Arylglyoxylic Acids Research Articles

Visible-Light-Promoted Metal- and Photocatalyst-Free Reactions between Arylglyoxylic Acids and Tetraalkylthiuram Disulfides: Synthesis of α-Ketoamides.

A convenient and new synthetic approach has been developed for the oxidative cross-coupling of the C-N bond through the reaction between arylglyoxylic acids and tetraalkylthiuram disulfides. The reaction proceeds under ambient air at room temperature in the presence of visible light. This reaction offers a metal-, base-, photocatalyst-, and solvent-free synthesis of various α-ketoamides with moderate to excellent yields via the radical pathway. In addition, this protocol demonstrates the potential application of a gram-scale synthesis.

Visible-Light-Induced Metal- and Photocatalyst-Free Radical Cascade Cyclization of Cinnamamides for Synthesis of Functionalized Dihydroquinolinones.

Visible-light-promoted metal- and photocatalyst-free radical cascade cyclization of cinnamamides with α-oxocarboxylic acids is described for sustainable synthesis of diverse pharmaceutically important dihydroquinolinone scaffolds in one pot under mild conditions. The decarboxylative cascade cyclization proceeded efficiently at room temperature without the need for expensive photocatalysts such as Ir or Ru complexes, which indicates the practicability and environmentally benign nature of this protocol. Preliminary mechanistic studies reveal that the blue LED irradiation efficiently cleaves the I-O bond of the hypervalent iodine reagent PhI(O2CCOAr)2 formed through ligand exchange between iodobenzene diacetate and arylglyoxylic acid to initiate the cascade reaction. The synthetic value of this operationally simple and energy-efficient method is further demonstrated by late-stage functionalization of drug molecules in excellent yields.

Synthesis of Thioamides via Decarboxylative/Oxidative Cross‐Coupling Reaction by Visible‐Light Photocatalysis

AbstractAn efficient and new approach has been developed for decarboxylative/oxidative cross‐coupling reaction between arylglyoxylic acids and N,N,N′,N′‐tetraalkylthiuram disulfides to afford aryl thioamide using a catalytic amount of Eosin Y as a photocatalyst. This reaction protocol offers a metal, base and sulfurating reagent‐free synthesis of a variety of aryl thioamides with moderate to excellent yields.

Site‐Selective Decarboxylative Direct Formylation of Nitrogen Heterocycles (Azaindoles, Indoles, Pyrroles) and Anilines Utilizing Glyoxylic Acid

AbstractA new method for formylation of nitrogen heterocycles overcoming the limitations of classical approaches using a cheap feedstock formylating agent especially under mild and neutral conditions is the subject of this current investigation. This work describes direct formylation of nitrogen heterocycles (azaindoles, indoles, pyrroles) and anilines using glyoxylic acid as the formyl source and K2S2O8 as the exclusive reagent. The key features include a general method for both C‐ and N‐formylation under neutral and mild reaction conditions. The application of the method is further demonstrated in the tandem synthesis of nitrogen heterocycles, pharmaceuticals, and a natural product. Unlike aroylation with arylglyoxylic acids, a previously unknown pathway for the direct formylation with glyoxylic acid in the presence of K2S2O8 is now unveiled.magnified image

Regioselective Pd-catalyzed decarboxylative C-6 acylation of 7-O-carbamate coumarins and their anti-inflammatory evaluation

O-Carbamate assisted Palladium (II) catalyzed regioselective C–H acylation of coumarins at C-6 position with arylglyoxylic acids has been achieved. The decarboxylative acylation of diverse 7-O-carbamate coumarins with wide range of arylglyoxylic acids produced solely the C-6 acylated coumarins. The synthesized molecules have been evaluated for their anti-inflammatory activity against RAW 264.7 macrophage cell line. Compounds 3aa, 3ab, and 3ia showed anti-inflammatory activity. Moreover, compound 3ia was found to be the most active with IC50 value of 5.471 μM in IL-1β expression. Further studies revealed that carbamate-based C-6 acylated coumarin derivatives 3aa, 3ab, and 3ia inhibits the nuclear translocation of p65 which mitigates the activation of inflammatory cascade by decreasing the expression of NF-κB. Compound 3ia was found to be the most active compound in inhibiting the NF-κB expression.

Dithiocarbamate-mediated thioamidation of arylglyoxylic acids by decarboxylative–decarbonylative C–C bond formation reactions

Dithiocarbamates are explored in decarboxylative–decarbonylative thioamidation of arylglyoxylic acids in the presence of Pd-catalyst. Cleavage of two C–C bonds and one C–S bond occurs along with the formation of a new C–C bond in a single strategy.

The Perkin Strategy for the Synthesis of Large Carboxy‐Substituted Polycyclic Aromatic Compounds

AbstractAn efficient and versatile synthetic approach has been developed for the synthesis of large carboxy‐substituted polycyclic arenes. This strategy relies on Perkin reactions between arylacetic and arylglyoxylic acids for the formation of flexible precursors. A subsequent rigidification step, by catalyst‐ or light‐induced intramolecular cyclization reactions, then yields fully condensed polycyclic aromatic compounds. Protection and deprotection techniques have been developed to allow the controlled assembly of a large number of building blocks. This method can now be applied to the formation of planar or non‐planar, linear or macrocyclic species of various sizes.

Diversity in Heterocycle Synthesis Using α-Iminocarboxylic Acids: Decarboxylation Dichotomy.

Despite the structural similarity with imines, α-iminocarboxylic acids have seldom been used in heterocycles synthesis. The reactions of ortho-substituted anilines and arylglyoxylic acids in DMSO at 40 °C gave various benzo-fused five- to six-membered N-heterocycles in good to excellent yields. The reaction proceeds via intramolecular Michael addition of α-iminocarboxylic acids, generated in situ, with an ortho-substituted nucleophile, yielding an isolable unprecedented tetrahedral carboxylic acids, which upon decarboxylation without any aid of additional reagents forms the N-heterocycles. DMSO is crucial in this reaction, perhaps because of improved solubility and the ease of decarboxylation of these tetrahedral carboxylic acids. However, a copper-catalyzed reaction of ortho-substituted anilines and 2-bromoarylglyoxylic acids gave a dibenzo-fused seven-membered N-heterocycle under a basic reaction condition. Unlike intramolecular cyclization with α-iminocarboxylic acids in the first case, α-iminocarboxylic acid undergoes a competitive decarboxylation under the copper-catalyzed conditions, which upon subsequent heteroarylation form the heterocycles. Taken together, the study described herein represents two different modes of decarboxylation observed with α-iminocarboxylic acids, leading to the synthesis of divergent heterocycles and pharmaceuticals, which remained unexplored previously.

K2S2O8 mediated synthesis of 5-aryldipyrromethanes and meso-substituted A4-tetraarylporphyrins

The synthesis of dipyrromethanes from pyrrole and arylglyoxylic acids in the presence of K2S2O8at 90 [Formula: see text]C is reported affording dipyrromethanes in very good yields. Unlike an excess pyrrole traditionally used in dipyrromethane synthesis, the current method uses a stoichiometric amount of pyrrole avoiding any use of Brønsted or Lewis acid. A gram scale synthesis of 5-phenyldipyrromethane is also achieved demonstrating potential scale up of dipyrromethanes using this method feasible. Subsequently, dipyrromethanes were converted to A4-tetraarylporphyrins also in the presence of K2S2O8at 90[Formula: see text]C. A direct synthesis of A4-tetraphenylporphyrin from excess pyrrole and phenylglyoxylic acid in the presence of K2S2O8 at 90[Formula: see text]C is also reported.

Catalytic N‐Acylation of Cyclic Amines by Arylglyoxylic Acids via Radical‐Radical Cross‐Coupling

AbstractA methodical mechanistic investigation allowed for the catalytic N‐acylation of secondary cyclic amine counterparts by arylglyoxylic acids through radical‐radical coupling. The reaction proceeds via a twofold SET‐promoted Cu(I)/Cu(II) catalytic cycle under mild conditions. An analogous reaction variant allows for the N‐acylation in a one‐pot fashion directly starting from a secondary cyclic amine even in the presence of a second amine or hydroxy group.

Minisci aroylation of N-heterocycles using choline persulfate in water under mild conditions

A modified Minisci aroylation of isoquinoline using arylglyoxylic acids in the presence of choline persulfate or pre-composition (choline acetate and K2S2O8) in water at ambient temperature affording aroylated isoquinolines is reported.

Possible competitive modes of decarboxylation in the annulation reactions of ortho-substituted anilines and arylglyoxylates.

Annulation reactions of ortho-substituted anilines and arylglyoxylates in the presence of K2S2O8 at 80 °C under metal-free neutral conditions have been investigated, which extended a platform for the tandem synthesis of nitrogen heterocycles. While arylglyoxylic acids are known to undergo decarboxylation to form an acyl radical in the presence of K2S2O8 and used in the Minisci acylation of electron-deficient (hetero)aromatics, their reactions with electron-rich ortho-substituted anilines to form nitrogen heterocycles have recently been studied. Depending upon the experimental conditions used in the reactions, the mechanism of the formation of heterocycles involving reactions of an acyl radical or aryl iminocarboxylic acids has been postulated. Given the subtle understanding of the mechanisms of annulation reactions of 2-substituted anilines and arylglyoxylates in the presence of K2S2O8, an extensive mechanistic investigation was undertaken. In the current study, the various mechanistic pathways including the generation of acyl, imidoyl, aminal, and N,O-hemiketal radicals have been postulated based on different possible decarboxylation modes. Some of the proposed intermediates are supported based on the available analytical data. The protocol uses a single, inexpensive reagent K2S2O8, which offers not only transition-metal-free conditions but also serves as the reagent for the key decarboxylation step. Taken together, this study complements the current development of the annulation reactions of 2-substituted anilines and arylglyoxylates in terms of synthesis and mechanistic understanding.

Synthesis of Unprotected 2-Arylglycines by Transamination of Arylglyoxylic Acids with 2-(2-Chlorophenyl)glycine.

The transamination of α-keto acids with 2-phenylglycine is an effective methodology for directly synthesizing unprotected α-amino acids. However, the synthesis of 2-arylglycines by transamination is problematic because the corresponding products, 2-arylglycines, transaminate the starting arylglyoxylic acids. Herein, we demonstrate the use of commercially available l-2-(2-chlorophenyl)glycine as the nitrogen source in the transamination of arylglyoxylic acids, producing the corresponding 2-arylglycines without interference from the undesired self-transamination process.

Aroylation of Electron-Rich Pyrroles under Minisci Reaction Conditions.

The development of Minisci acylation on electron-rich pyrroles under silver-free neutral conditions has been reported featuring the regioselective monoacylation of (NH)-free pyrroles. Unlike conventional Minisci conditions, the avoidance of any acid that could result in the polymerization of pyrroles was the key to success. The umpolung reactivity of the nucleophilic acyl radical, generated in situ from arylglyoxylic acid, could help explain the mechanism of product formation with electron-rich pyrroles. Alternatively, the nucleophilic substitution of the acyl radical on the electron-deficient pyrrole radical cation is proposed.

Metal-free spirocyclization of N-arylpropiolamides with glyoxylic acids: access to complex azaspiro-fused tricycles.

A metal-free oxidative cascade acylation and dearomatization of N-(p-methoxyaryl)propiolamides was achieved via K2S2O8 mediated decarboxylation of α-oxocarboxylic acids under operationally simple conditions to access azaspiro[4,5]-trienones in good to excellent yields. Furthermore, the utility of the protocol was illustrated in a one-pot reaction sequence consisting of Ugi-reaction/spirocyclization/aza-Michael transformation for the construction of complex tricyclic cores having quaternary spirocenters.

Metal-free benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids.

A simple and straightforward approach has been realized for the direct benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids in the presence of K2S2O8 as an oxidant. Various functional groups were tolerated on both imidazoheterocycles and arylglyoxylic acids and a wide range of C5-benzoyl-imidazoheterocycles were obtained in good to high yields (50-84%). Radical trapping experiments confirmed the involvement of the radical pathway. The developed protocol is amenable for a scale-up reaction.

A Mechanistic Insight into the Cu(II)‐Catalyzed C–N and C–O Coupling Reaction of Arylglyoxylic Acids with Isatins; A DFT Investigation

We carried out a DFT computational investigation on the mechanism of the copper(II) catalyzed C–N, C–O cross coupling reaction involving isatin and phenylglyoxylic acid recently reported by Gogoi. The mechanistic hypothesis proposed by this author is overall confirmed. Our computations demonstrated that the initial decarboxylation is an exergonic reaction (–15.3 kcal mol–1). This process, which can occur rather easily under the used experimental conditions (95 °C for 24 hours), triggers the catalytic cycle with the formation of the initial active organometallic complex (I1). A copper acetate ligand deprotonates the isatin nitrogen. This enhances its nucleophilic character and makes possible the attack of nitrogen on the Cu atom. A reversible transformation connects the initial encounter complex between isatin and the active intermediate I1 and the intermediate where the metal atom inserts into the amide bond. The decarbonylation step represents the rate‐determining step of the entire process (activation free energy = 23.3 kcal mol–1). Copper does not change its oxidation state (II) in the course of the catalytic reaction. The mechanism never involves directly the isatin benzene ring: this is consistent with the fact that only slight changes in the reaction yield are observed when substituents are inserted at different positions of the aromatic ring.

One-pot activation-alkynylation-cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion.

A consecutive three-component activation–alkynylation–cyclization reaction of (hetero)aryl glyoxylic acids, oxalyl chloride, arylacetylenes, and hydrazides efficiently forms 1,5-diacyl-5-hydroxypyrazolines in moderate to good yields. The structures were unambiguously corroborated by comprehensive NMR spectroscopy and X-ray structure analyses of selected derivatives.

Sequential Cu-Catalyzed Four- and Five-Component Syntheses of Luminescent 3-Triazolylquinoxalines.

3-Triazolylquinoxalines can be readily synthesized by applying two complementary synthetic protocols starting from heterocyclic π nucleophiles or (hetero)aryl glyoxylic acids in a consecutive four- or five-component reaction. Conceptually, the sequential use of a single cuprous salt for alkynylation and Cu-catalyzed alkyne-azide cycloaddition (CuAAC) in a one-pot fashion sets the stage for activation-alkynylation-cyclocondensation-CuAAC or glyoxylation-alkynylation-cyclocondensation-CuAAC sequences in good yields. The diversity-oriented generation of differently substituted 3-triazolylquinoxalines is an excellent entry to tunable emission solvatorchromic fluorophores with triazole ligation. The electronic structure, corroborated by DFT and TD-DFT calculations, rationalizes the charge transfer character of relevant absorptions and large Stokes shifts as well as the electronic innocence of the triazole substituents.

Decarboxylative [4+2] annulation of arylglyoxylic acids with internal alkynes using the anodic ruthenium catalysis

A new electrochemical decarboxylative [4+2] annulation of arylglyoxylic acids with internal alkynes involving C-H functionalization by means of a cooperative anode and ruthenium catalysis is presented. This reaction represents a mechanistically novel strategy as an ideal supplement to the decarboxylative [4+2] annulation methodology by employing an electrooxidative process to avoid the use of an additional external oxidizing reagent and utilizing H2O as the carboxyl oxygen atom source to be engaged in the synthesis of 1H-isochromen-1-ones.