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. 2024 Feb 5;63(6):e202316521.
doi: 10.1002/anie.202316521. Epub 2023 Dec 28.

Stereoselective Copper-Catalyzed Olefination of Imines

James E Baumann  1 , Crystal P Chung  1 , Gojko Lalic  1
Affiliations

Stereoselective Copper-Catalyzed Olefination of Imines

James E Baumann et al. Angew Chem Int Ed Engl. .

Abstract

Alkenes are an important class of organic molecules found among synthetic intermediates and bioactive compounds. They are commonly synthesized through stoichiometric Wittig-type olefination of carbonyls and imines, using ylides or their equivalents. Despite the importance of Wittig-type olefination reactions, their catalytic variants remain underdeveloped. We explored the use of transition metal catalysis to form ylide equivalents from readily available starting materials. Our investigation led to a new copper-catalyzed olefination of imines with alkenyl boronate esters as coupling partners. We identified a heterobimetallic complex, obtained by hydrocupration of the alkenyl boronate esters, as the key catalytic intermediate that serves as an ylide equivalent. The high E-selectivity observed in the reaction is due to the stereoselective addition of this intermediate to an imine, followed by stereospecific anti-elimination.

Keywords: Alkenes; Copper; Homogenous Catalysis; Stereoselective; Wittig.

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Figures

Scheme 1.
Scheme 1.
Stoichiometric and metal-catalyzed Wittig-type reactions.
Scheme 2.
Scheme 2.
π-Electrophiles. Reactions were performed on 0.05 mmol scale. Yields determined by GC using trimethoxybenzene as an internal standard. pin = pinacolato, dppbz = 1,2-Bis(diphenylphosphanyl)benzene, DMMS = dimethoxymethylsilane, KOPyr = potassium pyridoate, THF = tetrahydrofuran. R = Ph(CH2)3 and Ar = p-MeOC6H4.
Scheme 3.
Scheme 3.
Substrate scope. Yields of isolated products are reported. E:Z ratios were determined by GC. Reactions performed on 0.3 mmol scale with CuOAc (2.0 mol%), dppbz (3.0 mol%), TMDSO (2.0 equiv), KOPyr (0.2 equiv), and imine (1.5 equiv) at 45 °C for 24 h in a 1:1 mixture of THF and 2-MeTHF [0.1 M] with respect to alkenyl Bpin (1.0 equiv), unless otherwise stated. [a] Reaction was performed with CuOAc (2.0 mol%), (p-CF3)dppbz (3.0 mol%), TMDSO (2.0 equiv), KOPyr (0.4 equiv), and imine (2.0 equiv) at 45 °C for 24 h in a 1:1 mixture of THF and 2-MeTHF [0.1 M] with respect to alkenyl Bpin (1.0 equiv). [b] Reactions performed on 0.5 mmol scale with CuOAc (2.0 mol%), dppbz (3.0 mol%), HMTSO (1.5 equiv), KOPyr (0.2 equiv), and imine (2.0 equiv) at 60 °C for 48 h in 2-MeTHF [0.2 M] with respect to alkenyl Bpin (1.0 equiv). [c] Reaction performed on 0.3 mmol scale. [d] SciOPP (1,2-Bis[bis[3,5-di(t-butyl)phenyl]phosphino]benzene) used instead of dppbz. R = p-MeOC6H4O(CH2)3. Ar = p-MeOC6H4.
Scheme 4.
Scheme 4.
Heterobimetallic intermediate. Reactions were performed on 0.05 mmol scale. Ar = p-MeOC6H4.
Scheme 5.
Scheme 5.
Reaction intermediates and stereochemistry of olefination. Reactions performed on 0.05 mmol scale. Yields determined by 1H-NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard and E:Z ratios determined via GC analysis of crude reaction mixtures. [a] See Table 1. R = Ph(CH2)3 and Ar = p-MeOC6H4.
Scheme 6.
Scheme 6.
Proposed mechanism.
See this image and copyright information in PMC

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