Aryl Carboxylic Acids Research Articles

Nickel-Catalyzed Decarboxylative Alkylation of Aryl Iodides with Anhydrides

We present the anhydride-based decarboxylative alkylation of aryl iodides catalyzed by nickel. This method of decarboxylative coupling works with a broad scope of aliphatic carboxylic anhydrides and tolerates synthetically useful aromatic substituents. Assisted by a redox system of pyridine N-oxide and zinc additives, the current reaction occurs under mild conditions and without the assistance of photocatalyst. Notably, this method features high chemoselectivity toward alkyl migration with mixed aliphatic/aromatic anhydrides. Thus, it provides a powerful synthetic tool to modify high-valued aliphatic carboxylic acids by converting them into mixed anhydrides using readily available aryl carboxylic acids such as p-toluic acid. We propose a catalytic cycle that involves the key steps of free radical-based decarboxylation and subsequent alkyl transfer to nickel that precedes an oxidatively induced C–C reductive elimination from Ni(III).

Synthesis and biological activity of analogs of the antifungal antibiotic UK-2A. I. Impact of picolinamide ring replacement.

The antifungal antibiotic UK-2A strongly inhibits mitochondrial electron transport at the Qi site of the cytochrome bc1 complex. Previous reports have described semi-synthetic modifications of UK-2A to explore the structure-activity relationship (SAR), but efforts to replace the picolinic acid moiety have been limited. Nineteen UK-2A analogs were prepared and evaluated for Qi site (cytochrome c reductase) inhibition and antifungal activity. While the majority are weaker Qi site inhibitors than UK-2A (IC50 , 3.8nM), compounds 2, 5, 13 and 16 are slightly more active (IC50 , 3.3, 2.02, 2.89 and 1.55 nM, respectively). Compared to UK-2A, compounds 13 and 16 also inhibit growth of Zymoseptoria tritici and Leptosphaeria nodorum more strongly, while 2 and 13 provide stronger control of Z. tritici and Puccinia triticina in glasshouse tests. The relative activities of compounds 1-19 are rationalized based on a homology model constructed for the Z. tritici Qi binding site. Physical properties of compounds 1-19 influence translation of intrinsic activity to antifungal growth inhibition and in planta disease control. The 3-hydroxy-4-methoxy picolinic acid moiety of UK-2A can be replaced by a variety of o-hydroxy-substituted arylcarboxylic acids that retain strong activity against Z. tritici and other agriculturally relevant fungi. © 2018 Society of Chemical Industry.

Esterification of Aryl/Alkyl Acids Catalysed by N-bromosuccinimide under Mild Reaction Conditions.

N-halosuccinimides (NXSs) are well-known to be convenient, easily manipulable and low-priced halogenation reagents in organic synthesis. In the present work, N-bromosuccinimide (NBS) has been promoted as the most efficient and selective catalyst among the NXSs in the reaction of direct esterification of aryl and alkyl carboxylic acids. Comprehensive esterification of substituted benzoic acids, mono-, di- and tri-carboxy alkyl derivatives has been performed under neat reaction conditions. The method is metal-free, air- and moisture-tolerant, allowing for a simple synthetic and isolation procedure as well as the large-scale synthesis of aromatic and alkyl esters with yields up to 100%. Protocol for the recycling of the catalyst has been proposed.

The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides

Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides.

The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides

AbstractAmide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides.

Structure and photoluminescence property of Eu, Tb, Zn-containing macromolecular complex for white light emission

In this work, a new aryl carboxylic acid functionalized polymethyl methacrylate (PVM) was synthesized by p-vinybenzoic acid (p-VBA) and methyl methacrylate (MMA). By using PVM as macromolecular ligand, the macromlecular complex PVM-Eu, PVM-Tb, and PVM-Zn were prepared. And then, Eu, Tb, Zn-containing macromolecular complex was composited by PVM-Eu, PVM-Tb, and PVM-Zn for white light emission. The structure was characterized using 1H NMR, FT-IR and UV–vis absorption techniques. The luminescence property was measured by fluorescence spectrometry. When excited at 365 nm, the macromolecular complex exhibits emission peaks at 456 nm (blue emission); 488, 543 nm (green emission); and 588, 613 nm (red emission). The white light of the macromolecular complex can be obtained by tuning the ratios of the three complexes. The CIE coordinates of (0.330, 0.338) were calculated which is extremely close to pure white light. And, the CCT was 4555 K for the fabricated WLED using a 365 nm UV chip with the macromolecular complex phosphor, while the CRI was 87. The fluorescence lifetime was calculated to be 0.807 ms. All the results reveal that the macromolecular complex can be applied as a phosphor for the fabrication of NUV-based white LEDs.

New trends and applications in carboxylation for isotope chemistry.

Carboxylations are an important method for the incorporation of isotopically labeled 14CO2 into molecules. This manuscript will review labeled carboxylations since 2010 and will present a perspective on the potential of recent unlabeled methodology for labeled carboxylations. The perspective portion of the manuscript is broken into 3 major sections based on product type, arylcarboxylic acids, benzylcarboxylic acids, and alkyl carboxylic acids, and each of those sections is further subdivided by substrate.

Oxidative C–C Bond Cleavage for the Synthesis of Aryl Carboxylic Acids from Aryl Alkyl Ketones

A metal-free and one-pot two-step synthesis of aryl carboxylic acids from aryl alkyl ketones has been achieved. The reactions were performed with iodine as the catalyst, DMSO and TBHP as the oxidants. Under the optimal reaction conditions, a number of aryl alkyl ketones could be converted into their corresponding aryl carboxylic acids in good to excellent yields (up to 94%).

Ruthenium(II)-Catalyzed Positional Selective C-H Oxygenation of N-Aryl-2-pyrimidines.

Efficient Ru-catalyzed regioselective C-H oxygenation of N-aryl-2-pyrimidines is described with aryl carboxylic acids in the presence of AgSbF6 as an additive and Ag2CO3 as an oxidant. The reaction can be extended to alkyl, heteroaryl, and α,β-unsaturated carboxylic acids. The regioselectivity, broad substrate scope, and functional group tolerance are the significant practical advantages.

Substrates for Paraoxonase.

Paraoxonase (PON) is a family of calcium-dependent hydrolases, which is related to many diseases. Elucidation of PON physiological roles, active center and all applications in medical fields are dependent on its substrates. The reports about PON substrates scattered in a long span of period are collected to afford clue for drug design, diagnosis of PON status and other academic purposes. PON substrates from 133 references are classified and compared. Structurally, PON substrates are generally classified as organic phosphorous esters, lactones and arylesters. Some phosphoramidates, organophosphorous obidoximes, aryl carboxylic acid amides and special fatty alcohol esters as PON substrates are also included. The electron nature, steric hindrance and hydrophilicity of substrate substituents affecting the PON catalytic ability, binding ability and specificities are discussed. Drugs, prodrugs and naturally endogenous molecules in life processes activated or inactivate by PON are reviewed. Interestingly, some organophosphate and lactone substrates are preferably hydrolyzed by one of the PON1R192Q allozymes, and such a substrate is generally essential for differentiating the three PON1192R phenotypes by using a dual-substrate method. Intricately, some chiral substrates are hydrolyzed by PON stereoselectively. As more substrates are synthesized and characterized, more facts about PON structure and catalytic properties (including PON active center and catalytic mechanism) will be revealed, and therefore the use of PON as a drug target or as an accurate disease marker will be achieved.

Rh/Cu-Catalyzed Ketone β-Functionalization by Merging Ketone Dehydrogenation and Carboxyl-Directed C–H Alkylation

An efficient Rh/Cu-catalyzed method has been developed for the direct β-arylation or alkenylation of ketones using (hetero)aryl or alkenyl carboxylic acids as coupling partners. This direct ketone β-functionalization reaction proceeded via the merging of Cu-catalyzed ketone dehydrogenative desaturation and Rh-catalyzed carboxyl-directed C–H alkylation, exhibiting a broad substrate scope for both coupling partners. TEMPO proved to be essential for both dehydrogenation process and generation of the active Rh catalyst for C–H activation.

Decarboxylative Fluorination of Arylcarboxylic Acids Promoted by ortho‐Hydroxy and Amino Groups

AbstractA novel decarboxylative fluorination process has been developed for the synthesis of ortho‐hydroxy/amino arylfluorides from salicylic acid analogs, in which the ortho‐hydroxy/amino group plays an important role in the transformation. In addition, various arylfluorides are obtained in good to excellent yields under mild conditions.

Pd-Catalyzed Decarboxylative Sonogashira Reaction via Decarboxylative Bromination.

The decarboxylative alkynylation of (hetero)aryl carboxylic acids with terminal alkynes has been achieved by using a Pd(PPh3)4/PCy3 catalyst. This Pd-catalyzed method exhibits good functional group tolerance for both coupling partners and enables chemical modification of complex molecules. The establishment of this decarboxylative alkynylation reaction is attributed to the discovery of a highly selective decarboxylative bromination of (hetero)aryl carboxylic acids with NBS ( N-bromosuccinimide).

Palladium-Catalyzed Esterification of Carboxylic Acids with Aryl Iodides.

The first palladium-catalyzed esterification of carboxylic acids with aryl iodides is described. A palladium-based catalytic system consisting of IBnF (1,3-bis((pentafluorophenyl)methyl)imidazole-2-ylidene) ligand was found to significantly accelerate the aryl-O bond-forming esterification reaction. A series of aryl iodides and carboxylic acids undergoes a palladium-catalyzed coupling reaction to provide the corresponding aryl esters in moderate to good yields. In addition, sterically hindered aryl iodides and carboxylic acids were well-tolerated yielding the corresponding aryl esters.

Cu(I)‐Catalyzed Site Selective Acyloxylation of Indoline Using O2 as the Sole Oxidant

AbstractA Cu(I)‐catalyzed regioselective cross‐dehydrogenative coupling of indoline with a variety aryl and alkyl carboxylic acids is described. The divergent process for the oxygenation was achieved in satisfactory yields under additive free conditions, which provides an efficient strategy for the regioselective C7 functionalization of indolines using inexpensive copper catalyst. Oxygen as the sole oxidant is required in this protocol. The method is tolerated by a wide range of functional groups. Preliminary mechanistic study provided support for a reversible C−H bond metallation step.magnified image

Hydrochloric Acid-Promoted Intermolecular 1,2-Thiofunctionalization of Aromatic Alkenes

An efficient method for making 1,2-thiofunctionalized products via the difunctionalization of aromatic alkenes was developed. In this method, cheap and readily available hydrochloric acid was used to promote 1,2-thiofunctionalization of aryl alkenes with N-arylsulfenylphthalimide and different types of nucleophiles. Importantly, extension of nucleophiles can reach aryl ethers, indoles, and carboxylic acids with good reactivity. This practical and convenient method has broad substrate scope and high yields under metal-free and mild conditions. Furthermore, we achieved conversion and application for making sulfoxide and sulfone by oxidation.

Ru(II)-Catalyzed Oxidative Heck-Type Olefination of Aromatic Carboxylic Acids with Styrenes through Carboxylate-Assisted C-H Bond Activation.

A straightforward synthesis of 2-styrylbenzoic acids from aryl carboxylic acids is disclosed through a carboxylate-assisted coupling under Ru(II) catalysis. This protocol is simple and exhibits broad scope with high tolerance of common organic functional groups, providing good to excellent yields of diverse olefinated products. The efficacy of this protocol has been showcased through sequential syntheses of isochromanone, isocoumarin, and formal synthesis of anacardic acid derivative in good yields.

Copper-catalyzed oxidative coupling of arylboronic acids with aryl carboxylic acids: Cu3(BTC)2 MOF as a sustainable catalyst to access aryl esters

A straightforward and sustainable methodology for the synthesis of commercially important aryl esters via a C–O cross-coupling reaction was demonstrated using the Cu3(BTC)2 metal–organic framework.

Inexpensive NaX (X = I, Br, Cl) as a halogen donor in the practical Ag/Cu-mediated decarboxylative halogenation of aryl carboxylic acids under aerobic conditions.

Versatile and practical Ag/Cu-mediated decarboxylative halogenation between readily available aryl carboxylic acids and abundant NaX (X = I, Br, Cl) has been achieved under aerobic conditions in moderate to good yields. The halodecarboxylation is shown to be an effective strategy for S-containing heteroaromatic carboxylic acid and benzoic acids with nitro, chloro and methoxyl substituents at the ortho position. A gram-scale reaction and a three-step procedure to synthesize iniparib have been performed to evaluate the practicality of this protocol. A preliminary mechanistic investigation indicates that Cu plays a vital role and a radical pathway is involved in the transformation.

Kinetic Characterization of Prenyl-Flavin Synthase from Saccharomyces cerevisiae.

We have characterized the kinetics and substrate requirements of prenyl-flavin synthase from yeast. This enzyme catalyzes the addition of an isopentenyl unit to reduced flavin mononucleotide (FMN) to form an additional six-membered ring that bridges N5 and C6 of the flavin nucleus, thereby converting the flavin from a redox cofactor to one that supports the decarboxylation of aryl carboxylic acids. In contrast to bacterial enzymes, the yeast enzyme was found to use dimethylallyl pyrophosphate, rather than dimethylallyl phosphate, as the prenyl donor in the reaction. We developed a coupled assay for prenyl-flavin synthase activity in which turnover was linked to the activation of the prenyl-flavin-dependent enzyme, ferulic acid decarboxylase. The kinetics of the reaction are extremely slow: kcat = 12.2 ± 0.2 h-1, and KM for dimethylallyl pyrophosphate = 9.8 ± 0.7 μM. The KM for reduced FMN was too low to be accurately measured. The kinetics of reduced FMN consumption were studied under pre-steady state conditions. The reaction of FMN was described well by first-order kinetics with a kapp of 17.4 ± 1.1 h-1. These results indicate that a chemical step, most likely formation of the carbon-carbon bond between C6 of the flavin and the isopentenyl moiety, is substantially rate-determining in the reaction.