Double Nucleophilic Substitution Research Articles

Sequential Modification of Pyrrole Ring with up to Three Different Nucleophiles.

An umpolung strategy was used for the preparation of highly functionalized 3-pyrrolin-2-ones. This approach involves dearomative double chlorination of 1H-pyrroles to form highly reactive dichloro-substituted 2H-pyrroles. The resulting intermediate reacts selectively with wet alcohols to form the corresponding alkoxy-substituted 3-pyrrolin-2-ones via double nucleophilic substitution in up to 99% yield. The subsequent reaction with different N-, O-, and S-nucleophiles opens access to highly functionalized pyrrolinones bearing additional functionality. The overall outcome of the reported sequence is step-by-step nucleophilic modification of pyrroles with three different nucleophiles. All steps were found to be highly efficient and 100% regioselective. This transformation proceeds under mild conditions and does not require any catalyst to give final products in very high yields. The obtained experimental results are in perfect agreement with the data obtained by theoretical investigation of these reactions.

A semi-rigid co-poly(imide) derived from an isomeric mixture of monomers. Assessing gas transport properties in self-standing polymer membrane

Chemical structure and morphology of polymers are directly related with the membrane separation performance. Poly(imide)s (PIs) are the most widely used polymers in the preparation of membranes for gas separation applications; thus, research on the structural design of polymers is of great interest to develop new membranes. In the present work, we reported the synthesis, characterization, and measurement of the gas transport properties of a new co-poly(imide)s (PI-D2a-D2b-6FDA) prepared from a mixture of isomeric diamines. The co-poly(imide) synthetic route involved several steps, starting by a bromination reaction, followed by a double nucleophilic aromatic substitution giving an isomeric mixture of precursors, which suffered a Suzuki-Miyaura C–C cross-coupling reaction followed by the reduction of nitro groups to give two new isomeric diamines. Finally, diamines simultaneously reacted with the dianhydride 6FDA to obtain PI-D2a-D2b-6FDA. The co-poly(imide) had a Mn of 47.7 kDa and a Mw of 74.0 kDa with a PDI of 1.6. The sample exhibited a 10% weight loss at 540 °C, Tg of 280 °C, BET surface area of 110 m2 g−1, and wide-angle X-ray diffraction (WAXD) interchain d-spacing at 9.5 Å and 6.3 Å. Tensile strength, elongation at break and Young's modulus were 109.6 MPa, 6.66% and 2.18 GPa, respectively. co-Poly(imide) was soluble in various polar aprotic organic solvents such as DMSO, NMP, DMF, DMAc, THF, and chloroform, forming a self-standing dense film whose gas transport properties were measured. Pure gas permeability coefficients for H2, CO2, O2, N2, and CH4, were 47.28, 24.04, 4.35, 1.02, and 0.76 (Barrer), respectively, which follows a decreasing order by the increasing kinetic diameters of the respective gases. Ideal gas selectivities H2/N2, O2/N2, CO2/CH4, and CO2/N2 were 46.4, 4.3, 31.6, and 23.6, respectively. These gas transport properties were compared with the commercial polymer Matrimid®, showing higher gas permeability coefficients than Matrimid®.

Water soluble octa-imidazolium zinc phthalocyanine for nucleus/nucleolus cell fluorescence microscopy and photodynamic therapy.

A poly-cationic theranostic macrocycle was developed to perform confocal microscopy imaging and photodynamic therapy studies on a model of melanoma cancer, one of the most aggressive cancer. Hence, an octa-imidazolium zinc phthalocyanine was conveniently synthesized in large amount in three steps in a 44% overall yield: upon double nucleophilic aromatic substitution, cyclo-tetramerization and quaternization reactions. Such an octa-cationic molecule was readily soluble in physiological media, reaching concentrations beyond 1mM. It showed fluorescence properties in aqueous medium (ΦF = 0.31) with no noticeable aggregation, spectroscopy studies showed. In vitro confocal fluorescence microscopy studies carried out on murine melanoma model (B16F10 cells) showed that the fluorophore was mainly located in the cell nucleolus, an organelle of interest for the treatment of cancer. The anticancer photodynamic potential of the octa-cationic photosensitizer could be measured (IC50 = 5.4µM) using the MTS viability assay. Both fluorescence microscopy studies and photodynamic studies demonstrate the octa-cationic molecule is theranostic and could be further developed for future photodynamic diagnosis (PDD) and photodynamic inactivation of micro-organisms (PDI).

Effect of Chiral Purity on Adjuvanticity of Archaeol-Based Glycolipids.

Archaeosomes composed of sulfated lactosyl archaeol (SLA) glycolipids from stereoisomerically pure archaeol (1) are vaccine adjuvants that can boost immunogenicity and vaccine efficacy in preclinical models. Herein, we report a new synthesis of 2,3-bis((3,7,11,15-tetramethylhexadecyl)oxy) propan-1-ol (3) by treating (±)-3-benzyloxy-1,2-propanediol with a mesylated phytol derivative through a double nucleophilic substitution reaction, followed by reductive debenzylation. Three SLA archaeosomes from archaeols of different chiral purities were prepared, and the effect of stereochemistry on their adjuvanticity toward ovalbumin was investigated. It was found that all SLA archaeosomes induced strong humoral and cell-mediated antigen-specific immune responses following immunization of C57BL/6NCrl mice, with no significant differences, irrespective of the chiral purities. The responses were comparable or better than those obtained using mimetics of approved adjuvants. The performance of SLA archaeosomes during immunization and their lack of dependence on the stereochemistry of archaeol points toward a promising, safe, scalable, and economically viable vaccine adjuvant system.

Construction of pyrazolodiazepines using AuI, a dual functional gold catalyst.

N,N'-5,7-Fused compounds are important molecules exhibiting medicinal potential. Herein, we report a practical and robust method for synthesising pyrazolodiazepines from N-piperidinyl alkynylhydrazides using a AuI catalyst. The broad substrate scope of alkynylhydrazides and synthetic application of pyrazolodiazepines are demonstrated. In addition, control experiments provide detailed information on the reaction mechanism, in which AuI promotes both the sequential intramolecular nucleophilic addition and the double nucleophilic substitution reaction as a π-acidic and nucleophilic dual functional catalyst.

Photocatalytic Biheterocyclization of 1,7-Diynes for Accessing Skeletally Diverse Tricyclic 2-Pyranones.

A new and green route to skeletally diverse oxo-heterocyclic architectures such as pyrano[3,4-c]chromen-2-ones and pyrano[3,4-c]quinolin-2-ones is reported via an unprecedented photocatalytic Kharasch-type cyclization/1,5-(SN″)-substitution/elimination/6π-electrocyclization/double nucleophilic substitution cascade starting from easily available heteroatom-linked 1,7-diynes and low-cost CBrCl3. During this reaction process, the full scission of carbon-halogen bonds of BrCCl3 was realized to directly build two new rings, including a lactone scaffold, using H2O as the oxygen source of the ester group.

Recent Progress in Preparation and Applications of Oxazino[4,3-a] pyrroloimidazo[5,4-f]benzimidazole (imino)quinone as an Anti-Cancer Agent

The aim of this study is to prepare a novel precursor for the synthesis of imidazo[5,4- f]benzimidazole(imino)quinone. This will target the over-expression of the enzyme NAD(P)H: quinone oxidoreductase (NQO1) in solid tumours. An electron withdrawing group was incorporated into the structure, and the substituted ring size was reduced as this is hypothesised to increase its binding affinity to NQO1. The 2, 5-difluoroaniline was acetylated using acetic anhydride to produce N-(2,5-difluorophenyl) acetamide. The latter underwent selective nitration to produce N-(2,5-difluoro- 4-nitrophenyl) acetamide followed by oxidation using methane sulfonic acid and hydrogen peroxide to give 1,4-difluoro-2,5-dinitrobenzene. The synthesized precursor was achieved by the double nucleophilic aromatic substitution of morpholine and pyrrolidine onto 1,4-difluoro-2,5-dinitrobenzene. The 4-(2,5-dinitro-4-pyrrolid-1-yl) morpholine was successfully synthesized in four synthetic steps. The identity and purity were confirmed using NMR with peaks assigned using proton-fluorine coupling values. Further work is recommended for the developments of this study, additional synthetic steps using the novel precursor need to be carried out to achieve oxazino[4,3-a] pyrroloimidazo[5,4-f] benzimidazole(imino)quinone.

Diversity-orientated synthesis of macrocyclic heterocycles using a double SNAr approach.

An efficient macrocyclisation approach based on the double aromatic nucleophilic substitution (SNACK) was developed. This methodology allows a facile incorporation of heterocyclic motifs into macrocyclic rings and rapid synthesis of a significant number of structurally diverse macrocycles. SNACK macrocyclisation enables preparation of stable diastereoisomers of conformationally restricted macrocycles (atropisomers). Practical application of SNACK macrocyclisation in a drug discovery project was exemplified by the identification of high affinity macrocyclic binders of B-cell lymphoma 6 (BCL6).

Non-porous interpenetrating Co-bpe MOF for colorimetric iodide sensing.

MOFs with their accessible voids/channels have been explored immensely for sensing due to their exclusive host-guest chemistry. However, unavailability of pores/voids in interpenetrating non-porous MOFs limits their applications in sensing. We herein report for the first time, hitherto, a non-porous MOF with an interpenetrating ladder structure for iodide sensing. A Co-bpe MOF was synthesized by hydrothermal reaction between cobalt nitrate and 1,2-bis(4-pyridyl)ethylene (bpe) in methanol and tested against colorimetric sensing of halides. The supramolecular structure of the Co-bpe MOF was stabilized through strong hydrogen bonding. We propose a double nucleophilic substitution reaction mechanism for iodide detection, which is one of its own kind. While Co-bpe showed a significant color change from dark maroon to dark green in the presence of iodide, the rest of halides did not display any pronounced colorimetric effect. The limit of detection (LOD) of this material was found to be 2.7 × 10-7 M. This article focuses on the equal competency of non-porous MOF materials with the porous MOFs in sensing applications.

A common strategy towards the synthesis of 1,4-dideoxy-1,4-imino-l-xylitol, deacetyl (+)-anisomycin and amino-substituted piperidine iminosugars

A strategy towards the synthesis of three different target molecules, namely 1,4-dideoxy-1,4-imino-l-xylitol, deacetyl (+)-anisomycin and amino-substituted piperidine iminosugars, molecules of potential biological and medicinal significance, is reported from a common amino-vicinal diol intermediate derived from tri-O-benzyl-d-glucal. Construction of the key pyrrolidine ring present in 1,4-dideoxy-1,4-imino-l-xylitol and (+)-anisomycin was a consequence of thermodynamically driven concomitant intramolecular nucleophilic addition reaction of the amino group to the resultant aldehyde obtained by oxidative cleavage of the amino-vicinal diol. Alternatively, double nucleophilic substitution on an amino-diol, after mesylation, with various amines delivered amino-substituted piperidine iminosugars in good yields.

Synthesis of 3,5-dichloro-4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPYs) via Cu(OTf)2 mediated oxidative nucleophilic substitution of hydrogen by chloride

Regioselective halogenation is often a key step in the formation of substituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores, through the enablement of subsequent downstream C–C or C-X bond forming steps via SNAr or metal catalyzed cross-coupling reactions. Classical SEAr halogenation of unsubstituted BODIPYs results in 2/6-substitution, precluding easy access to 3/5-halogenated BODIPYs. Herein we present our development of a 3,5-dihalogenation reaction of unsubstituted BODIPYs, via a double oxidative nucleophilic substitution of hydrogen with chloride. Reaction of a range of meso-aryl, but otherwise unsubstituted, BODIPYs with stoichiometric Cu(OTf)2 in the presence of ethanolamine and tetrabutylammonium chloride gives high isolated yields of the corresponding 3,5-dichlorinated BODIPYs, facilitating access to these valuable synthetic intermediates.

Transition metal-free construction of trinuclear N-fused hybrid scaffolds by double nucleophilic aromatic substitution under microwave irradiation

A green construction of trinuclear N-fused hybrid scaffolds by transition metal-free double C(sp2)–N coupling of 2-(2-bromoaryl)- and 2-(2-bromovinyl)benzimidazoles with 2-aminoazoles under microwave irradiation has been developed.

Reversible Double Nucleophilic Substitution Reaction inside Single-Crystal MOF Tuned Remarkable Magnetic Behavior.

Chemical reactions inside single crystals are highly selective but quite challenging. We present herein an octahedral cobalt-oxygen chain-based 3D coordination network with sqc3868 topology, which underwent a reversible double nucleophilic substitution inside a single crystal involving encapsulated DMF molecules and was converted into a topologically highly related frl network, accompanied by magnetic tuning from antiferromagnetism to ferromagnetism. Combined UV-vis, XPS, EPR, and XANES showed most of the Co centers keep a divalent state with less remarkable electronic structure change during the substitution reaction, indicating magnetic tunability mainly comes from a minor change of local geometry of cobalt atoms with large anisotropy.

Base-promoted nucleophilic fluoroarenes substitution of C[sbnd]F bonds

With the use of KOH/DMSO as the superbase medium, the nucleophilic fluoroarene substitution for CF bonds is presented. The transformation proceeds smoothly with the use of fluoroarenes bearing not only electron-withdrawing group, but also electron-donating group and a variety of nucleophiles such as alcohols, phenols, amines, amides and nitrogen-heterocyclic compounds. The double nucleophilic substitution using ortho-difluoroarenes and nucleophiles bearing ortho-dinucleophilic groups results in the formation of 2,3-dihydro-1,4-benzodioxins, dibenzo[b,e][1,4]dioxins and 10H-phenoxazines in moderate to good yields.

Lewis base-catalyzed double nucleophilic substitution reaction of N -tosylaziridinofullerene with thioureas or guanidines

Abstract Lewis base-catalyzed double nucleophilic substitution reaction of N -tosylaziridinofullerene with thioureas or guanidines affords the fullerothiazolidin-2-imine or fulleroimidazolidin-2-imine derivatives, respectively. In the case of unsymmetrical thioureas connecting an alkyl and an aryl group on each of the nitrogen atom, the transformation exhibits excellent chemoselectivity with only the aryl substituted nitrogen atom bonding to C 60 . The generated tri-4-methoxyphenyl substituted fulleroimidazolidin-2-imine reacts with CS 2 smoothly to generate di-4-methoxyphenyl fulleroimidazolidin-2-thione.

Enantioselective synthesis and sensory properties of 3‐methylthiodecanal

AbstractThe enantioselective synthesis of two enantiomers of 3‐methylthiodecanal was described, in which the optically active 1‐undecen‐4‐ols prepared by asymmetric catalytic addition of n‐octanal with allyltributylstannane went through oxidation of double bond and nucleophilic substitution of hydroxy group via mesylate to afford the target molecules with about 90% ee values. Odour properties and approximate thresholds were determined by means of GC/Olfactory. The data indicated that two enantiomers of 3‐methylthiodecanal presented distinctive odour feature from each other and also a slight difference in odour intensity.

Straightforward Synthesis of a Vicinal Double‐Bridgehead Iodo Trimethylsilyl Octacycle: Unprecedented Lack of Reactivity of the Silyl Group in the Presence of Fluoride Anions

A convenient synthesis of an octacyclic compound containing an iodo and a trimethylsilyl group in vicinal double‐bridgehead positions, as a possible precursor of a pyramidalized alkene, is described. The key step of the synthesis consists of a double nucleophilic substitution of two neopentyl‐type iodides by cyclopentadienide anions followed by two intramolecular Diels–Alder cycloadditions. All attempts to generate the expected pyramidalized alkene from the above precursor on reaction with different sources of fluoride failed. This octacyclic compound, which contains two disubstituted C=C bonds, underwent a chemo‐ and stereoselective Pd0‐catalyzed co‐cyclotrimerization with dimethyl acetylenedicarboxylate to give a nonacyclic cyclohexadiene derivative that can be aromatized upon reaction with CsF or transformed into a related fluoride upon reaction with AgF.

Dual Gold‐Catalyzed Three‐Component Reaction: Efficient Synthesis of Indene‐Fused Esters, Acids, and Lactones through Gold Vinylidene Intermediates

A dual gold(I)‐catalyzed three‐component reaction was developed to prepare indene‐fused carboxylic acid derivatives from diynes, alcohols, and pyridine N‐oxides in both inter‐ and intramolecular fashions. The pyridine N‐oxides were found to exhibit distinct selectivity unlike the α‐oxo gold carbene intermediates in the well‐developed gold‐catalyzed oxidative functionalization of alkynes. Experimental studies and DFT calculations support double nucleophilic substitution of a gold vinylidene intermediate.

Metal–free One–pot Synthesis of Functionalized Carbazoles

AbstractA distinct dichotomy in product distribution was initially observed in metal‐free domino C−N and C−O bond forming reaction of carbazoles with aryl halides or benzyl halides. The fluoride group in halogenated fluorobenzenes almost exclusively undergoes double nucleophilic substitution with hydroxy group and amino group bearing carbazole ring. The reaction was found to occur preferentially at benzyl‐halogen atom when halobenzyl halides were present. Controlling experiments found that first coupling occurred with excellent site‐selectivity in favor of the hydroxy group on carbazole. A wide range of halogenated functionalized carbazoles, which have a wide utility for organic synthesis, polymer chemistry, and advanced functional materials application, were tolerated.

A Chiron Approach to Diversity-Oriented Synthesis of Aminocyclitols, (-)-Conduramine F-4 and Polyhydroxyaminoazepanes from a Common Precursor.

The total syntheses of aminocyclitols, (-)-conduramine F-4, and polyhydroxyaminoazepanes have been achieved from a common precursor derived from tri-O-benzyl-d-glucal through a 'diversity-oriented' approach. Tri-O-benzyl-d-glucal was converted into a protected 1,6-diol through a sequence of steps that include transformation to a 2-tosylamidoglucose derivative, selective deprotection of primary C-6 benzyloxy group, LiAlH4-mediated one-step reduction of acetate groups, and reductive ring opening of the resulting hemiacetal as the key steps. The 1,6-diol served as a common precursor in our diversity oriented approach toward the target molecules. Mesylation of the diol followed by double nucleophilic substitution reaction with primary amines led to the synthesis of amino-substituted polyhydroxyazepanes. On the other hand, dialdehyde obtained from the oxidation of 1,6-diol was found to be a convenient starting material for the synthesis of aminocyclitols and (-)-conduramine F-4. McMurry coupling of the dialdehyde was successfully employed, for the first time, to construct the carbocyclic framework of aminoyclitols, while bis-Wittig olefination of the dialdehyde followed by Grubb's(II)-catalyzed RCM delivered (-)-conduramine F-4. The stereochemistry of newly created chiral centers in aminocyclitols was established through single crystal X-ray crystallography and detailed NOE studies.