Recent advances in sulfur- and phosphorous-centered radical reactions for the formation of S–C and P–C bonds

Transition metal-catalyzed cross-coupling reactions have created an epoch in modern synthetic organic chemistry, offering a variety of insights into retrosynthetic tactics for synthesizing targeted complex molecules in medicine and materials-based applications. Despite numerous types of combinations of nucleophiles, electrophiles, and transition metal catalysts available for the cross-coupling reactions, construction of covalent bonds that include sp3-hybridized carbon(s) remains a challenge because of the inherent diverse reactivity of the alkyl species (i.e., alkyl halides and alkyl metals) involved in the catalytic cycle. Methods for leveraging alkyl radicals have recently emerged, which will aid in the realization of this goal. This perspective highlights and discusses recent advances in transition metal-catalyzed cross-coupling reactions that engage alkyl radicals for C(sp3)–N and C(sp3)–Si bond formation with alkyl halides as well as use of carboxylic acid derivatives as surrogates of alkyl halides ...

Engaging Radicals in Transition Metal-Catalyzed Cross-Coupling with Alkyl Electrophiles: Recent Advances

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.

http://pubs.acs.org/doi/pdf/10.1021/acscentsci.6b00187

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

Alkyl amines are an important class of organic compounds in medicinal and materials chemistry. Until now very have been very few methods for the synthesis of alkyl amines by metal-catalyzed cross-coupling of alkyl electrophiles with nitrogen nucleophiles. Described here is an approach to employ tandem photoredox and copper catalysis to enable the cross-coupling of alkyl N-hydroxyphthalimide esters, readily derived from alkyl carboxylic acids, with benzophenone-derived imines. Hydrolysis of the coupling products furnish alkylated primary amines. Primary, secondary, and tertiary alkyl groups can be transferred, and the coupling tolerates a diverse set of functional groups. The method allows rapid functionalization of natural products and drugs, and can be used to expedite syntheses of pharmaceuticals from readily available chemical feedstocks.

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Cross-Coupling of Alkyl Redox-Active Esters with Benzophenone Imines: Tandem Photoredox and Copper Catalysis.

A Cascade Phosphinoylation/Cyclization/Desulfonylation Process for the Synthesis of 3-Phosphinoylindoles

Radical Alkylphosphanylation of Olefins with Stannylated or Silylated Phosphanes and Alkyl Iodides

Radical Amination with Trimethylstannylated Benzophenone Imine

Contrary to the iodide, cyclohexyl bromide does not work and a primary alkyl moiety provides only low yields [cf.(IVc)].

Radical Alkylphosphanylation of Olefins with Stannylated or Silylated Phosphanes and Alkyl Iodides.

Amination reaction of a variety of primary, secondary and tertiary alkyl radicals using the title imine (II) and tBuOOtBu as an initiator affords the imines in good yields, but in many cases they decompose on purification.

Marie‐Celine Lamas

Papers

Radical Alkylphosphanylation of Olefins with Stannylated or Silylated Phosphanes and Alkyl Iodides

Radical Amination with Trimethylstannylated Benzophenone Imine

Radical Alkylphosphanylation of Olefins with Stannylated or Silylated Phosphanes and Alkyl Iodides.

Radical Amination with Trimethylstannylated Benzophenone Imine.