Catalytic Asymmetric γ-Alkylation of Carbonyl Compounds via Stereoconvergent Suzuki Cross-Couplings

With the aid of a chiral nickel catalyst, enantioselective γ- (and δ-) alkylations of carbonyl compounds can be achieved through the coupling of γ-haloamides with alkylboranes. In addition to primary alkyl nucleophiles, for the first time for an asymmetric cross-coupling of an unactivated alkyl electrophile, an arylmetal, a boronate ester, and a secondary (cyclopropyl) alkylmetal compound are shown to couple with significant enantioselectivity. A mechanistic study indicates that cleavage of the carbon–halogen bond of the electrophile is irreversible under the conditions for asymmetric carbon–carbon bond formation

Nickel-catalyzed cross-couplings of unactivated secondary and tertiary alkyl halides and photoinduced copper-mediated asymmetric C-N cross-couplings

Thesis (Ph. D. in Organic Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.Chapter 1 describes the development of two nickel-catalyzed Suzuki cross-coupling methodologies that employ alkyl halides as electrophiles. In Section 1.1, asymmetric [gamma]-alkylation relative to a carbonyl group is achieved via the stereoconvergent cross-coupling of racemic secondary [gamma]-chloroamides with primary alkylboranes. Section 1.2 describes the first Suzuki carbon-carbon bond-forming reaction using tertiary alkyl halides as electrophiles; specifically, unactivated tertiary alkyl bromides are cross-coupled with arylboranes. Chapter 2 describes the establishment of photoinduced asymmetric copper-mediated C-N Ullmann-type coupling processes between racemic secondary alkyl halides and N-heterocycles. Preliminary yields and enantioselectivities for a reaction between secondary benzylic halides and carbazoles, with the use of a monodentate chiral phosphine ligand, are presented. The methodology is then extended to secondary [alpha]-haloamides, including [alpha]-halolactams, which are found to afford very promising yields and enantioselectivities.by Susan L. Zultanski.Ph.D.in Organic Chemistr

Asymmetric copper-catalyzed C-N cross-couplings induced by visible light

Despite a well-developed and growing body of work in copper catalysis, the potential of copper to serve as a photocatalyst remains underexplored. Here we describe a photoinduced copper-catalyzed method for coupling readily available racemic tertiary alkyl chloride electrophiles with amines to generate fully substituted stereocenters with high enantioselectivity. The reaction proceeds at –40°C under excitation by a blue light-emitting diode and benefits from the use of a single, Earth-abundant transition metal acting as both the photocatalyst and the source of asymmetric induction. An enantioconvergent mechanism transforms the racemic starting material into a single product enantiomer

Nickel-Catalyzed Carbon–Carbon Bond-Forming Reactions of Unactivated Tertiary Alkyl Halides: Suzuki Arylations

The first Suzuki cross-couplings of unactivated tertiary alkyl electrophiles are described. The method employs a readily accessible catalyst (NiBr[subscript 2]·diglyme/4,4′-di-tert-butyl-2,2′-bipyridine, both commercially available) and represents the initial example of the use of a group 10 catalyst to cross-couple unactivated tertiary electrophiles to form C–C bonds. This approach to the synthesis of all-carbon quaternary carbon centers does not suffer from isomerization of the alkyl group, in contrast with the umpolung strategy for this bond construction (cross-coupling of a tertiary alkylmetal with an aryl electrophile). Preliminary mechanistic studies are consistent with the generation of a radical intermediate along the reaction pathway.National Institute of General Medical Sciences (U.S.) (R01-GM62871)Merck Research Laboratories (Summer Fellowship

Nickel-Catalyzed Carbon–Carbon Bond-Forming Reactions of Unactivated Tertiary Alkyl Halides: Suzuki Arylations

The first Suzuki cross-couplings of unactivated tertiary alkyl electrophiles are described. The method employs a readily accessible catalyst (NiBr₂·diglyme/4,4′-di-<i>tert</i>-butyl-2,2′-bipyridine, both commercially available) and represents the initial example of the use of a group 10 catalyst to cross-couple unactivated tertiary electrophiles to form C–C bonds. This approach to the synthesis of all-carbon quaternary carbon centers does not suffer from isomerization of the alkyl group, in contrast with the umpolung strategy for this bond construction (cross-coupling of a tertiary alkylmetal with an aryl electrophile). Preliminary mechanistic studies are consistent with the generation of a radical intermediate along the reaction pathway

A Widely Applicable Dual-Catalytic System for Cross-Electrophile Coupling

A new dual catalytic system for cross-electrophile coupling reactions between aryl and alkyl halides that features a Ni catalyst, a Co co-catalyst, and a mild homogeneous reductant, is described. This is a unique combination of reagents for cross-electrophile coupling reactions, which results in one of the most versatile systems reported to date. For example, the coupling of aryl bromides and aryl iodides with alkyl bromides, alkyl iodides, alkyl mesylates, and benzyl chlorides is demonstrated under similar reaction conditions. The system is tolerant of numerous functional groups and is capable of coupling heteroaryl halides, di-ortho-substituted aryl halides, pharmaceutically relevant drug-like aryl halides, and a diverse range of alkyl halides. Additionally, the dual catalytic platform facilitates a series of novel one-pot three-component cross-electrophile coupling reactions of bromo(iodo)arenes with two distinct alkyl halides. Mechanistic studies indicate that the Ni catalyst activates the aryl halide electrophile, while the Co catalyst activates the alkyl electrophile

Feedstocks to Pharmacophores: Cu-Catalyzed Oxidative Arylation of Inexpensive Alkylarenes Enabling Direct Access to Diarylalkanes

A Cu-catalyzed method has been identified for selective oxidative aryl­ation of benzylic C–H bonds with arylboronic esters. The resulting 1,1-diaryl­alkanes are accessed directly from inexpensive alkyl­arenes containing primary and secondary benzylic C–H bonds, such as toluene or ethyl­benzene. All catalyst components are commercially available at low cost, and the aryl­boronic esters are either commercially available or easily accessible from the commercially available boronic acids. The potential utility of these methods in medicinal chemistry applications is highlighted

Practical Synthesis of Amides via Copper/ABNO-Catalyzed Aerobic Oxidative Coupling of Alcohols and Amines

A modular Cu/ABNO catalyst system has been identified that enables efficient aerobic oxidative coupling of alcohols and amines to amides. All four permutations of benzylic/aliphatic alcohols and primary/secondary amines are viable in this reaction, enabling broad access to secondary and tertiary amides. The reactions exhibit excellent functional group compatibility and are complete within 30 min–3 h at rt. All components of the catalyst system are commercially available