Anhydride Research Articles

Merging C–H Bond Activation, Alkyne Insertion, and Rearrangements by Rh(III)-Catalysis: Oxindole Synthesis from Nitroarenes and Alkynes

We report a Rh(III)-catalyzed ortho-C-H bond functionalization of nitroarenes with 1,2-diarylalkynes and carboxylic anhydrides. The reaction unpredictably affords 3,3-disubstituted oxindoles with the formal reduction of the nitro group under redox-neutral conditions. Besides good functional group tolerance, this transformation allows the preparation of oxindoles with a quaternary carbon stereocenter using nonsymmetrical 1,2-diarylalkynes. This protocol is facilitated by the use of a functionalized cyclopentadienyl (CpTMP*)Rh(III) [CpTMP* = 1-(3,4,5-trimethoxyphenyl)-2,3,4,5-tetramethylcyclopentadienyl] catalyst we developed, which combines an electron-rich character with an elliptical shape. Mechanistic investigations, including the isolation of three rhodacyle intermediates and extensive density functional theory calculations, indicate that the reaction proceeds through nitrosoarene intermediates via a cascade of C-H bond activation─O-atom transfer─[1,2]-aryl shift─deoxygenation─N-acylation.

Carboxylic-Phosphoric Anhydrides as Direct Electrophiles for Decarbonylative Hirao Cross-Coupling of Carboxylic Acids: DFT Investigation of Mechanistic Pathway.

In this anniversary issue, we present a DFT study of the mechanism of decarbonylative Hirao cross-coupling of carboxylic-phosphoric anhydrides to afford aryl phosphonates. Traditionally, the direct activation of carboxylic acids to participate in decarbonylative couplings is performed in the presence of carboxylic acid anhydride activators. We discovered that direct dehydrogenative decarbonylative phosphorylation of benzoic acid can be performed in high yield via dehydrogenative and decarbonylative coupling in the presence of phosphite as dual activating and nucleophilic reagent, enabling direct decarbonylative phosphorylation. Control studies demonstrated that carboxylic-phosphoric anhydride (acyl phosphate) is an intermediate in this process. DFT studies were conducted to gain insight into this decarbonylative process and compare the selectivity of C-O and P-O bond activations. Considering the utility of ubiquitous carboxylic acids, this alternative activation pathway may find applications in decarbonylative coupling of carboxylic acids for the synthesis of valuable molecules in organic synthesis.

A novel L-phenylalanine dipeptide inhibits prostate cancer cell proliferation by targeting TNFSF9

In the present study, a series of novel L-phenylalanine dipeptides were designed and synthesized by a multi-step sequence of reactions, including carbodiimide-mediated condensation, hydrolysis, mixed anhydride condensation, and nucleophilic substitution. Among them, compound 7c exhibited potent antitumor activity against prostate cancer cell PC3 in vitro and in vivo via inducing apoptosis. We investigated the significantly differentially expressed proteins in the cells caused by the compound 7c to unravel the molecular mechanisms underlying the regulation of PCa cell growth, which indicated that 7c mainly regulated the protein expression of apoptosis-related transcription factors, including c-Jun, IL6, LAMB3, OSMR, STC1, OLR1, SDC4 and PLAU; and 7c also regulated the protein expression of inflammatory cytokines including IL6, CXCL8, TNFSF9, TNFRSF12A and OSMR, and the phosphorylation levels of RelA. The action target confirmed that TNFSF9 protein is the critical binding target of 7c. These findings suggested that 7c could regulate the apoptosis and inflammatory response related signaling pathways for the inhibition of the proliferation of PC3 cells, implying that 7c could be considered a promising therapeutic candidate for PCa therapy.

Efficient synthesis of mixed aliphatic benzoic anhydrides in a two-phase system

The reactions of benzoyl chloride and different aliphatic sodium carboxylates catalyzed by pyridine derivatives in a two-phase water/organic solvent system were studied. The effects of catalyst structure, initial concentration of catalyst and carboxylate ion in the aqueous phase, temperature, and polarity of organic solvent on the formation rate and yield of mixed anhydride were investigated in detail. 4-methylpyridine N-oxide, 4-methoxypyridine N-oxide, 4-morpholinopyridine N-oxide, and 4-dimethylaminopyridine were used as catalysts. A higher reaction rate was achieved with use of 4-methylpyridine N-oxide. In contrast to literature data, it was found that the reaction between ionic intermediate and carboxylate ion is a rate-determining step rather than the reaction of ionic intermediate formation. Both linear and branched carboxylates were used to study the effect of carboxylate ion structure on the reaction rate and yield of the mixed anhydrides.

A Simple and Modified One Pot Conversion of Carboxylic Acid to Ketone

Background: Ketone is one of the important functional groups in synthetic chemistry. For this reason, organic chemists focused on the synthesis of ketone starting from various functionalities since nineties. One of the method deals with the conversion of carboxylic acids to ketones in a one pot manner. We have recently reported a one pot transformation of carboxylic acid to ketone using TsCl or MsCl as an activator of carboxylc acid. In our previous reports, two equivalents of organometallic reagent have been used which may not be useful in medicinal chemistry. In this report, we have developed an alternative process for the transformation where only one equivalent of organometallic reagent has been employed. Objective: In present scenario, we are interested to develop a process for the transformation of carboxylic acid to ketone using one equivalent of an organometallic reagent. Methods: A carboxylic acid reacted with tosyl chloride in the presence of a sodium hydride to form a mixed anhydride. Here, the acidic proton was removed from the reaction mixture as hydrogen gas. This mixed anhydride was then treated with one equivalent of an organomagnesium reagent at -30°C to obtain the desired ketone. Results: Following the optimum conditions, a few commercially available carboxylic acids were treated with TsCl, followed by the treatment of phenyl magnesium and methyl magnesium bromide to obtain phenyl and methyl ketones, respectively, in good to excellent yields. Conclusion: A simple and modified one pot method for the conversion of carboxylic acids to ketone has been reported. In this developed process, one equivalent of the organomagnesium reagent has been used to obtain the desired ketone under the optimized reaction conditions.

New Semisynthetic Penicillins Obtained by Coupling of the 6-Aminopenicillanic Acid with 5-Mercapto-1,2,4-triazoles-3,4-disubstituted.

In a basic medium, 5-Mercapto-1,2,4-triazoles pass into the thiol form, allowing their transformation into sodium salts, which, in reaction with sodium monochloroacetate, lead to sodium 5-thioacetates of 1,2,4-triazoles-3,4-disubstituted. Sulfur derivatives converted to pivalic mixed anhydrides were used as active forms in the acylation of 6-amino penicillanic acid (6-AP) to obtain new semisynthetic penicillins. They contain in the molecule, together with the β-lactam ring, the nucleus 3-[(5-nitroindazol-1'-yl-methyl)]-4-aryl-5-mercapto-1,2,4-triazole, both contributing to an important antibacterial effect. The structure of the new antibiotics was confirmed by the results of elemental and spectral analysis (FT-IR, 1H- and 13C-NMR). The synthetic penicillins were tested for toxicological action and antibacterial activity and the obtained results were close to those for amoxicillin, the reference drug.

Alternate end-game strategies towards Nirmatrelvir synthesis: Defining a continuous flow process for the preparation of an anti-COVID drug

Scalable alternate end-game strategies for the synthesis of the anti-COVID drug molecule Nirmatrelvir (1, PF-07321332) have been described. The first involves a direct synthesis of 1 via amidation of the carboxylic acid 7 (suitably activated as a mixed anhydride with either pivaloyl chloride or T3P) with the amino-nitrile 10·HCl. T3P was found to be a more practical choice since the reagent promoted efficient and concomitant dehydration of the amide impurity 9 (derived from the amino-amide contaminant 8·HCl invariably present in 10·HCl) to 1. This observation allowed for the development of the second strategy, namely a continuous flow synthesis of 1 from 9 mediated by T3P. Under optimized conditions, this conversion could be achieved within 30 min in flow as opposed to 12–16 h in a traditional batch process. The final API had quality attributes comparable to those obtained in conventional flask processes.

Installation of electrophiles onto the C-terminus of recombinant ubiquitin and ubiquitin-like proteins.

Ubiquitin and related ubiquitin-like proteins (Ubls) influence a variety of cellular pathways including protein degradation and response to viral infections. The chemical interrogation of these complex enzymatic cascades relies on the use of tailored activity-based probes (ABPs). Herein, we report the preparation of ABPs for ubiquitin, NEDD8, SUMO2 and ISG15 by selective acyl hydrazide modification. Acyl hydrazides of Ubls are readily accessible by direct hydrazinolysis of Ubl-intein fusions. The suppressed pK a and superior nucleophilicity of the acyl hydrazides enables their selective modification at acidic pH with carboxylic acid anhydrides. The modification proceeds rapidly and efficiently, and does not require chromatographic purification or refolding of the probes. We modified Ubl-NHNH2 with various thiol-reactive electrophiles that couple selectively with E2s and DUBs. The ease of modification enables the rapid generation and screening of ubiquitin probes with various C-terminal truncations and warheads for the selection of the most suitable combination for a given E2 or DUB.

Interaction of Isonicotinic Acid Hydrazide with Carboxylic Acid Anhydrides

There has been presented data on the synthesis of monoamides and cyclic imides which are derivatives of isonicotinic acid hydrazide. Cyclic anhydrides of carboxylic acids (succinic, maleic and phthalic) easily react with the hydrazide of isonicotinic acid with cycle opening, forming isonicotinoylhydrazide of dicarboxylic acids, and under more severe conditions the latter are transformed into cyclic acid imides. The structures of the synthesized compounds were studied using 1H- and 13C-NMR spectroscopy, as well as data from twodimensional COSY (1H-1H) and HMQC (1H-13C) spectra. The values of chemical shifts, multiplicity and integral intensity of 1H and 13C signals in one-dimensional NMR spectra were determined. Homo- and heteronuclear interactions confirming the structure of the studied compounds were established using spectra in the COSY (1H-1H) and HMQC (1H-13C) formats. In the approximation of the density functional B3LYP with a base set of 6-31G(d), the enthalpy of the reactions ΔHr in the absence and in the presence of a solvent — isopropanol (self-consistent reaction field method) were calculated quantum-chemically

Exploring a general mechanistic map on NHC-catalyzed activation/transformation reactions of saturated carboxylic anhydrides

A general mechanistic map involving multiple intermediates and pathways has been proposed and systematically studied for NHC-catalyzed transformation reactions of saturated carboxylic anhydrides.

A one-step base-free synthesis of N-arylamides via modified pivaloyl mixed anhydride mediated amide coupling.

Pivalic anhydride is shown to be an effective reagent for direct amidation of carboxylic acids with N-alkyl anilines. The only by-product of this reaction is nontoxic pivalic acid, which can be easily removed by aqueous workup. The reactions are conducted under mild conditions and found to be compatible with a range of carboxylic acids, including aromatic, heterocyclic, acrylic, and aliphatic carboxylic acids and amino acids generating the desired amides in short reaction times.

Temperature effects on microbial dissolved organic matter metabolisms: Linking size fractions, fluorescent compositions, and functional groups

This study elucidated the compositional and structural variations of size fractions of microbially-induced dissolved organic matter (DOM) caused by short-term temperature changes (5 to 35 °C), taking riverine DOM as an example. A simple and efficient method combining fractionation-[parallel factor analysis and two-dimensional Fourier-transform infrared correlation spectroscopy (PARAFAC-2D FTIR COS)]-correlation was introduced to link fluorescent DOM components and their structures in terms of surface functional groups. Results indicated that the higher temperature stimulated the decomposition of aromatics (sizes decreased from 10 kDa-0.22 μm to <10 kDa) and the transformation of proteins to humics (with sizes <0.22 μm); while both the higher and lower temperatures inhibited the utilization of larger-sized DOM (>0.22 μm, especially the non-fluorescence part) and synthesis of larger-sized microbial-derived proteins and humics (>0.22 μm), which may result in more smaller-sized (<10 kDa) and refractory aromatics transported from rivers to oceans in the warming future. However, the structure-determined DOM behaviors could be less affected by temperature since the fluorescent proteins and humics revealed similar functional group compositions, such as carboxyl, hydroxyl, carbonyl/aldehyde, carboxylic anhydride, and carboxamide groups. These findings have strong implications for DOM biogeochemistry in future temperature-shock scenarios. The proposed method will support in-depth analyses of structure-regulated processes from a mechanistic perspective.

Green Synthesis of MgO Nanoparticles Using Caesalpinia Sappan Seeds and their Application for Direct Conversion of Alcohol to Azide

Azides have been considered as one of the energy rich functional groups as they are prominent precursors for reactive species like nitrenes and nitrenium ions. Also, they were utilized in synthesis of triazoles, triazolines and triazenes. The present work reports an eco- friendly synthesis of MgO NPs by utilizing Caesalpinia Sappan seeds as a novel fuel by solution combustion method. Multiple characterization techniques encompassing FTIR, UV- visible, XRD and SEM were used to study physico-chemical properties of synthesized MgO NPs. A convenient synthesis of amino alcohol via mixed anhydride method was carried out in the first step. Further, amino alkyl azide has been synthesized under mild condition by using the green synthesized MgO nanoparticles as a catalyst along with the addition of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate, a safe, stable and efficient diazo transfer reagent. Structures of newly synthesized compounds were well characterized by HRMS, Proton and C-13 analysis techniques.

Hybridization of Aminoadamantanes with Cinnamic Acid Analogues and Elucidation of Their Antioxidant Profile

A series of seventeen cinnamic acid hybrids (4ai–ci) were obtained through an amidation of aminoadamantanes (amantadine, rimantadine, and memantine) with mixed anhydride generated from different substituted cinnamic acid and ethyl chloroformate. 1H NMR, 13C NMR, IR, and HRMS were used for the confirmation of the structures of the synthesized hybrids. Moreover, the antioxidant profiles of amides were estimated as per five different in vitro methods: 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid cation radical (ABTS⁺), ferric reducing antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC) assay, and inhibition of Fe(III)/asc induced lipid peroxidation (LP) in brain homogenate. For comparison, caffeic acid (CaffA), known as a potent naturally occurring antioxidant, was used as a reference compound in our study. The results revealed that the most prominent antioxidant activity was demonstrated by compound 4b2, with excellent CUPRAC, FRAP, scavenging ABTS+˙ potential, and inhibition of Fe/asc–induced LP, followed by 4c6 &gt; 4a6 &gt; CaffA &gt; 4c5 and 4a5 &gt; 4a7. Overall, the results suggest that the hybrids (4b2, 4c6, and 4a6) consisting of a caffeoyl moiety and lipophilic adamantane core endow the molecules with the higher antioxidant activity than their parent compound (caffeic acid), especially against LP. Thus, these promising antioxidants could have beneficial effects in various pathological conditions, where oxidative stress is implicated.

Previous Exercise on a Water Treadmill at Different Depths Affects the Accelerometric Pattern Recorded on a Track in Horses.

During a water treadmill (WT) exercise, horses change their accelerometric patterns. We aimed to analyze if these changes persist during terrestrial locomotion. Six horses were randomly subjected to 40 min duration WT exercises, without water (WW), at the depth of fetlock (FET), carpus (CAR) and stifle (STF), with a day off between them. Before and after 30 min after WT, horses were evaluated at walk and at trot on a track with a triaxial accelerometer fixed on the pectoral (PECT) and sacrum (SML) regions. The percent of change from baseline (before WT and after each exercise session) were calculated. Total, dorsoventral, longitudinal and mediolateral accelerometric activities and dorsoventral displacement increased with the accelerometer in PECT but decreased after WT at STF. Velocity increased with the accelerometer in PECT but decreased with the accelerometer in SML, particularly after WT at STF. A reduction in stride frequency was found with the accelerometer in PECT. SL increased with the accelerometer in SML but decreased with WT at STF. Some accelerometric changes that happened on WT remained shortly in terrestrial locomotion. The reduction in some parameters after WT at STF depth seems to indicate fatigue. This should be considered in training or rehabilitation programs for unfit animals.

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection invitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Squarephaneic Tetraanhydride: A Conjugated Square-Shaped Cyclophane for the Synthesis of Porous Organic Materials.

Aromatic carboxylic anhydrides are ubiquitous building blocks in organic materials chemistry and have received considerable attention in the synthesis of organic semiconductors, pigments, and battery electrode materials. Here we extend the family of aromatic carboxylic anhydrides with a unique new member, a conjugated cyclophane with four anhydride groups. The cyclophane is obtained in a three-step synthesis and can be functionalised efficiently, as shown by the conversion into tetraimides and an octacarboxylate. Crystal structures reveal the high degree of porosity achievable with the new building block. Excellent electrochemical properties and reversible reduction to the tetraanions are shown for the imides; NMR and EPR measurements confirm the global aromaticity of the dianions and evidence the global Baird aromaticity of the tetraanions. Considering the short synthesis and unique properties, we expect widespread use of the new building block in the development of organic materials.

Squarephaneic Tetraanhydride: A Conjugated Square-Shaped Cyclophane for the Synthesis of Porous Organic Materials.

Aromatic carboxylic anhydrides are ubiquitous building blocks in organic materials chemistry and have received considerable attention in the synthesis of organic semiconductors, pigments, and battery electrode materials. Here we extend the family of aromatic carboxylic anhydrides with a unique new member, a conjugated cyclophane with four anhydride groups. The cyclophane is obtained in a three-step synthesis and can be functionalised efficiently, as shown by the conversion into tetraimides and an octacarboxylate. Crystal structures reveal the high degree of porosity achievable with the new building block. Excellent electrochemical properties and reversible reduction to the tetraanions are shown for the imides; NMR and EPR measurements confirm the global aromaticity of the dianions and evidence the global Baird aromaticity of the tetraanions. Considering the short synthesis and unique properties, we expect widespread use of the new building block in the development of organic materials.

Green diastereospecific synthesis of various medicine analogues containing dipeptides and release of the medicines by Baker's yeast

We have succeeded green and economical synthesis of various dipeptides in 76–99% yields with 70–>99% de and dipeptides-containing medicine analogues in 74–99% yields with 79–97% de in aqueous THF at −15 °C via the mixed carbonic carboxylic anhydrides by the activation of the corresponding carboxylic acids. We observed that the anilide l-Phe-l-Phe-NHC6H4-4-OH, one of the deprotecting medicine analogues, was cleaved at the C-terminal of l-phenylalanine (l-Phe) by Baker's yeast under starvation conditions followed by treatment of a freshly prepared PhCH2CH2CO2CO2Et from 3-phenylpropanoic acid, ClCO2Et, and Et3N in MeCN to afford PhCH2CH2CONHC6H4-4-OH and PhCH2CH2CO-l-Phe-NHC6H4-4-OH in 46% and 42% yields, respectively. Interestingly, biocatalytic hydrolysis of l-Phe-d-Phe-NHC6H4-4-OH by Baker's yeast gave PhCH2CH2CO-d-Phe-NHC6H4-4-OH in 20% yield and PhCH2CH2CO-l-Phe-d-Phe-NHC6H4-4-OH 60% recovery yield.

Continuous Histone Deacylase Activity Assays.

Protein lysine acylation represents one of the most common post-translational modifications. Obviously, highly reactive metabolic intermediates, like thioesters and mixed anhydrides between phosphoric acid and organic acids, modify lysine residues spontaneously. Additionally, enzymes using acyl-CoAs as co-substrates transfer the acyl residue specifically to defined sequences within proteins. The counteracting enzymes are called histone deacetylases (HDACs), releasing the free lysine side chain. Such enzymatic activities are involved in different cellular processes like tumor progression, immune response, regulation of metabolism, and aging. Modulators of such enzymatic activities represent valuable tools in drug discovery. Therefore, direct and continuous assays to monitor enzymatic activity of HDACs are needed. Here we describe different assay formats allowing both monitoring of Zn2+-dependent HDACs via UV-Vis-spectroscopy and NAD+-dependent HDACs (sirtuins) by fluorescence-based assay formats. Additionally, we describe methods enabling efficient screening of HDAC-inhibitors via fluorescence displacement assays.