture, easier to operate, have a simple purification process, and are relatively environment-friendly. In this article, we have summarized all the α-C-H functionalization reactions of tertiary amines performed without using any external catalysts. The content of this article will undoubtedly encourage readers to do more work in this area.

Adsorptive Removal of Direct Azo Dyes from Textile Wastewaters Using Weakly Basic Anion Exchange Resin

Direct dyes are still widely used for coloring a variety of materials due to their ease of use and the wide range of colors available at a moderate cost of production. In the aquatic environment, some direct dyes, especially the azo type and their biotransformation products, are toxic, carcinogenic and mutagenic. Hence the need for their careful removal from industrial effluents. It was proposed adsorptive retention of C.I. Direct Red 23 (DR23), C.I. Direct Orange 26 (DO26) and C.I. Direct Black 22 (DB22) from effluents using anion exchange resin of tertiary amine functionalities Amberlyst A21 (A21). Applying the Langmuir isotherm model, the monolayer capacities were calculated as 285.6 mg/g for DO26 and 271.1 mg/g for DO23. The Freundlich isotherm model seems to be the better one for the description of DB22 uptake by A21, and the isotherm constant was found to be 0.609 mg1-1/n L1/n/g. The kinetic parameters revealed that the pseudo-second-order model could be used for the description of experimental data rather than the pseudo-first-order model or intraparticle diffusion model. The dye adsorption decreased in the presence of anionic and non-ionic surfactants, while their uptake was enhanced in the presence of Na2SO4 and Na2CO3. Regeneration of the A21 resin was difficult; a slight increase in its efficiency was observed using 1M HCl, 1 M NaOH and 1 M NaCl solutions in 50% v/v methanol.

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

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

Tumor acidity-induced surface charge modulation in covalent nanonetworks for activated cellular uptake: targeted delivery of anticancer drugs and selective cancer cell death.

A β-thioester and tertiary amine based covalently cross-linked nanoassembly coined as a nanonetwork (NN) endowed with dual pH responsive features (tumor acidity induced surface charge modulation and endosomal pH triggered controlled degradation) has been designed and synthesized for stable sequestration and sustained release of drug molecules in response to endosomal pH. An amphiphile integrated with tertiary amine and acrylate (ATA) functionalities was synthesized to fabricate the nanonetwork. This amphiphile showed entropically driven self-assembly and micellar nanostructures (nanoassemblies), which can sequester hydrophobic drug molecules at neutral pH. To further stabilize the nanoassemblies and the sequestered drug molecules even below its critical aggregation concentration (CAC), the micellar core was cross-linked via the thiol-acrylate Michael addition click reaction to generate multiple copies of acid labile β-thioester functionalities in the core, which undergo slow hydrolysis at endosomal pH (∼5.0), thus enabling sustained release of the anti-cancer drug doxorubicin at endosomal pH. The nanonetworks showed a significant decrease in drug leakage compared to the nanoassemblies (NAs), which was also justified by a low leakage coefficient calculated from the fluorescence resonance energy transfer experiment. The NN also exhibited dilution insensitivity and high serum stability, whereas the NA disassembled upon dilution and during serum treatment. The biological evaluation revealed tumor extracellular matrix pH (∼6.4-6.8) induced surface charge modulation and cancer cell (HeLa) selective activated cellular uptake of the doxorubicin loaded nanonetwork (NN-DOX). In contrast, the benign nature of NN-DOX towards normal cells (H9c2) suggests excellent cell specificity. Thus, we believe that the ease of synthesis, nanonetwork fabrication reproducibility, robust stability, smart nature of tumor microenvironment sensitive surface charge modulation, boosted tumoral-cell uptake, and triggered drug release will make this system a potential nanomedicine for chemotherapeutic treatments.

Deaminative Cyclization of Tertiary Amines for the Synthesis of 2-Arylquinoline Derivatives with a Nonsubstituted Vinylene Fragment

With triethylamine as a vinylene source, a convenient protocol for the regioselective synthesis of β,γ-nonsubstituted 2-arylquinolines from aldehydes and arylamines has been accomplished. The deaminative cyclization is also extended to long-chain tertiary alkylamines, enabling diverse alkyl groups to be concurrently installed into the pyridine rings. This process demonstrates a new conversion pathway for the simultaneous dual C(sp3)-H bond functionalization of tertiary amines, wherein the transient acyclic enamines generated in situ undergo the Povarov reaction.

Steric, Electronic and Conformational Synergistic Effects in the Gold(I)-catalyzed α-C-H Bond Functionalization of Tertiary Amines.

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.

Steric, Electronic and Conformational Synergistic Effects in the Gold(I)‐catalyzed α‐C−H Bond Functionalization of Tertiary Amines**

AbstractDirect 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.

Highly Efficient and Biologically Compatible Photoremovable Protecting Group for Releasing Tertiary Amines through Two‐Photon Excitation

AbstractPhotoremovable protecting groups (PPGs) releasable by two‐photon excitation (2PE) provide spatio‐temporal control over the photoactivation of biological effectors to study biological systems. We synthesized four derivatives of the (8‐cyano‐7‐hydroxyquinolin‐2‐yl)methyl (CyHQ) chromophore by functionalization of position C4 to generate four different derivatives (MeO‐CyHQ, Mor‐CyHQ, pTol‐CyHQ, and TMP‐CyHQ) for studying the release of tertiary amines via 2PE. Sulpiride, an anti‐dopaminergic drug, was selected as a model substrate. All probes had excellent properties for use in biological settings, including high quantum yield (Φu), hydrolytic stability, and good aqueous solubility in simulated physiological buffer. The TMP‐CyHQ probe enhanced the two‐photon uncaging action cross‐section (δu) 8‐fold (2.64 GM) compared to the parent CyHQ‐sulpiride. The optimized PPG was used to mediate the photoactivation of various biological effectors containing the tertiary amine functionality (tamoxifen, 4‐hydroxytamoxifen, yohimbine) using 2PE. All constructs showed excellent efficiency with δu ranging from 1.21 to 2.42 GM and moderate to excellent yields of tertiary amines released.

Progress of Metal‐Free Visible‐Light‐Driven α‐C−H Functionalization of Tertiary Amines: A Decade Journey

AbstractThis review article gives an update on the metal‐free photocatalyzed and photocatalyzed‐free α‐C−H functionalizations of tertiary amines promoted by visible light. C−H activation is one of the easiest and step‐economic strategies to functionalize the α‐C−H bond of tertiary amines. Various important nitrogen heterocycles having biological significance can be synthesized using α‐C−H functionalization of tertiary amines. In addition to thermal reactions, many such reactions have been reported using visible light as it is abundant, renewable and green alternative for organic transformations. However, the high price of transition metal photocatalyst prevents its use. In contrast, organic photocatalysts are inexpensive, environment friendly and easy to handle. Therefore, visible‐light‐promoted metal‐free photoredox catalysis (or photocatalyst‐free reactions) is being used recently. Although several research articles have been published in this area, no review articles have been reported recently. Here, we have discussed the reactions from the year 2011 to till date with concise discussion about their plausible mechanisms. We believe that the content of this review will guide the readers to develop more such visible‐light‐promoted reactions using metal‐free photocatalysts or avoiding catalysts if possible.

Electronic transitions in noncovalent BODIPY dimers: TD-DFT study

Theoretical computations have been performed on the absorption spectra of (8-R-TMB)2 dimers with varying character of substituents at the 8 position (meso) at monomers units (R = NH2, OH, CH3, H, COH, CF3, CN). The obtained results (TD-CAM-B3LYP) show that the first four lower transitions of studied dimers (S0 → Si, i = 1–4) are intrinsically linked with delocalized HOMO and LUMO orbitals of the two monomers, which constitute a dimer. For all the dimers, S0 → S1 and S0 → S3 transitions are strongly forbidden, whereas S0 → S2 and S0 → S4 are allowed. There is a good agreement between the TD-CAM-B3LYP theory and the simple model of exciton coupling for two identical chromophores with the planes of two moieties, which are stacked upon each other. Intensities of the allowed transitions depend strongly on the nature of the substituent at the meso position. For the dimers with monomer units bearing electron-donor groups, S0 → S2 transitions are more intense compared with S0 → S4 ones. As the donor properties of the meso substituents diminish and electron acceptor properties enlarge, the intensity of these transitions becomes lower, whereas that of S0 → S4 transitions becomes higher. For the dimers with NH2 and CN substituents, the almost inverse ratio of intensities of the transitions discussed is observed (for example, f = 0.80 and 0.06 (in the case of NH2) and f = 0.09 and 0.72 (CN) for S0 → S2 and S0 → S4, respectively). Protonation of the tertiary amine function drastically ‘switches off’ its electron-donating properties. As a result, the red shift of the bands and redistribution of intensities of the allowed S0 → S2 and S0 → S4 transitions is predicted for protonated forms of the (8-NH2-TMB)2 dimer. This peculiarity can be of especial importance for the design of dimers with a sensor function.