Benzyl Iodide Research Articles

Electrochemical Functionalization of Methylarenes Initiated By Hydrogen Atom Transfer and Comparison to Electron-Transfer-Initiated Functionalization

Aerobic oxidations catalyzed by N-hydroxyphthalimide (NHPI) are commonly utilized for the oxygenation of activated C–H bonds (allylic, benzylic, adjacent to heteroatoms).[i] NHPI undergoes proton-coupled oxidation to afford phthalimido-N-oxyl (PINO), which then mediates HAT from weak C–H bonds. In 1983, prior to the development of aerobic methods to generate PINO, Masui and co-workers demonstrated the ability to access PINO from NHPI under electrochemical conditions [ii] and site-selective oxygenation of the electrochemically generated radical using O2 as radical trap.[iii] Electrochemical PINO generation was utilized recently for scalable oxidation of terpenes[iv] and benzylic oxygenation of heterocyclic compounds.[v] In the latter reactions, metal-free electrochemical oxygenation overcomes the challenges encountered with chelating substrates that inhibit Co/NHPI-catalyzed aerobic oxidation reactions. Electrochemical oxidation of NHPI to PINO additionally presents the opportunity to trap organic radicals with reagents other than O-atom sources. This presentation will describe the first example of this concept, showing that iodine (I2) is an effective radical trap for electrochemical NHPI-mediated oxidation of methyl­arenes to benzyl iodides. The method provides the basis for direct (in situ) or sequential benzylation of diverse nucleophiles using methylarenes as the alkylating agent. Voltammetric studies demonstrate that this mediated HAT mechanism for C–H iodination allows C–H oxidation to proceed with minimal dependence on the substrate electronic properties, contrasting benzylic C–H functionalization methods that proceed via direct electron transfer. The operating potential of the NPHI-mediated process is 0.5 – 1.2 V lower than that of direct electrochemical C–H oxidation. [i]. Recupero, F.; Punta, C. Chem. Rev. 2007, 107, 3800. [ii]. Masui, M; Hara, S.; Ueshima, T.; Kawaguchi, T.; Ozaki, S. Chem. Pharm. Bull. 1983, 31, 4209. [iii]. Masui, M.; Hosomi, K.; Tsuchida, K.; Ozaki, S. Chem. Pharm. Bull. 1985, 33, 4798. [iv]. Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.; Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77. [v]. Hruszkewycz, D. P.; Miles, K. C.; Thiel, O. R.; Stahl, S. S. Chem. Sci. 2017, 8, 1282. Figure 1

Stereocontrolled [11C]Alkylation of N‐Terminal Glycine Schiff Bases To Obtain Dipeptides

The use of various quaternary ammonium salts as chiral phase‐transfer catalysts allowed effective and stereoselective radiochemical [11C]alkylation to obtain functionalized dipeptides. We herein report a broadly applicable procedure for the asymmetric [11C]alkylation of dipeptides to give labeled N‐terminal peptides by using different [11C]alkyl halides. Contended stereoselectivities of the reactions were observed by using 11C‐labeled alkyl halides, [11C]methyl iodide and [11C]benzyl iodide, and diastereomeric ratios with different specialized catalysts of 95:5 and 90:10 were achieved, respectively. Accordingly, the straightforward synthesis of enantioenriched compounds should play a vital role in peptide‐based radiopharmaceutical development and positron emission tomography imaging.

Palladium-catalyzed Heck reaction of in-situ generated benzylic iodides and styrenes

A palladium-catalyzed Heck reaction of in-situ generated benzylic iodides and styrenes has been achieved. The reaction proceeds in a one-pot manner through 1) addition perfluoroalkyl iodides to styrenes to give benzylic iodides, 2) followed by a palladium-catalyzed Heck coupling of the resulting benzylic iodides with the same alkenes in high regio- and stereoselectivity. A variety of perfluoroalkylated alkenes were obtained in moderate to excellent yields.

A rapid and highly enantioselective C-11C bond formation of l-[11C]phenylalanine via chiral phase-transfer catalysis.

A rapid method for the synthesis of carbon-11 radiolabeled phenylalanine was developed using a chiral phase-transfer catalyst and a sub-nanomolar quantity of [11C]benzyl iodide as a radio-precursor. Based on a reported synthesis of [11C]benzyl iodide, a Schiff base precursor was evaluated for stereoselective [11C]benzylation. Extensive and interactive screening of the precursor, catalyst, base, stirring and temperature was required to achieve high stereoinduction. The result is an efficient 5-step radiolabeling method to reliably synthesize l- or d-[11C]phenylalanine with an excellent enantiomeric excess of >90% and almost quantitative radiochemical conversion of >95% (n > 5). Additionally, a phase-transfer catalyzed alkylation was utilized on the preparative scale using automated platform. The application resulted in high specific activity ranging from 85-135 GBq μmol-1 of the enantiomerically pure [11C]phenylalanine, showing that the process is robust and amenable to broad use in PET.

Calcium Complexes Having Different Amidinate Ligands ‐ Synthesis and Structural Diversity

AbstractA one‐pot reaction of α‐diimine ligand 1,4‐disubstituted diazabutadienes (DAD) with potassium benzyl and anhydrous calcium iodide in 1:1:1 molar ratio afforded unprecedented 3‐phenylprop‐2‐ene‐di‐amido calcium compound [κ2‐(THF)4Ca{DippNC(=CHPh)CH2NDipp}] (1) (Dipp = 2,6‐diisopropylphenyl) in good yield. The solid‐state structure of the compound 1 revealed the formation of dianionic 3‐phenylprop‐2‐ene‐di‐amido ligand having an exocyclic olefinic bond derived from neutral α‐diimine fragment. However, analogous reactions with three different carbodiimides (RN=C=NR; R=Cy, iPr and tBu) with alkyl potassium and anhydrous calcium diiodide yielded corresponding homoleptic calcium compounds with amidinato ligand [κ2‐(THF)2Ca{RN=C(CH2Ph)NR}2] [R=Cy (2), iPr (3) and tBu (4)]. A separate reaction of DAD ligand, LiCH2SiMe3 and anhydrous ZnCl2 in diethylether solvent produced tri‐coordinated zinc compound [κ2‐ {DippN=C(CH2SiMe3)CH2NDipp}Zn[κ1‐{DippN=C(CH2SiMe3)CH2N‐Dipp}] (5) having amidinato moieties in the zinc coordination sphere in high yield. Molecular structures of compounds 2–5 in their solid states were also established.

ChemInform Abstract: Stereoselective Alkylation of the Vinylketene Silyl N,O‐Acetal and Its Application to the Synthesis of Mycocerosic Acid.

AbstractApplication of various allylic, propargylic and benzylic iodides allows for the diastereoselective preparation of various polyketides.

Stereoselective Alkylation of the Vinylketene Silyl N,O-Acetal and Its Application to the Synthesis of Mycocerosic Acid.

Stereoselective alkylation of the vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved by using activated alkyl halides including allyl iodides, benzyl iodides, and propargyl iodide with Ag(I) ion in the presence of BF3·OEt2. The reaction proceeded to give reduced polyketides in high stereoselectivity. The synthesis of mycocerosic acid, a component of the cell envelope of Mycobacterium tuberculosis, has been accomplished by this methodology. During the synthetic studies, 2-methylbenzimidazole was found to be a bulky proton source which worked in the presence of liquid ammonia.

Zinc-Mediated Allylation and Benzylation of Phenylazocarboxylic Esters.

Allylation and benzylation of phenylazocarboxylic tert-butyl esters have been achieved under Barbier-type reaction conditions and in very short reactions times using the corresponding allyl and benzyl bromides or iodides in combination with zinc powder. Whereas all reactions occurred exclusively at the β-nitrogen atom of the azocarboxylic esters, the linkage of allyl units was shown to depend on the substitution pattern at the double bond of the allyl halide. The hydrazines obtained are useful precursors for indoles and indazoles.

Improved synthesis and application of [(11) C]benzyl iodide in positron emission tomography radiotracer production.

Positron emission tomography has increased the demand for new carbon-11 radiolabeled tracers and building blocks. A promising radiolabeling synthon is [(11) C]benzyl iodide ([(11) C]BnI), because the benzyl group is a widely present functionality in biologically active compounds. Unfortunately, synthesis of [(11) C]BnI has received little attention, resulting in limited application. Therefore, we investigated the synthesis in order to significantly improve, automate, and apply it for labeling of the dopamine D2 antagonist [(11) C]clebopride as a proof of concept. [(11) C]BnI was synthesized from [(11) C]CO2 via a Grignard reaction and purified prior the reaction with desbenzyl clebopride. According to a one-pot procedure, [(11) C]BnI was synthesized in 11 min from [(11) C]CO2 with high yield, purity, and specific activity, 52 ± 3% (end of the cyclotron bombardment), 95 ± 3%, and 123 ± 17 GBq/µmol (end of the synthesis), respectively. Changes in the [(11) C]BnI synthesis are reduced amounts of reagents, a lower temperature in the Grignard reaction, and the introduction of a solid-phase intermediate purification. [(11) C]Clebopride was synthesized within 28 min from [(11) C]CO2 in an isolated decay-corrected yield of 11 ± 3% (end of the cyclotron bombardment) with a purity of >98% and specific activity (SA) of 54 ± 4 GBq/µmol (n = 3) at the end of the synthesis. Conversion of [(11) C]BnI to product was 82 ± 11%. The reliable synthesis of [(11) C]BnI allows the broad application of this synthon in positron emission tomography radiopharmaceutical development.

ChemInform Abstract: Threefold and Chemoselective Couplings of Triarylbismuths with Benzylic Chlorides and Iodides Using Palladium Catalysis.

This paper describes the palladium-catalyzed studies on threefold coupling of triarylbismuth reagents with benzylic chlorides and iodides. The optimized protocol conditions are operationally simple, delivering threefold coupling of a variety of triarylbismuths in combination with benzylic chlorides and iodides. The two optimized protocols allowed the synthesis of a diverse range of unsymmetrical diarylmethanes in an efficient manner. As part of this study, chemoselective transformation of benzylic chlorides and iodides was also achieved.

SINTESIS SENYAWA ANTIMALARIA BARU TURUNAN FENANTROLIN N-(2-NITROBENZIL)-1,10-FENANTROLINIUM IODIDA DAN (1) N-(4-NITROBENZIL)-1,10-FENANTROLINIUM IODIDA

Malaria is a global health problem, especially in the tropics. Efforts to decrease the incidence of malaria plagued the plasmodium resistance to existing antimalarial drugs. Benzyl Phenanthrolium Iodide derivates have been proved has antimalarial activity. The aim of this study is synthesis the nitro benzyl phenanthrolium.The research that has been done was the synthesis of (1)-N-(2-nitrobenzyl) phenantrolium iodide and(1)-N-(4-nitrobenzyl)-1,10-phenantrolium iodide. Synthesis of (1)-N-(2-nitrobenzyl)-1,10-phenantrolium iodide through a two-steps reaction SN-2 is the reaction of (1)N-(2- nitrobenzyl) chloride and potassium iodide followed by reaction phenantroline 1:10 monohydrate, whether the second product was 4-nitrobenzil bromida as starting material. The reaction were started by reflucting the nitro subtituted benzil halida with potassium iodide for 1 hour, yielded nitro subtituted benzyl iodide. Then followed by reflucting nitro substituted benzyl iodide with 1,10-phenanthroline for 11 hours. The final product isolated and purificated by suitable solvent. The melting point was conducted by melting poin apparatus. The structures of product was characterized by IR and UV-Vis spectroscopy.Results obtained in the form of thick liquid light yellow with a melting point of 54.2-63.5oC. While the compound (1)-N-(4-nitrobenzyl)-1,10-phenantrolium iodide is synthesized from 4-nitrobenzylbromide and potassium iodide followed by reaction phenantroline 1:10 monohydrate. Synthesis results in the form of pale yellow crystals with a melting point of 221–225oC . The resulting yield of 32.87%. The interpretation of UV-Vis and Infra red spectras indicated that nitro benzyl iodide have been condensed with 1,10 phenantroline as the end of the product.

A Direct Transformation of Aryl Aldehydes to Benzyl Iodides Via Reductive Iodination

A facile transformation of aryl aldehydes to benzyl iodides through one-pot reductive iodination is reported. This protocol displays remarkable functional group tolerance and the title compound was obtained in good to excellent yield.

Threefold and chemoselective couplings of triarylbismuths with benzylic chlorides and iodides using palladium catalysis

This paper describes the palladium-catalyzed studies on threefold coupling of triarylbismuth reagents with benzylic chlorides and iodides. The optimized protocol conditions are operationally simple, delivering threefold coupling of a variety of triarylbismuths in combination with benzylic chlorides and iodides. The two optimized protocols allowed the synthesis of a diverse range of unsymmetrical diarylmethanes in an efficient manner. As part of this study, chemoselective transformation of benzylic chlorides and iodides was also achieved.

Synthesis of I-131 labelled iodine species relevant during severe nuclear accidents in light water reactors

Summary Methods for the small scale synthesis of I-131 labelled iodine species relevant to severe nuclear accidents in light water reactors have been developed. The introduced methods allow the synthesis of impurity free, volatile, inorganic elemental iodine and volatile, organic iodides such as methyl- and ethyl iodide, as well as butyl iodide, chloroiodomethane, allyl iodide and benzyl iodide with ease. The radioactive iodine containing products are sufficiently stable to allow their storage for later use. Due to their volatility the liquid species can be easily converted into gaseous species and thus can be used in research in liquid and gaseous phase. The primary motivation for the development of these synthesis methods is to study the behaviour of volatile iodine species under the conditions of a severe nuclear accident in a light water reactor. Thus, the chemicals involved in the synthesis are chosen in a way to not generate impurities (chlorine and organic solvents) in the products which interfere with competing reactions relevant during a severe nuclear accident. Teknopox Aqua VA epoxy paint, which is used in Swedish light water reactor containments, and its reactions with the produced iodine species are described. The synthesised iodine species undergo chemisorption on paint films. Different to elemental iodine, the organic iodides are non-reactive with copper surfaces. The sorbed iodine species are partly re-released mainly in form of organic iodides and not as elemental iodine when the exposed paint films are heat treated. The partitioning and hydrolysis behaviour of gaseous methyl- and ethyl iodide between containment gas phase and water pools is found to be similar. The methods have been designed to minimise the use of harmful materials and the production of radioactive waste.

Total Synthesis of Linoxepin

Significance: Lautens and co-workers report the synthesis of linoxepin, a lignin isolated from Linum perennne L. (Linaceae). The elegant strategy relies on the Catellani reaction, in which a strained olefin (norbornene) is used to couple an iodoarene, an alkyl halide, and a terminal olefin using palladium catalysis. This is the first application of the Catellani reaction in the synthesis of a natural product and underscores the power of processes that form multiple bonds in a single step. In this context, it is worth highlighting the recent synthesis of linoxepin by Tietze and co-workers (Angew. Chem. Int. Ed. 2013, 52, 3191), which relies on a different palladium-catalyzed domino reaction. Comment: Alkylation of phenol A with benzyl iodide B gave Catellani precursor C in 94% yield. The norbornene-mediated domino process involving aryl iodide C, enantiopure alkyl iodide D and acrylate E delivered key intermediate F in 89% yield. Oxidative cleavage of the olefin followed by TiCl4-promoted aldol condensation furnished G, which in the presence of catalytic amounts of a palladium catalyst underwent a Mizoroki–Heck reaction to give (+)-linoxepin in 76% yield. O O

Copper(I) iodide catalyzes odorless thioarylation of phenolic esters with alkyl derivatives using thiourea in wet polyethylene glycol (PEG 200)

In this study, we have presented a useful catalytic application of copper(I) iodide for one pot odor-free generation of unsymmetrical aryl alkyl thioethers. The process proceeds by the reaction of phenolic esters such as acetates, triflates, tosylates and phosphonates with benzyl, n-octyl, cyclohexyl, cyclopentyl, n-hexyl and n-butyl iodides, bromides, chlorides and tosylates in wet polyethylene glycol (PEG 200) by using thiourea as the sulfur source under homogeneous conditions. The method is applicable for the gram-scale preparation of the desired alkyl aryl thioethers.

ChemInform Abstract: Palladium‐Free Aminocarbonylation of Aryl, Benzyl, and Styryl Iodides and Bromides by Amines Using Mo(CO)6 and Norbornadiene.

Abstract A simple and efficient method is described for aminocarbonylation of aryl, benzyl, and styryl iodides and bromides using the in situ generated molybdenum tetracarbonyl norbornadiene [Mo(CO)4(nbd)] complex as a suitable source of carbon monoxide.

Palladium-free aminocarbonylation of aryl, benzyl, and styryl iodides and bromides by amines using Mo(CO)6 and norbornadiene

A simple and efficient method is described for aminocarbonylation of aryl, benzyl, and styryl iodides and bromides using the in situ generated molybdenum tetracarbonyl norbornadiene [Mo(CO)4(nbd)] complex as a suitable source of carbon monoxide.

SYNTHESIS AND ANTIPLASMODIAL ACTIVITY TESTING OF (1)-N-ALKYL- AND (1)-N-BENZYL-6-NITRO-1,10-PHENANTHROLINIUM SALTS AS NEW POTENTIAL ANTIMALARIAL AGENTS

The synthesis of 5-nitro-1,10-phenanthroline hydrate 2 derivatives from 1,10-phenanthroline monohydrate as starting material has been carried out. The 5-nitro-1,10-phenanthroline hydrate 2 was obtained through nitration reaction using H2SO4 and HNO3 as catalyst and reagent, respectively. Synthesis of (1)-N-alkyl-6-nitro- and (1)-N-benzyl-6-nitro-1,10-phenanthrolinium have been prepared using dimethyl sulphate (DMS), diethyl sulphate (DES), benzyl chloride, benzyl bromine, and benzyl iodide. The reagents of benzyl bromine, and benzyl iodide were synthesized from benzyl chloride using NaBr in ethanol absolute and NaI in acetone, respectively. The five compounds of 5-nitro-1,10-phenanthroline hydrate 2 derivatives were conducted to evaluate the in vitro antiplasmodial activity. The in vitro antiplasmodial was evaluated on strains of Plasmodium falciparum FCR-3 resistant chloroquine and D10 sensitive chloroquine. The 50% inhibition concentration (IC50) of the five compounds ranged from 2.41±1.41 to 0.07±0.01 μM. The results showed that the (1)-N-benzyl-6-nitro-1,10-phenanthrolinium iodide had highest antiplasmodial activity.

Synthesis of new 2-sulfanyl- and 2-aminopyrimidines

Alkylation of 4,5,6-substituted 2-sulfanylpyrimidines with alkyl and benzyl iodides and chlorides gave the corresponding 2-alkylsulfanyl and 2-benzylsulfanyl derivatives. 2-Methylsulfanylpyrimidines reacted with morpholine, benzylamine, and 4-methoxyaniline in butanol to produce 2-amino derivatives.