Alkyl Iodides Research Articles

Regioselective Hydroalkylation of Vinyl- and Allylsilanes as Well as Vinylgermanes under Ni-H Catalysis.

A Ni-H-catalyzed hydroalkylation of vinylsilanes and -germanes as well as allylsilanes with unactivated alkyl iodides is reported. Unlike related reactions of styrene or vinyl boronate esters, the addition across the C-C double bond proceeds with anti-Markovnikov selectivity to deliver the linear regioisomer. Mechanistic control experiments support a radical mechanism, and a competition experiment reveals that the chemoselectivity is in favor of the vinyl over the allyl group.

Aryl Radicals as XAT Promotors Enable Modular Alkyl Iodide Functionalization

Key words copper catalysis - piperidines - indazoles - azetidines - pyrrolidines - photoredox - halogen atom abstraction

Fluoroalkyl Iodides in Fluoroalkylative Difunctionalization of C−C Multiple Bonds

AbstractFluorinated alkyl iodides serve as a convenient and inexpensive source of fluoroalkyl radicals that can readily undergo addition to the C−C unsaturated bonds of alkynes and alkenes which is the foundation for a variety of useful synthetic protocols. Since 2010 this field has witnessed huge progress in several respects. First the portfolio of fluorinated alkyl iodides was extended beyond only simple perfluoroalkyl iodides (CnF2n+1I). In particular, employment of iododifluoro−methyl‐ carbonyls and phosphonates has enabled facile installation of the medicinally relevant difluoromethylene motif. Secondly, from a conceptual point of view, novel strategies for activation of fluoroalkyl iodides towards radical formation have been introduced, relying on the formation of electron donor‐acceptor (EDA) complexes, photoredox catalysis, frustrated Lewis pairs and transition metal catalysis, complementing prior approaches based on heat and UV induced C−I homolysis, radical initiators, and simple electron transfer processes. Based on these strategies a range of novel fluoroalkylative transformations of unsaturated systems have been added to classical iodoperfluoroalkylation. Broadly applicable protocols for simple fluoroalkylation and hydrofluoroalkylation, as well as for more sophisticated, complexity‐building methods of fluoroalkylation‐annulation and tandem multicomponent fluoroalkylations with concomitant installation of another functionality have been recently disclosed. This review summarizes the progress achieved since 2010 in the reactivity of fluoroalkyl iodides towards alkenes and alkynes with emphasis placed on the above‐mentioned advances.

Nickel-Catalyzed Highly Selective Reductive Carbonylation Using Oxalyl Chloride as the Carbonyl Source

Nickel-catalyzed carbonylative cross-electrophile coupling which emerges as a powerful, efficient, and low-cost method for constructing challenging carbonyl derivatives has attracted increasing attention of organic chemists. To avoid the generation of a poisonous, volatile, and inert nickel carbonyl complex, it is critical to develop an efficient, cheap, and easily available CO surrogate. Oxalyl chloride, a cheap commercially available chemical, is one of the most versatile organic reagents used in chemical reactions. In this work, high chemoselectivity can be achieved with a 1:1:1 ratio of Ar–I to alkyl-I to oxalyl chloride. A wide range of alkyl aryl ketones which present an important class of molecules in synthetic and medicinal chemistry are accessed from alkyl halides, aryl iodides, under mild conditions. Primary and secondary alkyl iodides were suitable substrates. Various functional groups were well tolerated, affording up to 90% yields. This protocol was also used in the derivatization of natural products and drug molecules. Mechanistic investigation indicates that the reaction of Zn and oxalyl chloride under mild reaction conditions could release CO slowly. This knowledge should be useful for the further development of multicomponent carbonylative cross-coupling reactions.

Facilely Control Grafting Density and Side Chain Composition of Bottlebrush Polymer.

Control over polymer architecture and composition is essential for disclosing structure-property relationships and developing high-performance materials. Herein, a new method is successfully developed to synthesize bottlebrush polymer (BP) with controllable graft density and side chain composition by "grafting-from" strategy using in situ halogen exchange and reversible chain transfer catalyzed polymerization (RTCP). The main chain of the BP is first synthesized by the polymerization of methacrylates containing alkyl bromide as a side group. Then, the alkyl bromine is quantitatively converted to alkyl iodide with sodium iodide (NaI) via in situ halogen exchange to efficiently initiate the RTCP of methacrylates. By adjusting the input amount of NaI and monomers in sequence, BP named PBPEMA-g-PMMA/PBzMA/PPEGMEMA which contains three different kinds of polymer side chains including hydrophilic PPEGMEMA, hydrophobic PMMA, and PBzMA is synthesized with narrow molecular weight distribution (Mw /Mn ≤1.36). The grafting density and the chain length of each polymer side chain are well controlled by the addition of NaI in batches and following RTCP. Moreover, the obtained BP self-assembled into spherical vesicles in aqueous with hydrophilic coronal structure, core region, and the hydrophobic wall between the former two, which enables to wrap hydrophobic pyrene and hydrophilic Rhodamine 6G separately or simultaneously.

BF2‐Chelates of N‐Acylhydrazones as Versatile Coupling Partners in Photoredox Promoted Reactions

AbstractFive‐membered difluoroboryl chelate complexes are competent substrates for radical reactions with various radical precursors including potassium trifluoroborates, bis(catecholato)siliconates, 4‐alkyl‐substituted Hantzsch esters, dihydroquinazolinones, esters of N‐hydroxyphthalimide, Katritzky salts, alkyl iodides and thiols. Using these reagents, primary, secondary, and tertiary radicals can be generated under oxidative or reductive conditions and add at the C=N bond of the difluoroboryl chelates leading to hydrazide products.

Cu-Catalyzed C(sp3) Amination of Unactivated Secondary Alkyl Iodides Promoted by Diaryliodonium Salts.

Herein, we describe the development of a copper-catalyzed C(sp3) amination of unactivated secondary alkyl iodides mediated by diaryliodonium salts. Our protocol is enabled by the intermediacy of aryl radical species that undergo halogen atom transfer prior to interfacing with copper catalysts, thus setting the basis for a C-N bond formation at sp3-hybridized carbons. The method is characterized by its mild reaction conditions, excellent regioselectivity, and wide substrate scope.

C-H bond functionalization of aryl acids and amines by 'on-water' reaction: Bi-dentate directing group enabled synthesis of biaryl and m-teraryl carboxamides.

Herein, we report a palladium-catalyzed 'on-water' methodology for the synthesis of biaryl and m-teraryl derivatives of aryl carboxamides by selective mono and bis C-H bond functionalization. 8-aminoquinoline and 2-thiomethylaniline were used as directing groups for C-H bond functionalization of aryl carboxamides with various aryl and alkyl iodides using 3.0-4.0 mol% of Pd(OAc)2as catalyst and water as the solvent resulting in 45-97% isolated yields of the mono and bis C-H bond functionalized products. Using an 8-aminoquinoline carboxamide core, C-H bond functionalization of indole-3-carboxylic acid and a late-stage functionalization of aspirin molecule have also been carried out. Reactions of benzyl/naphthyl picolinamides with aryl iodides gave 60-96% yield of the arylated products using the picolinamide directing group. Moreover, the insoluble nature of products in an aqueous medium enabled us to explore the reusability of the solvent, i.e., water and the catalyst. Control experiments and structural studies were carried out which confirmed thein situformation of unique palladacycles during the reaction. Removal of the directing groups has been carried out to convert the functionalized products into amines and fluorenone compounds useful in industrial and pharmaceutical applications.

Phosphine-catalyzed photo-induced alkoxycarbonylation of alkyl iodides with phenols and 1,4-dioxane through charge-transfer complex

The combining of charge-transfer complex and light irradiation offers a promising solution for the requests of sustainable chemistry. Herein, we developed a phosphine-catalyzed visible light-induced alkoxycarbonylation of alkyl iodides with phenols and ethers. Based on the electron donor-acceptor photoactivation strategy, the reaction can be realized at atmospheric pressure of CO under transition metal-free conditions. This promising approach demonstrates high functional group tolerance and excellent chemoselectivity. Additionally, five-component perfluoroalkylative carbonylation for the synthesis of β-perfluoroalkyl acyloxy esters from unactivated olefins and perfluoroalkyl iodides can be realized as well. Moreover, due to the excellent performance of the gram-scale reaction and 13CO results, it provides potential opportunities for large-scale production and other applications.

Flipping the Switch on Palladium-Catalyzed Carboiodination: Accessing Kinetic and Thermodynamic Products

A palladium-catalyzed epimerization reaction of stereogenic alkyl iodides is reported. This transformation involves use of an air-stable precatalyst that efficiently epimerizes the C–I bond from the exo to the endo face of [2.2.1] bicyclic compounds. Mechanistic experiments support the stereoinversion of the C–I bond via reversible bond formation to generate the antiproduct bearing an endo iodide. Density functional theory studies were conducted to support a thermodynamically driven epimerization. Stoichiometric experiments suggested that irradiation of isolable alkyl–Pd(II) complexes promoted the C–I reductive elimination, which could even be applied to C–Br bond formation.

Copper-Catalyzed Carbonylative Cross-Coupling of Alkyl Iodides with Alcohols and Sodium Hydroxide: Synthesis of Esters and Carboxylic Acids

AbstractA general and inexpensive catalytic system is reported for the copper-catalyzed carbonylative coupling between alkyl iodides and alcohols or sodium hydroxide. Upon reaction with catalytic amounts of copper(I) chloride and N,N,N′,N′′,N′′-pentamethyldiethylenetriamine under a mild pressure of carbon monoxide (5 bar), a range of secondary and tertiary alkyl iodides are readily converted into the corresponding esters and carboxylic acids without competing direct nucleophilic substitution. Main advantages of this procedure include its broad applicability, the use of an especially inexpensive and available catalytic system, and its user-friendliness.

Copper(I)-catalyzed asymmetric alkylation of α-imino-esters

Asymmetric alkylation of enolates is one of the most direct and important reactions to prepare α-chiral carbonyl compounds. Except for the classical methods that rely on the use of chiral auxiliaries, asymmetric catalysis emerged as a powerful tool, especially asymmetric phase-transfer catalysis. However, in the field of transition metal catalysis, only limited success with asymmetric alkylation of enolates was achieved. Hereby, we disclose a copper(I)-catalyzed asymmetric alkylation of α-imino-esters with various alkyl halides, including allyl bromides, propargyl bromide, benzyl bromides, α-bromo carbonyl compounds, and alkyl iodides. Both linear and cyclic α-imino-esters serve as competent pronucleophiles in the alkylation, which affords α-amino acid derivatives bearing either a trisubstituted or a tetrasubstituted stereogenic carbon center in high to excellent enantioselectivity. Control experiments indicate that the α-imino-ester is activated by a chiral copper(I)-phosphine complex through coordination, thus enabling facile deprotonation to provide a stabilized copper(I)-enolate in the presence of a mild base. Finally, the mildly basic nature allows the asymmetric alkylation of chiral dipeptides with excellent both chemo- and enantioselectivities.

The Merger of Aryl Radical-Mediated Halogen-Atom Transfer (XAT) and Copper Catalysis for the Modular Cross-Coupling-Type Functionalization of Alkyl Iodides

The Merger of Aryl Radical-Mediated Halogen-Atom Transfer (XAT) and Copper Catalysis for the Modular Cross-Coupling-Type Functionalization of Alkyl Iodides

Synthesis of Sulfilimines via Selective S–C Bond Formation in Water

Sulfilimines are valuable compounds both in organic synthesis and in pharmaceuticals. Here we developed a mild and simplified method for preparation of sulfilimines via selective S-C bond formation rather than traditional S-N bond formation. The method is both attractive and useful for the following reasons: it uses a readily available alkylation reagent such alkyl bromide or alkyl iodide, it uses water as solvent, it is easy to perform, and it is convenient for late-stage diversification of drugs.

Stereochemistry of the Reactions between Palladacycle Complexes and Primary Alkyl Iodides

As an important elementary step in organometallic chemistry, the alkylation reaction of palladacycle complexes and alkyl halides has attracted much attention in recent years due to their presence as a key step in palladium-catalyzed C–H alkylation reactions. In principle, several alkylation mechanisms, such as the stereoinvertive SN2-type mechanism and the stereoretentive oxidative addition mechanism, can be operative, and mechanistic insights can be obtained from the stereochemical outcomes of these alkylation reactions. Previous stereochemical investigations on the alkylation reaction of palladacycle complexes mainly focused on the use of chiral secondary alkyl halides as stereochemical probes, leaving more synthetically relevant primary alkyl iodides untouched. In this work, deuterium-labeled primary alkyl iodides were selected as a stereochemical probe, and their reaction with C,C- and C,N-type palladacycle complexes, namely, Catellani-type palladacycle intermediates and directing group (DG)-coordinated palladacycle complexes, were investigated both experimentally and computationally to elucidate the alkylation mechanism. We found that the C,C-ligated palladacycle intermediates undergo alkylation through the SN2-type mechanism, while the C,N-ligated 8-aminoquinoline-derived palladacycle complex favors a stereoretentive oxidative addition mechanism. In addition, the 2-phenylpyridine-derived C,N-type palladacycle dimer complex was found to react through the SN2-type mechanism due to its stable dimer structure and the d8–d8 interaction between two palladium atoms.

Alkylation of N,N-Dibenzylaminoacetonitrile: From Five- to Seven-Membered Nitrogen-Containing Heterocyclic Systems.

The syntheses of several alkaloids and nitrogen-containing compounds including N-Boc-coniine (14b), pyrrolizidine (1), δ-coniceine (2), and pyrrolo[1,2a]azepine (3) are described. New C-C bonds in the α position relative to the nitrogen atom were formed by the alkylation of metalated α-aminonitriles 4 and 6a-c with alkyl iodides possessing the requisite size and functionality. In all of the reported cases, the pyrrolidine ring was formed in the aqueous medium through a favorable 5-exo-tet process involving a primary or a secondary amino group and a terminal δ-leaving group. Conversely, the azepane ring was efficiently formed in N,N-dimethylformamide (DMF), as the preferred aprotic solvent, through an unreported 7-exo-tet cyclization process involving a more nucleophilic sodium amide and a terminal mesylate borne by a saturated six carbon chain unit. In this way, we successfully synthesized pyrrolo[1,2a]azepane 3 and 2-propyl-azepane 14c in good yields from inexpensive and readily available materials without tedious separation methods.

Aryl Radical Enabled, Copper-Catalyzed Sonogashira-Type Cross-Coupling of Alkynes with Alkyl Iodides.

Despite the success of Sonogashira coupling for the synthesis of arylalkynes and conjugated enynes, the engagement of unactivated alkyl halides in such reactions remains historically challenging. We report herein a strategy that merges Cu-catalyzed alkyne transfer with the aryl radical activation of carbon-halide bonds to enable a general approach for the coupling of alkyl iodides with terminal alkynes. This unprecedented Sonogashira-type cross-coupling reaction tolerates a broad range of functional groups and has been applied to the late-stage cross-coupling of densely functionalized pharmaceutical agents as well as the synthesis of positron emission tomography tracers.

Enantioselective C(sp3)–C(sp3) Reductive Cross-Electrophile Coupling of Unactivated Alkyl Halides with α-Chloroboronates via Dual Nickel/Photoredox Catalysis

Substantial advances in enantioconvergent C(sp3)-C(sp3) bond formations have been made with nickel-catalyzed cross-coupling of racemic alkyl electrophiles with organometallic reagents or nickel-hydride-catalyzed hydrocarbonation of alkenes. Herein, we report an unprecedented enantioselective C(sp3)-C(sp3) reductive cross-coupling by the direct utilization of two different alkyl halides with dual nickel/photoredox catalysis system. This highly selective coupling of racemic α-chloroboronates and unactivated alkyl iodides furnishes chiral secondary alkyl boronic esters, which serve as useful and important intermediates in the realm of organic synthesis and enable a desirable protocol to fast construction of enantioenriched complex molecules.

Photoredox Promoted Barbier-Type Reaction of Alkyl Iodides with N-Alkyl and N-Aryl Imines

The reaction of organozinc reagents with unactivated imines is accelerated when performed in the presence of a photocatalyst under blue light irradiation. Coordination between Lewis acidic zinc iodide and the imine is a key factor responsible for the reaction efficiency. The method can be carried out using alkyl iodides under Barbier conditions.

1,2-Aminoxyalkylation of alkenes with alkyl iodides and TEMPONa through SET- and XAT-processes.

1,2-Aminoxyalkylation of alkenes with alkyl iodides and TEMPONa in combination with an aryldiazonium salt as an XAT mediator is reported. Various primary, secondary and tertiary alkyl iodides engage as C-radical precursors in the 1,2-aminoxyalkylation with electrophilic alkenes as radical acceptors. The product alkoxyamines are readily transformed to the corresponding alcohols or ketones upon reduction or oxidation, respectively. Mechanistic investigations reveal that aryl radicals, generated through SET-reduction of the aryl diazonium salt with TEMPONa, engage in XAT from unactivated alkyl halides to give alkyl radicals that can add to alkenes. Trapping of the adduct radicals with TEMPO provides the 1,2-aminoxyalkylation products. Transition metals are not required for these transformations that are conducted under mild conditions. Perfluoroalkyl halides directly react with TEMPONa and an aryldiazonium salt as XAT-mediator is not required for alkene 1,2-aminoxyperfluoroalkylation.