Unactivated Alkyl Research Articles

Facile and general electrochemical deuteration of unactivated alkyl halides

Herein, a facile and general electroreductive deuteration of unactivated alkyl halides (X = Cl, Br, I) or pseudo-halides (X = OMs) using D2O as the economical deuterium source was reported. In addition to primary and secondary alkyl halides, sterically hindered tertiary chlorides also work very well, affording the target deuterodehalogenated products with excellent efficiency and deuterium incorporation. More than 60 examples are provided, including late-stage dehalogenative deuteration of natural products, pharmaceuticals, and their derivatives, all with excellent deuterium incorporation (up to 99% D), demonstrating the potential utility of the developed method in organic synthesis. Furthermore, the method does not require external catalysts and tolerates high current, showing possible use in industrial applications.

Palladium-catalyzed four-component difluoroalkylative carbonylation of aryl olefins and ethylene

Compared with unactivated alkyl olefins, the corresponding fluorinative carbonylation of styrenes has remained a challenge due to its strong tendency for oligomerization and polymerization. In this communication, we developed a palladium-catalyzed four-component difluoroalkylative carbonylation of aryl olefins for the first time. A wide range of β-difluoromethylene substituted amide derivatives were prepared in moderate to high yields with excellent regioselectivity. Notably, ethylene gas, as an original C2 synthon, can also be transformed to the corresponding products with moderate yields. Furthermore, some natural product or bio-active molecule related compounds, such as estrogen, benzocaine, and menthol derivatives can be reacted as well. This reaction can be scaled up smoothly and the obtained product can be further transformed into amidic acid and aminol efficiently.

Nickel-Catalyzed Reductive Coupling of γ-Metalated Ketones with Unactivated Alkyl Bromides.

A nickel-catalyzed reductive cross-coupling reaction of aryl cyclopropyl ketones with easily accessible unactivated alkyl bromides to access aryl alkyl ketones has been developed. This strategy facilitates access to various of γ-alkyl-substituted ketones via ring opening of cyclopropyl ketones (26 examples, 50-90% yield). Initial mechanistic studies revealed that the reaction proceeds via radical cleavage of the alkyl bromide.

Efficient preparation of unsymmetrical disulfides by nickel-catalyzed reductive coupling strategy

Disulfides are widely found in natural products and find a wide range of applications in life sciences, materials chemistry and other fields. The preparation of disulfides mainly rely on oxidative couplings of two sulfur containing compounds. This strategy has many side reactions and other shortcomings. Herein, we describe the reductive nickel-catalyzed cross-electrophile coupling of unactivated alkyl bromides with symmetrical alkyl- and aryltetrasulfides to form alkyl-alkyl and aryl-alkyl unsymmetrical disulfides. This approach for disulfide synthesis is practical, relies on easily available, unfunctionalized substrates, and is scalable. We investigated the mechanism of this transformation and found that the tetrasulfide compound does not selectively break the central S–S bond, but regio-selectively generates trisulfide intermediates.

Nickel-Catalyzed C(sp3)-C(sp3) Cross-Electrophile Coupling of In Situ Generated NHP Esters with Unactivated Alkyl Bromides.

The formation of C(sp3)-C(sp3) bonds by cross-coupling remains a challenge in synthesis. Here, we demonstrate a two-step, one-pot protocol for the in situ generation of N-hydroxyphthalimide esters and their nickel-catalyzed cross-electrophile coupling with unactivated alkyl bromides for the construction of 1°/1 ° C(sp3)-C(sp3) bonds. The conditions tolerate an array of functional groups, and mechanistic studies indicate that both substrates are converted to alkyl radicals during the reaction.

Manganese-Catalyzed C(sp2 )-H Alkylation of Indolines and Arenes with Unactivated Alkyl Bromides.

Selective C(sp2 )-H bond alkylation of indoline, carbazole and (2-pyridinyl)arenes with unactivated alkyl bromides is achieved using MnBr2 catalyst in the absence of an external ligand. The alkylation uses a simple LiHMDS base and avoids the necessity of Grignard reagent, unlike other Mn-catalyzed C-H functionalization. This reaction proceeded either through a five- or a less-favored six-membered metallacycle, and tolerated diverse functionalities, including alkenyl, alkynyl, silyl, aryl ether, pyrrolyl, indolyl, carbazolyl and alkyl bearing fatty alcohol and polycyclic-steroid moieties. Alkylation follows a single electron transfer (SET) pathway involving 1e oxidative addition of alkyl bromide and a rate-limiting C-H metalation.

Visible-Light Enabled C(sp3)-C(sp2) Cross-Electrophile Coupling via Synergistic Halogen-Atom Transfer (XAT) and Nickel Catalysis.

We herein report the first visible-light-mediated cross-coupling of unactivated alkyl iodides with aryl bromides through synergistic halogen atom transfer (XAT) and nickel catalysis. This simple protocol operates under mild reaction conditions and tolerates a variety of functional groups affording C(sp3)-C(sp2) cross-coupling products in good to moderate yields.

Nickel‐Catalyzed Reductive Acylation of Carboxylic Acids with Alkyl Halides and N‐Hydroxyphthalimide Esters Enabled by Electrochemical Process

AbstractA sustainable Ni‐catalyzed reductive acylation reaction of carboxylic acids via an electrochemical pathway is presented, affording a variety of ketones as major products. The reaction proceeds at ambient temperature using unactivated alkyl halides and N‐hydroxyphthalimide (NHP) esters as coupling partners, which exhibits several synthetic advantages, including mild conditions and convenience of amplification (58% yield for 6 mmol scale reaction).magnified image

Redox-Neutral Ni-Catalyzed sp3 C–H Alkylation of α-Olefins with Unactivated Alkyl Bromides

A light-induced redox-neutral Ni-catalyzed sp3 C–H alkylation of unactivated alkenes with alkyl bromides possessing β-hydrogens is described herein. The method is distinguished by its simplicity, wide scope, and exquisite regio- and chemoselectivity profile, thus offering an entry point to forge sp3–sp3 architectures.

Electrochemically driven cross-electrophile coupling of alkyl halides.

Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp3 carbons-those bonded to four other atoms-in drug candidates and their improved success rate in clinical trials1. As such, the development of robust and selective methods for the construction of carbon(sp3)-carbon(sp3) bonds remains a critical problem in modern organic chemistry2. Owing to the broad availability of alkyl halides, their direct cross-coupling-commonly known as cross-electrophile coupling-provides a promising route towards this objective3-5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp3)-carbon(sp3) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon-carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst,and shows improved chemoselectivity compared with existing methods.

Access to 3-alkylselenindoles by multicomponent reaction of indoles, selenium powder and unactivated alkyl halides under transition-metal-free conditions

Herein, we reported a convenient and efficient multicomponent reaction of indoles, selenium powder and unactivated alkyl halides. This protocol provides a practical, and facile approach for the synthesis of 3-alkylselenindole derivatives. The advantages of this strategy include mild and transition-metal-free conditions, broad functional group tolerance, the use of simple and easily accessible seleniium powder and alkyl halides as coupling partners. More importantly, the reaction proceeded smoothly with a large scale (>10 g, >90% yield), which further highlighted the potential application of this selenation strategy.

Photoredox Polyfluoroarylation of Alkyl Halides via Halogen Atom Transfer.

Polyfluoroarene moieties are of interest in medicinal chemistry, agrochemicals, and material sciences. Herein, we present the first polyfluoroarylation of unactivated alkyl halides via a halogen atom transfer process. This method converts primary, secondary, and tertiary alkyl halides into the respective polyfluoroaryl compounds in good yields in the presence of amide, carbamate, ester, aromatic, and sulfonamide moieties, including derivatives of complex bioactive molecules. Mechanistic work revealed that this transformation proceeds through an alkyl radical generated after the halogen atom transfer.

Electrochemical radical–radical cross-coupling: direct access to β-amino nitriles from unactivated imines and alkyl nitriles

The direct access to β-amino nitriles from unactivated imines and alkyl nitriles by electrochemical radical–radical cross-coupling was described.

Photocatalyzed alkylative cyclization of 2-isocyanobiphenyls with unactivated alkyl iodides.

We herein report the first photocatalyzed radical cascade cyclization of 2-isocyanobiaryls with unactivated alkyl iodides. This simple protocol operates under mild reaction conditions and affords 6-alkyl phenanthridines in good yields. To elucidate the reaction mechanism, Stern-Volmer quenching studies were carried out and these studies revealed that the photocatalyst is not directly involved in a single electron transfer process with the alkyl iodide.

Rh-catalyzed alkoxycarbonylation of unactivated alkyl chlorides.

A general rhodium-catalyzed selective carbonylative coupling of unactivated alkyl chlorides with aliphatic alcohols or phenols to the corresponding esters is presented for the first time. Crucial for this transformation is the addition of sodium iodide, which provides in situ more active alkyl iodides. In the presence of a Rh(i)-DPPP catalyst system diverse esters (81 examples) including industrially relevant acetates from chloro- and dichloromethane can be prepared in a straightforward manner in up to 95% isolated yield. The used ligand not only affects the selectivity of the carbonylation reaction but also controls the selectivity of the preceding halide exchange step.

Efficient preparation of unsymmetrical alkyl–aryl tellurides via a nickel-catalyzed reductive coupling strategy

A selective cross-coupling between unactivated alkyl bromides and diaryl tellurides through reductive nickel-catalysis is described, which efficiently led to unsymmetrical alkyl–aryl tellurides.

Metal-free visible-light-initiated direct C3 alkylation of quinoxalin-2(1H)-ones and coumarins with unactivated alkyl iodides

A visible-light-mediated direct C3-alkylation of quinoxalin-2(1H)-ones and coumarins with unactivated alkyl iodides under metal- and external photocatalyst-free conditions is described.

Cu-catalyzed coupling of unactivated tertiary alkyl alcohols with thiols via C–O bond cleavage

Herein we present the plain manufacture of sterically hindered tertiary alkyl thioethers via the Cu-catalyzed coupling of unactivated tertiary alkyl alcohols with thio-alcohols/phenols. The present strategy with easy-to-operate reaction conditions represents one of the most effective unactivated tertiary C(sp 3 )–S bond-forming methods via readily accessible Lewis acid catalysis. Moreover, this protocol has high functional group compatibility and wide substrate adaptability.

Nickel-catalyzed electrochemical carboxylation of unactivated aryl and alkyl halides with CO2

Electrochemical catalytic reductive cross couplings are powerful and sustainable methods to construct C−C bonds by using electron as the clean reductant. However, activated substrates are used in most cases. Herein, we report a general and practical electro-reductive Ni-catalytic system, realizing the electrocatalytic carboxylation of unactivated aryl chlorides and alkyl bromides with CO2. A variety of unactivated aryl bromides, iodides and sulfonates can also undergo such a reaction smoothly. Notably, we also realize the catalytic electrochemical carboxylation of aryl (pseudo)halides with CO2 avoiding the use of sacrificial electrodes. Moreover, this sustainable and economic strategy with electron as the clean reductant features mild conditions, inexpensive catalyst, safe and cheap electrodes, good functional group tolerance and broad substrate scope. Mechanistic investigations indicate that the reaction might proceed via oxidative addition of aryl halides to Ni(0) complex, the reduction of aryl-Ni(II) adduct to the Ni(I) species and following carboxylation with CO2.

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

AbstractThe engagement of unactivated alkyl halides in copper‐catalyzed cross‐coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper‐catalyzed Negishi‐type cross‐coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon–iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi‐type difluoromethylation approach has been applied to the late‐stage modification of densely functionalized pharmaceutical agents and natural products.