Sulfur Nucleophiles Research Articles

An efficient d-glucosamine-based copper catalyst for C–X couplings and its application in the synthesis of nilotinib intermediate

d-Glucosamine has been studied for C–N and C–S bond formations via cross-coupling reactions of nitrogen and sulfur nucleophiles with both aryl iodides and bromides.

Functionalization of the meso‐Phenyl Ring of Rhodamine Dyes Through SNAr with Sulfur Nucleophiles: Synthesis, Biophysical Characterizations, and Comprehensive NMR Analysis (Eur. J. Org. Chem. 2/2015)

Functionalization of the <i>meso</i>‐Phenyl Ring of Rhodamine Dyes Through S_NAr with Sulfur Nucleophiles: Synthesis, Biophysical Characterizations, and Comprehensive NMR Analysis (Eur. J. Org. Chem. 2/2015)

Sulfurtransferase and thioredoxin specifically interact as demonstrated by bimolecular fluorescence complementation analysis and biochemical tests

Sulfurtransferases (Strs) and thioredoxins (Trxs) are members of large protein families. Trxs are disulfide reductases and play an important role in redox-related cellular processes. They interact with a broad range of proteins. Strs catalyze the transfer of a sulfur atom from a suitable sulfur donor to nucleophilic sulfur acceptors in vitro, but the physiological roles of these enzymes are not well defined. Several studies in different organisms demonstrate protein–protein interactions of Strs with members of the Trx family. We are interested in investigating the specificity of the interaction between Str and Trx isoforms. In order to use the bimolecular fluorescence complementation (BiFC), several Str and Trx sequences from Arabidopsis thaliana were cloned into the pUC-SPYNE and pUC-SPYCE split-YFP vectors, respectively. Each couple of plasmids containing the sequences for the putative interaction partners were transformed into Arabidopsis protoplasts and screened using a confocal laser scanning microscope. Compartment- and partner-specific interactions could be observed in transformed protoplasts. Replacement of cysteine residues in the redox-active site of Trxs abolished the interaction signal. Therefore, the redox site is not only involved in the redox reaction but also responsible for the interaction with partner proteins. Biochemical assays support a specific interaction among Strs and certain Trxs. Based on the results obtained, the interaction of Strs and Trxs indicates a role of Strs in the maintenance of the cellular redox homeostasis.

ChemInform Abstract: Selective Synthesis of cis‐ and trans‐2‐(Methyl/phenyl)‐3‐(trifluoromethyl)aziridines and Their Regio‐ and Stereospecific Ring Opening.

A convenient and stereoselective approach toward cis- and trans-1-alkyl-2-(methyl/phenyl)-3-(trifluoromethyl)aziridines was developed starting from the corresponding α,α,α-trifluoroketones via imination, α-chlorination, and hydride-induced ring closure. The reactivity of these newly synthesized nonactivated α-CF3-aziridines was evaluated by applying N-protonation or N-alkylation to effect regio- and stereospecific aziridine ring opening by oxygen, halogen, sulfur, and nitrogen nucleophiles. Furthermore, nonactivated α-CF3-aziridines were easily transformed into their activated analogues by replacing the N-benzyl protecting group with a N-tosyl group, rendering these α-CF3-aziridines much more susceptible to nucleophilic ring opening.

ChemInform Abstract: Oxygen Nucleophiles as Reaction Partners in Photoinduced, Copper‐Catalyzed Cross‐Couplings: O‐Arylations of Phenols at Room Temperature.

Most copper-catalyzed cross-couplings require an elevated reaction temperature. Recently, a photoinduced variant has been developed that enables C–X bond-forming reactions of certain nitrogen and sulfur nucleophiles to proceed under unusually mild conditions (−40 °C to room temperature). In view of the importance of carbon–oxygen bond construction in organic chemistry, the expansion of this photochemical approach to oxygen nucleophiles is an important objective. In this report, we establish that, in the presence of light and an inexpensive copper pre-catalyst (CuI), a wide array of phenols and aryl iodides can be coupled to generate diaryl ethers under mild conditions (room temperature) in the presence of a variety of functional groups. Our studies indicate that a Cu(I)–phenoxide complex is a viable intermediate in photoinduced C–O bond-formation.

Functionalization of the meso‐Phenyl Ring of Rhodamine Dyes Through SNAr with Sulfur Nucleophiles: Synthesis, Biophysical Characterizations, and Comprehensive NMR Analysis

AbstractAromatic nucleophilic substitution (SNAr) of fluorine in 9‐(3′‐carboxy‐4′,5′,6′,7′‐tetrafluorophenyl) groups of xanthene dyes constitutes a powerful tool in dye design. Thiols and amines regioselectively replace F‐6′. This approach enables additional hydrophilic residues or functional groups required for bioconjugation to be introduced. By using this methodology, a “bright” and photostable dye for two‐color superresolution microscopy was synthesized (with absorption and emission maxima at 604 and 627 nm, respectively). In the case of red‐emitting rhodamine dyes with 3′‐carboxy‐4′,5′,7′‐trifluorophenyl residues, two‐dimensional NMR techniques and a chemical transformation were used to prove the precise position of the additional substituent – a carboxylic acid group linked through the S‐atom at C‐6′. Furthermore, simple 1H NMR spectra reliably permit the position of the additional carboxy substituent in the 3′‐carboxyphenyl ring (at C‐5′ or C‐6′) to be established. Information on the exact position of this substituent is significant for the design of molecular probes and for the prediction of the properties of their bioconjugates.

Straightforward functionalization of acrylated soybean oil by Michael-addition and Diels–Alder reactions

A straightforward Michael-addition reaction of acrylated soybean oil (AESO) with different nitrogen and sulfur nucleophiles is reported. The reaction proceeded under mild conditions and the products were obtained in good yields. The reaction product of AESO with furfurylamine (FA) was used in Diels–Alder (DA) reactions with a bifunctional (1,1′-(methylenedi-4,1-phenylene) bismaleimide (BMI) and a monofunctional maleimide (N-phenylmaleimide, PMI), in different solvents. The 1H NMR spectroscopic analysis of the AESO-FA-PMI revealed the presence of both exo and endo DA adducts. The reverse DA reaction (rDA) of the AESO-FA-PMI (BMI) derivatives was shown to take place at temperatures between 103 and 134°C, with enthalpy changes ranging from 4.7 to 29.5J/g. The results indicate that the solvent used in the furan–maleimide DA reaction has an important role in determining the properties of the adduct formed.

Catalytic activation of pre-substrates via dynamic fragment assembly on protein templates.

Sensitive detection of small molecule fragments binding to defined sites of biomacromolecules is still a considerable challenge. Here we demonstrate that protein-binding fragments are able to induce enzymatic reactions on the protein surface via dynamic fragment ligation. Fragments binding to the S1 pocket of serine proteases containing a nitrogen, oxygen or sulphur nucleophile are found to activate electrophilic pre-substrates through a reversible, covalent ligation reaction. The dynamic ligation reaction positions the pre-substrate molecule at the active site of the protein thereby inducing its enzymatic cleavage. Catalytic activation of pre-substrates is confirmed by fluorescence spectroscopy and by high-performance liquid chromatography. The approach is investigated with 3 pre-substrates and 14 protein-binding fragments and the specific activation and the templating effect exerted by the enzyme is quantified for each protease-fragment-pre-substrate combination. The described approach enables the site-specific identification of protein-binding fragments, the functional characterization of enzymatic sites and the quantitative analysis of protein template-assisted ligation reactions.

Fast and highly chemoselective alkynylation of thiols with hypervalent iodine reagents enabled through a low energy barrier concerted mechanism.

Among all functional groups, alkynes occupy a privileged position in synthetic and medicinal chemistry, chemical biology, and materials science. Thioalkynes, in particular, are highly useful, as they combine the enhanced reactivity of the triple bond with a sulfur atom frequently encountered in bioactive compounds and materials. Nevertheless, general methods to access these compounds are lacking. In this article, we describe the mechanism and full scope of the alkynylation of thiols using ethynyl benziodoxolone (EBX) hypervalent iodine reagents. Computations led to the discovery of a new, three-atom concerted transition state with a very low energy barrier, which rationalizes the high reaction rate. On the basis of this result, the scope of the reaction was extended to the synthesis of aryl- and alkyl-substituted alkynes containing a broad range of functional groups. New sulfur nucleophiles such as thioglycosides, thioacids, and sodium hydrogen sulfide were also alkynylated successfully to lead to the most general and practical method yet reported for the synthesis of thioalkynes.

Conjugate addition nitro-Mannich reaction of carbon and heteroatom nucleophiles to nitroalkenes

The conjugate addition nitro-Mannich reactions of ethyl-β-nitroacrylate (1) and β-nitrostyrene (2) with electron rich aromatic nucleophiles, stabilized carbanions, alcohols, amines, thiols, and diphenyl phosphine oxide were investigated. The one pot conjugate addition nitro-Mannich reaction was unsuccessful except for the addition of alkoxides to 2 in alcohol as solvent. Isolation of the conjugate addition products followed by deprotonation with nBuLi and treatment with a simple imine in the presence of TFA led to β-nitroamine derived products. Products derived from 1 spontaneously cyclised in only a few examples and on the whole led to inherently unstable products. Products derived from 2 were isolated as their trifluoroacetamides, gave good yields of single diastereoisomers for aromatic and alkoxide nucleophiles and the structures were verified by single crystal X-ray crystallography. Products derived from amine nucleophiles were isolated in low yields while sulfur nucleophiles gave poor diastereoselectivities.

ChemInform Abstract: Synthesis of New Asymmetric Xanthene Dyes via Catalyst‐Free SNAr with Sulfur Nucleophiles.

Addition of a single functional handle to the tricyclic moiety of fluorescein results in asymmetric xanthene dyes. Our synthesis of a new class of asymmetric xanthenes proceeds via an unusual SNAr with sulfur nucleophiles on electron rich aromatic xanthenes scaffolds in the absence of a metal catalyst. The resulting 3′-thioethers exhibit high photostability and are conveniently converted into reactive dyes for macromolecule labelling.

Synthesis of Biphenyl-Based Ligand: Application in Copper-Mediated Chemoselective Michael Reaction

A biphenyl-based ligand attached was synthesized and screened in copper-mediated Michael reaction. The catalyst system works well with carbon or sulfur nucleophiles as Michael donors and cyclohexenone or chalcones as the acceptors under mild and neutral reaction conditions in a chemoselective manner.

Synthesized 2-Substituted-3-Phenylthiazolidine-4-ones as Potent Antioxidants and Antidiabetic Agents

Purpose: To employ intramolecular cyclization of Schiff bases of pyrazole-4-carboxaldehydes to form thiazolidine-4-ones and determine the antioxidant and antidiabetic activity of the synthesized compounds. Methods: The Schiff bases were obtained upon reaction between the electrophillic carbon atom of pyrazole-4-carboxaldehyde and the nucleophillic nitrogen atom of the amine. Preparation of thiazolidine4-one was preceded by attack of sulphur nucleophile of thioglycollic acid on imine carbon followed by intramolecular cyclization using acid catalyst. In vitro antioxidant activity was determined by 1, 1diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay method using ascorbic acid as standard. Evaluation of antidiabetic activity was carried out in streptazotocine-induced diabetes in Wister rats using rosiglitazone as reference drug. Blood glucose levels were estimated by GOD-POD kit. Serum biochemical parameters like total cholesterol, triglyceride, urea, creatinine and total protein level were also measured. Results: Compounds 7a, 7b, 7c, 7e, 7j showed higher IC 50 [Half maximal inhibitory concentration] values than the reference antioxidant, ascorbic acid. On the 21st day of treatment, there was significant fall and rise blood glucose level and body weight, respectively, compared to the anti-diabetic standard. There was decrease in serum cholesterol, triglyceride, creatinine and urea levels while high density lipoprotein (HDL) level and total protein levels increased after 21 days of treatment. Compared to rosiglitazone, compounds 7a, 7b, 7c, 7h, 7j showed stronger significant antidiabetic effect in hyperglycemic rats due, probably, to the presence of thiazolidine-4-one nucleus as well as parasubstitution on phenyl ring. Conclusion: The 2-(3-Methyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-ones possess potent antioxidant and antidiabetic activity but further studies are required to develop them for clinical use.

Direct enantiospecific substitution of primary α-aminoalkylferrocenes via Lewis acid-catalyzed C-N bond cleavage.

Highly enantioenriched primary α-aminoalkylferrocenes were found to undergo zinc chloride-catalyzed substitution with various carbon, nitrogen, and sulfur nucleophiles in an enantiospecific fashion through C-N bond cleavage. The reaction tolerates air and moisture and exhibits high atom-economy by releasing ammonia as the sole byproduct.

ChemInform Abstract: Neutral Sulfur Nucleophiles: Synthesis of Thioethers and Thioesters by Substitution Reactions of N‐Heterocyclic Carbene Boryl Sulfides and Thioamides.

AbstractBoryl sulfide (I) and N‐borylthioamide (IV) are employed as neutral sources of sulfur nucleophiles in substitution reactions with alkyl‐ and acyl halogenides.

Synthesis and Antimicrobial Activity of Some Novel Heterocyclic Candidates via Michael Addition Involving 4-(4-Acetamidophenyl)-4-oxobut-2-enoic Acid

This paper discusses the utility of 4-(4-acetamidophenyl)-4-oxobut-2-enoic acid as a key starting material for the preparation of a novel series of pyridazinones, thiazoles derivatives, and other heterocycles via interaction with nitrogen, sulfur, and carbon nucleophiles under Michael addition conditions and studies the antimicrobial activities of some of these compounds.

ChemInform Abstract: The Hexadehydro‐Diels—Alder Reaction: A New Chapter in Aryne Chemistry

AbstractReview: 22 refs.

Ring-opening and -expansion of 2,2'-biaziridine: access to diverse enantiopure linear and bicyclic vicinal diamines.

The chiral pool-derived 1,1'-ditosyl-2,2'-biaziridine has been established as a valuable building block for the divergent synthesis of enantiopure vicinal diamines. Efficient procedures for the regioselective ring opening of the biaziridine with oxygen, sulfur, nitrogen, and carbon nucleophiles are described. The strategic use of nucleophiles bearing pendant functionality allows further elaboration of the acyclic products to a variety of 2,2'-bicyclic-embedded diamines. Desymmetrization of the biaziridine has also been accomplished via the selective monoaddition of organocuprates.

Energy Efficient Capture and Release of Carbon Dioxide in Tetraalkyl Phosphonium and Tetraalkyl Ammonium Ionic Liquids

Described herein is an electrochemical method for the energy efficient capture and release of CO2 that employs electrochemically-generated thiolates as the CO2 capture agents. In N,N-dimethylformamide at glassy carbon electrodes the onset of CO2 reduction precludes capture by electrochemically generated thiolates. This is not the case in tetraalkyl phosphonium and tetraalkyl ammonium ionic liquids. In these media saturated with CO2, electrochemical reduction of disulfides to thiolates proceeds via a two-electron process with potential inversion.1 One-electron reduction of the disulfide results in dissociative electron transfer (DET), the first step of which is the formation of a short-lived radical anion.2 The S–S σ bond of the radical anion is subsequently cleaved leading to a thiolate and a sulfur-based radical.2 Resultant sulfur radicals are reduced at potentials positive of the potential applied for reduction of the corresponding disulfide. Thus, electrochemical thiolate generation is best formulated as a two-electron reduction with concomitant disulfide cleavage.3 In this presentation we will show that the potent, electrochemically generated sulfur nucleophiles capture CO2 via a facile SN2 reaction leading to formation of a thiocarbonate (Scheme 1). We will further demonstrate that the mechanism for the release of CO2 and regeneration of the disulfide is the one-electron Kolbe oxidation of the thiocarbonate followed by coupling of two sulfur radicals (Scheme 2).4 Cyclic voltammograms show that thiocarbonate oxidation occurs at potentials positive of thiolate oxidation. Increases in the peak-to-peak separation between thiolate oxidation and thiocarbonate oxidation have been ameliorated by targeted modifications to the disulfide. (1) Evans, D. H. Chem. Rev. 2008, 108, 2113–2144.(2) (a) Antonello, S.; Benassi, R.; Gavioli, G.; Taddei, F.; Maran, F. J. Am. Chem. Soc. 2002, 104, 7529–7538. (b) Meneses, A. B.; Antonello, S.; Arévalo, M. C.; Gonzáles, C. C.; Sharma, J.; Wallette, A. N.; Workentin, M. S.; Maran, F. Chem. Eur. J. 2007, 13, 7983–7995.(3) Hall, G. B.; Kottani, R.; Felton, G. A. N.; Yamamoto, T.; Evans, D. H.; Glass, R. S.; Lichtenberger, D. L. J. Am. Chem. Soc. 2014, 136, 4012–4018.(4) Vijh, A. K.; Conway, B. E.; Chem. Rev. 1967, 67, 623–664.

ChemInform Abstract: Direct Imine Acylation for Molecular Diversity in Heterocyclic Synthesis.

Imines and carboxylic acids have been directly coupled using propylphosphonic acid anhydride and NEt(i-Pr)2 to give N-acyliminium ions, which were intramolecularly trapped with oxygen, nitrogen, sulfur, and carbon nucleophiles to provide a wide range of structurally diverse heterocycles.