Facile nucleophilic fluorination by synergistic effect between polymer-supported ionic liquid catalyst and tert-alcohol reaction media system

A highly efficient method was developed for nucleophilic fluorination using an alkali metal fluoride through the synergistic effect of the polymer-supported ionic liquid (PSIL) as a catalyst and tert-alcohol as an alternative reaction media. This PSIL/tert-alcohol system not only enhances the reactivity of alkali metal fluorides and reduces the formation of by-products but also allows the use of a polymer-supported catalyst protocol. As an example, the nucleophilic fluorinations of the model compound, 2-(3-bromopropoxy)naphthalene, with CsF using only tert-amyl alcohol as solvent (for 2 h reaction time), 0.5 equiv of PS[hmim][BF₄] in CH₃CN (for 12 h reaction time), and 0.5 equiv of PS[hmim][BF₄] in tert-amyl alcohol (which is a PSIL/tert-alcohol system for the synergistic effect; for 2 h reaction time) provided 18, 40, and 84% yield, respectively. The characteristics of the nucleophilic fluorination reactions of some halo- and alkanesulfonyloxyalkane systems to the corresponding fluoroalkanes using various alkali metal fluorides are also reported.     

多氟芳烃的亲核反应II: 一氯五氟苯的亲核环化

本文报道一氯五氟苯与双官能团亲核试剂反应制备环化产物的研究结果, 发现应用NaH-DMF体系制备醇钠, 有利于亲核反应的顺利进行, 环化产物产率有较大幅度提高.     

Facile and highly efficient synthesis of fluorinated heterocycles via Prins cyclization in ionic liquid hydrogen fluoride salts

Prins cyclization of homoallylic alcohols, thiols, and amines with various aldehydes in an ionic liquid HF salt (Et(4)NF.5HF) afforded the corresponding 4-fluorinated heterocycles in excellent yields.     

The nucleophilic reaction of polyfluoroaromatic compounds: II. The nucleophilic cyclization of chloropentafluorobenzene

The results of cyclization reaction between chloropentafluorobenzene and bifunctional nucleophiles such as XCH₂CH₂OH(X=OH, NHMe, NHEt) and HN (CH₂CH₂OH)₂, NH₂CH₂CH₂NH₂ were reported. It was found that the NaH/DMF system was a better reagent for the preparation of sodium alcoholates and the yields of cyclic products ranged from 50–80% which were much higher than that reported by previous workers.³     

Mono- and dialkylations of pyrrole at C2 and C5 positions by nucleophilic substitution reaction in ionic liquid

[reaction: see text] A novel ionic liquid methodology for pyrrole C-alkylation is described. The pyrrole alkylation is achieved with various simple alkyl halides and mesylates selectively at C2 and C5 positions in good yields with minimal byproducts under relatively mild conditions in various ionic liquids. 2-(3-Phenylpropyl)pyrrole (2a) was synthesized from pyrrole and 1-bromo-3-phenylpropane in a mixture solvent system, [bmim][SbF6] and CH3CN, in 81% yield at 115 degrees C for 44 h with 5% yield of dialkylated compound 3a.     

Facile synthesis of thiourea derivatives in ionic liquid

The synthesis of cinnamoyl thiourea derivatives from cinnamoyl isothiocyanate (CIT) with substituted aniline (RC6H4NH2) was investigated in the mostly used ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, [Bmim][BF4]. Significant enhance-ments in reactivity, yield and reaction rate were achieved. The products could be recovered by simple filtration. [Bmim][BF4] couldbe recycled simply by removing water under vacuum and reused at least 9 times without significant decrease in activity.     

Tandem nucleophilic addition/cyclization reaction in the synthesis of ketimine-type iminosugars

The biological activity of unsaturated iminosugars has not yet been extensively studied because of a lack of general synthetic methods. A practical synthesis of these cyclic ketimine sugars was developed, which was based on a tandem addition-cyclization reaction of a Grignard reagent to a omega-methanesulfonylglycononitrile.     

Solvent effects on kinetics of an heteroatomic nucleophilic substitution reaction in ionic liquid and molecular solvents mixtures

Rate constants, k _A, for the aromatic nucleophilic substitution reaction of 2-chloro-3,5-dinitropyridine with aniline were determined in different compositions of 2-propanol mixed with hexane, benzene, and 2-methylpropan-2-ol and 1-ethyl-3-methylimidazolium ethylsulfate ([Emim][EtSO₄]) with dimethyl sulfoxide at 25°C. The obtained rate constants of the reaction in pure solvents are in the following order: 2-methylpropan-2-ol > dimethyl sulfoxide > 2-propanol > hexane > benzene > [Emim][EtSO₄]. Molecularmicroscopic solvent parameters corresponding to the selected binary mixtures were utilized to study the kinetics of a nucleophilic substitution reaction in order to investigate and compare the effects of the solvents on a chemical process. The influence of solvent parameters including normalized polarity (E _T ^N ), dipolarity/polarizability (π*), hydrogen bond donor acidity (α), and hydrogen bond acceptor basicity (β) on the second-order rate constants were investigated and multiple linear regressions gave much better results with regard to single parameter regressions. The dipolarity/polarizability of media has a positive effect in all mixtures regarding zwitterionic character of the reaction intermediate and the hydrogen bond acceptor basicity of the solvent by stabilizing of activated complex increases the reaction rate.     

Gold-catalyzed hydrative cyclization of 1,6-diynes in ionic liquid media

Gold-catalyzed hydrative cyclization of terminal 1,6-diynes proceeds in ionic liquid with methanol as co-solvent. The solvent-catalyst could be recycled, after separation of the product by extraction with ether.     

Significantly enhanced reactivities of the nucleophilic substitution reactions in ionic liquid

We have investigated the reactivities of various metal fluorides in the nucleophilic fluorination of 2-(3-methanesulfonyloxypropyl)naphthalene (1) as a model compound in the presence of 1-n-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]). The higher periodic alkali metal fluorides demonstrate greater reactivity. The fluorination using CsF among the alkali metal fluorides was completed in 20 min, affording the desired product 2-(3-fluoropropyl)naphthalene (2a, 95%) without any byproducts. However, the fluorinations using alkali earth, transition, and low periodic alkali metal fluorides under the same conditions occurred rarely or not at all. We have also carried out the various facile nucleophilic substitutions such as halogenations, acetoxylation, nitrilation, and alkoxylations of mesyloxyalkane 1 and 2-(3-bromopropyl)naphthalene (6) at the primary aliphatic position using the potassium halides, acetate, cyanide, and alkoxides, respectively, in the presence of ionic liquids. These reactions provided the desired products, such as 2-(3-halopropyl)naphthalenes 5-7 (95% for Cl, 96% for Br, and 93% for I), 2-(3-acetoxypropyl)naphthalene (8, 95%), 2-(3-cyanopropyl)naphthalene (9, 93%), and 2-(3-methoxypropyl)naphthalene (10, 92%).     

Amino-functionalized ionic liquid as a nucleophilic scavenger in solution phase combinatorial synthesis

A new functionalized ionic liquid, 1-aminoethyl-3-methylimidazolium hexafluorophosphate was synthesized from 1-methylimidazole and 2-bromoethylamine hydrobromide. This ionic liquid was found to be an efficient scavenger for removing excess electrophiles, such as benzoyl chloride, p-toluenesulfochloride, phenyl isothiocyanate, and p-chlorophenyl isocyanate, in a solution-phase parallel synthesis. The resulting ionic liquid derivatives can be separated directly from the reaction mixture. Desired products were obtained with high purity. Only 1.5-2.0 equiv of this scavenger was needed with a sequestration time of less than 35 min. In addition, the used ionic liquid can be regenerated and recycled several times without significant loss of activity.     

Facile construction of a novel aminoquinazolinate anionic ligand through organolanthanide-mediated intermolecular nucleophilic addition/cyclization of anthranilonitrile

Compounds Cp 2Ln[kappa (3)-(4-NH(C 8N 2H 4)(2-NH 2C 6H 4)] [Cp = C 5H 5; Ln = Er ( 1), Y ( 2)] were synthesized by the reaction of Cp 2LnN (i) Pr 2(THF) with anthranilonitrile, indicating a novel organolanthanide-mediated intermolecular nucleophilic addition/cyclization of anthranilonitrile. To trap the intermediate I, a probe reaction of Cp 2ErN (i) Pr 2(THF) with anthranilonitrile and carbodiimide has also been investigated.     

Efficient nucleophilic substitution reactions of highly functionalized allyl halides in ionic liquid media

Nucleophilic substitution reactions of highly functionalized allyl halides with three anions, N₃⁻, AcO⁻, and PhSO₂⁻, in ionic liquid media were conducted. The ionic liquid, [Bmim][BF₄], was found to be superior to classical organic solvents to give higher yields and faster reaction rates. The resulting products belong to multifunctionalized trisubstituted α,β-unsaturated ketones, which are useful building blocks for organic synthesis.     

Asymmetric aldol reaction catalyzed by the anion of an ionic liquid

Herein we report the synthesis of a chiral imidazolium salt derived from trans-L-hydroxyproline and its applications as a catalyst for the asymmetric aldol reaction. By performing the aldol reaction in [Bmim]NTf(2) as a solvent, we report excellent isolated yields of the aldol product (up to 99%), as well as modest to excellent selectivities (dr superior to 99:1. ee up to 89%). Mechanistic insights and the origins of the selectivity of the aldol reaction are discussed on the basis of the results obtained with two catalytic imidazolium salts having different H-bonding potential.     

Pd/C-catalyzed Heck reaction in ionic liquid accelerated by microwave heating

Pd/C-catalyzed Heck reaction was conducted in ionic liquid 1-octanyl-3-methylimidazolium tetrafluoroborate ([OMIm]BF₄) in absence of phosphine ligand, which was promoted by microwave irradiation. The ionic liquid containing catalyst system can be used five times with a little loss of activity.     

Head-to-backbone cyclization of peptides on solid support by nucleophilic aromatic substitution

A new versatile synthetic route is presented for the cyclization of tripeptides on solid support using nucleophilic aromatic substitution in the cyclization step. Identification of all conformers within a limit of 3 kcal/mol from the identified global minimum conformations by Monte Carlo conformational searching reveals that five out of six synthesized compounds have well-defined peptide backbone conformational properties. This was determined by clustering the identified conformers against a filter of seven to nine torsion angles in the peptide backbone. Thus, the results meet our goal to find synthetic routes to peptides that are conformationally sufficiently locked to serve as convenient leads for further development of pharmacophoric models. The strategy is based on Fmoc-peptide chemistry on a N-aminoethyl-substituted glycine bound to the commercially available Rink amide PS-resin. After deprotection of the N-terminus of the tripeptide, it is acylated with a fluoronitrobenzoic acid. Subsequently, a Boc group on the N-bound aminoethyl substituent is selectively deprotected allowing cyclization from the head (N-terminus) to the backbone substituent, thereby leading to the desired cyclized tripeptides. A number of representative examples of peptides cyclized by this method have been synthesized and characterized by NMR. Protecting groups that allow the incorporation of side chain functionalized amino acids have been found. Thus, the route provides access to generic libraries of conformationally restricted peptide sequences expressing a range of proteinogenic pharmacophores.     

Calixarene ionic liquids: excellent phase transfer catalysts for nucleophilic substitution reaction in water

The first examples of calixarene ionic liquids 3 and 6 with 3D-shaped cavities were obtained in high yields by reacting calix[4]arene or thiacalix[4]arene with 1,6-dibromohexane and then refluxing in 1-methylimidazole. The experiments of phase transfer catalysis in water suggested that they possessed excellent catalytic properties of aromatic nucleophilic substitution reaction and benzyl nucleophilic substitution. The optimized yields of product in catalytic reaction were as high as approximate 97% under mild reaction conditions. The cavities of calixarene skeleton played the crucial roles in catalysis and the stable cone conformation was favorable for catalysis.     

The heterogeneous catalytic heck reaction in an ionic liquid

The C-C cross coupling reaction between bromobenzene and styrene in the presence of Pd deposited on mesoporous acetylene soot (Pd/C) occurred in a tetraalkylammonium ionic liquid (IL) as a truly heterogeneous catalytic process. The active palladium form was not transferred into the reaction solution. Deposited palladium activation was observed when the Pd/C catalyst was preliminarily heated in the IL in the presence of dibutylamine as a base.     

Facile preparation of indoles and 1,2-benzothiazine 1,1-dioxides: nucleophilic addition of sulfonamides to bromoacetylenes and subsequent palladium-catalyzed cyclization

Bromine as a double agent: The bromine atom in 1-bromo-1-alkynes works as an electron-withdrawing group to effect the nucleophilic addition of sulfonamides. It again plays a pivotal role in the palladium-catalyzed cyclization of the resultant (Z)-2-(sulfonylamino)-1-bromoalkenes into nitrogen heterocycles (see scheme).