Alkyl Iodides Research Articles

Phosphine Ligand Effects in Nickel-Catalyzed Alkene Migratory Hydroalkylation

AbstractCatalytic alkene hydroalkylation has provided to be an efficient method for synthesizing C(sp3) centers, from readily available and inexpensive alkene starting materials through alkene hydrometallation followed by cross-coupling. One of the major tasks in this field is to develop diverse ligands to achieve regioselective control. Herein, we report the investigation of nickel–triphenylphosphine-catalyzed remote hydroalkylation of alkenyl amides to access α-branched amines. Various alkenes and alkyl iodides are suitable substrates to deliver the desired products with excellent regioselectivities (>20:1 regioisomeric ratio). Density functional theory calculations reveal the reaction mechanism.

Cobalt-Catalyzed Electroreductive Alkylation of Unactivated Alkyl Chlorides with Conjugated Olefins.

Reactions of unactivated alkyl chlorides under mild and sustainable conditions are rare compared to those of alkyl bromides or iodides. As a result, synthetic methods capable of modifying the vast chemical space of chloroalkane reagents, wastes, and materials are limited. We report the cobalt-catalyzed reductive addition of unactivated alkyl chlorides to conjugated alkenes. Co-catalyzed activation of alkyl chlorides is performed under electroreductive conditions, and the resulting reactions constitute formal alkyl-alkyl bond formation. In addition to developing an operationally simple methodology, detailed mechanistic studies provide insights into the elementary steps of a proposed catalytic cycle. In particular, we propose a switch in the mechanism of C-Cl bond activation from nucleophilic substitution to halogen atom abstraction, which is critical for efficiently generating alkyl radicals. These mechanistic insights were leveraged in designing ligands that enable couplings of primary, secondary, and tertiary alkyl chlorides.

Cobalt‐Catalyzed Electroreductive Alkylation of Unactivated Alkyl Chlorides with Conjugated Olefins

AbstractReactions of unactivated alkyl chlorides under mild and sustainable conditions are rare compared to those of alkyl bromides or iodides. As a result, synthetic methods capable of modifying the vast chemical space of chloroalkane reagents, wastes, and materials are limited. We report the cobalt‐catalyzed reductive addition of unactivated alkyl chlorides to conjugated alkenes. Co‐catalyzed activation of alkyl chlorides is performed under electroreductive conditions, and the resulting reactions constitute formal alkyl‐alkyl bond formation. In addition to developing an operationally simple methodology, detailed mechanistic studies provide insights into the elementary steps of a proposed catalytic cycle. In particular, we propose a switch in the mechanism of C−Cl bond activation from nucleophilic substitution to halogen atom abstraction, which is critical for efficiently generating alkyl radicals. These mechanistic insights were leveraged in designing ligands that enable couplings of primary, secondary, and tertiary alkyl chlorides.

Reductive Cross-Coupling of a Vinyl Thianthrenium Salt and Secondary Alkyl Iodides.

We report the first reductive vinylation of alkyl iodides. The reaction uses a vinyl thianthrenium salt, a palladium catalyst, and an alkyl zinc intermediate formed in situ to trap the Ln PdII (vinyl) complex formed after oxidative addition before it undergoes undesired homocoupling to form butadiene.

Reductive Cross‐Coupling of a Vinyl Thianthrenium Salt and Secondary Alkyl Iodides

AbstractWe report the first reductive vinylation of alkyl iodides. The reaction uses a vinyl thianthrenium salt, a palladium catalyst, and an alkyl zinc intermediate formed in situ to trap the LnPdII(vinyl) complex formed after oxidative addition before it undergoes undesired homocoupling to form butadiene.

Electrochemical halogen-atom transfer alkylation via α-aminoalkyl radical activation of alkyl iodides

Alkyl halides, widely recognized as important building blocks and reagents in organic synthesis, can serve as versatile alkyl radical precursors in radical-based transformations. However, generating alkyl radicals directly from unactivated alkyl halides under mild conditions remains a challenge due to their extremely low reduction potentials. To address this issue, α-aminoalkyl radicals were employed as efficient halogen-atom transfer (XAT) reagents in the photoredox activation of unactivated alkyl halides. Here, we report an effective electrooxidation strategy for generating alkyl radicals from unactivated alkyl iodides via an electrochemical halogen-atom transfer (e-XAT) process under mild conditions. The α-aminoalkyl radicals generated by anodic oxidation are demonstrated to be efficient XAT reagents in these transformations. This facile electricity-driven strategy obviates the need for sacrificial anodes and external chemical oxidants. The method successfully applies to a wide variety of alkyl iodides, including primary, secondary, and tertiary, as well as structurally diverse olefins, exhibiting excellent functional group tolerance. Moreover, we further demonstrate the utility of this strategy by rapidly functionalizing complex molecules and biomolecules.

Novel Mitochondria-Targeted Amphiphilic Aminophosphonium Salts and Lipids Nanoparticles: Synthesis, Antitumor Activity and Toxicity.

The creation of mitochondria-targeted vector systems is a new tool for the treatment of socially significant diseases. Phosphonium groups provide targeted delivery of drugs through biological barriers to organelles. For this purpose, a new class of alkyl(diethylAmino)(Phenyl) Phosphonium halides (APPs) containing one, two, or three diethylamino groups was obtained by the reaction of alkyl iodides (bromides) with (diethylamino)(phenyl)phosphines under mild conditions (20 °C) and high yields (93-98%). The structure of APP was established by NMR and XRD. A high in vitro cytotoxicity of APPs against M-HeLa, HuTu 80, PC3, DU-145, PANC-1, and MCF-7 lines was found. The selectivity index is in the range of 0.06-4.0 μM (SI 17-277) for the most active APPs. The effect of APPs on cancer cells is characterized by hyperproduction of ROS and depolarization of the mitochondrial membrane. APPs induce apoptosis, proceeding along the mitochondrial pathway. Incorporation of APPs into lipid systems (liposomes and solid lipid nanoparticles) improves cytotoxicity toward tumor cells and decrease toxicity against normal cell lines. The IC50s of lipid systems are lower than for the reference drug DOX, with a high SI (30-56) toward MCF-7 and DU-145. APPs exhibit high selective activity against Gram-positive bacteria S. aureus 209P and B. segeus 8035, including methicillin-resistant S. aureus (MRSA-1, MRSA-2), comparable to the activity of the fluoroquinolone antibiotic norfloxacin. A moderate in vivo toxicity in CD-1 mice was established for the lead APP.

Understanding the Reaction Mechanism of Ni-Catalyzed Regio- and Enantioselective Hydroalkylation of Enamines: Chemoselectivity of (Bi-oxazoline)NiH.

This density functional theory study explores the detailed mechanism of nickel-catalyzed hydroalkylation of the C═C bond of N-Cbz-protected enamines (Cbz = benzyloxycarbonyl) with alkyl iodides to give chiral α-alkyl amines. The active catalyst (biOx)NiH, a chiral bioxazoline (biOx)-chelated Ni(I) hydride, exhibits chemoselectivity that favors single electron transfer to the alkyl iodide over C═C hydrometalation with the enamine. This generates an alkyl radical and a Ni(II) intermediate, which takes up the enamine substrate CbzNHCH═CH2CH3 via a regio- and enantioselective C═C insertion into the NiII-H bond. The resulting Ni(II) alkyl complex combines with the alkyl radical, forming a Ni(III) intermediate, from which the alkyl-alkyl reductive elimination delivers the chiral amine product. The regioselectivity arises from a combination of orbital and noncovalent interactions, both of which are induced by the Cbz group. Thus, Cbz plays an additional role in controlling regioselectivity. The enantioselectivity stems from the differing distortion energies of CbzNHCH═CH2CH3. The reductive elimination is the rate-determining step (ΔG⧧ = 18.7 kcal/mol). In addition, the calculations show a noninnocent behavior of the biOx ligand induced by the insertion of CbzNHCH═CH2CH3 into the Ni-H bond of (biOx)NiH. These computationally gained insights can have implications for developing new Ni(I)-catalyzed reactions.

Nickel-Catalyzed Reductive Cross-Coupling of Allylammonium Salts with Alkyl Iodides.

An unprecedented reductive cross-coupling reaction of allylammonium salts with alkyl electrophiles has been established through C-N bond cleavage. A range of allylammonium bromides smoothly participated in the nickel-catalyzed zinc-mediated allyl-alkyl cross-electrophile coupling reaction with alkyl iodides, delivering structurally diverse alkene products in moderate to good yields with high linear selectivity. Preliminary mechanistic experiments are consistent with the formation of an alkyl radical from the alkyl iodide.

Methyl Ketones as Alkyl Halide Surrogates: A Deacylative Halogenation Approach for Strategic Functional Group Conversions.

Alkyl halides are versatile precursors to access diverse functional groups (FGs). Due to their lability, the development of surrogates for alkyl halides is strategically important for complex molecule synthesis. Given the stability and ease of derivatization inherent in common alkyl ketones, here we report a deacylative halogenation approach to convert various methyl ketones to the corresponding alkyl chlorides, bromides, and iodides. The reaction is driven by forming an aromatic byproduct, i.e., 1,2,4-triazole, in which N'-methylpicolinohydrazonamide (MPHA) is employed to form a prearomatic intermediate and halogen atom-transfer (XAT) reagents are used to quench the alkyl radical intermediate. The reaction is efficient in yielding primary and secondary alkyl halides from a wide range of methyl ketones with broad FG tolerance. It also works for complex natural-product-derived and fluoro-containing substrates. In addition, one-pot conversions of methyl ketones to various other FGs and annulations with alkenes and alkynes through deacylative halogenation are realized. Moreover, an unusual iterative homologation of alkyl iodides is also demonstrated. Finally, mechanistic studies reveal an intriguing double XAT process for the deacylative iodination reaction, which could have implications beyond this work.

The Merger of Halogen Atom Transfer (XAT) and Energy Transfer Catalysis (EnT) for the Modular 1,2-Iminylalkylation of Diazenes.

The 1,2-iminylalkylation of diazenes using alkyl iodides in combination with an O-benzoyl oxime is reported. In this transformation, O-benzoyl oxime acted as a radical precursor and XAT mediator. In addition to common alkyl iodides, other alkyl iodides such as iodomethane, iodomethane-d3, trifluoroiodomethane, ethyl difluoroiodoacetate, and iodoalkanes containing unprotected hydroxyl and amide groups can also serve as C-radical precursors in the 1,2-iminylalkylation with electrophilic diazenes as radical acceptors.

Acetate/Alkoxide/Halide Shuttle Systems Mediated by Lewis Acid Catalysts for Insertion Reaction of a One-Carbon Unit into Carbon–Carbon or Carbon–Halogen Bonds

AbstractIn this account, we describe our research on a Lewis acid-catalyzed insertion reaction of α-diazo esters into a carbon–carbon or carbon–halogen bond. Indium catalysts mediated not only the insertion of α-diazo esters into a carbon–carbon bond of alkyl acetates, alkyl ethers, acetals, and alkyl halides, but also a carbon–halogen bond of alkyl chlorides, bromides, and iodides. BF3 specifically accelerated the insertion of α-diazo esters into a carbon–fluorine bond. The key to this catalysis is acetate, alkoxide, and halide shuttle systems mediated by a Lewis acid, in which the Lewis acid abstracts a leaving group from a starting substrate and releases the leaving group to the appropriate carbocation intermediate in the catalytic cycle.1 Introduction2 Acetate/Alkoxide Shuttle: Insertion Reaction of α-Diazo Esters into a Carbon–Carbon Bond of Alkyl Acetates, Alkyl Ethers, and Acetals3 Halide Shuttle: Insertion Reaction of α-Diazo Esters into a Carbon–Carbon Bond of Alkyl Halides4 Halide Shuttle: Insertion of α-Diazo Esters into a Carbon–Halogen Bond of Alkyl Halides5 Conclusion

Antimicrobial agents based on new lipophilic alkyl (N-alkyl-N,N-dioctylammoniomethyl)phosphonates

(N-Alkyl-N,N-dioctylammoniomethyl)phosphonates were obtained by alkylation of amino phosphonate potassium salt with alkyl iodides or benzyl chloride. All synthesized compounds demonstrated high antibacterial and antifungal activity against Gram-positive bacterial strains B. cereus and S. aureus and were not active against Gram-negative strains Ps. aeruginosa. Some regularity connecting the structure of the obtained compounds with their antimicrobial action has been established.

Photocatalytic Multicomponent 1,n-Carboimination with Alkyl Iodides and O-Benzoyl Oxime through EnT and XAT Processes.

In this study, we developed a strategy using commercially available alkyl iodides and O-benzoyl oxime to efficiently introduce alkyl and iminyl groups via energy transfer and halogen-atom transfer processes. We performed three-component 1,2-carboimination of olefins and four-component 1,4-carboimination across olefins and alkynes, resulting in the synthesis of over 60 nitrogen-containing molecules. Moreover, this transformation enables the synthesis of molecules with sensitive groups that were previously difficult to achieve.

Nickel catalysis synthesis of 2,5-disubstituted furans from aryl (alkyl) iodide

A new methodology using various aryl(alkyl)iodides and CaC2 as coupling partners has been developed for the successful preparation of 2,5-disubstituted furans in good to excellent yields. The broad substrate range makes this method a practical and versatile approach for the preparation of (hetero)aryl- and alkyl-substituted furans, which are valuable building blocks in many biologically active compounds and functional materials.

Design, Synthesis and Application of a Robust d3‐Methylthiolating Reagent†

Comprehensive SummaryA deuterated methylthiolating reagent with a broad spectrum, designated as DMTP, has been ingeniously formulated. This new reagent can be produced with high efficiency through the simple combination of commercially available methyl 3‐thiopropanoate and CD3I. This novel SCD3 reagent exhibits excellent reactivity with electrophiles such as alkyl iodides, benzyl chlorides, aryl halides (I, Br) and aryl triflates, resulting in high levels of deuterium content (99% D). Representative deuterated methylthiolated biomolecules, such as Sulfoxaflor, have been synthesized for use in pharmaceutical discovery and development.

Stark control of multiphoton ionization through Freeman resonances in alkyl iodides.

Multiphoton ionization (MPI) of alkyl iodides (RI, R = CnH2n+1, n = 1-4) has been investigated with femtosecond laser pulses centered at 800 and 400nm along with photoelectron imaging detection. In addition, the ultraviolet (UV)-vacuum ultraviolet (VUV) absorption spectra of gas-phase RIs have been measured in the photon energy range of 5-11eV using the VUV Fourier transform spectrometer at the VUV DESIRS beamline of the synchrotron SOLEIL facility. The use of high-laser-field strengths in matter-radiation interaction generates highly non-linear phenomena, such as the Stark shift effect, which distorts the potential energy surfaces of molecules by varying both the energy of electronic and rovibrational states and their ionization energies. The Stark shift can then generate resonances between intermediate states and an integer number of laser photons of a given wavelength, which are commonly known as Freeman resonances. Here, we study how the molecular structure of linear and branched alkyl iodides affects the UV-VUV absorption spectrum, the MPI process, and the generation of Freeman resonances. The obtained results reveal a dominant resonance in the experiments at 800nm, which counter-intuitively appears at the same photoelectron kinetic energy in the whole alkyl iodide series. The ionization pathways of this resonance strongly involve the 6p(2E3/2) Rydberg state with different degrees of vibrational excitation, revealing an energy compensation effect as the R-chain complexity increases.

Photosensitized O2 enables intermolecular alkene cyclopropanation by active methylene compounds.

Cyclopropanes are key features in many preclinical, clinical, and commercial drugs, as well as natural products. The most prolific technique for their synthesis is the metal-catalyzed reaction of an alkene with a diazoalkane, a highly energetic reagent requiring stringent safety precautions. Discovery of alternative innocuous reagents remains an ongoing challenge. Herein, we report a simple photoredox-catalyzed intermolecular cyclopropanation of unactivated alkenes with active methylene compounds. The reaction proceeds in neutral solvent under air or dioxygen (O2) with a photoredox catalyst excited by blue light-emitting diode light and an iodine co-catalyst that is either added as molecular iodine or generated in situ from alkyl iodides. Mechanistic investigations indicate that photosensitized O2 plays a vital role in the generation of carbon-centered radicals for both the addition of active methylene compounds to alkenes and the ring closure.

Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation.

Alkenes are ubiquitous in organic chemistry, yet many classes of alkenes remain challenging to access by current synthetic methodology. Herein, we report a copper hydride-catalyzed approach for the synthesis of Z-configured trisubstituted alkenes with high stereo- and regioselectivity via alkyne hydroalkylation. A DTBM-dppf-supported Cu catalyst was found to be optimal, providing a substantial increase in product yield compared to reactions conducted with dppf as the ligand. DFT calculations show that the DTBM substitution leads to the acceleration of alkyne hydrocupration through combined ground and transition state effects related to preventing catalyst dimerization and enhancing catalyst-substrate dispersion interactions, respectively. Alkyne hydroalkylation was successfully demonstrated with methyl and larger alkyl tosylate electrophiles to produce a variety of (hetero)aryl-substituted alkenes in moderate to high yields with complete selectivity for the Z stereochemically configured products. In the formation of the key C-C bond, computational studies revealed a direct SN2 pathway for alkylation of the vinylcopper intermediate with in situ-formed alkyl iodides.

Multicomponent Reaction of Aliphatic Organozinc Reagents, Acrylates and Acyl chlorides: Synthesis of α‐Substituted β‐Ketoesters

AbstractAn uncatalyzed three‐component reaction employing aliphatic organozinc reagents for the preparation of α‐substituted β‐ketoesters is described. This modular procedure, which relies on a formal conjugate addition/crossed‐Claisen domino reaction between an organozinc, an acrylate and an acyl chloride, allows the straightforward synthesis of the reaction products under mild conditions. The three‐component coupling can also be conducted from alkyl iodides, in an even more simple procedure. Experimental findings account for a probable polar concerted mechanism involving at least two organozinc compounds at the stage of the transition state.