Chloride Donors Research Articles

Mild method for the synthesis of α-glycosyl chlorides: A convenient protocol for quick one-pot glycosylation

A simple and efficient protocol for the preparation of α-glycosyl chlorides within 15–30 min is described which employs a stable, cheap, and commercially available Trichloroisocyanuric acid (TCCA) as non-toxic chlorinating agent along with PPh3. This process involved a wide range of substrate scope and is well-suited with labile hydroxyl protecting groups such as benzyl, acetyl, benzoyl, isopropylidene, benzylidene, and TBDPS (tert-butyldiphenylsilyl) groups. This process is operationally simple, mild conditions and obtained good yields with excellent α selectivity. Moreover, a multi-catalyst one-pot glycosylation can be carried out to transform the glycosyl hemiacetals directly to a various O-glycosides in high overall yields without the need for separation or purification of the α-glycosyl chloride donors.

Stereoselective Aromatic O-Glycosylation of Glycosyl Chloride with Arylboronic Acid under an Air Atmosphere.

A novel exclusive β-selective O-aryl glycosylation was developed using glycosyl chloride and arylboronic acid with a palladium catalyst under an air atmosphere. The reaction was insensitive to moisture and characterized using readily available and bench-stable glycosyl chloride and arylboronic acid as substrates. A diverse range of substrate scopes, including various arylboronic acids and glycosyl chloride donors, was well-tolerated in this method. Arylboronic acid was oxidized by O2 in air to produce phenol as the aromatic source. This new strategy provides an alternative route and may find broad applications in efficient synthesis of bioactive O-aryl glycosides in the future.

Ruthenium-Catalyzed Pyridine-Directed Aryl C-H Glycosylation with Glycosyl Chlorides.

Metal-catalyzed C-H glycosylation reactions with glycosyl chloride donors have emerged as a useful strategy for the synthesis of C-glycosides. Previously, palladium and nickel complexes were reported to catalyze C-H glycosylation reactions using amide-linked bidentate auxiliaries. Herein, a ruthenium-catalyzed ortho C-H glycosylation reaction of arenes with various glycosyl chloride donors using a monodentate pyridine directing group is developed. Preliminary mechanistic studies indicated that two-electron oxidative addition and reductive elimination of ruthenocycle intermediate led to the glycosylation products.

One-Pot Stereoselective Synthesis of 2,3-Diglycosylindoles and Tryptophan-C-glycosides via Palladium-Catalyzed C-H Glycosylation of Indole and Tryptophan.

We described a novel palladium-catalyzed C-H glycosylation of indole or tryptophan for a one-pot stereoselective synthesis of 2,3-diglycosylindoles and tryptophan-C-glycosides. In this strategy, the use of air and base-free and ligand-free conditions provided a highly efficient route to construct C-glycosides. The method can be applied to a wide range of cost-effective and convenient glycosyl chloride donors. Mechanistic studies indicated that the indole 2,3-diglycosylation sequence was C3 and then C2.

Stereoselective Synthesis of C‐Vinyl Glycosides via Palladium‐Catalyzed C−H Glycosylation of Alkenes

AbstractC‐vinyl glycosides are an important class of carbohydrates and pose a unique synthetic challenge. A new strategy has been developed for stereoselective synthesis of C‐vinyl glycosides via Pd‐catalyzed directed C−H glycosylation of alkenes with glycosyl chloride donors using an easily removable bidentate auxiliary. Both the γ C−H bond of allylamines and the δ C−H bond of homoallyl amine substrates can be glycosylated in high efficiency and with excellent regio‐ and stereoselectivity. The resulting C‐vinyl glycosides can be further converted to a variety of C‐alkyl glycosides with high stereospecificity. These reactions offer a broadly applicable method to streamline the synthesis of complex C‐vinyl glycosides from easily accessible starting materials.

Stereoselective Synthesis of C-Vinyl Glycosides via Palladium-Catalyzed C-H Glycosylation of Alkenes.

C-vinyl glycosides are an important class of carbohydrates and pose a unique synthetic challenge. A new strategy has been developed for stereoselective synthesis of C-vinyl glycosides via Pd-catalyzed directed C-H glycosylation of alkenes with glycosyl chloride donors using an easily removable bidentate auxiliary. Both the γ C-H bond of allylamines and the δ C-H bond of homoallyl amine substrates can be glycosylated in high efficiency and with excellent regio- and stereoselectivity. The resulting C-vinyl glycosides can be further converted to a variety of C-alkyl glycosides with high stereospecificity. These reactions offer a broadly applicable method to streamline the synthesis of complex C-vinyl glycosides from easily accessible starting materials.

Synthesis, characterization and reactivity of thiolate-bridged cobalt-iron and ruthenium-iron complexes

Thiolate-bridged hetero-bimetallic complexes [Cp*M(MeCN)N2S2FeCl][PF6] (2, M = Ru; 3, M = Co, Cp* =η5-C5Me5, N2S2 = N,N'-dimethyl-3,6-diazanonane-1,8-dithiolate) were prepared by self-assembly of dimer [N2S2Fe]2 with mononuclear precursor [Cp*Ru(MeCN)3][PF6] or [Cp*Co(MeCN)3][PF6]2 in the presence of CHCl3 as a chloride donor. Complexes 2 and 3 exhibit obviously different redox behaviors investigated by cyclic voltammetry and spin density distributions supported by DFT calculations. Notably, iron-cobalt complex 3 possesses versatile reactivities that cannot be achieved for complex 2. In the presence of CoCp2, complex 3 can undergo one-electron reduction to generate a stable formally CoIIFeII complex [Cp*CoN2S2FeCl] (4). Besides, the terminal chloride on the iron center in 3 can be removed by dehalogenation agent AgPF6 or exchanged with azide to afford the corresponding complexes [Cp*Co(MeCN)N2S2Fe(MeCN)][PF6]2 (5) and [Cp*Co(MeCN)N2S2Fe(N3)][PF6] (6). In addition, complexes 2, 3 and 4 show distinct catalytic reactivity toward the disproportionation of hydrazine into ammonia. These results may be helpful to understand the vital role of the heterometal in some catalytic transformations promoted by heteromultinuclear complexes.

Optimization of 1,3-butadiene monomer coordination polymerization using response surface methodology (RSM)

Laboratory runs can be minimized via experimental design which yields the optimum and best data regarding the independent parameters. In this research work, response surface methodology (RSM) based on a threelevel central composite design (CCD) was utilized to optimize and evaluate the interactive effects of processing conditions for polymerization of 1,3-butadiene (Bd) diene monomer using Ziegler-Natta catalyst. The polybutadiene rubber (PBR) having different cis content and molecular weight was obtained. The catalyst components included neodymium versatate (NdV3) as catalyst, triethyl aluminum (TEAL) as cocatalyst or activator, and ethylaluminum sesquichloride (EASC) as chloride donor. For the modeling, three independent variables, namely monomer concentration (8-28 wt%), reaction time (1.5-2.5 h), and reaction temperature (45-75oC) at three levels were selected to optimize the dependent variables or responses including monomer conversion, viscosity-average molecular weight and the cis isomer content of the obtained polymer. The interaction between three crucial parameters was studied and modeled. Quadratic models were obtained to relate process conditions to dependent variables. It was observed that the optimal conditions predicted by RSM were consistent with the experimental data. Statistical analysis demonstrated that concentration of the monomer and the time of reaction significantly affected cis content. Moreover, processing conditions to achieve the desired response variables were predicted and experimentally approved. The optimal reaction conditions derived from RSM are monomer concentration = 19 wt%, polymerization time = 2 hours, and polymerization temperature = 50oC. Polymerization was carried out at optimum conditions. The appropriate level of dependent variables including 94.2% monomer conversion, 151812 g/mol viscosity-average molecular weight and 98.8% cis content was acquired.

Pd‐Catalyzed Ortho‐Directed C—H Glycosylation of Arenes Using N‐linked Bidentate Auxiliaries

Main observation and conclusionA set of Pd‐catalyzed ortho‐directed C—H glycosylation reactions with glycosyl chloride donors using various N‐linked bidentate auxiliaries has been developed for synthesis of C‐aryl glycosides. A broad range of pyranose and furanose moieties can be installed on the ortho position of arylamine, carbazole, indole and benzylamine type substrates in high yield and with high regio‐ and diastereoselectivity. These auxiliaries can be readily installed and removed under relatively mild conditions.

Palladium-Catalyzed O - and N -Glycosylation with Glycosyl Chlorides

Despite the significant progress in carbohydrate chemistry, there remains a pressing need for efficient and practical glycosylation methods using simple glycosyl donors and with high atom economy. ...

Di-chlorido-bis-[2-(pyridin-2-yl-κN)-1H-benzimidazole-κN 3]nickel(II) monohydrate.

In the title complex, [NiCl2(C12H9N3)2]·H2O, a divalent nickel atom is coordinated by two 2-(pyridin-2-yl)-1H-benzimidazole ligands in a slightly distorted octa-hedral environment defined by four N donors of two N,N'-chelating ligands, along with two cis-oriented anionic chloride donors. The title complex crystallized with a water mol-ecule disordered over two positions. In the crystal, a combination of O-H⋯Cl, O-H.·O and N-H⋯Cl hydrogen bonds, together with C-H⋯O, C-H⋯Cl and C-H⋯π inter-actions, links the complex mol-ecules and the water mol-ecules to form a supra-molecular three-dimensional framework. The title complex is isostructural with the cobalt(II) dichloride complex reported previously [Das et al. (2011 ▸). Org. Biomol. Chem. 9, 7097-7107].

Solvent-free, under air selective synthesis of α-glycosides adopting glycosyl chlorides as donors.

α-Glycosides are highly relevant synthetic targets due to their abundance in natural oligosaccharides involved in many biological processes. Nevertheless their preparation is hampered by several issues, due to both the strictly anhydrous conditions typically required in glycosylation procedures and the non-trivial achievement of high α-stereoselectivity, one of the major challenges in oligosaccharide synthesis. In this paper we report a novel and efficient approach for the highly stereoselective synthesis of α-glycosides. This is based on the unprecedented solvent-free combination of triethylphosphite, tetrabutylammonium bromide and N,N-diisopropylethylamine for the activation of glycosyl chlorides under air. Despite the relative stability of glycosyl chlorides with respect to more reactive halide donors, the solvent-free procedure allowed a wide set of α-glycosides, including biorelevant fragments, to be obtained in much shorter times compared with similar glycosylation approaches in solution. The presented method features a wide target scope and functional group compatibility, also serving with partially disarmed substrates, and it does not require a high stoichiometric excess of reagents nor the preparation of expensive precursors. The solvent-free glycosylation can be even directly performed from 1-hydroxy sugars without purification of the in situ generated chloride, providing an especially useful opportunity in the case of highly reactive and labile glycosyl donors.

Polymerization of 1,3-butadiene using neodymium versatate: optimization of NdV3/TEAL/EASC molar ratios via response surface methodology (RSM)

Response surface methodology (RSM) with central composite design was used to optimize and analyze the molar ratio of catalyst components for polymerization of 1,3-butadiene (Bd) using Ziegler–Natta catalyst. In this research work, the catalyst component includes neodymium versatate (NdV3) as catalyst, triethylaluminum as cocatalyst or activator and ethylaluminum sesquichloride as chloride donor. The symbols [Nd], [Al], [Cl] and [Bd] were used for catalyst, cocatalyst, donor and monomer concentration, respectively. The interaction between three important and critical variables was studied and modeled. For this purpose, independent variables are [Bd]/[Nd], [Al]/[Nd] and [Cl]/[Nd] molar ratios at three levels to optimize the dependent or response ones which are monomer conversion, molecular weight and cis content of resulting polymer. Quadratic models were achieved and developed to correlate the catalyst components’ molar ratio with dependent variables. The optimum conditions predicted via RSM were in good agreement with experimental data obtained from the experimental runs. The statistical analysis of the results showed that [Cl]/[Nd] molar ratio had a significant effect on monomer conversion and cis content. Furthermore, the catalyst components’ molar ratio to reach the desirable response parameters is forecasted and experimentally verified. The optimum catalyst components’ molar ratio derived via RSM is as follows: [Bd]/[Nd] = 5363.0, [Al]/[Nd] = 27.2 and [Cl]/[Nd] = 2.2.

Palladium-catalysed C−H glycosylation for synthesis of C-aryl glycosides

C-aryl glycosides are widely found in nature and play important roles in drug design. Despite the significant progress made over the past few decades, efficient and stereoselective synthesis of complex C-aryl glycosides remains challenging, lagging far behind the state of the art of the synthesis of O- or N-glycosides. Here, we report a simple and powerful bioinspired strategy for the stereoselective synthesis of C-aryl glycosides via palladium-catalysed ortho-directed C(sp2)−H functionalization of arenes and heteroarenes with easily accessible glycosyl chloride donors. The catalytic palladacycle intermediate generated via C−H palladation provides a soft aryl nucleophile that can react with glycosyl oxocarbenium ion partners with high efficiency and excellent stereocontrol. The method can be applied to a wide range of arene and heteroarene substrates, glycosyl chloride donors and auxiliary groups. It can simplify the synthesis of a variety of complex C-aryl glycosides and offers a tool for late-stage modification of drug molecules. C-aryl glycosides are present in many natural products and of interest in drug design, but their chemical synthesis is challenging. This work reports an efficient and diastereoselective ortho-directed C−H glycosylation of arenes and heteroarenes with glycosyl chloride using a palladium catalyst.

Integrating Activity with Accessibility in Olefin Metathesis: An Unprecedentedly Reactive Ruthenium-Indenylidene Catalyst.

Access to leading olefin metathesis catalysts, including the Grubbs, Hoveyda, and Grela catalysts, ultimately rests on the nonscaleable transfer of a benzylidene ligand from an unstable, impure aryldiazomethane. The indenylidene ligand can be reliably installed, but to date yields much less reactive catalysts. A fast-initiating, dimeric indenylidene complex (Ru-1) is reported, which reconciles high activity with scaleable synthesis. Each Ru center in Ru-1 is stabilized by a state-of-the-art cyclic alkyl amino carbene (CAAC, C1) and a bridging chloride donor: the lability of the latter elevates the reactivity of Ru-1 to a level previously attainable only with benzylidene derivatives. Evaluation of initiation rate constants reveals that Ru-1 initiates >250× faster than indenylidene catalyst M2 (RuCl2(H2IMes)(PCy3)(Ind)), and 65× faster than UC (RuCl2(C1)2(Ind)). The slow initiation previously regarded as characteristic of indenylidene catalysts is hence due to low ligand lability, not inherently slow cycloaddition at the Ru=CRR' site. In macrocyclization and "ethenolysis" of methyl oleate (i.e., transformation into α-olefins via cross-metathesis with C2H4), Ru-1 is comparable or superior to the corresponding, breakthrough CAAC-benzylidene catalyst. In ethenolysis, Ru-1 is 5× more robust to standard-grade (99.9%) C2H4 than the top-performing catalyst, probably reflecting steric protection at the quaternary CAAC carbon.

Efficient Synthesis of α‐Glycosyl Chlorides Using 2‐Chloro‐1,3‐dimethylimidazolinium Chloride: A Convenient Protocol for Quick One‐Pot Glycosylation

A mild and convenient method for the synthesis of α‐glycosyl chlorides in high 80–96 % yields within 15–30 min using 2‐chloro‐1,3‐dimethylimidazolinium chloride (DMC) is disclosed. The method has a wide substrate scope and is compatible with labile OH protecting groups, including benzyl, acetyl, benzoyl, isopropylidene, benzylidene, TBDMS (tert‐butyldimethylsilyl), and TBDPS (tert‐butyldiphenylsilyl) groups. The excellent α selectivity obtained in this reaction is attributed to in‐situ isomerization of β‐glycosyl chlorides to the more stable α‐glycosyl chlorides, as demonstrated by 1H NMR spectroscopic studies. Disarmed sugars with OBz or OAc groups at C‐2 were chlorinated at a faster rate but ismomerized (β→α) at a slower rate than armed sugars with an OBn group at C‐2. More importantly, the method enables highly desirable one‐pot glycosylation reactions to take place, thus allowing efficient syntheses of disaccharides and simple O‐glycosylated sugars in high overall yields without the need for separation or purification of the α‐glycosyl chloride donors. This method will be especially useful for direct glycosylation reactions using glycosyl chloride donors that are unstable upon separation and purification.

Using the Lewis Acid Me3 Si-F-Al(ORF )3 To Prepare Phosphino-Phosphonium Cations with the Least-Coordinating Anion [(RF O)3 Al-F-Al(ORF )3

By reaction of two equivalents of Me3 Si-F-Al(ORF )3 1 with an equimolar amount of PPh2 Cl, the salt [Ph2 P-PPh2 Cl]+ [(RF O)3 Al-F-Al(ORF )3 ]- 2 is prepared smoothly in 91 % yield (NMR, XRD). The synthesis of [Ph2 P-PPh3 ]+ [(RF O)3 Al-F-Al(ORF )3 ]- 3 is best achieved by a two-step reaction: first, two equivalents of 1 react with one PPh3 to give [Me3 Si-PPh3 ]+ [(RF O)3 Al-F-Al(ORF )3 ]- 4 (NMR, XRD), which, upon reaction with PPh2 Cl, yields pure 3 and Me3 SiCl (NMR, XRD). Typically, a stoichiometry of two equivalents of 1 with respect to one equivalent of the chloride donor should be used. Otherwise, the residual strong Lewis acidity of the [(RF O)3 Al-F-Al(ORF )3 ]- anion in the presence of the [F-Al(ORF )3 ]- anion-that forms with less than two equivalents of 1-leads to further chloride exchange reactions that complicate work-up. This route presents the easiest way to introduce the least-coordinating [(RF O)3 Al-F-Al(ORF )3 ]- anion into a system. We expect a wide use of this route in all areas, in which chloride-bond heterolysis in combination with very weakly coordinating anions is desirable. Additionally, we performed calculations on the bond dissociation mechanisms of [R2 P-PMe3 ]+ and the isoelectronic Me2 P-SiMe3 and Me2 Si-PMe3 in dependence of the solvent permittivity. These calculations show, especially for the neutral reference compounds, a heavy influence of the solvent on the dissociation mechanism, which is why we suggest investigating these properties in solution instead of gas phase.

Analysis and occurrence of dichloropropanol fatty acid esters and related process‐induced contaminants in edible oils and fats

A new sensitive method for the indirect determination of ester‐bound 2,3‐dichloro‐1‐propanol (2,3‐DCP), 1,3‐dichloro‐2‐propanol (1,3‐DCP), 2‐chloro‐1,3‐propanediol (2‐MCPD), 3‐chloro‐1,2‐propanediol (3‐MCPD) and 2,3‐epoxy‐1‐propanol (glycidol) in oil matrices is presented. It is based on a mild alkaline‐catalysed release of chlorohydrins and glycidol, followed by a transformation of glycidol to monobromopropanediol (MBPD) according to a modification of the AOCS Official Method Cd 29b‐13 (3‐in‐1 method). The dichloropropanols are separated from the monohalogenated diols and the oil matrix by l/l extraction and determined separately by headspace gas chromatography‐mass spectrometry (GC‐MS‐HS). Both MCPD isomers and the glycidol derivative are derivatised with phenylboronic acid (PBA) and analysed by GC‐MS separately. Method validation was performed in an oil matrix using isotopic labelled esterified standards. Linearity was verified for all analytes (r2 > 0.998). The limit of detection (LOD) for all analytes was ≤5 μg/kg. The modified determination of ester‐bound MCPD and glycidol was tested for accuracy by analysing reference samples. All free and bound analytes were investigated regarding their stability against undesired alkaline‐induced transformation. It was also demonstrated that bound MCPD and bound DCP might be generated in oil by heat treatment in the presence of a strong chloride donor. The method was applied to the analysis of a variety of different edible oils. None of the two tested dichloropropanols was detected. By contrast and as might be expected, both bound MCPD and bound glycidol were consistently detected in refined oils.Practical applications: The presented application is suitable for the parallel determination of ester‐bound dichloropropanols and monochloropropanols and ester‐bound glycidol in edible oils and fats using simple techniques for sample preparation. It covers more analytes and is more sensitive than other previously reported methods. Substitution of the double sample preparation, (a part of the AOCS Official Method Cd 29b‐13), by determining a correction factor for a whole set of samples, may reduce the effort required for sample preparation and raw data analysis. Furthermore, the investigation of basic transformations that may occur during sample preparation can be helpful for a better understanding of the complex chemistry in MCPD and glycidol analysis. Similarly, the results from heating frying fat in the presence of aluminium chloride might help to understand the distribution of chlorohydrin isomers in heat‐treated oils and fats.Assumed heat‐induced formation pathways of ester‐bound chlorohydrins in an edible oil.

Organoboron-catalyzed regio- and stereoselective formation of β-2-deoxyglycosidic linkages.

A borinic acid derived catalyst enables regioselective and β-selective reactions of 2-deoxy- and 2,6-dideoxyglycosyl chloride donors with pyranoside-derived acceptors having unprotected cis-1,2- and 1,3-diol groups. The use of catalysis to promote a β-selective pathway by enhancement of acceptor nucleophilicity constitutes a distinct approach from previous work, which has been aimed at modulating donor reactivity by variation of protective and/or leaving groups.

Synthesis of Polyisoprene with Narrow Relative Molecular Mass Distribution Using Nd(OiPr)3-based Catalytic System

The effects of chloride donor and aging temperature of neodymium isopropoxide /diisobutylaluminum hydride / chloride donor( Nd( OiPr)3/ Al( iBu)2H / RCl) catalyst on isoprene polymerization were investigated. The resulting polymer was fully assessed by NMR,IR and GPC. Chloride donors greatly influenced the relative molecular mass distribution( MWD) of plyisoprene and only Nd( OiPr)3/ Al( iBu)2H / Me2SiCl2catalytic system could afford polyisoprene with a narrow MWD. In the Nd( OiPr)3/ Al( iBu)2H / Me2SiCl2catalytic system,the polymerization results showed that MWD of polyisoprene kept around 1. 5 when the catalyst was aged at 0 ~ 50 ℃ and became much broader( MWD 6. 0) when the aging temperature was above 50 ℃. Additionally,the yield and 1,4-content of polyisopere increased with the aging temperature.