Tertiary Alkyl Bromides Research Articles

Dual nickel- and photoredox-catalyzed reductive cross-coupling of aryl vinyl halides and unactivated tertiary alkyl bromides.

A novel reductive cross-coupling of aryl vinyl halides and unactivated tertiary alkyl bromides has been realized via photoredox/nickel dual catalysis to produce vinyl arene derivatives bearing all-carbon quaternary centers with excellent E-selectivity. A stoichiometric metal reductant could be avoided by employing commercially available N,N,N',N'-tetramethylethylenediamine (TMEDA) as the terminal reductant.

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.

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.

Nickel-Catalyzed Remote Arylation of Alkenyl Aldehydes Initiated by Radical Alkylation with Tertiary α-Carbonyl Alkyl Bromides.

A novel nickel-catalyzed remote arylation of alkenyl aldehydes triggered by radical alkylation with tertiary α-carbonyl alkyl bromides is described, thus producing a quaternary carbon center containing ketones in promising yields with broad functional group compatibility. Preliminary mechanistic studies suggest that the combination of a 1,n-HAT (n = 5 or 6) from alkyl radicals to aldehyde C-H bonds with nickel catalysis may account for the realization of this reaction.

Irradiation-Induced Heck Reaction of Unactivated Alkyl Halides at Room Temperature.

The palladium-catalyzed Mizoroki-Heck reaction is arguably one of the most significant carbon-carbon bond-construction reactions to be discovered in the last 50 years, with a tremendous number of applications in the production of chemicals. This Nobel-Prize-winning transformation has yet to overcome the obstacle of its general application in a range of alkyl electrophiles, especially tertiary alkyl halides that possess eliminable β-hydrogen atoms. Whereas most palladium-catalyzed cross-coupling reactions utilize the ground-state reactivity of palladium complexes under thermal conditions and generally apply a single ligand system, we report that the palladium-catalyzed Heck reaction proceeds smoothly at room temperature with a variety of tertiary, secondary, and primary alkyl bromides upon irradiation with blue light-emitting diodes in the presence of a dual phosphine ligand system. We rationalize that this unprecedented transformation is achieved by utilizing the photoexcited-state reactivity of the palladium complex to enhance oxidative addition and suppress undesired β-hydride elimination.

Visible-Light-Driven Palladium-Catalyzed Radical Alkylation of C-H Bonds with Unactivated Alkyl Bromides.

Reported herein is a novel visible-light photoredox system with Pd(PPh3 )4 as the sole catalyst for the realization of the first direct cross-coupling of C(sp3 )-H bonds in N-aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra- and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp3 )-C(sp3 ) and C(sp2 )-C(sp3 ) bonds in moderate to excellent yields. These redox-neutral reactions feature broad substrate scope (>60 examples), good functional-group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible-light photocatalyst and radicals are involved in the process.

Visible‐Light‐Driven Palladium‐Catalyzed Radical Alkylation of C−H Bonds with Unactivated Alkyl Bromides

AbstractReported herein is a novel visible‐light photoredox system with Pd(PPh3)4 as the sole catalyst for the realization of the first direct cross‐coupling of C(sp3)−H bonds in N‐aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra‐ and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp3)−C(sp3) and C(sp2)−C(sp3) bonds in moderate to excellent yields. These redox‐neutral reactions feature broad substrate scope (>60 examples), good functional‐group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible‐light photocatalyst and radicals are involved in the process.

Selective Radical Fluorination of Tertiary Alkyl Halides at Room Temperature

AbstractDirect fluorination of tertiary alkyl bromides and iodides with Selectfluor is described. The halogen‐exchange fluorination proceeds efficiently in acetonitrile at room temperature under metal‐free conditions and exhibits a wide range of functional group compatibility. Furthermore, the reactions are highly selective in that alkyl chlorides and primary and secondary alkyl bromides remain intact. A radical mechanism is proposed for this selective fluorination.

Selective Radical Fluorination of Tertiary Alkyl Halides at Room Temperature.

Direct fluorination of tertiary alkyl bromides and iodides with Selectfluor is described. The halogen-exchange fluorination proceeds efficiently in acetonitrile at room temperature under metal-free conditions and exhibits a wide range of functional group compatibility. Furthermore, the reactions are highly selective in that alkyl chlorides and primary and secondary alkyl bromides remain intact. A radical mechanism is proposed for this selective fluorination.

Copper-catalyzed direct alkylation of heteroarenes

An efficient and broadly applicable process is reported for the direct alkylation of C-H bonds in heteroarenes, privileged scaffolds in many areas of science. This reaction is based on the copper-catalyzed addition of alkyl radicals generated from activated secondary and tertiary alkyl bromides to a wide range of arenes, including furans, thiophenes, pyrroles, and their benzo-fused derivatives, as well as coumarins and quinolinones.

ChemInform Abstract: Nickel‐Catalyzed Reductive Amidation of Unactivated Alkyl Bromides.

AbstractA user‐friendly, Ni‐catalyzed reductive amidation of unactivated primary, secondary, and tertiary alkyl bromides with isocyanates is described.

Palladium-Catalyzed Cross Coupling of Secondary and Tertiary Alkyl Bromides with a Nitrogen Nucleophile.

We report a new class of catalytic reaction: the thermal substitution of a secondary and or tertiary alkyl halide with a nitrogen nucleophile. The alkylation of a nitrogen nucleophile with an alkyl halide is a classical method for the construction of C–N bonds, but traditional substitution reactions are challenging to achieve with a secondary and or tertiary alkyl electrophile due to competing elimination reactions. A catalytic process could address this limitation, but thermal, catalytic coupling of alkyl halides with a nitrogen nucleophile and any type of catalytic coupling of an unactivated tertiary alkyl halide with a nitrogen nucleophile are unknown. We report the coupling of unactivated secondary and tertiary alkyl bromides with benzophenone imines to produce protected primary amines in the presence of palladium ligated by the hindered trialkylphosphine Cy2t-BuP. Mechanistic studies indicate that this amination of alkyl halides occurs by a reversible reaction to form a free alkyl radical.

Intermolecular Photocatalyzed Heck‐like Coupling of Unactivated Alkyl Bromides by a Dinuclear Gold Complex

A practical protocol for a photocatalyzed alkyl-Heck-like reaction of unactivated alkyl bromides and different alkenes promoted by dinuclear gold photoredox catalysis in the presence of an inorganic base is reported. Primary, secondary, and tertiary unactivated alkyl bromides with β-hydrogen can be applied. Esters, aldehydes, ketones, nitriles, alcohols, heterocycles, alkynes, alkenes, ethers, and halogen moieties are all well tolerated. In addition to 1,1-diarylalkenes, silylenolethers and enamides can also be applied, which further increases the synthetic potential of the reaction. The mild reaction conditions, broad substrate scope, and an excellent functional-group tolerance deliver an ideal tool for synthetic chemists that can even be used for challenging late-stage modifications of complex natural products.

Nickel‐Catalyzed Reductive Amidation of Unactivated Alkyl Bromides

AbstractA user‐friendly, nickel‐catalyzed reductive amidation of unactivated primary, secondary, and tertiary alkyl bromides with isocyanates is described. This catalytic strategy offers an efficient synthesis of a wide range of aliphatic amides under mild conditions and with an excellent chemoselectivity profile while avoiding the use of stoichiometric and sensitive organometallic reagents.

Nickel-Catalyzed Reductive Amidation of Unactivated Alkyl Bromides.

A user-friendly, nickel-catalyzed reductive amidation of unactivated primary, secondary, and tertiary alkyl bromides with isocyanates is described. This catalytic strategy offers an efficient synthesis of a wide range of aliphatic amides under mild conditions and with an excellent chemoselectivity profile while avoiding the use of stoichiometric and sensitive organometallic reagents.

Synthesis of 4-(alkoxyamino)chroman-2-ones via 6-exo-trig cyclization of carbon-centered radicals into oxime ethers

4-(Alkoxyamino)chroman-2-ones were synthesized via a 6-exo-trig cyclization of alkyl radicals obtained from α-bromoesters containing an oxime ether group. In the case of secondary bromides, the best results were achieved using tris(trimethylsilyl)silane as the chain transfer agent and Et3B as the initiator in dichloromethane at room temperature; the corresponding chromanones were produced in 58–70% yield. Low yields of the cyclized compounds were obtained in the case of tertiary alkyl bromides (20–25%). Products of premature reduction of carbon-centered radicals and addition of ethyl radicals to C=N bond were also observed.

ChemInform Abstract: Nickel‐Catalyzed Reductive Cross‐Coupling of (Hetero)Aryl Iodides with Fluorinated Secondary Alkyl Bromides.

AbstractThe reaction fails for trifluoromethylated tertiary alkyl bromides and gives only poor yields for trifluoromethylated primary alkyl chlorides (not shown).

ChemInform Abstract: Nickel‐Catalyzed Reductive Coupling of Aryl Bromides with Tertiary Alkyl Halides.

AbstractElectron‐deficient aryl bromides react with tertiary alkyl bromides under mild conditions in the presence of pyridine or DMAP and imidazolium salts.