A novel synthetic strategy involving the Eschenmoser coupling reaction of 4-bromoisoquinoline-1,3(2H,4H)-diones with substituted thioformanilides, thioacetanilides, and thiobenzanilides gave 18 (Z)-4-((substituted phenylamino)methylidene)isoquinoline-1,3(2H,4H)-diones. The reaction occurs under mild conditions (DMF or MeCN, 25- 60 degrees C) without any base or thiophile and in good yields (43-95%). Furthermore, for the synthesis of starting thioformanilides carrying basic substituents, a new thioacylation protocol was developed that involves a thioacylating agent formed from carbon disulfide and lithium triethylborohydride.

Aromatic azo compounds stand as a highly sought-after class of substances owing to their extensive array of applications across various fields. Despite their significance, their synthesis often presents challenges, requiring either multistep reactions or being restricted to specific substrate types. In this study, we are showing the universality and mechanistic aspects of a one-step approach for synthesis of nonsymmetrical azoarenes via the Buchwald-Hartwig amination reaction of (pseudo)haloaromatics with arylhydrazines, conducted in the presence of atmospheric oxygen. This reaction protocol yields products in up to 85% yield and is compatible with a wide class of substituents, making it highly adaptable. Notably, the inclusion of BINAP as a ligand plays a pivotal role in achieving favorable outcomes. This study not only offers a versatile solution to a long-standing synthetic challenge but also provides experimental and computational insights into the mechanisms driving the reaction.

Reactions of thiobenzamide or thioacetamide with 4-bromo-1,1-dimethyl-1,4-dihydroisoquinoline-3(2H)-one, 4-bromoisoquinoline-1,3(2H,4H)-dione and two α-bromo(phenyl)acetamides were examined under various conditions (base, solvent, thiophile, temperature) and structure/medium features that influence product distribution (Eschenmoser coupling reaction, Hantzsch thiazole synthesis and elimination to nitriles) were identified. The key factor that enables the successful Eschenmoser coupling reaction involves the optimum balance in acidity of nitrogen and carbon atoms of the intermediary α-thioiminium salts.

AbstractA novel synthetic strategy involving the Eschenmoser coupling reaction of 4-bromoisoquinoline-1,3(2H,4H)-diones with substituted thioformanilides, thioacetanilides, and thiobenzanilides gave 18 (Z)-4-((substituted phenylamino)methylidene)isoquinoline-1,3(2H,4H)-diones. The reaction occurs under mild conditions (DMF or MeCN, 25–60 °C) without any base or thiophile and in good yields (43–95%). Furthermore, for the synthesis of starting thioformanilides carrying basic substituents, a new thioacylation protocol was developed that involves a thioacylating agent formed from carbon disulfide and lithium triethylborohydride.

Simple switching of the site-selectivity of C-H activation reactions of substrates containing multiple directing groups is particularly important for the so-called late stage functionalization synthetic approach. In this work, we verified the possibility of achieving this by adding acids of different strengths. Using a substrate containing two differently strong (and basic) directing groups, the influence of the addition of acids on the regioselectivity of the C-H activation step of the reaction with palladium acetate was thoroughly studied. The addition of no or weak acids results in cyclopalladation being controlled by a stronger directing group. However, the addition of a strong acid causes protonation of this group and the reaction is then controlled by a weaker directing group. Finally, this approach enables double C-H activation leading to a unique class of compounds: "non-symmetrical" [2.2]-dipalladaparacyclophanes.

The Eschenmoser coupling reaction (ECR) of thioamides with electrophiles is believed to proceed via thiirane intermediates. However, little is known about converting the intermediates into ECR products. Previous mechanistic studies involved external thiophiles to remove the sulfur atom from the intermediates. In this work, an ECR proceeding without any thiophilic agent or base is studied by electrospray ionization-mass spectrometry. ESI-MS enables the detection of the so-far elusive polysulfide species Sn, with n ranging from 2 to 16 sulfur atoms, proposed to be the key species leading to product formation. Integrating observations from ion mobility spectrometry, ion spectroscopy, and reaction monitoring via flow chemistry coupled with mass spectrometry provides a comprehensive understanding of the reaction mechanism and uncovers the autocatalytic nature of the ECR reaction. Piecing the puzzle together. Mass spectrometry reveals the autocatalytic behavior of the Eschenmoser coupling reaction. Combining the results from ESI-MS coupled with various add-on methods, such as IR spectroscopy, ion mobility, or flow chemistry, leads to a comprehensive view of the reaction mechanism.+image

The novel dimeric iodo-iridium(III) complex, [Ir(Cp*CONMe2)I2]2, (Cp*CONMe2 = η5-N,N-2,3,4,5-hexamethylcyclopenta-2,4-diene carboxamide) bearing an amide moiety within the tetramethylcyclopentadiene ring, has been synthesised and characterised. The ligand Cp*CONMe2 is synthesised as two regioisomers, however the 2-substituted isomer exists as two distinguishable conformers due to restricted rotation about the amide carbonyl carbon and the ring carbon. The relative acidities of Cp*CONMe2 and Cp* are compared by their relative rates of H/D exchange. The iridium complex of N,N-2,3,4,5-hexamethylcyclopenta-2-4-diene carboxamide [IrCp*CONMe2] and (R,R)-1,2-diphenyl-N'-tosylethane-1,2-diamine ((R,R)-TsDPEN) has been evaluated in the transfer hydrogenation of imines under acidic conditions - a 5 : 2 molar ratio of formic acid : triethylamine as the hydride source for the transfer hydrogenation of 1-methyl-3,4-dihydroisoquinoline (DHIQ) and its 6,7-dimethoxy derivative in acetonitrile. A decreasing enantiomeric excess with reaction progress is attributed to different kinetic orders for formation of the two product amine enantiomers. The pseudo zero-order formation of the R-amine may be due to a pre-steady-state formation of the less stable form of the diastereomeric catalyst. By contrast, both enantiomeric amines from 1-fluorinated methyl DHIQs as substrates for reduction are formed by pseudo first-order processes.

A highly modular method for the synthesis of (Z)-3-[amino(phenyl/methyl)methylidene]-1,3-dihydro-2H-indol-2-ones starting from easily available 3-bromooxindoles or (2-oxoindolin-3-yl)triflate and thioacetamides or thiobenzamides is described. A series of 49 compounds, several of which have previously been shown to possess significant tyrosin kinase inhibiting activity, was prepared in yields varying mostly from 70 to 97% and always surpassing those obtained by other published methods. The method includes an Eschenmoser coupling reaction, which is very feasible (even without using a thiophile except tertiary amides) and scalable. The (Z)-configuration of all products was confirmed by NMR techniques.

A novel synthetic approach involving an Eschenmoser coupling reaction of substituted 3-bromooxindoles (H, 6-Cl, 6-COOMe, 5-NO2) with two substituted thiobenzanilides in dimethylformamide or acetonitrile was used for the synthesis of eight kinase inhibitors including Nintedanib and Hesperadin in yields exceeding 76%. Starting compounds for the synthesis are also easily available in good yields. 3-Bromooxindoles were prepared either from corresponding isatins using a three-step synthesis in an average overall yield of 65% or by direct bromination of oxindoles (yield of 65-86%). Starting N-(4-piperidin-1-ylmethyl-phenyl)-thiobenzamide was prepared by thionation of the corresponding benzanilide in an 86% yield and N-methyl-N-(4-thiobenzoylaminophenyl)-2-(4-methylpiperazin-1-yl)acetamide was prepared by thioacylation of the corresponding aniline with methyl dithiobenzoate in an 86% yield.

Finding optimal reaction conditions is usually complex, requires many experiments, and is therefore demanding in terms of human, financial, and environmental resources. This work provides a simple workflow for easier design of popular palladium-catalyzed C-H functionalization reactions, where the active palladium catalysts contain carboxylate ligands. The key factor for optimizing reaction conditions is to find a balance between two opposing effects of the carboxylic acid in the reaction mixture: generation of more reactive palladium catalyst versus deactivation of a substrate by its protonation.

An intramolecular base-catalyzed nitroaldol reaction of three newly prepared 2-(2-nitroalkyl)benzaldehydes (1a-c) giving corresponding 2-nitroindan-1-ols (2a-c) was studied in water and five non-aqueous solvents. Whilst for the parent 2-(2-nitroethyl)benzaldehyde (1a) the reaction takes place in two kinetically discernible steps - deprotonation and cyclization, for 2-(2-nitropropyl)- and 2-(2-nitro-2-phenylethyl)benzaldehydes 1b and 1c general base-catalyzed formation of a reactive carbanion is rate-limitting. An unusually high Bronsted coefficient (beta(B)=1.12 +/- 0.03) was found for 1b indicating smaller imbalance of the transition state whose structure therefore resembles a nitronate. Cyclization products 2a-c prefer relative trans-configuration in ratios from 55:45 to 83:17 depending on the solvent. Mutual interconversion of the cis-/trans-diastereoisomers occurs either via nitronate species 2a(-) or via a reverse ring opening/ring closing pathway through the nitronate species 1b(-) and 1c(-). The mechanism was also supported by quantum calculations.

Five substituted 2-aryl-4-hydroxy-5-(2'-aminophenyl)-1,3-thiazoles have been studied for their fluorescence properties under neutral and alkaline conditions in solutions of various organic solvents. From comparison with the analogous 2-aryl-4-hydroxy-5-(2'-hydroxyphenyl)-1,3-thiazoles it is clear that both in neutral as well as in the deprotonated state the presence of the 2'-amino group lowers the fluorescence quantum yields (Phi). Introduction of an electron withdrawing groups into the 2-aryl group further decreases Phi. Upon deprotonation of the 4-hydroxy group a large bathochromic shift of the absorption (Delta lambda(A)=100-125 nm) as well as emission (Delta lambda(F)=100-120 nm) bands occurs. An intramolecular hydrogen bond between the amino and hydroxyl groups is obvious. The first absorption band of all studied compounds corresponds to a pi-pi* HOMO-LUMO transition with a CT character. Thiazoles 3b-f and their deprotonated forms 3b(-)-f(-) display fluorescence properties with large Stokes shift (ca 9000 cm(-1) and 6000 cm(-1), respectively) and moderate quantum yields (0.11-0.41), both are connected with the presence of inter and intramolecular hydrogen bonds.(C) 2018 Elsevier B.V. All rights reserved.

The role of polynuclear species in C-H activations assisted by palladium carboxylates has not been clear so far. The summary of the key findings covering this issue shows its important role under certain conditions. However, much more effort is necessary for a deeper understanding of the whole issue.

This review covers all known examples of [3 + 2]-cycloaddition between sydnones and both terminal as well as internal alkynes/cycloalkynes taken from literature since its discovery by Huisgen in 1962 up to the current date. Except enumeration of synthetic applications it also covers mechanistic studies, catalysis, effects of substituents and reaction conditions influencing reaction rate and regioselectivity.

Reactions catalyzed by palladium(ii) acetate and trifluoroacetic acid (TFA) have a clear preactivation phase. However, the structure of real catalytic species remains unclear. We show that the key species are cyclic trinuclear complexes of composition [Pd3(OAc)6-x(OTFA)x] (x = 1-6) formed by a sequential ligand exchange from [Pd3(OAc)6]. Furthermore, we prove that the trinuclear palladium backbone of the precatalyst remains preserved during the first phase of the C-H activation reaction of acetanilides. In other words, the reaction pathway including the trinuclear species should be taken into account in discussion about mechanisms of the reactions catalyzed by palladium acetates.

The reaction of 3-bromooxindole with substituted (hetero)aromatic thioamides in acetonitrile was studied. At room temperature the reaction preferably gives products of ring transformation i.e. 2-aryl-5-(2-aminophenyl)-4-hydroxy-1,3-thiazoles (3b-f,h) whereas at elevated temperature products of an Eschenmoser coupling reaction, i.e. 3-[amino(aryl)-methylidene]-1,3-dihydro-2H-indol-2-ones (2b-f), are formed exclusively. There exist only two exceptions (4-methoxy and 2-pyridinthioamide) in which the Eschenmoser coupling reaction always takes place giving 2a and 2g. Also N-methylation of the starting 3-bromooxindole completely prevents formation of thiazoles. The prepared thiazoles 3b-f are unstable in solution and they undergo slow ring transformation to 2b-f. The rate limiting step of this rearrangement involves cleavage of an intermediary thiirane ring, which is slowed down by electron withdrawing substituents on the thioamide (rho = -1.15). (C) 2017 Elsevier Ltd. All rights reserved.

Eight substituted 2-aryl-4-hydroxy-5-(2'-hydroxyphenyl)-1,3-thiazoles have been prepared and their fluorescence properties have been investigated under neutral and alkaline conditions in solutions of various organic solvents. From the comparison with analogous 4-hydroxy-2,5-diphenyl-1,3-thiazole it is clear that both in neutral as well as in the deprotonated state the presence of the 2'-hydroxy group substantially (2-4 times) enhances fluorescence quantum yields (Phi) - most probably due to formation of an intramolecular hydrogen bond. Introduction of an electron withdrawing substituent into the 2-aryl group (2-pyridyl and 4-trifluormethylphenyl derivatives) further enhances Phi up to 0.93 (in dioxane). Upon deprotonation of the 4-hydroxy group a large bathochromic shift of the absorption (Delta lambda(max) = 70 nm) as well as emission (Delta lambda(em approximate to) 110 nm) bands occurs and the Phi-s are typically between 0.3 and 0.7. On the basis of quantum chemical calculations and spectral results, a hydrogen bond interaction between two hydroxyl groups is obvious. The first absorption band of all studied compounds corresponds to pi-pi* HOMO LUMO transition possessing a CT character. (C) 2016 Elsevier Ltd. All rights reserved.

This review summarizes recently published results of research on the enantioselective catalysts based on copper (II) complexes of substituted 4,5-dihydro-1H-imidazol-5-one and imidazolidine-4-one derivatives and their application in asymmetric Henry reaction. The enantioselectivity of 4,5-dihydro-1H-imidazol-5-one derivatives was generally low, nonetheless the transformation of the original 4,5-dihydro-1H-imidazol-5-one into the imidazolidine-4-one ring led to a fundamental enhancement of enantioselectivity (19 % ee to 92 % ee). The most efficient homogeneous catalysts based on imidazolidine-4-one derivatives were anchored to three different supports: a block copolymer; a swelling pearl-like polymer and magnetic nanoparticles. The influence of the type of the immobilization on the chemical yields and the enantioselectivity of Henry reaction was compared and discussed. Immobilized catalysts were reused and their catalytic efficiency after several cycles of application was studied.

The aminolysis of ezetimibe (1) and the structurally similar (3R*,4S*)-(4-fluoropheny1)-4-(4-hydroxyphenyl)-3-methylazetidin-2-one (4a) giving the corresponding beta-aminoamides 2a-d and 5a-c was studied spectrophotometrically under pseudo-first order conditions in aqueous butylamine, 3-methoxypropylamine, 2-methoxyethylamine and 2-hydroxyethylamine buffer solutions at 39 degrees C. It was found that the reaction mechanism involves uncatalyzed nucleophilic attack of an amine on the azetidinone carbonyl group as the rate-limiting step. On the basis of the Bronsted beta(Nuc) value (0.58 and 0.55 respectively) an early transition state was proposed in which the extent of C-N-amine bond formation is low and the C-N-lactam bond remains almost intact. It was also found that the presence of the phenolic group has a crucial role in the aminolysis because the analogous O-methyl derivative 4b does not react with amines at all. This observation would explain the fact that aminolysis of ezetimibe was not observed in human serum albumins where faster glucuronidation which blocks the phenolic hydroxide group occurs. (C) 2015 Elsevier B.V. All rights reserved.

The reactions of 3-bromo-1-benzofuran-2(3H)-one (1a) and 3-bromo-1,3-dihydro-2H-indol-2-one (1b) with 4-methoxythiobenzamide and thiourea under mildly basic conditions are reported. While brominated lactone 1a gave the expected 5-(2-hydroxyphenyl)-2-(4-methoxyphenyl)-1,3-thiazol-4-ol (2) or 2-amino-5-(2-hydroxyphenyl)-1,3-thiazol-4(5H)-one (5) products, the analogous brominated lactam 1b reacted with the thioamide via an unexpected Eschenmoser coupling reaction to give (3Z)-3-[amino(4-methoxyphenyl)-methylidene]-1,3-dihydro-2H-indol-2-one (3). When lactam 1b was treated with thiourea, isoindigo (4) was the only isolated product. The reaction mechanisms, involving formation of α-thioiminium or isothiouronium salts and their base-catalyzed decomposition are also proposed.