Tertiary Thioamides Research Articles

Coupling of acceptor-substituted diazo compounds and tertiary thioamides: synthesis of enamino carbonyl compounds and their pharmacological evaluation.

This paper describes the synthesis of enamino carbonyl compounds by the copper(i)-catalyzed coupling of acceptor-substituted diazo compounds and tertiary thioamides. We plan to use this method to synthesize indolizidine (−)-237D analogs to find α6-selective antismoking agents. Therefore, we also performed in silico α6-nAchRs binding studies of selected products. Compounds with low root-mean-square deviation values showed more favorable binding free energies. We also report preliminary pharmacokinetic data on indolizidine (−)-237D and found it to have weak activity at CYP3A4. In addition, as enamino carbonyl compounds are also known for antimicrobial properties, we screened previously reported and new enamino carbonyl compounds for antibacterial, antimicrobial, and antifungal properties. Eleven compounds showed significant antimicrobial activities.

Mechanochemical synthesis of thiolactams and other thioamides using Lawesson’s reagent

A mechanochemical method has been developed for the synthesis of primary, secondary, and tertiary thioamides from their corresponding amides using Lawesson’s reagent for the first time. The mechanochemical thionation reactions reported herein produced thiolactams 2-pyrrolidinethione, 1, 2-piperidinethione, 2, 1-aza-2-cycloheptanthione, 3, 1-aza-2-cyclooctanthione, 4, and N-methylpyrrolidine-2-thione, 5, as well as acyclic thioamide-containing species, thioacetamide, 6, thiobenzamide, 7, and thionicotinamide, 8. In the course of these syntheses, the solid-state structure of 2-pyrrolidinethione, 1, was determined by single crystal X-ray diffraction and compared to 2-pyrrolidinone.

Highly fluorinated 2,3-dihydro-1,3,4-thiadiazole derivatives via [3+2]-cycloadditions of tertiary thioamides with nitrile imines derived from trifluoroacetonitrile

Fluorine-rich 1,3,4-thiadiazole derivatives were prepared by 1,3-dipolar cycloaddition of the in situ generated N-aryl-trifluoroacetonitrile imines with tertiary polyfluoroalkanethioamides (N,N-dialkyl thioamides). Reactions were performed under mild conditions in THF solutions at room temperature. The 1,3,4-thiadiazole derivatives were formed in a fully regioselective manner in high yields. In a competition experiment, the non-fluorinated 1-(morpholin-4-yl)ethanethione was shown to be more reactive towards a model nitrile imine than its 2,2,2-trifluoromethylated analogue.

Chemo- and regioselective synthesis of polysubstituted 2-aminothiophenes by the cyclization of gem-dibromo or gem-dichloroalkenes with β-keto tertiary thioamides.

A facile and practical method for the synthesis of 2,3,4-trisubstituted 2-aminothiophenes by the cyclization of gem-dibromoalkenes or gem-dichloroalkenes with β-keto tertiary thioamides has been developed. The cyclization reaction proceeded chemoselectively and regioselectively under metal-catalyst-free conditions, providing various structurally diverse 2,3,4-trisubstituted N,N'-dialkyl 2-aminothiophenes in good to excellent yields.

Copper-catalyzed chemoselective cross-coupling reaction of thioamides and α-diazocarbonyl compounds: Synthesis of enaminones

The development of operationally simple and cost-effective methods for CC bond formation reactions are highly important in pharmaceutical, agrochemical and material research. In this article we describe the first copper-catalyzed cross-coupling reaction of thioamides with acceptor/acceptor-substituted and acceptor-only substituted α-diazocarbonyl compounds to yield enaminones. The reaction shows broad substrate scope in terms of thioamides and diazocarbonyl compounds. Primary, secondary and tertiary thioamides all give enanminones when reacted with α-diazodiesters, α-diazoketoesters, α-diazodiketones, α-diazoketoamides, α-diazoesteramides, α-diazoketosulfones and α-diazomonoketones.

Synthesis of N,N-disubstituted 2-aminothiophenes by the cyclization of gem-difluoroalkenes with β-keto thioamides.

A novel and effective method for the construction of highly functionalized aminothiophenes via the cyclization of gem-difluoroalkenes with β-keto tertiary thioamides is described. The reactions proceed smoothly with the assistance of K2CO3 under transition-metal-free conditions, affording a variety of valuable N,N-disubstituted 2-aminothiophenes in moderate to good yields.

ChemInform Abstract: Phosphovanadomolybdic Acid Catalyzed Desulfurization—Oxygenation of Secondary and Tertiary Thioamides into Amides Using Molecular Oxygen as the Terminal Oxidant.

In the presence of phosphovanadomolybdic acids, e.g., H6PV3Mo9O40, desulfurization–oxygenation of various kinds of structurally diverse secondary and tertiary thioamides proceeded efficiently using molecular oxygen as the terminal oxidant, affording the corresponding amides in moderate to excellent yields. In addition, 18O-labeled amides could readily be synthesized using H218O as the oxygen source.

One-step three-component and solvent-free synthesis of thiazoles from tertiary thioamides

A novel one-pot three-component reaction has been developed for construction of thiazole derivatives under solvent-free conditions. Hence, tertiary thioamides, α-haloketones, and NH4OAc were grinded together and allowed to react thermally at 110 °C and/or under microwave irradiation to produce the corresponding thiazole derivatives in very good yields.

Phosphovanadomolybdic acid catalyzed desulfurization–oxygenation of secondary and tertiary thioamides into amides using molecular oxygen as the terminal oxidant

In the presence of phosphovanadomolybdic acids, secondary and tertiary thioamides could be converted into amides using molecular oxygen and water.

ChemInform Abstract: Novel Route to Thiophene‐2,4‐diamines.

AbstractThiophenediamines are prepared by self‐condensation of tertiary thioamides in the presence of I2 and K2CO3.

Novel Route to Thiophene-2,4-diamines

A novel and simple procedure for the construction of fully substituted thiophene-2,4-diamines using tertiary thioamides was developed. Thus, thioacetomorpholides undergo self-condensation to the corresponding 3,5-diarylthiophene-2,4-diamine derivatives in the presence of iodine and potassium carbonate in a suitable solvent and under mild conditions.

Identification of Novel Proteasome Inhibitors from an Enaminone Library.

A library of structurally distinct enaminones was synthesized using sonication or Ru(II) catalysis to couple primary, secondary, and tertiary thioamides with α-halocarbonyls or α-diazocarbonyls. Screening the library for proteasome inhibition using a luciferase-based assay identified seven structurally diverse compounds. Two of these molecules targeted luciferase, while the remaining five exhibited varying potency and specificity for the trypsin-like, chymotrypsin-like, or caspase-like protease activities of the proteasome. Physiological relevance was confirmed by showing these molecules inhibited proteasomal degradation of the full-length protein substrate p21cip1 expressed in tissue culture cells. A cell viability analysis revealed that the proteasome inhibitors differentially affected cell survival. Results indicate a subset of enaminones and precursor molecules identified in this study are good candidates for further development into novel proteasome inhibitors with potential therapeutic value.

Development of tertiary thioamide derivatives to recover palladium(II) from simulated complex chloride solutions

Two thioamide derivatives, N-methyl-N-phenyl-octanthioamide (MPHTA) and N-methyl-N-cyclohexyl-octanthioamide (MCHTA), were synthesized from their amide analogues, adequately characterized, and systematically evaluated as extractants for palladium(II) from chloride media. In sequence of previous research, which revealed the adequacy of both compounds, when dissolved in toluene, to efficiently recover Pd(II) from a wide range of differently concentrated hydrochloric acid solutions, the Pd(II) solvent extraction performance of both MPHTA and MCHTA dissolved in commercial diluents is evaluated in this work. Additionally, results obtained on successive extraction–stripping cycles, involving thiourea as stripping agent, confirm the robustness and stability of these Pd(II) solvent extraction systems, even when commercial diluents are employed. Equilibrium extraction isotherms, obtained for both compounds in toluene, show a high Pd(II) loading capacity. Selectivity data has been collected for complex 4.0M and 6.0M HCl mixtures containing two, three, four or five metal ions — palladium(II), platinum(IV), rhodium(III), aluminum(III), and iron(III). Fe(III) is the only metal that affects Pd(II) extraction of both MPHTA and MCHTA, as Pd(II) distribution ratios are significantly reduced; on the other hand, the other metals are practically not extracted. These selectivity results are encouraging from a practical point of view, since both extractants may prove suitable to efficiently and selectively recover Pd(II) from hydrometallurgical solutions coming from the leaching of secondary raw material sources.

Reactions of Malonothioamide Derivatives with Azides*

The reactions of primary and tertiary malonothioamides with aryl and sulfonyl azides can take place in three directions, depending on the nature of the thioamides and azides. Ethoxycarbonylthioacetamide reacts with aryl azides with the formation of ethyl 5-amino-1-aryl-1,2,3-triazole-4-carboxylates. In reaction with aryl azides tertiary thioamides of cyanoacetic acid form 5-amino-1-aryl-1,2,3-triazole-4-carbothioamides, and in reaction with tosyl azide they form 5-amino-4-carboxamidino-1,2,3-thia-diazoles. Hypothetical mechanisms for the transformations are discussed.

Enaminones via ruthenium-catalyzed coupling of thioamides and α-diazocarbonyl compounds.

Enaminones can be prepared via the Rh2(OAc)4-catalyzed coupling of α-diazocarbonyl compounds with thioamides. However, rhodium is the most expensive and least abundant among the dominant precious metals used for catalysis. Furthermore, a very limited substrate scope is known for the intermolecular rhodium catalyzed coupling reaction. Therefore, there is a need to find a more economical catalyst substitute with a broad substrate scope. In this paper, we describe the use of Ru(II) catalysts for the synthesis of enaminones. The reaction can be performed efficiently with the Grubbs first-generation catalyst or [(Ph)3P]3RuCl2 in a sealed tube. Both catalysts are much less expensive than Rh2(OAc)4. Secondary and tertiary thioamides, when reacted with α-diazodiesters, α-diazoketoesters, α-diazodiketones, and α-diazomonoketones give enaminones. Primary thioamides give thiazole derivatives when reacted with α-diazomonoketones. However, with other diazo compounds, primary thioamides also give enaminones. All enaminones are obtained in good yields and with good diastereoselectivity. Accordingly, the method described in this paper is an efficient and economical alternative to the Rh2(OAc)4-catalyzed coupling process.

ChemInform Abstract: Formation of Benzo[c]thiophen‐1‐aminium Iodide by the Reaction of O‐Alkynylbenzothioamide with Iodine.

Abstract Reaction of o -alkynylbenzothioamide with molecular iodine was investigated. Unique benzo[ c ]thiophen-1-aminium iodide was obtained when the tertiary thioamide was used as a reactant. The reaction proceeded efficiently in less polar solvent, whereas the corresponding product was also obtained in a polar solvent. Single crystal X-ray analysis revealed that the benzo[ c ]thiophen-1-aminium structure possesses a resonance structure in N–C–S bond. Its stabilization shows a clear difference in the result from the reaction of amide analogue with iodine to give no stable compound.

Formation of benzo[c]thiophen-1-aminium iodide by the reaction of o-alkynylbenzothioamide with iodine

Reaction of o-alkynylbenzothioamide with molecular iodine was investigated. Unique benzo[c]thiophen-1-aminium iodide was obtained when the tertiary thioamide was used as a reactant. The reaction proceeded efficiently in less polar solvent, whereas the corresponding product was also obtained in a polar solvent. Single crystal X-ray analysis revealed that the benzo[c]thiophen-1-aminium structure possesses a resonance structure in N–C–S bond. Its stabilization shows a clear difference in the result from the reaction of amide analogue with iodine to give no stable compound.

Acceleration of the Eschenmoser coupling reaction by sonication: efficient synthesis of enaminones

Enaminones are commonly prepared by the Eschenmoser coupling reaction. The duration of the reaction is often long. Here, we describe how sonication can accelerate this reaction. The reaction conditions provide an efficient method for the coupling of primary, secondary and tertiary thioamides with α-bromocarbonyl compounds.

A simple and novel method for the direct conversion of carboxylic acids into thioamides

We report here a simple, efficient, practical and direct method for the conversion of carboxylic acids into thioamides. As described below, the reaction of a variety of aromatic and aliphatic carboxylic acids in the presence of ammonium phosphorodithioates proceeded effectively to afford the corresponding thioamides in good yields. This thioamidation reaction is operationally straightforward and provides primary, secondary and tertiary thioamides from corresponding carboxylic acids.

ChemInform Abstract: CuBr‐Catalyzed Oxidative Desulfurization of Thiobenzamides.

AbstractOxidative desulfurization of secondary or tertiary thioamides (I) provides access to the corresponding amides, while primary thioamides (III) undergo cyclization to afford thiadiazoles (IV).