Mechanistic Basis for Regioselection and Regiodivergence in Nickel-Catalyzed Reductive Couplings

Abstract

CONSPECTUS The control of regiochemistry is a considerable challenge in the development of a wide array of catalytic processes. Simple π-components such as alkenes, alkynes, 1,3-dienes, and allenes are among the many classes of substrates that present complexities in regioselective catalysis. Considering an internal alkyne as a representative example, when steric and electronic differences between the two substituents are minimal, differentiating among the two termini of the alkyne presents a great challenge. In cases where the differences between the alkyne substituents are substantial, overcoming those biases to access the regioisomer opposite that favored by substrate biases often presents an even greater challenge. Nickel-catalyzed reductive couplings of unsymmetrical π-components make up a group of reactions where control of regiochemistry presents a challenging but important objective. In the course of our studies of aldehyde-alkyne reductive couplings, complementary solutions to challenges in regiocontrol have been developed. Through careful selection of the ligand and reductant, as well as the more subtle reaction variables such as temperature and concentration, effective protocols have been established that allow highly selective access to either regiosiomer of the the allylic alcohol products using a wide range of unsymmetrical alkynes. Computational studies and an evaluation of reaction kinetics have provided an understanding of the origin of the regioselectivity control. Throughout the various procedures described, the development of ligand-substrate interactions play a key role, and the overall kinetic descriptions were found to differ between protocols. Rational alteration of the rate-determining step plays a key role in the regiochemistry reversal strategy, and in one instance, the two possible regioisomeric outcomes in a single reaction were found to operate by different kinetic descriptions. With this mechanistic information in hand, the empirical factors that influence regiochemistry can be readily understood, and more importantly, the insights suggest simple and predictable experimental variables to achieving a desired reaction outcome. These studies thus present a detailed picture of the influences that control regioselectivity in a specific catalytic reaction, but they also delineate strategies for regiocontrol that may extend to numerous classes of reactions. The work provides an illustration of how insights into the kinetics and mechanism of a catalytic process can rationalize subtle empirical findings and suggest simple and rational modifications in procedure to access a desirable reaction outcome. Furthermore, these studies present an illustration of how important challenges in organic synthesis can be met by novel reactivity afforded by base metal catalysis. The use of nickel catalysis in this instance not only provides an inexpensive and sustainable method for catalysis, but also enables unique reactivity patterns not accessible to other metals.

Stable, Well-Defined Nickel(0) Catalysts for Catalytic C–C and C–N Bond Formation

“…It should be noted that the catalyst loading can be reduced to 2 mol %, which is a lower than typically used in this reaction class. 18 Aliphatic aldehydes work well as shown in 15b , which also demonstrates the tolerance of protected amines in this chemistry. Additionally, both triethylsilane and di- tert -butylsilane can be used, as shown in 15c and 15d .…”

Synthesis of bridged tricyclo[5.2.1.01,5]decanes via nickel-catalyzed asymmetric domino cyclization of enynones

“…The second is to control the enantioselectivity of the Heck-cyclization process. Another challenge is that ketones are more electrophilic than unactivated alkenes, the direct cyclization of alkynes and ketones may take place preferentially, while unactivated alkenes do not participate in the cyclization process [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] .…”

Brønsted Acid Enabled Nickel‐Catalyzed Hydroalkenylation of Aldehydes with Styrene and its Derivatives

“…[1] Thet raditional method uses preformed alkenylmetal reagents to couple with various carbonyl compounds (Scheme 1a). [4] Another important alternative method employs transitionmetal-catalyzed reductive coupling of alkynes with carbonyls in the presence of metallic reductants, [5] hydrogen gas,o r hydrogen donors, [6,7] thereby avoiding the use of pre-formed alkenylmetal reagents (Scheme 1b). [4] Another important alternative method employs transitionmetal-catalyzed reductive coupling of alkynes with carbonyls in the presence of metallic reductants, [5] hydrogen gas,o r hydrogen donors, [6,7] thereby avoiding the use of pre-formed alkenylmetal reagents (Scheme 1b).…”