Secondary Alkyl Bromides Research Articles

Nickel-Catalyzed Directed Cross-Electrophile Coupling of Phenolic Esters with Alkyl Bromides.

Herein, we demonstrate the successful use of robust phenolic esters as an electrophilic acyl source in the reaction with diverse primary and secondary unactivated alkyl bromides. The cleavage of the relatively inert C-O bond is facilitated by the neighboring coordinating hydroxyl or sulfonamide moiety. By circumventing the use of pregenerated organometallics, this method allows efficient preparation of a variety of o-hydroxyl and tosyl-protected o-amino aryl ketones with high compatibility with a wide range of functionalities.

Synthesis of Oxygen-Containing Heterocyclic Compounds by Iron-Catalyzed Alkylative Cyclization of Unsaturated Carboxylic Acids and Alcohols.

Iron-catalyzed alkylative cyclization of alkenes bearing oxygen nucleophiles with secondary and tertiary alkyl bromides through carbon-carbon and carbon-oxygen bond formations has been developed. A broad substrate scope is an attractive feature of this synthetic method, providing a variety of potentially bioactive five- and six-membered oxygen-containing heterocycles. The reaction pathway is proposed to involve a radical addition of the in situ-formed alkyl radical to an alkene followed by carbon-oxygen bond-forming intramolecular cyclization.

Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl Bromides

Summary Although Ru-catalyzed meta-selective sp2 C–H alkylation with secondary alkyl halides is well established, ortho selectivity has never been achieved. We demonstrate that the use of a cyclometalated Ru-complex, RuBnN, as the catalyst results in a complete switch of the inherent meta-selectivity to ortho selectivity in the Ru-catalyzed sp2 C–H alkylation reaction with unactivated secondary alkyl halides. The high catalytic activity of RuBnN allows mild reaction conditions that result in a transformation of broad scope and versatility. Preliminary mechanistic studies suggest that a bis-cycloruthenated species is the key intermediate undergoing oxidative addition with the alkyl bromides, thus avoiding the more common SET pathway associated with meta-selectivity.

General C(sp2)-C(sp3) Cross-Electrophile Coupling Reactions Enabled by Overcharge Protection of Homogeneous Electrocatalysts.

Cross-electrophile coupling (XEC) of alkyl and aryl halides promoted by electrochemistry represents an attractive alternative to conventional methods that require stoichiometric quantities of high-energy reductants. Most importantly, electroreduction can readily exceed the reducing potentials of chemical reductants to activate catalysts with improved reactivities and selectivities over conventional systems. This work details the mechanistically-driven development of an electrochemical methodology for XEC that utilizes redox-active shuttles developed by the energy-storage community to protect reactive coupling catalysts from overreduction. The resulting electrocatalytic system is practical, scalable, and broadly applicable to the reductive coupling of a wide range of aryl, heteroaryl, or vinyl bromides with primary or secondary alkyl bromides. The impact of overcharge protection as a strategy for electrosynthetic methodologies is underscored by the dramatic differences in yields from coupling reactions with added redox shuttles (generally >80%) and those without (generally <20%). In addition to excellent yields for a wide range of substrates, reactions protected from overreduction can be performed at high currents and on multigram scales.

Ruthenium-Catalyzed Heck-Type Alkenylation of Alkyl Bromides.

The complex [Cp*RuCl(PPh3)2] displays a high catalytic activity for the Heck-type alkenylation of alkyl bromides in the first example using this metal under thermal conditions. The coupling reaction proceeds efficiently with a variety of functionalized tertiary, secondary, and primary alkyl bromides. The presence of Hünig's base has been revealed to be crucial for this transformation. Preliminary mechanistic studies support the participation of alkyl radicals in the reaction.

Nickel-catalyzed, ring-forming aromatic C–H alkylations with unactivated alkyl halides

The development of a nickel-catalyzed C–H alkylation of aromatic substrates with unactivated alkyl halides is described. This carbocyclization facilitates the synthesis of diverse fused ring systems from simple aromatic substrates and is an attractive alternative to traditional polar or radical-mediated ring formations. The present system uses unactivated primary and secondary alkyl bromides and chlorides, while avoiding the use of precious palladium catalysts and more reactive alkyl halides commonly used in related C–H alkylations.

Reactions of the electrochemically generated dianion of [60]fullerene with bulky secondary alky bromides

Reactions of the electrochemically generated dianion of [60]fullerene (C602−) with bulky secondary alkyl bromides exhibit different reaction behaviors. Reaction of C602− with diphenylbromomethane gives rise to 1,2-C60HR or 1,4-C60R2 (R = CHPh2) adducts, while reaction of C602− with diethyl 2-bromomalonate unexpectedly affords methanofullerene C60 > CR2 (R = CO2Et). Plausible reaction mechanisms have been proposed to explain the formation of the observed products.

Oxidative Addition to Palladium(0) Made Easy through Photoexcited-State Metal Catalysis: Experiment and Computation.

Visible-light induced, palladium catalyzed alkylations of α,β-unsaturated acids with unactivated alkyl bromides are described. A variety of primary, secondary, and tertiary alkyl bromides are activated by the photoexcited palladium metal catalyst to provide a series of olefins at room temperature under mild reaction conditions. Mechanistic investigations and density functional theory (DFT) studies suggest that a photoinduced inner-sphere mechanism is operative in which a barrierless, single-electron transfer oxidative addition of the alkyl halide to Pd0 is key for the efficient transformation.

Oxidative Addition to Palladium(0) Made Easy through Photoexcited‐State Metal Catalysis: Experiment and Computation

AbstractVisible‐light induced, palladium catalyzed alkylations of α,β‐unsaturated acids with unactivated alkyl bromides are described. A variety of primary, secondary, and tertiary alkyl bromides are activated by the photoexcited palladium metal catalyst to provide a series of olefins at room temperature under mild reaction conditions. Mechanistic investigations and density functional theory (DFT) studies suggest that a photoinduced inner‐sphere mechanism is operative in which a barrierless, single‐electron transfer oxidative addition of the alkyl halide to Pd0 is key for the efficient transformation.

Nickel-catalyzed alkyl-alkyl cross-coupling reactions of non-activated secondary alkyl bromides with aldehydes as alkyl carbanion equivalents.

A novel nickel-catalyzed alkyl-alkyl cross coupling of non-activated secondary alkyl bromides with aldehydes via hydrazone intermediates has been developed. Aldehydes as alkyl carbanion equivalents replace traditional organometallic reagents. This coupling occurs on the carbon of the hydrazone rather than the nitrogen. In addition, non-activated primary and tertiary alkyl bromides also undergo the cross-coupling reaction to form new C(sp3)-C(sp3) bonds in moderate yields.

Nickel‐Catalyzed Mizoroki–Heck‐Type Reactions of Unactivated Alkyl Bromides

AbstractThe development of a general, nickel‐catalyzed alkyl‐Mizoroki–Heck reaction of unactivated alkyl bromides is described. The mild reaction proceeds efficiently using a wide range of primary and secondary alkyl bromides, and examples of intermolecular cross‐couplings are provided. Reaction alkene regioselectivity is significantly enhanced over prior carbocyclizations using palladium catalysis. Mechanistic investigations are consistent with a direct carbocyclization in contrast to the auto‐tandem atom‐transfer cyclization and halide elimination previously observed with palladium catalysis.

Nickel-Catalyzed Mizoroki-Heck-Type Reactions of Unactivated Alkyl Bromides.

The development of a general, nickel-catalyzed alkyl-Mizoroki-Heck reaction of unactivated alkyl bromides is described. The mild reaction proceeds efficiently using a wide range of primary and secondary alkyl bromides, and examples of intermolecular cross-couplings are provided. Reaction alkene regioselectivity is significantly enhanced over prior carbocyclizations using palladium catalysis. Mechanistic investigations are consistent with a direct carbocyclization in contrast to the auto-tandem atom-transfer cyclization and halide elimination previously observed with palladium catalysis.

Nickel-Catalyzed Cyanation of Unactivated Alkyl Chlorides or Bromides with Zn(CN)2.

A nickel-catalyzed cyanation of unactivated secondary alkyl chlorides or bromides using less toxic Zn(CN)2 as the cyanide source has been developed. The reaction features the use of air-stable and inexpensive NiCl2·6H2O or Ni(acac)2 as the precatalysts and offers an efficient synthesis of a broad range of alkyl nitriles. Cyanation of primary alkyl chlorides or bromides was also achieved by reaction with Zn(CN)2 in the presence of n-Bu4NCl without the need of nickel catalyst.

Copper/iron co-catalyzed alkoxycarbonylation of unactivated alkyl bromides

Carbonylative transformations of alkyl bromides have been explored less than those of aryl halides, in part because of the high barrier to activation of aryl bromides. Additionally, alkyl-metal reagents formed in situ can tend to undergo β-hydride elimination. Here we describe a copper/iron co-catalyzed alkoxycarbonylation of unactivated alkyl bromides. In the presence of catalytic quantities of iron and copper catalysts, primary, secondary, and tertiary alkyl bromides are carbonylatively transformed into the corresponding aliphatic esters in good yields. A potential reaction mechanism is proposed based on control experiments.

Nickel-catalyzed reductive thiolation and selenylation of unactivated alkyl bromides

Chalcogen-containing compounds have received considerable attention because of their manifold applications in agrochemicals, pharmaceuticals, and material science. While many classical methods have been developed for preparing organic sulfides, most of them exploited the transition-metal-catalyzed cross-couplings of aryl halides or pseudo halides with thiols or disulfides, with harsh reaction conditions usually being required. Herein, we present a user-friendly, nickel-catalyzed reductive thiolation of unactivated primary and secondary alkyl bromides with thiosulfonates as reliable thiolation reagents, which are easily prepared and bench-stable. Furthermore, a series of selenides is also prepared in a similar fashion with selenosulfonates as selenolation reagents. This catalytic method offers a facile synthesis of a wide range of unsymmetrical alkyl-aryl or alkyl-alkyl sulfides and selenides under mild conditions with an excellent tolerance of functional groups. Likewise, the use of sensitive and stoichiometric organometallic reagents can be avoided.

Oxy-Alkylation of Allylamines with Unactivated Alkyl Bromides and CO2 via Visible-Light-Driven Palladium Catalysis.

A selective oxy-alkylation of allylamines with unactivated alkyl bromides and CO2 via visible-light-driven palladium catalysis is reported. The commercially available Pd(PPh3)4 is used as the sole catalyst in this three-component reaction. A variety of tertiary, secondary, and primary alkyl bromides undergo reactions to generate important 2-oxazolidinones in high yields and selectivity. The mild reaction conditions, easy scalability, and facile derivatization of products provide great potential for application in organic synthesis and pharmaceutical chemistry.

Direct β-Alkylation of Ketones and Aldehydes via Pd-Catalyzed Redox Cascade

We report a direct β-alkylation of ketones and aldehydes with simple alkyl bromides through a Pd-catalyzed redox-cascade strategy. The use of a Cu cocatalyst is important for improved efficiency. The reaction is redox-neutral, without the need for strong acids or bases. Both cyclic and acyclic ketones, as well as α-branched aldehydes, are suitable substrates for coupling with secondary and tertiary alkyl bromides. Concise formal synthesis of Zanapezil is achieved using this β-alkylation method.

Irradiation-Induced Palladium-Catalyzed Direct C–H Alkylation of Heteroarenes with Tertiary and Secondary Alkyl Bromides

A palladium catalyst in combination with two types of phosphine ligands efficiently catalyzes direct C–H alkylation of heteroarenes with secondary and tertiary alkyl bromides under irradiation conditions. Irradiation of blue light-emitting diodes (blue LEDs) effectively excites phosphine-ligated palladium catalyst to facilitate oxidative addition with alkyl bromides, and also excites the alkylpalladium species to enable the generation of alkyl radicals to react with heteroarenes.

Photochemical Nickel-Catalyzed Reductive Migratory Cross-Coupling of Alkyl Bromides with Aryl Bromides.

A novel method to access 1,1-diarylalkanes from readily available, nonactivated alkyl bromides and aryl bromides via visible-light-driven nickel and iridium dual catalysis, wherein diisopropylamine ( iPr2NH) is used as the terminal stoichiometric reductant, is reported. Both primary and secondary alkyl bromides can be successfully transformed into the migratory benzylic arylation products with good selectivity. Additionally, this method showcases tolerance toward a wide array of functional groups and the presence of bases.

Highly Efficient Barbier–Negishi Coupling of Secondary Alkyl Bromides

Highly Efficient Barbier–Negishi Coupling of Secondary Alkyl Bromides