Amidine-based Ligands for Cross-coupling Reactions of Aryl Bromides and Redox-active Esters

The introduction of alkyl groups onto aromatic rings has become increasingly important in recent years for drug discovery research and the development of functional compounds.¹⁾ Especially, organometallic reagent-free reactions and the extension of the scope to strained cyclic alkyls are of increasing interest, and reactions using alkyl halides and carboxylic acids as coupling partners have been vigorously developed.²⁾ For instance, the cross-coupling of aryl halides with redox-active esters (RAEs) using a nickel catalyst and ^tBuBpyCam^CN as a ligand is well known.³⁾
5-Methoxypicolinimidamide hydrochloride (1) is an electron-rich amidine ligand with a methoxy group⁴⁾ and can be used in cross-couplings between aryl bromides and RAEs. Due to the electron-donating character of the methoxy group in 1, the oxidative addition to the aryl bromide becomes faster thus shortening the reaction time. It also has the advantage that the reaction can proceed at room temperature. Furthermore, the addition of TBAI improves catalyst turnover by facilitating electron transfer from metallic zinc to nickel. This reaction also tolerates strained tertiary cyclic alkyls.
5-(1-Pyrrolidinyl)-2-pyridinecarboximidamide hydrochloride (2), which has a more electron-rich pyrrolidinyl group, is expected to be used as a potent ligand as well as 1.

Related Products

M3794

5-Methoxypicolinimidamide Hydrochloride

P3202

5-(Pyrrolidin-1-yl)picolinimidamide Hydrochloride

N1051

Nickel(II) Chloride Ethylene Glycol Dimethyl Ether Complex (= NiCl₂(dme))

N1298

Nickel(II) Bromide Ethylene Glycol Dimethyl Ether Complex (= NiBr₂(dme))

C3803

4,4'-Di-tert-Butyl-N-cyano[2,2'-bipyridine]-6-carboximidamide (= ^tBuBpyCam^CN)

Z0015

Zinc (Powder)

T0057

Tetrabutylammonium Iodide (= TBAI)

T0431

Trifluoroacetic Acid (= TFA)

References

• 1) Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp²)-C(sp³) Cross-Coupling Methods by Library Synthesis
  • A. W. Dombrowski, N. J. Gesmundo, A. L. Aguirre, K. A. Sarris, J. M. Young, A. R. Bogdan, M. C. Martin, S. Gedeon, Y. Wang, ACS Med. Chem. Lett. 2020, 11, 597.
• 2) New Ligands for Nickel Catalysis from Diverse Pharmaceutical Heterocycle Libraries
  • E. C. Hansen, D. J. Pedro, A. C. Wotal, N. J. Gower, J. D. Nelson, S. Caron, D. J. Weix, Nat. Chem. 2016, 8, 1126.
• 3) Control of Redox-Active Ester Reactivity Enables a General Cross-Electrophile Approach to Access Arylated Strained Rings
  • D. C. Salgueiro, B. K. Chi, I. A. Guzei, P. G. Reynaga, D. J. Weix, Angew. Chem. Int. Ed. 2022, 61, e202205673.
• 4) Decarboxylative Cross-Electrophile Coupling of (Hetero)Aromatic Bromides and NHP Esters
  • E. M. DeCicco, S. Berritt, T. Knauber, S. B. Coffey, J. Hou, M. S. Dowling, J. Org. Chem. 2023, 88, 12329.

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