Carboxylic Acid Amides Research Articles

Trimethoxy(methyl)silane-Mediated Amidation of Carboxylic Acids

Key words trimethoxymethylsilane - amidation - amines - carboxylic acids

PcCesA1 is involved in the polar growth, cellulose synthesis, and glycosidic linkage crosslinking in the cell wall of Phytophthora capsici

Phytophthora capsici is a destructive plant pathogen that infects a wide range of hosts worldwide. The P. capsici cell wall, rich in cellulose, is vital for hyphal growth and host interactions. However, the enzymes involved in its synthesis remain largely unelucidated. In the current study, we functionally characterized the cellulose synthase gene PcCesA1, which is highly conserved in Phytophthora. By using CRISPR/Cas9-mediated gene replacement and in situ complementation system, it was found PcCesA1 is essential for the mycelial growth, cystospore germination, and pathogenicity of P. capsici. The normal deposition of newly synthesized cell wall components and the polar growth point formation were disrupted in PcCesA1 knockout mutants, suggesting that PcCesA1 plays an important role in the polar growth of P. capsici. Compared with the wild-type strains, PcCesA1 knockout mutants displayed a thicker inner layer cell wall and were more sensitive to carboxylic acid amide fungicides (CAAs). The contents of the cell wall polysaccharides 1,4-Glc, 1,4,6-Glc, and 1,3,4-Glc were reduced in PcCesA1 knockout mutants, suggesting that PcCesA1 affected cellulose content and glycosidic linkage crosslinking in the cell wall. Our findings demonstrate that PcCesA1 is required for cell wall biogenesis. Therefore, PcCesA1 may be a potential target for Phytophthora disease control.

Synthesis, Anti-Arrhythmic, Hemostatic, Anthelmintic, and Larvicidal Activity of 2-(3-spiro-cycloalkyl-3,4-dihydroisoquinolin-1-yl)-Carboxylic Acid Amide Hydrochlorides

Synthesis, Anti-Arrhythmic, Hemostatic, Anthelmintic, and Larvicidal Activity of 2-(3-spiro-cycloalkyl-3,4-dihydroisoquinolin-1-yl)-Carboxylic Acid Amide Hydrochlorides

Methyltrimethoxysilane (MTM) as a Reagent for Direct Amidation of Carboxylic Acids.

Methyltrimethoxysilane [MTM, CH3Si(OMe)3] has been demonstrated to be an effective, inexpensive, and safe reagent for the direct amidation of carboxylic acids with amines. Two simple workup procedures that provide the pure amide product without the need for further purification have been developed. The first employs an aqueous base-mediated annihilation of MTM. The second involves simple product crystallization from the reaction mixture providing a low process mass intensity direct amidation protocol.

KPF6-Mediated Esterification and Amidation of Carboxylic Acids.

A novel KPF6-promoted green method has been developed for the synthesis of esters and amides. A wide range of carboxylic acids and alcohols or amines worked well under the developed reaction conditions, thus providing good to excellent (61-98%) yields of the corresponding esters and amides. The method worked well with bioactive substrates such as cholesterol, levulinic acid, and linoleic acid. Wide substrate scope, operational simplicity, scalability, and sustainability make this protocol a practical and economically attractive approach for the preparation of ester and amides.

Efficient catalyst-free direct amidation of non-activated carboxylic acids from carbodiimides

A novel and efficient catalyst- and activating agent-free amidation method via direct amidation of carboxylic acids where carbodiimides act as a reagent instead of an activating agent is reported. The reaction is conducted under non-traditional coupling conditions where a higher temperature is employed. Besides not using stoichiometric ratios of activating agent or catalyst, this approach is made even more attractive by occurring in the presence of the environmentally friendly and recyclable non-toxic solvent of DMSO. A wide variety of benzylic, aliphatic, α,β-unsaturated and aromatic carboxylic acids provide related amides in up to 95% yield. The excellent yield from a gram-scale reaction shows that this application is particularly convenient for larger-scale synthesis applications.

Catalytic N-methyl amidation of carboxylic acids under cooperative conditions

Amide is a fundamental group that is present in molecular structures of all domains of organic chemistry and the construction of this motif with high atom economy is the focus of the current research. Specifically, N-methyl amides are valuable building blocks in natural products and pharmaceutical science. Due to the volatile nature of methyl amine, the generation of N-methyl amides using simple acids with high atom economy is rare. Herein, we disclose an atom economic protocol to prepare this valuable motif under DABCO/Fe3O4 cooperative catalysis. This protocol is operationally simple and compatible with a range of aliphatic and (hetero)aromatic acids with very good yields (60–99%). Moreover, the Fe3O4 can be easily recovered and high efficiency is maintained for up to ten cycles.

Multiple mutations in the predicted transmembrane domains of the cellulose synthase 3 (CesA3) of Phytophthora capsici can confer semi-dominant resistance to carboxylic acid amide fungicides

The current study established a clearer understanding of the molecular basis for resistance to carboxylic acid amide (CAA) fungicides. Although four cellulose synthase (CesA) genes were investigated, only F1073L, G1105A, V1109L in CesA3 were found to link to CAA-resistance in Phytophthora capsici. Back-transformation experiments confirmed the role of the three mutations in CAA-resistance. Inheritance studies also confirmed the link and indicated the resistance was semi-dominant with the heterozygous F1 and F2 progeny exhibiting intermediate resistance levels compared to the homozygous parents, which was validated by the pyrosequencing results. The semi-dominant nature of CAA-resistance implies that it could be easy for resistance to spread once resistance emerged, being facilitated by both sexual and asexual reproduction. Bioinformatic analysis indicated all mutations occurred in either the first or second of the predicted transmembrane domains at C-terminus of CesA3. Resistant isolates bearing different combinations of mutations were found to exhibit different resistance levels to different CAAs, indicating that each mutation could make different contributions to resistance phenotype depending on structural differences in different CAAs. The current results highlight the complex combinations of mutations and resistance phenotype, and further reinforces the research necessity to completely characterize CAA-resistance to develop appropriate strategies to manage resistance development.

Hydrogenation of Secondary Amides using Phosphane Oxide and Frustrated Lewis Pair Catalysis.

The metal‐free catalytic hydrogenation of secondary carboxylic acid amides is developed. The reduction is realized by two new catalytic reactions. First, the amide is converted into the imidoyl chloride by triphosgene (CO(OCCl3)2) using novel phosphorus(V) catalysts. Second, the in situ generated imidoyl chlorides are hydrogenated in high yields by an FLP‐catalyst. Mechanistic and quantum mechanical calculations support an autoinduced catalytic cycle for the hydrogenation with chloride acting as unusual Lewis base for FLP‐mediated H2‐activation.

Site-specific Umpolung amidation of carboxylic acids via triplet synergistic catalysis

Development of catalytic amide bond-forming methods is important because they could potentially address the existing limitations of classical methods using superstoichiometric activating reagents. In this paper, we disclose an Umpolung amidation reaction of carboxylic acids with nitroarenes and nitroalkanes enabled by the triplet synergistic catalysis of FeI2, P(V)/P(III) and photoredox catalysis, which avoids the production of byproducts from stoichiometric coupling reagents. A wide range of carboxylic acids, including aliphatic, aromatic and alkenyl acids participate smoothly in such reactions, generating structurally diverse amides in good yields (86 examples, up to 97% yield). This Umpolung amidation strategy opens a method to address challenging regioselectivity issues between nucleophilic functional groups, and complements the functional group compatibility of the classical amidation protocols. The synthetic robustness of the reaction is demonstrated by late-stage modification of complex molecules and gram-scale applications.

Fungicide Efficacy Against Pseudoperonospora humuli and Point Mutations Linked to Carboxylic Acid Amide Resistance in Michigan.

Hops have expanded as a niche crop in Michigan and other production areas in the eastern United States, but growers in these regions face annual downy mildew outbreaks incited by Pseudoperonospora humuli, exacerbated by frequent rainfall and high relative humidity. We evaluated the efficacy of foliar- and drench-applied fungicides against downy mildew and examined Michigan isolates for point mutations linked to carboxylic acid amide (CAA) resistance. Disease severity and density were assessed weekly in 2016 and 2017 in nontrellised research hop yards in Michigan. Area under the disease progress curve values for disease severity were significantly lower for plants treated with oxathiapiprolin, ametoctradin/dimethomorph, fluopicolide, cyazofamid, or mandipropamid (90.6 to 100% control) compared with those treated with fosetyl-Al (64.3 to 93.0% control) at both locations for both years. Drench treatments of fluopicolide and oxathiapiprolin/mefenoxam reduced disease density and severity at both locations but were only moderately effective (76.4 to 91.5% control). To assess CAA resistance, the cellulose synthase CesA3 gene was aligned using reference downy mildew species and primers designed to amplify the 1105 and 1109 amino acids. Point mutations conferring CAA resistance were not detected at these loci for sporangia from 42 symptomatic shoots collected from 11 commercial hop yards. These efficacy results for hop downy mildew are needed to guide disease recommendations in this expanding Michigan industry. The absence of resistant genotypes indicates that Michigan growers can continue to utilize CAA-containing commercial fungicides as part of an overall downy mildew management program.

Quinazoline-containing Hydrazydes of Dicarboxylic Acids and Products of Their Structural Modification: A Novel Class of Anti-inflammatory Agents

The synthesis of hydrazides formed by quinazolin-4(3H)-ylidenehydrazine and dicarboxylic acids, as well as their further modification are described in the present manuscript. It was shown that above-mentioned hydrazides may be obtainedviaacylation of initial quinazolin-4(3H)-ylidenehydrazine by corresponding acylhalides, cyclic anhydrides and imidazolides of dicarboxylic acids monoesters. Obtained hydrazides were converted into [1,2,4]triazolo[1,5-c]quinazolines that were used as initial compounds for chemical modification aimed to the introduction of amide fragment to the molecule. The IR,1H NMR and chromato-mass spectral data of obtained compounds were studied and discussed. Obtained substances were studied for anti-inflammatory activity using carrageenan-induced paw inflammation model. Amides of ([1,2,4]triazolo[1,5-c]quinazoline-2-yl)alkyl carboxylic acids were detected as promising class of anti-inflammatory agents for further purposeful synthesis and profound study of anti-inflammatory activity.

Catalytic and non-catalytic amidation of carboxylic acid substrates.

The present review offers an apt summary of amide bond formation with carboxylic acid substrates by taking advantage of several methods. Carboxamides can be regarded as a substantial part of organic and medicinal chemistry due to their utility in synthesizing peptides, lactams, and more than 25% of familiar drugs. Moreover, they play a leading role in the synthesis of bioactive products with anticancer, antifungal, and antibacterial properties. The data are arranged based on the type and amount of reagents used to conduct amidation and are also divided into the following categories: catalytic amidation of carboxylic acids, non-catalytic amidation, and transamidation.

Iridium(III)-Catalyzed Direct Intermolecular Chemoselective α-Amidation of Masked Aliphatic Carboxylic Acids with Dioxazolones via Nitrene Transfer

The Ir(III)-catalyzed direct α-C–H amidation of imidazole-masked aliphatic carboxylic acids with dioxazolones is reported. The presence of an imidazole moiety as a directing group is a key to the success of the reaction. The products can be easily converted to esters and amides in a simple procedure. The reaction shows a broad substrate scope for various substituted 2-acylimidazoles, as well as a variety of dioxazolone derivatives with important functional groups being tolerated. The reaction mechanism was investigated by deuterium-labeling experiments, Hammett plots, NMR, and FAB-MS, and we propose the generation of an iridium nitrene intermediate.

Ammonia-borane as a Catalyst for the Direct Amidation of Carboxylic Acids.

Ammonia-borane serves as an efficient substoichiometric (10%) precatalyst for the direct amidation of both aromatic and aliphatic carboxylic acids. In situ generation of amine-boranes precedes the amidation and, unlike the amidation with stoichiometric amine-boranes, this process is facile with 1 equiv of the acid. This methodology has high functional group tolerance and chromatography-free purification but is not amenable for esterification. The latter feature has been exploited to prepare hydroxyl- and thiol-containing amides.

Amidation of Carboxylic Acids with Amine–Borane Complexes

Amidation of Carboxylic Acids with Amine–Borane Complexes

A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects.

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over-addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale-up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre-activated amides, as recommended.

Stepwise accumulation of mutations in CesA3 in Phytophthora sojae results in increasing resistance to CAA fungicides.

Flumorph is a carboxylic acid amide (CAA) fungicide with high activity against oomycetes. However, evolution to CAAs from low resistance to high resistance has never been reported. This study investigated the basis of resistance evolution of flumorph in Phytophthora sojae. Total of 120 P. sojae isolates were collected and their sensitivity to flumorph was evaluated. Although no spontaneous resistance was found among the field isolates, adaptation on flumorph‐amended media resulted in the selection of five stable mutant types exhibiting varying degrees of resistance to CAAs. Type I, which exhibited the lowest resistance level, was obtained when the wild‐type isolate was exposed to a low concentration of flumorph, but no resistant mutants were obtained by direct exposure to higher concentrations. However, the more resistant types (Type II, III, IV and V) were obtained when Type I were exposed to higher concentrations of flumorph. Similar results were obtained when the entire screening process was repeated, which implied that evolution of resistance to flumorph in P. sojae could be a two‐step process, where high resistance phenotypes could develop gradually from low resistance ones. Further investigation into molecular mechanism strongly confirmed that evolution of isolates highly resistant to flumorph occurs in a stepwise process with Type I as intermediary, through accumulation of mutations in their target protein of CAAs (CesA3). Together, our findings indicate that application of low rates of flumorph in field could result in selection of low resistance Type I isolates, but that raising dosage to maintain comparable levels of control could elicit rapid evolution of more resistant Type II, III, IV and V isolates with stepwise accumulation of mutations in CesA3, which would render flumorph ineffective as a control method. Precautionary resistance management strategy should be implemented. The phenomenon described in the study could have broader biological significance.

Quarternary α-cyanobenzylsulfonamides: A new subclass of CAA fungicides with excellent anti-Oomycetes activity

A bioisosteric carboxamide - sulfonamide replacement explored during the optimization of an insecticide lead compound led to the surprising discovery of a formerly unknown subclass of the Carboxylic Acid Amide (CAA) fungicides, which is the very first CAA fungicide group without a carboxamide function. In this paper we present invention pathway, racemic and stereoselective synthesis routes, structure–activity relationship studies as well as resistance profile of this novel family of fungicides.

SYNTHESIS AND BROMINATION OF PROPARGYLIC TRIFLUOROUTIC ACID AMIDE

Carboxylic acid amides are convenient reagents for organic synthesis, and are promising building blocks for obtaining a large number of acyclic and heterocyclic compounds.Among the various aliphatic, aromatic and heterocyclic amides, fluorine-containing derivatives are the least studied. The presence of a carbonyl group, a fluoroalkyl substituent and an alkyl-substituted amino functional groups determines the variety of transformations for this class of compounds. The introduction of an unsaturated alkyl substituent to the amide nitrogen atom and the presence of an additional nucleophilic center of the oxygen or nitrogen atom makes such amides promising for the study of their reactions with electrophilic reagents.The aim of this work is the synthesis of propargyl trifluoroacetic acid amide and the study of its interaction with bromine.Trifluoroacetic acid propargylamide was prepared from trifluoroacetic acid ethyl ester and propargylamine in tetrahydrofuran medium, its structure was confirmed by NMR1H and NMR19F spectra.It is known from the literature sources that the presence of a multiple bond and an additional intramolecular nucleophilic center in propargyl amines and amides creates the pre-conditions for the cyclization reaction under the action of halogen-containing electrophilic reagents. Such structural features are also characteristic for N-propargyltrifluoroacetamide, namely the multiple bond of the propargyl moiety and additional intramolecular nucleophilic centers of nitrogen and oxygen atoms. Under the action of bromine as an electrophilic reagent on N-propargyltrifluoroacetamide, the formation of both the coupling product and the cyclization with the formation of azetidine, oxazoline or oxazine heterocycles is possible.The bromination reaction of N-propargyltrifluoroacetamide was performed in dichloromethane with an equimolar amount of reagents in the presence of potash. According to the spectral data, the coupling product N- (2,3-dibromoprop-2-en-1-yl) trifluoroacetamide is formed, which is confirmed by the NMR1H and NMR19F spectra. The absence of the cyclization process can be explained via the lower nucleophilicity of the oxygen atom compared to sulfur.