Synthesis of Thionated Perylenediimides: State of the Art and First Investigations of an Alternative to Lawesson's Reagent.

Perylenediimides (PDIs) are composed of a central perylene ring, on which are grafted two imide groups at the peri positions. Thionated PDIs are characterized by the substitution of one or more oxygen atoms of these imide functions with sulfur atoms. This structural modification alters the electronic properties with a redshift of the optical absorption accompanied by modification of the charge transport characteristics compared to their non-thionated counterparts. These properties make them suitable candidates for applications in optoelectronic devices, such as organic light-emitting diodes and organic photovoltaics. Moreover, the presence of sulfur atom(s) can favor the promotion of reactive oxygen species production for photodynamic and photothermal therapies. These thionated PDIs can be synthesized through the post-functionalization of PDIs by using a sulfurizing reagent. Nevertheless, the main drawbacks remain the difficulties in adjusting the degree of thionation and obtaining tri- and tetrathionated PDIs. Up to now, this thionation reaction has been described almost exclusively using Lawesson's reagent. In the current study, we present our first investigations into an alternative reagent to enhance selectivity and achieve a greater degree of thionation. The association of phosphorus pentasulfide with hexamethyldisiloxane (Curphey's reagent) clearly demonstrated higher reactivity compared with Lawesson's reagent to attain multi-thionated PDIs.

Biocatalytic Thionation of Epoxides for Enantioselective Synthesis of Thiiranes.

Expanding the enzymatic toolbox for the green synthesis of valuable molecules is still of high interest in synthetic chemistry and the pharmaceutical industry. Chiral thiiranes are valuable sulfur-containing heterocyclic compounds, but relevant methods for their enantioselective synthesis are limited. Herein, we report a biocatalytic thionation strategy for the enantioselective synthesis of thiiranes, which was developed based on the halohydrin dehalogenase (HHDH)-catalyzed enantioselective ring-opening reaction of epoxides with thiocyanate and a subsequent nonenzymatic rearrangement process. A novel HHDH was identified and engineered for enantioselective biocatalytic thionation of various aryl- and alkyl-substituted epoxides on a preparative scale, affording the corresponding thiiranes in up to 43 % isolated yield and 98 % ee. Large-scale synthesis and useful transformations of chiral thiiranes were also performed to demonstrate the utility and scalability of the biocatalytic thionation strategy.

Novel Ring Systems: Spiro[Cycloalkane] Derivatives of Triazolo- and Tetrazolo-Pyridazines.

In orderto synthesize new pyridazine derivatives anellated with different nitrogen heterocyclic moieties, spiro[cycloalkane]pyridazinones were transformed into the corresponding thioxo derivatives via a reaction with phosphorus pentasulfide. The reaction of the formed 2,3-diazaspiro[5.5] undec-3-ene-1-thiones with hydrazine provided the corresponding 1-hydrazono-2,3-diazaspiro[5.5] undec-3-ene, whose diazotization led to the desired spiro[cyclohexane-1,8'-tetrazolo[1,5-b]pyridazines. The reaction of dihydropyridazinethiones with benzhydrazide afforded the corresponding 7H-spiro[[1,2,4]triazolo[4,3-b]pyridazin-8,1'-cyclohexanes]. As a result of our work, seven new pyridazinethione intermediates were prepared, which served as starting materials for the synthesis of two kinds of new ring systems: tetrazolo-pyridazines and triazolo-pyridazines. The six new annulated derivatives were characterized by physicochemical parameters. The new N-heterocycles are valuable members of the large family of pyridazines.

A chromatography-free and aqueous waste-free process for thioamide preparation with Lawesson's reagent.

After completing the thio-substitution with Lawesson's reagent, ethanol was found to be effective in the decomposition of the inherent stoichiometric six-membered-ring byproduct from the Lawesson's reagent to a highly polarized diethyl thiophosphonate. The treatment significantly simplified the following chromatography purification of the desired thioamide in a small scale preparation. As scaling up the preparation of two pincer-type thioamides, we have successfully developed a convenient process with ethylene glycol to replace ethanol during the workup, including a traditional phase separation, extraction, and recrystallization. The newly developed chromatography-free procedure did not generate P-containing aqueous waste, and only organic effluents were discharged. It is believed that the optimized procedure offers the great opportunity of applying the Lawesson's reagent for various thio-substitution reactions on a large scale.

Synthesis and biological evaluation of thioadatanserin and its dialkylated products as partial 5-HTR1A agonists and 5-HTR2A antagonists for potential use in depression and anxiety disorders.

Thionation of adatanserin hydrochloride (2) with Lawesson's reagent in toluene/triethylamine afforded novel compound, (3r,5r,7r)-N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)adamantane-1-carbothioamide (thioadatanserin, 3) in 84-90% isolated yield. Thioadatanserin underwent a tandem double alkylation with methyl iodide and benzyl bromide in NaH/THF to produce novel dialkylated products 6 and 7 respectively. The single X-ray crystal structure of 7 was determined to be 1-(2-((E- ((3r,5r,7r)-adamantan-1-yl)benzylthio)methylene)amino)ethyl)-1-benzyl-4- (pyrimidin-2-yl)piperazin-1-ium bromide showing that the piperazine ring adopts a chair-like configuration that is not co-planar with the pyrimidine ring. Thioadatanserin emerged as a dual potent partial agonist with activity against 5-HTR1A (EC50 6.7 nM) and antagonist activity against 5-HTR2A (IC50 62.3 nM) and was selective over 5-HTR2C receptor (IC50 > 3333 nM) in the PathHunter® ß-arrestin assays.

1,3,5-Triaryl-1,3,5-Triazinane-2,4,6-Trithiones: Synthesis, Electronic Structure and Linear Optical Properties.

The synthesis of four new 1,3,5-triaryl-1,3,5-triazinane-2,4,6-trithione derivatives (thioisocyanurates) and two new partially thionated analogues from the corresponding 1,3,5-triaryl-1,3,5-triazinane-2,4,6-triones (isocyanurates) is reported, together with their spectroscopic properties. DFT calculations and comparison with the corresponding isocyanurates evidence the impact of the oxygen-for-sulfur replacement on the electronic structure and linear optical properties of these heterocycles. A bathochromic shift of the absorption bands and more efficient quenching of the fluorescence was observed.

Applications of Lawesson's reagent in the synthesis of naturally occurring steroids and terpenoids.

Steroids and terpenoids are among the most biologically significant classes of natural products possessing a variety of biological activities. The replacement of one or more oxygen atoms in a steroid or terpenoid molecule by a heteroatom affects the chemical properties of that particular steroid or terpenoid, and that replacement often results in alterations of its biological properties, which is sometimes valuable. One possible modification is the thionation that could have some influence on such activity. Among the various thionating reagents, Lawesson's reagent was found to be most suitable and showed versatile properties, including chemoselectivity and functional group tolerance. In this review, we present the role of Lawesson's reagent in the synthesis of thioanalogues of natural steroids and terpenoids.

Scalable syntheses of the BET bromodomain inhibitor JQ1.

We have developed methods involving the use of alternate, safer reagents for the scalable syntheses of the potent BET bromodomain inhibitor JQ1. A one-pot three step method, involving the conversion of a benzodiazepine to a thioamde using Lawesson's reagent, followed by amidrazone formation and installation of the triazole moiety furnished JQ1. This method provides good yields and a facile purification process. For the synthesis of enantiomerically enriched (+)-JQ1, the highly toxic reagent diethyl chlorophosphate, used in a previous synthesis, was replaced with the safer reagent diphenyl chlorophosphate in the three-step one-pot triazole formation without effecting yields and enantiomeric purity of (+)-JQ1.

Towards Symmetric Thioamides: Microwave-Aided Synthesis of Terephthalic Acid Derivatives.

The multistep synthesis of novel bis-terephthalthioamides based on methyl esters of amino acids (AAs) was proposed using conventional heating and microwave-assisted approaches. In fact, the comparative case study on the thionation of new symmetrical diamides with Lawesson's reagent (LR) was performed. The microwave-accelerated small-scale methodology was successfully employed on the whole pathway from substrates (Gly, Ala, Val, Tyr, Ser) to products (symmetrical dithioamides of terephthalic acid), resulting in significantly reduced reaction time, energy requirements, and slightly increased reaction yields when compared to conventional heating. Moreover, the intermolecular similarity of novel terephthalic acid derivatives was estimated in the multidimensional space (mDS) of the structure/property-related in silico descriptors using principal component analysis (PCA) and hierarchical clustering analysis (HCA). The distance-oriented structure/property distribution was also correlated with the experimental lipophilic data.

Regioselective synthesis of 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives: A new drug-like heterocyclic scaffold.

Dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives were prepared by successive N3- and N1-alkylation of hydantoins, followed by regioselective thionation and subsequent cyclization under mild conditions. In a final alkylation step a further substituent may be introduced. The synthetic strategy allows broad structural variation of this new drug-like heterobicyclic scaffold. In addition to extensive NMR and MS analyses, the structure of one derivative was confirmed by X-ray crystallography.

Thionation of quinolizidine alkaloids and their derivatives via Lawesson's reagent.

Direct thionation of quinolizidine alkaloids (-)-cytisine, methylcytisine, thermopsine and some of their carbonyl derivatives was realized. It was established that carrying out of the reaction in the boiling toluene with 0.5 eq. of Lawesson's reagent (LR) is most effective for synthesis of thio analogues of methyl-, allyl-, benzylcytisine and thermopsine. It was found, that formation of thioamides is preferable in the case with starting 3-carboxamides of (-)-cytisine or 2-oxo and 4-oxo derivatives of methylcytisine; and an excess of LR is needed for their exhaustive thionation. It was shown, that thionation of 'cytisine substituted' urea and thiourea, as well as Diels-Alder adducts of methylcitisine with phenylmaleimide on basis of this approach was not quite successful: only thionation of the 2-pyridone core has occurred. It should be noted that transformation of urea and thiourea is complicated by side reactions leading to low yields of thio products, and the result of LR interaction with mentioned above diastereomeric Diels-Alder adducts depends on their stereochemistry and thermodynamic stability under reaction conditions.

Opportunities and challenges in the synthesis of thioamidated peptides.

Chemical modifications of peptides hold great promise for modulating their pharmacological properties. In the last few decades amide to thioamide substitution has been widely explored to modulate the conformation, non-covalent interactions, and proteolytic stability of peptides. Despite widespread utilization, there are some potential limitations including epimerization and degradation under basic and acidic conditions, respectively. In this chapter, we present the synthetic method to build thio-precursors, their site-specific incorporation onto a growing peptide chain, and troubleshooting during the elongation of thioamidated peptides. This highly efficient, rapid, and robust method can be used for positional scanning of the thioamide bond.

Contrasting effects of iron reduction on thionation of diphenylarsinic acid in a biostimulated Acrisol.

Diphenylarsinic acid (DPAA) is an emerging phenylarsenic compound derived from chemical warfare agents. It has been suggested that biostimulation of sulfate reduction decreases the concentrations of DPAA in soils. However, biostimulation often induces Fe(III) reduction which may affect the mobility and thereby the transformation of DPAA. Here, a soil incubation experiment was carried out to elucidate the impact of Fe(III) reduction on the mobilization and transformation of DPAA in a biostimulated Acrisol with the addition of sulfate and lactate. DPAA was significantly mobilized and then thionated in the sulfide soil (amended with sulfate and sodium lactate) compared with the anoxic soil (without addition of sulfate or sodium lactate). At the start of the incubation period, 41.8% of the total DPAA in sulfide soil was mobilized, likely by the addition of sodium lactate, and DPAA was then almost completely released into the solution after 2 weeks of incubation, likely due to Fe(III) reduction. The relatively low fraction of oxalate-extractable Fe in Acrisol, which contributes significantly to DPAA sorption and is more active and reduction-susceptible, may explain the observation that only < 40% of the Fe(III) (hydr)oxides were reduced when DPAA was completely released into the solution. A more rapid and final enhanced elimination of DPAA was observed in sulfide soil and the fraction of total DPAA decreased to 60.1 and 91.0%, respectively, at the end of the incubation in sulfide soil and anoxic soil. The difference appears to result from increased DPAA mobilization and sulfate reduction in sulfide soil. On the other hand, the formation of FeS precipitate, a product of Fe and sulfate reduction, may reduce the efficiency of DPAA thionation. Accordingly, the potentially contrasting effects of Fe(III) reduction on DPAA thionation need be considered when planning biostimulated sulfate reduction strategies for DPAA-contaminated soils.

Microwave-Assisted Synthesis of Sulfurated Heterocycles with Herbicidal Activity: Reaction of 2-Alkynylbenzoic Acids with Lawesson's Reagent.

The reactivity of 2-alkynylbenzoic acids toward Lawesson's reagent (LR) under microwave irradiation (300 W, 100 °C, CH2 Cl2 ) was assessed. It was found that, depending on reaction conditions, either a dithionation- or a monothionation-cycloisomerization process takes place with formation of important sulfurated heterocycles. In particular, using 1 equivalent of LR for 1 h, dithionation occurred, with formation of benzo[c]thiophene-1(3H)-thiones or 1H-isothiochromene-1-thiones, while with 0.5 equiv. of LR for 10-30 min, monothionated products were selectively obtained (benzo[c]thiophen-1(3H)-ones or 1H-isothiochromen-1-ones). The regiochemical output of the process strongly depended on the substitution pattern of the starting 2-alkynylbenzoic acid derivatives. These compounds were also assayed as potential herbicides by assessing their phytotoxic activity on seedling growth and development of the model species Arabidopsis thaliana. All compounds, to different extents, influenced the morpho-physiological parameters that were monitored; in particular, the fresh weight (FW) was significantly affected, with ED50 values ranging from 4.81-63.7 µM.

The Construction and Application of C=S Bonds.

The current section presents an overview of the fundamental aspects of thiocarbonyl compounds, such as thioaldehydes and thioketones. Firstly, a theoretical approach and a physical-organic experimental approach disclose their properties. Secondly, their synthetic reactions are introduced. Finally, a focus is given to their synthetic applications, including nucleophilic and electrophilic reactions, as well as concerted reactions.

Identification and derivatization of selected cathinones by spectroscopic studies.

In this study we identified three novel hydrochloride salts of cathinones 2-(pyrrolidin-1-yl)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)pentan-1-one (1a) (TH-PVP), 2-(methylamino)-1-(2-methylphenyl)-1-propanone (1b) (2-MMC) and 1-(4-chlorophenyl)-2-(methylamino)propan-1-one (1c) (4-CMC). Their properties have been examined through combinations of GC-MS, IR, NMR, electronic absorption spectroscopy and single crystal X-ray diffraction method. NMR solution spectra showed readily diagnostic H-1 and C-13 signals from methyl, N-methyl and carbonyl groups. Additionally the use of thionation and amination reactions for identification of selected cathinones was presented.

Solid-solution partitioning and thionation of diphenylarsinic acid in a flooded soil under the impact of sulfate and iron reduction.

Diphenylarsinic acid (DPAA) is a major organic arsenic (As) compound derived from abandoned chemical weapons. The solid-solution partitioning and transformation of DPAA in flooded soils are poorly understood but are of great concern. The identification of the mechanisms responsible for the mobilization and transformation of DPAA may help to develop effective remediation strategies. Here, soil and Fe mineral incubation experiments were carried out to elucidate the partitioning and transformation of DPAA in anoxic (without addition of sulfate or sodium lactate) and sulfide (with the addition of sulfate and sodium lactate) soil and to examine the impact of sulfate and Fe(III) reduction on these processes. Results show that DPAA was more effectively mobilized and thionated in sulfide soil than in anoxic soil. At the initial incubation stages (0-4weeks), 6.7-74.5% of the total DPAA in sulfide soil was mobilized likely by sorption competition with sodium lactate. At later incubation stage (4-8weeks), DPAA was almost completely released into the solution likely due to the near-complete Fe(III) reduction. Scanning transmission X-ray microscopy (STXM) results provide further direct evidence of elevated DPAA release coupled with Fe(III) reduction in sulfide environments. The total DPAA fraction decreased significantly to 24.5% after two weeks and reached 3.4% after eight weeks in sulfide soil, whereas no obvious elimination of DPAA occurred in anoxic soil at the initial two weeks and the total DPAA fraction decreased to 10.9% after eight weeks. This can be explained in part by the enhanced mobilization of DPAA and sulfate reduction in sulfide soil compared with anoxic soil. These results suggest that under flooded soil conditions, Fe(III) and sulfate reduction significantly promote DPAA mobilization and thionation, respectively, and we suggest that it is essential to consider both sulfate and Fe(III) reduction to further our understanding of the environmental fate of DPAA.

Formation of diphenylthioarsinic acid from diphenylarsinic acid under anaerobic sulfate-reducing soil conditions.

Diphenylarsinic acid (DPAA) is a toxic phenylarsenical compound often found around sites contaminated with phenylarsenic chemical warfare agents, diphenylcyanoarsine or diphenylchloroarsine, which were buried in soil after the World Wars. This research concerns the elucidation of the chemical structure of an arsenic metabolite transformed from DPAA under anaerobic sulfate-reducing soil conditions. In LC/ICP-MS analysis, the retention time of the metabolite was identical to that of a major phenylarsenical compound synthesized by chemical reaction of DPAA and hydrogen sulfide. Moreover the mass spectra for the two compounds measured using LC/TOF-MS were similar. Subsequent high resolution mass spectral analysis indicated that two major ions at m/z 261 and 279, observed on both mass spectra, were attributable to C12H10AsS and C12H12AsSO, respectively. These findings strongly suggest that the latter ion is the molecular-related ion ([M+H](+)) of diphenylthioarsinic acid (DPTA; (C6H5)2AsS(OH)) and the former ion is its dehydrated fragment. Thus, our results reveal that DPAA can be transformed to DPTA, as a major metabolite, under sulfate-reducing soil conditions. Moreover, formation of diphenyldithioarsinic acid and subsequent dimerization were predicted by the chemical reaction analysis of DPAA with hydrogen sulfide. This is the first report to elucidate the occurrence of DPAA-thionation in an anaerobic soil.