Stereospecific nickel-catalyzed cross-coupling reactions of benzylic ethers and esters

Abstract

This Account presents the development of a suite of stereospecific alkyl-alkyl cross-coupling reactions employing nickel catalysts. Our reactions complement related nickel-catalyzed stereoconvergent cross-coupling reactions from a stereochemical and mechanistic perspective. Most reactions of alkyl electrophiles with low-valent nickel complexes proceed through alkyl radicals and thus are stereoablative; the correct enantioselective catalyst can favor the formation of one enantiomer. Our reactions, in contrast, are stereospecific. Enantioenriched ethers and esters are cleanly converted to cross-coupled products with high stereochemical fidelity. While mechanistic details are still to be refined, our results are consistent with a polar, two-electron oxidative addition that avoids the formation of radical intermediates. This reactivity is unusual for a first-row transition metal. The cross-coupling reactions engage a range of benzylic ethers and esters, including methyl ethers, tetrahydropyrans, tetrahydrofurans, esters, and lactones. Coordination of the arene substituent to the nickel catalyst accelerates the reactions. Arenes with low aromatic stabilization energies, such as naphthalene, benzothiophene, and furan, serve as the best ligands and provide the highest reactivity. Traceless directing groups that accelerate reactions of sluggish substrates are described, providing partial compensation for arene coordination. Kumada, Negishi, and Suzuki reactions provide incorporation of a broad range of transmetalating agents. In Kumada coupling reactions, a full complement of Grigard reagents, including methyl, n-alkyl, and aryl Grignard reagents, are employed. In reactions employing methylmagnesium iodide, ligation of the nickel catalyst by rac-BINAP or DPEphos provides the highest yield and stereospecificity. For all other Grignard reagents, Ni(dppe)Cl2 has emerged as the best catalyst. Negishi cross-coupling reactions employing dimethylzinc are reported as a strategy to increase the functional group tolerance of the reaction. We also describe Suzuki reactions using arylboronic esters. These reactions provided the first example in the series of a switch in stereochemical outcome. The reactions maintain stereospecificity, but reactions employing different achiral ligands provide opposite enantiomers of the product. Use of an N-heterocyclic carbene ligand, SIMes, provides inversion, consistent with our prior work in Kumada and Negishi coupling reactions. Use of the electron-rich phosphine PCy3, however, provides retention with stereospecificity, signaling a change in the mechanistic details. Potential applications of the reported cross-coupling reactions include the synthesis of medicinal agents containing the 2-arylalkane and 1,1-diarylalkane moieties, which are pharmacophores in medicinal chemistry. These moieties are found in compounds with activity against a broad range of indications, including cancer, heart disease, diabetes, osteoporosis, smallpox, tuberculosis, and insomnia. We highlight representative examples of bioactive compounds that we have prepared with high enantioselectivity employing our methods, as well as the discovery of a new anti-cancer agent.

Scheme 1. Alkyl–Alkyl Cross-Coupling Reaction en Route to Pyranicin

Scheme 2. Strategies for Control of Stereochemistry in Alkyl–Alkyl Cross-Coupling Reactions

Scheme 3. Influence of the Mechanism of Oxidative Addition on the Stereochemical Outcome

Scheme 4. Nickel-Catalyzed Reactions of Allylic and Benzylic Ethers

Scheme 5. Enantioenriched Secondary Alcohols as Key Synthetic Intermediates

Figure 1

Representative medicinal agents bearing benzylic methyl substituents.

Scheme 6. Proof of Concept: Stereospecific Kumada Coupling Reactions of Benzylic Ethers

Scheme 7. Lack of a Match/Mismatch Effect

Scheme 8. Ligand Tuning To Suppress β-Hydride Elimination

Scheme 9. Scope of Cross-Coupling Reactions with Alkyl and Aryl Grignard Reagents

Ni(dppe)Cl₂ was added in two aliquots of 10 mol %. The reaction was run at 5 °C for 48 h.

Scheme 10. Mechanism for the Formation of Racemic Product

Scheme 11. Activation of Benzylic Ethers by Arenes with Low Aromatic Stabilization Energies

Scheme 12. Traceless Directing Group Strategy

Scheme 13. Cross-Coupling Reactions Facilitated by a Traceless Directing Group

Scheme 14. Identification of a Traceless Directing Group for Negishi Coupling Reactions

Scheme 15. Examples of Stereospecific Negishi Coupling Reactions

Scheme 16. Ring Opening of δ-Valerolactones

Scheme 17. Stereospecific Suzuki Coupling with Inversion or Retention

Scheme 18. Suzuki Coupling of Simple Benzhydryl Esters Using an NHC-Ligated Catalyst

Figure 2

Medicinal agents prepared by stereospecific cross-coupling reactions.