Finkelstein Reaction Research Articles

Enhanced Delivery of the RAPTA-C Macromolecular Chemotherapeutic by Conjugation to Degradable Polymeric Micelles

Macromolecular ruthenium complexes are a promising avenue to better and more selective chemotherapeutics. We have previously shown that RAPTA-C [RuCl2(p-cymene)(PTA)], with the water-soluble 1,3,5-phosphaadamantane (PTA) ligand, could be attached to a polymer moiety via nucleophilic substitution of an available iodide with an amide in the PTA ligand. To increase the cell uptake of this macromolecule, we designed an amphiphilic block copolymer capable of self-assembling into polymeric micelles. The block copolymer was prepared by ring-opening polymerization of d,l-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) using a RAFT agent with an additional hydroxyl functionality, followed by the RAFT copolymerization of 2-hydroxyethyl acrylate (HEA) and 2-chloroethyl methacrylate (CEMA). The Finkelstein reaction and reaction with PTA led to polymers that can readily react with the dimer of RuCl2(p-cymene) to create a macromolecular RAPTA-C drug. RAPTA-C conjugation, micellization, and subsequent cytotoxicity and cell uptake of these polymeric moieties was tested on ovarian cancer A2780, A2780cis, and Ovcar-3 cell lines. Confocal microscopy images confirmed cell uptake of the micelles into the lysosome of the cells, indicative of an endocytic pathway. On average, a 10-fold increase in toxicity was found for the macromolecular drugs when compared to the RAPTA-C molecule. Furthermore, the cell uptake of ruthenium was analyzed and a significant increase was found for the micelles compared to RAPTA-C. Notably, micelles prepared from the polymer containing fewer HEA units had the highest cytotoxicity, the best cell uptake of ruthenium and were highly effective in suppressing the colony-forming ability of cells.

Synthesis of BODIPY Derivatives Substituted with Various Bioconjugatable Linker Groups: A Construction Kit for Fluorescent Labeling of Receptor Ligands

The goal of the present study was to design small, functionalized green-emitting BODIPY dyes, which can readily be coupled to target molecules such as receptor ligands, or even be integrated into their pharmacophores. A simple two-step one-pot procedure starting from 2,4-dimethylpyrrole and ω-bromoalkylcarboxylic acid chlorides was used to obtain new ω-bromoalkyl-substituted BODIPY fluorophores (1a-1f) connected via alkyl spacers of different length to the 8-position of the fluorescent dye. The addition of radical inhibitors reduced the amount of side products. The ω-bromoalkyl-substituted BODIPYs were further converted to introduce various functional groups: iodo-substituted dyes were obtained by Finkelstein reaction in excellent yields; microwave-assisted reaction with methanolic ammonia led to fast and clean conversion to the amino-substituted dyes; a hydroxyl-substituted derivative was prepared by reaction with sodium ethylate, and thiol-substituted BODIPYs were obtained by reaction of 1a-1f with potassium thioacetate followed by alkaline cleavage of the thioesters. Water-soluble derivatives were prepared by introducing sulfonate groups into the 2- and 6-position of the BODIPY core. The synthesized BODIPY derivatives showed high fluorescent yields and appeared to be stable under basic, reducing and oxidative conditions. As a proof of concept, 2-thioadenosine was alkylated with bromoethyl-BODIPY 1b. The resulting fluorescent 2-substituted adenosine derivative 15 displayed selectivity for the A3 adenosine receptor (ARs) over the other AR subtypes, showed agonistic activity, and may thus become a useful tool for studying A3ARs, or a lead structure for further optimization. The new functionalized dyes may be widely used for fluorescent labeling allowing the investigation of biological targets and processes.

ChemInform Abstract: Stereoselective Synthesis of anti‐1,3‐Aminoalcohols via Reductive Opening of 4‐Amidotetrahydropyrans Derived from the Prins/Ritter Sequence.

Abstract4‐Amidotetrahydropyrans (IV), prepared by a Prins/Ritter reaction sequence, are readily converted into desired N‐acyl‐aminoalcohols (VI) by a Finkelstein reaction of tosylates (IV) followed by reductive opening of the tetrahydropyran ring of resulting iodides (V).

Ionic liquid mediated synthesis, reactions, and insecticidal activity of 1-[(1H-benzoimidazol-2-yl)amino]spiro[azetidine-4,4'-[4'H]chroman]-2-ones

Ionic liquid mediated synthesis of novel heterocyclic compounds 1-[(1H-benzoimidazol-2-yl)amino]-2'-phenylspiro[azetidine- 4,4'-[4'H]chroman]-2-ones (3) and 1-[(1H-benzoimidazol-2-yl)amino]- 3-chloro-2'-phenylspiro[aze tidine-4,4'-[4'H] chroman]-2-ones (4) was accomplished by condensing substituted 2-hydrazino benzimidazole (1), flavanone (2), and acetyl chloride/chloroacetyl chloride in ionic liquid, [bmim]PF_6 with or without using catalyst in excellent yield (90%--95%). Further, compounds 3 and 4 were acylated with trifluoroacetic anhydride to give N-acylated products (5 and 10); 3 when treated with HCHO and (C_2H_5)_2NH gave Mannich bases (6) and with aldehydes afforded 3-arylidene-2-azetidinone (7). Compounds 4 underwent nucleophilic substitution with (i) KI (Finkelstein reaction) and (ii) phenols to give the corresponding iodo and phenoxy derivatives (8 and 9). The synthesized compounds were characterized by analytical and spectral (IR, ^1 H NMR, ^{13}C NMR, and HRMS) data and evaluated for insecticidal activity against Periplaneta americana using cypermethrin as standard and found to exhibit excellent results.

Macromolecular ruthenium complexes as anti-cancer agents

Ruthenium complexes have shown promise as anti-cancer therapeutics. Among them, RAPTA-C [RuCl2(p-cymene)(PTA)] with the water-soluble 1,3,5-triaza-7-phosphaadamantane (PTA) ligand holds great promise as an alternative to platinum drugs. This paper explores synthetic pathways by which RAPTA-C can be attached to polymer moieties to create a water-soluble macromolecular drug that can potentially display an enhanced permeation and retention (EPR) effect. A reactive scaffold for RAPTA-C conjugation, poly(2-chloroethyl methacrylate) [PCEMA], was prepared via RAFT polymerisation. To increase the reactivity of the substrate, poly(2-iodoethyl methacrylate) [PIEMA] was prepared from PCEMA via the Finkelstein reaction. Two pathways were employed to conjugate RAPTA-C to the polymer, either by attachment of PTA first followed by reaction with the RuCl2(p-cymene) dimer, or by the direct conjugation of RAPTA-C to the polymer. Prior to the study with the polymer, both routes were tested using n-butyl iodide as a model compound. Several NMR experiments, namely 31P, 1H, [1H–31P] HMBC, [1H–13C] HMBC and [1H–15N] HMBC confirmed that both routes lead to the complete reaction of n-butyl iodide and that only the desired product was obtained. However, the direct reaction of RAPTA-C with the polymer required elevated temperature, which led to the loss of the p-cymene ligand. The two-step process at ambient temperature led to the successful formation of the product, albeit the amount of iodide reacted was now only 50% due to steric hindrance. Subsequently, a copolymer based on 2-hydroxypropyl methacrylamide [HPMA] and IEMA was synthesised. The two-step reaction with PTA and RuCl2(p-cymene) dimer led to a water-soluble polymer with an intense orange colour, indicative of the pendant RAPTA-C complex. The monomodal molecular weight distribution monitored using UV-VIS detection of the macromolecular ruthenium complex confirmed drug attachment and indicates the absence of crosslinking events during drug conjugation. A cytotoxicity profile for the copolymer–RAPTA-C product was measured on the ovarian cancer cell line OVCAR-3 and compared with the profile of the lone RAPTA-C drug.

Nickel-catalysed aromatic Finkelstein reaction of aryl and heteroaryl bromides

A fast and efficient nickel-catalysed iodination reaction of aryl and heteroaryl bromides has been developed. The transformation was found to be general for a wide range of substrates and was used for the synthesis of iodo-PK11195, an imaging agent of Alzheimer's disease and iniparib, a compound used in the treatment of breast cancer.

Synthesis and hydrolysis studies of novel glyco-functionalized platinum complexes

Cisplatin and some of its derivatives are among the most active cytostatics for cancer treatment. Unfortunately, application of platinum complexes always indicates side effects, and frequently primary or developed resistance of tumour cells appear. Therefore, development of novel analogues especially with natural ligands is expedited. Glyco-functionalized ligands were obtained via ether synthesis with ω-halo ethers, Finkelstein reaction, with further treatment with malonate and final deprotection followed by preparation of the disodium salts. Subsequent complexation led to novel platinum derivatives, the stabilities of which in aqueous solution media were studied.

Application of Ullmann and Ullmann–Finkelstein reactions for the synthesis of N-aryl-N-(1 H-pyrazol-3-yl) acetamide or N-(1-aryl-1 H-pyrazol-3-yl) acetamide derivatives and pharmacological evaluation

Ullmann-type reactions are becoming a major tool in medicinal chemistry. In this article, we describe the use of these Copper-catalyzed reactions with various precursors, acyl-heteroarylamines or pyrazoles of interest for pharmacomodulation. To the medicinal chemist they offer new, usually untapped disconnection approaches to compounds of interest. They thus open the way to new original analogues of bioactive compounds possibly not patented, from common building-blocks. They also allow C to N bioisosteric replacements, which sometimes are synthetically challenging. We report for the first time the critical effect of acetylamino substituents on the regioselective arylation of unsymmetrical pyrazoles that are useful for medicinal chemists. Finally, we have applied this strategy to the design of novel AT 1 receptor antagonists. Though this family has been extensively investigated in the past 30 years, N-arylation and C to N replacement made possible by Ullmann chemistry, can produce original antagonists.

Sodium Iodide

Sodium iodide (NaI) occurs as colorless, odorless or as a white crystalline solid; it is slightly hygroscopic, and a commercially available reagent. It is soluble in water, ­alcohols, acetone, and other organic solvents and stable under normal temperature and pressure (mp: 651 ˚C, d = 3.67 g/cm³). [¹] On a laboratory scale, sodium iodide may be prepared by neutralizing a solution of sodium hydroxide or sodium carbonate with hydriodic acid. [²] Sodium iodide is a very useful and versatile reagent for the synthesis of various types of organic compounds. For example, an important application of this reagent involves the conversion of an alkyl chloride or alkyl bromide to an alkyl iodide by the addition of sodium iodide in acetone (Scheme [¹] ). [³] This nucleophilic substitution reaction, also known as Finkelstein reaction, may proceed via either an SN1 or SN2 mechanism depending on the nature of the alkyl halide. [4] [5]

ChemInform Abstract: Efficient Preparation of E-β-Iodovinyl Phenylsulfone by Finkelstein Reaction at a Vinylic Center.

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Solute Descriptors for Phenoxide Anions and Their Use To Establish Correlations of Rates of Reaction of Anions with Iodomethane

Partition coefficients from water to organic solvents for phenoxide anions have been obtained using a method based on the variation of pK(a) of phenols with solvent. From these partition coefficients, the Abraham descriptors for phenoxide anions, on the same scale as descriptors for neutral molecules, have been obtained. Equations have been constructed for the prediction of descriptors, and values of the Abraham descriptors E, S, A (equal to zero for the phenoxide anions we have studied), B, V, and J(-) have been determined or estimated for some 60 substituted phenoxide anions. These anions are characterized by very large values of the dipolarity/polarizability descriptor S and the hydrogen bond basicity descriptor B. In order to show the utility of the obtained phenoxide descriptors, we demonstrate that they can be combined with descriptors for carboxylate anions and permanent anions to yield equations for the Finkelstein reaction of anions with iodomethane in methanol, N,N-dimethylformamide, and water.

Chemical Modification of the Insecticidal Briantheins X and Y

Manipulation of the allylic chloride functionality in briantheins X and Y provided 10 new analogues of these gorgonian diterpenes as part of a continuing study of structure-activity relationships in this family of insecticidal compounds. Modified Finkelstein reaction conditions led not only to halogen substitution products but also to rearrangement, dehydrohalogenation, and dehydration products. None of the new compounds showed superior insecticidal activity to brianthein X or Y, although most did result in lower weight gains versus controls.

Synthesis of Novel gluco‐ and galacto‐Functionalized Platinum Complexes

AbstractCisplatin, carboplatin, oxaliplatin and further derivatives are worldwide established cytostatics for the treatment of a vast range of tumours. These drugs showed extraordinary success; however, side effects and primary or developed secondary resistance of tumour cells represent severe problems, which prompt the development of novel functionalized platinum complexes. Selectively protected monohydroxy derivatives of glucose and galactose could be etherified by ω‐halo ethers. Further, Finkelstein reaction and malonate synthesis gave precursor glycoconjugates which were easily transformed into their (diammine)platinum complexes. First tests with different tumour cell lines show biological activity of the gluco‐functionalized platinum complex.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Facile synthesis of 4,5-disubstituted-3(2 H)-pyridazinones

4,5-Disubstituted-3(2 H)-pyridazinones were initially synthesized via sodium alkoxide additions to an advanced bromide intermediate. A small parallel chemistry effort resulted in a poor success rate, and we thus increased the reactivity of the reaction partner by performing a copper-catalyzed Finkelstein reaction. Copper-catalyzed coupling of a diverse set of alcohols with the resulting iodide resulted in a more successful effort. A number of alternative syntheses of this series of compounds are also described and these methods proved to be versatile, efficient, and amenable to parallel synthesis.

N-alkylation of amidothiophosphoryl compounds under phase-transfer catalysis conditions. Synthesis and properties of 1,3,2-thiazaphosphacyclanes

N (ω-Haloalkyl)amidothiophosphates, N (ω-Haloalkyl)amidothiophosphonates, and N- (ω-Haloalkyl)amidothiophosphinates (Hal = Cl or Br) were obtained in high yields by alkylation of phosphorus(V) acid thioamides with 6h,ω-dihaloalkanes under phase-transfer catalysis (PTC) conditions or through the use of NaH as a base. Thermal rearrangement of N (3-iodopropyl)-or N (4-iodobutyl)amidothiophosphate and N (3-iodopropyl)-or N (4-iodo-butyl)amidothiophosphonate obtained in situ by the Finkelstein reaction provides a convenient route to 2-oxo-1,3,2-thiazaphosphinanes and 2-oxo-1,3,2-thiazaphosphepanes. Reactions of N (ω-Haloalkyl)amidothiophosphinates with NaClO4 in MeCN afforded the first example of stable 1,3,2-thiazaphosphacyclanium salts containing P—C bonds.

Early Ontogeny, Growth and Mortality of Common Carp (Cyprinus carpio) at Low Concentrations of Dimethyl Sulfoxide

Dimethyl sulphoxide (DMSO) is an important polar aprotic solvent, less toxic than other members of this class. Because of its excellent solvating power, DMSO is frequently used as solvent for chemical reactions involving salts, especially Finkelstein reactions and other nucleophilic substitutions. Furthermore, DMSO is used as auxiliary substance in toxicity tests on aquatic organisms, usually at concentrations of 0.2 and 0.5 ml l-1. The aim of the present study was to evaluate the effect of DMSO on early development, growth and mortality of early life stages in common carp. Tests were performed from fertilized egg to the end of the larval period with continuous exposure to DMSO at concentrations of 0.2, 0.5, 1.0 and 5.0 ml l-1. Mortality of embryos and larvae, intensity of development and growth, weight and occurrence of abnormalities were analyzed. DMSO exposure at all the tested concentrations did not result in any lethal effects or abnormalities compared to the control over the entire test period (29 days). Growth indicators were similar in DMSO treated (at concentrations of 0.2, 0.5 and 1.0 ml l-1) and control groups. However, mean body weight (35 ± 9 mg) of larvae exposed to the highest DMSO concentration (5 ml l-1) tested was significantly lower compared to the control (45 ± 14 mg).

A simple and efficient synthesis of 3-substituted derivatives of pentane-2,4-dione

AbstractA novel and efficient method of synthesis of 3-substituted derivatives of pentane-2,4-dione is proposed, wherein cheaper and easily accessible chloro derivatives are conversed into more reactive iodo derivatives. The method is based on the Finkelstein reaction for which the literature suggests highly polar organic solvents as ideal reaction media. In the presented work, the use of industrially used ketones, especially methyl isobutyl ketone, is proposed. The use of MIBK as a solvent additionally allows an azeotropic removal of water from the reaction mixture, enabling the application of moisture sensitive alkylating agents i.e. (3-chloropropyl)trimethoxysilane. The obtained products are isolated through distillation, which does however not allow the separation of C-alkylation products from O-alkylation ones. The products not containing water-sensitive substituents were isolated as copper complexes. The pure product of C-alkylation was obtained by decomposition of the copper complex with a hydrochloric acid solution and extraction of the formed ligand to an organic phase i.e. hexane. The obtained ligand can be further purified by distillation.

A novel approach for the synthesis of the peripheral benzodiazepine receptor ligand, PK11195

A new synthesis of the peripheral benzodiazepine receptor ligand, PK11195 has been developed in only six-steps using a Heck-type reaction and a Suzuki coupling to effect the key transformations. The flexibility of this new approach is demonstrated by the synthesis of an iodo-analogue of PK11195 prepared from the corresponding bromide using a copper catalysed aromatic Finkelstein reaction.

The Finkelstein Reaction: Quantitative Reaction Kinetics of an SN2 Reaction Using Nonaqueous Conductivity

Two essential concepts for students to grasp in the undergraduate organic chemistry sequence are substitution chemistry and elimination chemistry (SN1/SN2 and E1/E2). However, students are often confounded by the seemingly endless series of structure–reactivity relationships. This dualistic relationship of conceptual essentialness and student confusion usually results in a line of demarcation for many second-year organic chemistry students. It is at this point that students either pull together the fundamental structure–reactivity relationships and go on to draw relevant mechanistic conclusions that underpin the balance of their organic chemistry experience or the flood of material washes over them and they wind up in a miserable struggle to keep their heads above water until the end of the spring semester. Therefore, we have developed a quantitative kinetics laboratory exercise featuring the Finkelstein reaction (SN2) for use in the first-semester organic chemistry course that utilizes nonaqueous conductivity as the method by which relevant structure–temperature–solvent effects are examined.

SNAr iodination of 6-chloropurine nucleosides: aromatic Finkelstein reactions at temperatures below -40 degrees C.

Mesitoyl or toluoyl esters of inosine and 2'-deoxyinosine were deoxychlorinated at C6 to give the crystalline 6-chloropurine nucleoside derivatives, which underwent quantitative conversion to the 6-iodo analogues with NaI/TFA/butanone at -50 to -40 degrees C. The 6-iodo compounds were efficient substrates for SNAr, Sonogashira, and Suzuki-Miyaura reactions, in contrast with the 6-chloro analogues, and gave good to high yields of C-N and C-C coupled products.