Amide Products Research Articles

Accessing Tetrahydroquinaldic Amide and Homoproline Derivatives by Dearomative Difunctionalization of Heteroaromatics

AbstractThis study reports the first synthesis of tetrahydroquinaldic and tetrahydropicolinic amides using readily available quinolines and pyridines through dearomative difunctionalization and hydrolysis under transition‐metal‐ and reductant‐free conditions. The prepared amide products could be easily oxidized to the corresponding quinaldic and picolinic amides. Furthermore, the chemical reactivity of the amide group has been explored to develop convenient methods for their conversion to other common organic functional groups.

Experimental and DFT study on the effect of typical component interaction on nitrogen conversion during pyrolysis of food waste

Pyrolysis technology is an effective way to realize the reduction and recycling of food waste (FW), but the generation of N-containing substances has a great impact on the quality of pyrolysis products and the environment. The present study mainly focused on the effect of typical component interaction on nitrogen conversion during the pyrolysis of FW, which was investigated by TG-FTIR, GC-MS, and DFT calculation. The experimental results show that during pyrolysis at 500 ℃, compared with soybean protein pyrolysis, co-pyrolysis of soybean protein with rice starch reduces the production of NH3 and HCN in the pyrolysis gas and reduces the production of nitriles in the pyrolysis oil, while the production of N-containing heterocycles and amides in the pyrolysis oil increases. Soybean protein and rice starch promote the immobilization of N in pyrolysis oil through Maillard reaction and produce Maillard reaction products (MRPs). MRPs can be converted to nitrogenous heterocycles by ring formation reactions, and to amides by continued cleavage, which results in the increased yields of N-containing heterocycles and amides in the pyrolysis oil.

Illuminating the mechanism and allosteric behavior of NanoLuc luciferase

NanoLuc, a superior β-barrel fold luciferase, was engineered 10 years ago but the nature of its catalysis remains puzzling. Here experimental and computational techniques are combined, revealing that imidazopyrazinone luciferins bind to an intra-barrel catalytic site but also to an allosteric site shaped on the enzyme surface. Structurally, binding to the allosteric site prevents simultaneous binding to the catalytic site, and vice versa, through concerted conformational changes. We demonstrate that restructuration of the allosteric site can boost the luminescent reaction in the remote active site. Mechanistically, an intra-barrel arginine coordinates the imidazopyrazinone component of luciferin, which reacts with O2 via a radical charge-transfer mechanism, and then it also protonates the resulting excited amide product to form a light-emitting neutral species. Concomitantly, an aspartate, supported by two tyrosines, fine-tunes the blue color emitter to secure a high emission intensity. This information is critical to engineering the next-generation of ultrasensitive bioluminescent reporters.

Efficient Synthesis of N‐Pyridinylamides Using a Bimetallic Co/Fe‐Metal‐Organic Framework Heterogeneous Catalyst

AbstractThe synthesis of N‐pyridinylamides has been realized by particularly efficient technologies via bimetallic organic (Co/Fe‐MOF) catalyzed oxidative amidation between 2‐aminopyridine and benzaldehyde. The C−N bond was formed with the presence of a catalyst (Co/Fe‐MOF) as a Lewis acid and the oxidant as DTBP. The oxidative amidation reaction was conducted in 1,4‐dioxane at 120 °C with a wide range of substrates producing the corresponding amide products in good to 94 % yields. Experimental results illustrated that This accessibly offers a significant improvement over the earlier successful attempts in forming N‐pyridinyl amides. The Co/Fe‐MOF material was synthesized by solvothermal methods with the salt mixture of Fe(NO3)3.9H2O and Co(NO3)2.6H2O. The material was determined by modern analytic methods like X‐ray diffraction (XRD), Fourier‐transform Infrared spectroscopy (FT‐IR), Scanning Electron Microscope (SEM), and N2 adsorption/desorption isotherms.

Dehydrogenative Conversions of Aldehydes and Amines to Amides Catalyzed by a Nickel(II) Pincer Complex

A C-N cross-coupling approach involving oxidative amidations of aromatic aldehydes in the presence of an amide-based nickel(II) pincer catalyst (2) is demonstrated. Upon optimization, quick reaction times (15 min) and an ideal temperature (25 °C) were established and implemented for the conversion of 33 different amide products using only 0.2 mol% of catalyst. Moderate to good turnover numbers (TONs) were obtained for secondary benzamide products, and moderate TONs were obtained for tertiary benzamide products, with the highest turnover number calculated for the 4-chloro-N-(3-phenylpropyl)benzamide product (4i, 309). Gas chromatographic–mass spectrometric (GC–MS) analysis also indicates the formation of alcohols in different reactions, indicating an oxidative amidation process. Kinetic studies were performed by varying the amount of catalyst, aldehyde, LiHMDS base, and amine substrate to determine the order of reaction for each component. Benzaldehyde and benzaldehyde-d6 were reacted with benzylamine, and the kH/kD ratio was determined to understand the rate-determining step. Isotope labeling further revealed that deuterium was being transferred to both the alcohol side product and the target amide product. With the help of kinetic data and UV–visible spectra, a mechanism for the amidation process via the catalyst (2) is proposed through a Ni(I)–Ni(III) pathway.

Atmospheric Oxygen Facilitated Oxidative Amidation to α-Ketoamides and Unusual One Carbon Degradative Amidation to N-Alkyl Amides.

A mild, transition-metal-free novel synthetic approach for the construction of C═O and C-N bonds has been demonstrated. Easily accessible gem-dibromoalkenes under similar conditions form oxidative amidation product α-ketoamides and unusual degradative amidation product N-alkyl amides by simply changing the amine substitute. Atmospheric air containing molecular oxygen proved to be an ideal oxidant for an amidation reaction. Under similar conditions, the electron-deficient gem-dibromoalkenes play a dual role with different formamides forming novel oxidative amidation products and by the state of art neighboring group participation of amine to unusual one-carbon degradative amidation products.

Mechanistic Evidence of a Ni(0/II/III) Cycle for Nickel Photoredox Amide Arylation.

This work demonstrates the dominance of a Ni(0/II/III) cycle for Ni-photoredox amide arylation, which contrasts with other Ni-photoredox C-heteroatom couplings that operate via Ni(I/III) self-sustained cycles. The kinetic data gathered when using different Ni precatalysts supports an initial Ni(0)-mediated oxidative addition into the aryl bromide. Using NiCl2 as the precatalyst resulted in an observable induction period, which was found to arise from a photochemical activation event to generate Ni(0) and to be prolonged by unproductive comproportionation between the Ni(II) precatalyst and the in situ generated Ni(0) active species. Ligand exchange after oxidative addition yields a Ni(II) aryl amido complex, which was identified as the catalyst resting state for the reaction. Stoichiometric experiments showed that oxidation of this Ni(II) aryl amido intermediate was required to yield functionalized amide products. The kinetic data presented supports a rate-limiting photochemically-mediated Ni(II/III) oxidation to enable C-N reductive elimination. An alternative Ni(I/III) self-sustained manifold was discarded based on EPR and kinetic measurements. The mechanistic insights uncovered herein will inform the community on how subtle changes in Ni-photoredox reaction conditions may impact the reaction pathway, and have enabled us to include aryl chlorides as coupling partners and to reduce the Ni loading by 20-fold without any reactivity loss.

Mechanistic Evidence of a Ni(0/II/III) Cycle for Nickel Photoredox Amide Arylation

AbstractThis work demonstrates the dominance of a Ni(0/II/III) cycle for Ni‐photoredox amide arylation, which contrasts with other Ni‐photoredox C‐heteroatom couplings that operate via Ni(I/III) self‐sustained cycles. The kinetic data gathered when using different Ni precatalysts supports an initial Ni(0)‐mediated oxidative addition into the aryl bromide. Using NiCl2 as the precatalyst resulted in an observable induction period, which was found to arise from a photochemical activation event to generate Ni(0) and to be prolonged by unproductive comproportionation between the Ni(II) precatalyst and the in situ generated Ni(0) active species. Ligand exchange after oxidative addition yields a Ni(II) aryl amido complex, which was identified as the catalyst resting state for the reaction. Stoichiometric experiments showed that oxidation of this Ni(II) aryl amido intermediate was required to yield functionalized amide products. The kinetic data presented supports a rate‐limiting photochemically‐mediated Ni(II/III) oxidation to enable C−N reductive elimination. An alternative Ni(I/III) self‐sustained manifold was discarded based on EPR and kinetic measurements. The mechanistic insights uncovered herein will inform the community on how subtle changes in Ni‐photoredox reaction conditions may impact the reaction pathway, and have enabled us to include aryl chlorides as coupling partners and to reduce the Ni loading by 20‐fold without any reactivity loss.

Novel System for the Production of the Bioactive N-alkylamide ‘Spilanthol’ Through Somatic Embryogenesis in Acmella ciliata Kunth (Cass.)

Acmella ciliata Kunth (Cass.), a medicinally important plant in the family Asteraceae, has high commercial value because of its traditional phytomedicinal uses. The plant contains many phytochemicals like alkyl amides, alkaloids, tannins, saponins and flavonoids accountable for most of its pharmacological applications. The study presented here reports the callus culture and somatic embryogenesis of this plant thereby raising a novel system for the subsequent production of the N-alkyl amide ‘spilanthol’, the valuable secondary metabolite presents in it. Murashige and Skoog (MS) medium supplemented with auxins either alone or in combination with cytokinins were used for the induction and maturation of somatic embryos. MS medium supplemented with 2,4-D (0.5, 1.0 and 2.0 mg.L-1) produced black friable callus whereas, 1.0 mg.L-1 NAA in combination with 0.5 mg.L-1 BA induced white, slightly purple coloured friable callus which on further subculture to fresh medium induced somatic embryos that germinated into plantlets upon transfer to MS basal medium. The mode of regeneration via somatic embryogenesis was confirmed by histological analysis through free-hand sectioning and stereomicroscopic observation. The plantlets raised through somatic embryogenesis after a short hardening period, were found to acclimatise in the field at 83.33% efficiency and exhibited genetic uniformity with 96.6% similarity in the ISSR analysis. HPLC analysis of in vitro raised embryogenic callus showed 239.512 µg.g-1 spilanthol content which was comparatively higher than the mother plants (92.19 µg.g-1). The bioproduction of the N-alkylamide ‘spilanthol’ through embryogenic callus can be extended for the scale-up production of this bioactive compound using bioreactor technology for the formulation of phytodrugs.

Two Satellite Gene Clusters Enhance Ergot Alkaloid Biosynthesis Capacity of Aspergillus leporis.

Ergot alkaloids are fungal specialized metabolites that are important in agriculture and serve as sources of several pharmaceuticals. Aspergillus leporis is a soil saprotroph that possesses two ergot alkaloid biosynthetic gene clusters encoding lysergic acid amide production. We identified two additional, partial biosynthetic gene clusters within the A. leporis genome containing some of the ergot alkaloid synthesis (eas) genes required to make two groups of clavine ergot alkaloids, fumigaclavines and rugulovasines. Clavines possess unique biological properties compared to lysergic acid derivatives. Bioinformatic analyses indicated the fumigaclavine cluster contained functional copies of easA, easG, easD, easM, and easN. Genes resembling easQ and easH, which are required for rugulovasine production, were identified in a separate gene cluster. The pathways encoded by these partial, or satellite, clusters would require intermediates from the previously described lysergic acid amide pathway to synthesize a product. Chemical analyses of A. leporis cultures revealed the presence of fumigaclavine A. However, rugulovasine was only detected in a single sample, prompting a heterologous expression approach to confirm functionality of easQ and easH. An easA knockout strain of Metarhizium brunneum, which accumulates the rugulovasine precursor chanoclavine-I aldehyde, was chosen as expression host. Strains of M. brunneum expressing easQ and easH from A. leporis accumulated rugulovasine as demonstrated through mass spectrometry analysis. These data indicate that A. leporis is exceptional among fungi in having the capacity to synthesize products from three branches of the ergot alkaloid pathway and for utilizing an unusual satellite cluster approach to achieve that outcome. IMPORTANCE Ergot alkaloids are chemicals produced by several species of fungi and are notable for their impacts on agriculture and medicine. The ability to make ergot alkaloids is typically encoded by a clustered set of genes that are physically adjacent on a chromosome. Different ergot alkaloid classes are formed via branching of a complex pathway that begins with a core set of the same five genes. Most ergot alkaloid-producing fungi have a single cluster of genes that is complete, or self-sufficient, and produce ergot alkaloids from one or occasionally two branches from that single cluster. Our data show that Aspergillus leporis is exceptional in having the genetic capacity to make products from three pathway branches. Moreover, it uses a satellite cluster approach, in which gene products of partial clusters rely on supplementation with a chemical intermediate produced via another gene cluster, to diversify its biosynthetic potential without duplicating all the steps.

Lewis acid/acetic acid-catalysed electrophilic amidation of simple arenes with O-acetyl acetohydroxamic acid

Electrophilic arene CH amination constitutes an intrinsically more atom- and step-economical pathway towards arylamines than CX → CN methods. However, most literature examples are restricted to arenes with extensive directing groups (DG) and/or nitrogen coupling partners with large leaving groups (LG). Moreover, only few cases of EAs using cheap metals (e.g., Fe) have been reported. Herein, we demonstrate the catalytic activity of various Lewis acids in the electrophilic amidation of simple arenes with O-acetyl acetohydroxamic acid in acetic acid. With 5 mol% FeIII(citrate)·H2O, up to 27 % yield was achieved, whereas 5 mol% BiCl3 gave up to 31 % yield. Instability of the amidation agent and product inhibition were identified as the yield-limiting factors. The observed regioselectivity, as well as kinetic and spectroscopic data suggest an electrophilic aromatic substitution mechanism, in which acetic acid and the Lewis acid generate a highly electrophilic species from AcNHOAc.

Electrochemical Oxidative C-H Amination through a Ritter-Type Reaction.

A straightforward strategy for direct benzylic C-H bond amination via an electrochemical Ritter-type reaction is developed. The reaction demonstrates simpler and milder reaction conditions over the existing methods without extra mediator. Moderate to excellent yields up to 94% of the desired amide products were obtained with a broad substrate scope. The removal of the Ac group by a simple step can afford NH-free benzylic amines, providing a suitable approach for the late-stage functionalization of bioactive molecules.

Accelerated Amidation of a Glycine Propargyl Ester on a Polymer and the Two-Way Use of One-Pot Double Postpolymerization Modification with Click Chemistry

Abstract The glycine propargyl (GP) ester moiety, as a newly activated ester, is a candidate for amidation in modification reactions and can be combined with click chemistry. Here, the amidation of GP esters on a polymer side chain was investigated using various amino-group-containing compounds. The amidation on the GP ester proceeded well when n-alkyl, cycloalkyl, and aromatic-group-containing primary amines were used without a catalyst under neutral conditions. Hydrophilic amines containing hydroxy and carboxy groups provided no amidation products. The amidation on the polymer was accelerated by the neighboring group effect on the polymer side chain. One-pot double postpolymerization modification was achieved using a GP ester-bearing polymer by combining amidation with the Huisgen cycloaddition.

Brønsted Base Prompted sp3 C-H Latent Nucleophiles to Access α-Branched Amines Bearing β-Carbonyl by Cleaving Amide and Ester Bonds.

α-Branched amines are key motifs that exist in a plethora of natural products and pharmaceuticals. Herein we disclose the first convergent synthesis of α-branched amines bearing β-carbonyl in isoindolinones by employing unactivated tertiary amides and unactivated alkyl esters as benign electrophile sources. The reaction proceeds by the direct aroylation of a C(sp3)-H carbon adjacent to the nitrogen atom in core isoindolinones. Several amides and esters were screened to choose the potential acyl source for the substrate scope. The reaction is carried out with a repertoire of substrates under mild conditions and shows high functional group compatibility. Remarkably the reaction is amenable to organometallic ferrocenyl ester and indole methyl esters bearing an acidic NH moiety. Strikingly no trace of amidation product 8 is observed. In particular α-branched amines bearing β-carbonyl synthesized from indole methyl esters are considered important targets, as both motifs are prevalent in many drugs. This protocol is scalable, and products obtained from indole methyl esters show strong solid-state emission properties which are complementary with DFT calculations.

Amides inventory towards the G+0.693−0.027 molecular cloud

ABSTRACT Interstellar amides have attracted significant attentions as they are potential precursors for a wide variety of organics essential to life. However, our current understanding of their formation in space is heavily based on observations in star-forming regions and hence the chemical networks lack the constraints on their early origin. In this work, unbiased sensitive spectral surveys with IRAM 30 m and Yebes 40 m telescopes are used to systematically study a number of amides towards a quiescent Galactic centre molecular cloud, G+0.693−0.027. We report the first detection of acetamide (CH3C(O)NH2) and trans-N-methylformamide (CH3NHCHO) towards this cloud. In addition, with the wider frequency coverage of the survey, we revisited the detection of formamide (NH2CHO) and urea (carbamide; NH2C(O)NH2), which had been reported previously towards G+0.693−0.027. Our results are compared with those present in the literature including recent laboratory experiments and chemical models. We find constant abundance ratios independently of the evolutionary stages, suggesting that amides related chemistry is triggered in early evolutionary stages of molecular cloud and remain unaffected by the warm-up phase during the star formation process. Although a correlation between more complex amides and NH2CHO have been suggested, alternative formation routes involving other precursors such as acetaldehyde (CH3CHO), methyl isocyanate (CH3NCO), and methylamine (CH3NH2) may also contribute to the production of amides. Observations of amides together with these species towards a larger sample of sources can help to constrain the amide chemistry in the interstellar medium.

Alleviating the trade-off by site-guided function switch of nitrilase to nitrile hydratase

Catalytic promiscuity makes nitrilase-mediated unnatural reactivity a promising pathway in the production of primary amides. However, during the functional switch of nitrilase, a trade-off between the newly developed hydration activity and relative activity hinders the application of nitrilase in the production of amides. Our previous study showed that the mutant F193N (Mut0) of nitrilase NIT6803 from Synechocystis sp. PCC6803 improved the hydration activity as the amide ratio increased to 73.4%, whereas the relative activity was only 50.1% of that of the wild-type (WT). In this study, we succeeded in alleviating the trade-off of Mut0 through an evolutionary combination of the key identified sites 101, 192, and 201. Inside the active pocket, the co-evolution of residue Q192 was identified by hotspot prediction to correlate with N193, and Q192H exhibited an improved amide ratio of 76.9% with a relative activity of up to 72%. Outside the active pocket, the flexible loop surface residue G101 and homodimer “A” interface residue I201 were identified using sequence alignment-based mutations. Further evolutionary combination of the three key sites yielded the best triple mutant G101K/Q192H/I201M, which had the highest amide ratio of 98.5% and considerably recovered relative activity of 82.6% while retaining only 1.5% of the carboxylic acid ratio. The transition-state analogue sheds light on the basis of the almost identical switch of the reaction pathways, and our results expand the toolbox of nitrilase-catalysed promiscuity for amide formation.

Simple methods for the synthesis of N-substituted acryl amides using Na2CO3/SiO2 or NaHSO4/SiO2

A simple and efficient procedure for the synthesis of N-substituted acryl amides has been developed using Na2CO3/SiO2 or NaHSO4/SiO2. Na2CO3/SiO2 smoothly acts as a base in the reaction between acryloyl chloride and a variety of amines to obtain their corresponding products in good to excellent yield. Additionally, NaHSO4/SiO2 catalyzed the Ritter reaction between acryl nitrile and sec-benzylic alcohols to give the expected N-substituted acryl amide product. In both reactions, Na2CO3/SiO2 and NaHSO4/SiO2 were removed from the reaction mixture using filtration.

C–N bond formation by a polyketide synthase

Assembly-line polyketide synthases (PKSs) are molecular factories that produce diverse metabolites with wide-ranging biological activities. PKSs usually work by constructing and modifying the polyketide backbone successively. Here, we present the cryo-EM structure of CalA3, a chain release PKS module without an ACP domain, and its structures with amidation or hydrolysis products. The domain organization reveals a unique “∞”-shaped dimeric architecture with five connected domains. The catalytic region tightly contacts the structural region, resulting in two stabilized chambers with nearly perfect symmetry while the N-terminal docking domain is flexible. The structures of the ketosynthase (KS) domain illustrate how the conserved key residues that canonically catalyze C–C bond formation can be tweaked to mediate C–N bond formation, revealing the engineering adaptability of assembly-line polyketide synthases for the production of novel pharmaceutical agents.

The reaction of acetonitrile with hydrogen peroxide in alkaline medium: a DFT mechanistic study of green production of amides.

We have investigated using DFT methods the reaction mechanism of the Radzisewski reaction to obtain an amide via the reaction of ACN and H2O2 under alkaline conditions. The direct reaction between ACN and H2O2 showed a quite high activation energy (about 45 kcal mol-1) rendering this path unreliable. Instead, a fast reaction between ACN and HOO- forming the deprotonated species (PAIA-) of the peroxyacetimidic acid (PAIA) was observed. From this, PAIA- was guessed to form PAIA through a fast reaction of hydrolysis. Moreover, a second way of formation of PAIA, through an OH- catalyzed path, made the rate determining step (RDS) in very good agreement with experimental data, hence neglecting the contribution of the kinetically favored hydrolysis of PAIA-. This discrepancy was reconciled by considering that the final amide was obtained through a regioselective path forming the PAIA and the further reaction involving the decomposition of PAIA and PAIA-. Indeed, the PAIA obtained from the hydrolysis reaction showed a configuration which did not match the configurational behavior required. Conversely, the PAIA formed from the RDS path matched the required configuration needed to obtain the amide. Our findings also disentangled the experimenal debate on the assignment of the RDS.

Copper-Catalyzed Claisen Rearrangement with AIBN and Allylic Alcohols.

A novel and succinct method for the synthesis of N-cyanomethyl amides from allylic alcohols with AIBN as the nitrile source is developed. Owing to the coordination effect with the copper catalyst, a ketenimine intermediate is formed via couplings of isobutyronitrile radicals. The copper-activated ketenimine could subsequently be intercepted by allylic alcohols and undergo Claisen rearrangement to furnish N-cyanomethyl amides. Further functional group transformations of the N-cyanomethyl amide products are also described.