Tri and tetrasubstituted alkenes are often the starting point, but how to get them

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By Sander Kluwer

Alkenes, and particularly substituted alkenes form an important class of compounds are commonly part of biologically active molecules or form the substrate for numerous catalytic conversions such as hydroformylation and (asymmetric) hydrogenation. The synthetic efforts increase with the number of substituents present on the C=C double bond as the possible arrangements increases and different levels of selectivity (chemo-, regio-, and stereoselectivity) needs to be controlled. A general, stereochemically-defined production of acyclic tri and tetrasubstituted has therefore been longstanding challenge. Existing protocols for such tri- and tetrasubstituted alkenes have inherent limitations and often suffer from unsatisfactory regio- or stereoselectivity control and/or are not sufficiently general to allow a broad range of functional groups. A particular challenge is to obtain the desired cis/ trans isomer as the energy difference for this class of highly substituted alkenes is typically in the range of 0.4 kcal/mol and precludes thermodynamic control to obtain either isomer in useful amounts.

Nickel catalyst, couplings reaction, stereoselective isomnerization

Figure 1. Stereoselective production of tri and tetrasubstituted alkenes starting from simple and accessible a-alkenes.

In this light, the recent publication by Osvaldo Gutierrez, Ming Joo Koh and coworkers in Nature Catalysis (Nat. Cat. 2021, 4, 674–683, is a valuable contribution to the field. They investigated the catalytic approach using simple and abundant monosubstituted α-olefins substrates which, in the presence of an appropriate transition metal-based catalyst and an electrophilic reagent, results in a tandem process featuring a regioselective (net) olefin C–H functionalization followed by stereoselective C=C bond isomerization. Preliminary exploratory experiments were conducted, and a limited catalyst screening identified the dinuclear nickel(I)-catalyst [{NiCl(IPr)}2] (IPr is NHC ligand) as most efficient catalyst yielding 95% of the most-substituted alkene with a formidable E/Z ratio of 93/7.

Mechnism of reacion- nickel catalyzed Heck reaction and stereoselective isomerization

Figure 2. Proposed mechanism for the coupled Mizoroki–Heck-type reaction and stereoselective 1,3-hydrogen shift isomerization.

Mechanistic and computation studies revealed that the reaction proceeds via a               Mizoroki–Heck-type functionalization and a stereoselective isomerization. The isomerization pathway is proposed non-radical 1,3-hydrogen shift mechanism which was further substantiated by deuterium labeling studies and suggest that a free nickel-hydride species is less likely to be involved in the C=C bond isomerization step. The applicability of this new method was illustrated by an extended substrate scope of which a selection is provided in Figure 3. The Ni-catalyzed protocol offers new opportunities to devise more concise preparative routes for various important biologically active molecules such as protein tyrosine phosphatase inhibitor, signal transducer and activator of transcription-6 inhibitor which have been described.

substrate scope

Figure 3. Selected substrate scope.

Interestingly in this synthetic methodology the aryl triflate coupling partner can be replaced by borylated building blocks such as (BPin)2, allowing for subsequent cross-couplings technology. A nice example is presented in the Prokineticin receptor I antagonist, going via the tetrasubstituted alkenyl boronate followed by a Pd-catalyzed Suzuki reaction, which is depicted in Figure 4.

nice example - pharmaceutical product

Figure 4. Synthetic scheme for Prokineticin receptor I antagonist via borylated building blocks.

The synthetic strategy described by Osvaldo Gutierrez, Ming Joo Koh and coworkers will have also effect on other areas of catalysis as alkenes are often the feedstock for other catalytic reactions such as hydroformylation, asymmetric hydrogenation, epoxidation etc. Easily accessible, multi-substituted alkenes are of key importance for further development of these catalytic applications.

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Article: “Olefin functionalization/isomerization enables stereoselective alkene synthesis”

By: Chen-Fei Liu, Hongyu Wang, Robert T. Martin, Haonan Zhao, Osvaldo Gutierrez  and Ming Joo Koh 

Nature Catalysis,  VOL 4, August 2021. 674–683